2017 WHO CLASSIFICATION OF HEAD & NECK TUMORS 2017

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.~World Health Organization Classification of Tl.lmours 
Delellis HA. Lloyd R.V., 
Heítz P.U., Eng C. (Eds): World 
Health Organization Classification of 
Tumours. Pathology ard Genetics of 
Tumours of Endocrine Orga.ns 
(3rd ed:ion). IARC p,ass: ryo·i 2004. 
ISBN 978·92·832·2416-7 
LeBoit P.E., Burg G , Weedon D .. 
Sarasin A. (Eds): World Health 
Organiz::1.ticn Class'ticalion o"' 
Tumours. Patt1ology a:1d Genetics of 
Skin Tumours (3rd edltlor). 
IARC Press: Lyon 2006. 
ISBN 978\)2·832·2414-0 
Swerdlow S.H., Campo S., 
Harris NL, Jaffe E.S., Pile<' S.A., 
Stein H., Thieie J., Vardiman r.W. 
(Eds): WH:J Classification of Tumours 
of Haematopoletic and Lymphoid 
Tissues (4th ed:tíon). 
IARC: Lyor 2008. 
ISBN 978-92·832-243!-J 
Bosman F.T., C:srneiro F .. 
Hruban R.H., Theiss ND. 
WHO Class1ficatim·cf T umours o: tne 
Oigest:ve System ( 4th edífon). 
IARC: Lyon 2010. 
ISBN 978-92-832-2432-7 
Lakhani S.fi., Eilis 10., Schnitt S J. 
T2n P.H, var. de Vijver M.J, (Eds) 
WHO Classmc2íicn of Tumours of the 
Breast (4th editior). IARC: Lyon 2012. 
ISBN 978-92-832-2,]33-4 
Hetcher C.O.M., Bridge J.A, 
Hogendoom P,C.W., fv'ler:ens F. 
(Eas): \/JHO Ciassification of Twnours 
of Soft T:ssue and Bone (4th edition). 
iARC: Lyon 2013. 
iSBN 978-92·832-2434-1 
Kurmar RJ . Carcangiu M L., 
Herr cgton C S, Young R.H. (Eds): 
WHO C:assifícat:or: of TuGours of 
Fema:e Rep:oductive Organs 
(4:h edition). IARC: Lyon 2014. 
ISBN 978-92-832-2435-8 
Trav's W.D., Brambília E .. 
Buri,;e A.P .. Marx A .. Nícho'son A.G. 
WHO Classiicatíon of T Jrrours 
ot tre Lung, ?leura, Thymus & Heact 
(4th ed:tion). IARC· Lyon 20' 5. 
ISBN 978-92-832-2436-5 
Mooh H., Hucnphrey PA, 
e! bright T.M., Reuter V.E. (Eds): 
WHO C1assificator: ot Tumo:.rs ot 
the Ur,nary Systerc 2nd Male Ger:ital 
Organs ( 4th edition). 
IARC Lyon 2016. 
'.SBN 978-92-832-2437-2 
Louis D.N , Ohgaki ½ .. 
W.est!er O.O., Cavenee \/íJ.f<. 
WHO Classiticatíon of T Jmcurs of the 
Centrai Nervous System (Rev:sed 
4t1 edltion). IARC: Lycn 2016. 
ISBN 978·92 832-4492-9 
Ei-Naggar AK, Chan J.K.C .. 
Grandis J.R, Takata ,., Slo:,tweg .:>J. 
(Eds): WHO Classlfication af Heaa 
and Neck Tumours (.!t\¡ editio;1). 
:ARC: Lyon 2017 
iSBN 978-92 832-2438-9 
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World Health Organization Classification of Tumours 
~-) WHO ~ , ~ f OMS \\ ,¡, IJ! -~ 
lnternational Agency for Research on Cancer (IARC) 
4th Edition 
WHO Classification of 
Head and Neck Tumours 
Edited by 
Adel K. EI-Naggar 
John K.C. Chan 
Jennifer R. Grandis 
Takashi Takata 
Pieter J. Slootweg 
lnternational Agency for Research on Cancer 
Lyon, 2017 
World Health Organization Classification of Tumours 
Series Editors Fred T. Bosman, MD PhD 
Elaine S. Jaffe, MD 
Sunil R. Lakhani, MD FRCPath 
Hiroko Ohgaki, PhD 
WHO Classification of Head and Neck Tumours 
Editors Adel K. El-Naggar, MD, PhD 
John K.C. Chan, MBBS 
Jennifer R. Grandis, MD 
Takashi Takata, DOS, PhD 
Pieter J. Slootweg, MD, DMD, PhD 
Project Assistants Asiedua Asante 
Anne-Sophie Hameau 
Technical Editor Jessica Cox. 
Database Alberto Machado 
Delphine Nicolas 
Layout Julia Brinkmann 
Printed by Maestro 
38330 Saint-lsmíer, France 
Publisher lnternational Agency for 
Research on Cancer (lARC) 
69372 Lyon Cedex 08, France 
The WHO Classification of Head and Neck Tumours presented in this book reflects the views 
of a Working Group that convened for a Consensus and Editorial Meeting at the lnternational 
Agency for Research on Cancer, 
Lyon, 14-16 January 2016. 
Members of the Working Group are indicated 
in the list of contributors on pages 285-292. 
Published by the lnternational Agency for Research on Cancer (IARC), 
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© /nternational Agency far Research on Cancer, 2017 
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First print run (10 000 copies) 
Formal for bibliographic citations: 
EI-Naggar A.K., Chan J.K.C., Grandis J.R., Takata T., Slootweg P.J. (Eds): 
WHO Classification of Head and Neck Tumours (4th edition). 
IARC: Lyon 2017 
IARC Library Cataloguing in Publication Data 
WHO classification of head and neck tumours / edited by Adel K. EI-Naggar, John K.C. Chan, 
Jennifer R. Grand is, Takashi Takata, Pieter J. Slootweg. - 4th edition. 
(World Health Organization classification of tumours) 
1. Head and neck neoplasms - genetics 
3. Odontogenic tumours - genetics 
l. EI-Naggar, Adel K. 11. Series 
ISBN 978-92-832-2438-9 
2. Head and neck neoplasms - pathÓlogy 
4. Odontogenic tumours - pathology 
(NLM Classification: WE 707) 
Contents 
Tumours of the nasal cavity, paranasal sinuses and 11 lntroduction 65 
skull base Nasopharyngeal carcinoma 65 
WHO and TNM classifications 12 Nasopharyngeal papillary adenocarcinoma 70 
lntroduction 14 Salivary gland tumours 71 
Carcínomas 14 Adenoid cystic carcinoma 71 
Keratinizing squamous cell carcinoma 14 Salivary gland anlage tumour 71 
Non-keratinizing squamous cell carcinoma 15 Benign and borderline lesions 72 
Spindle cell (sarcomatoid) squamous cell carcinoma 17 Hairy polyp 72 
Lymphoepithelial carcinoma 18 Ectopic pituitary adenoma 72 
Sinonasal undifferentiated carcinoma 18 Craniopharyngioma 73 
NUT carcinoma 20 Soft tissue tumours 74 
Neuroendocrine carcinoma 21 Nasopharyngeal angiofibroma 74 
Adenocarcinoma 23 Haematolymphoid tumours 75 
lntestinal-type adenocarcinoma 23 Notochordal tumours 76 
Non-intestinal-type adenocarcinoma 24 Chordoma 76 
Teratocarcinosarcoma 26 
Sinonasal papillomas 28 3 Tumours of the hypopharynx, larynx, trachea and 77 
Sinonasal papilloma, inverted type 28 parapharyngeal space 
Sinonasal papilloma, oncocytic type 29 WHO and TNM classifications 78 
Sinonasal papilloma, exophytic type 30 lntroductíon 81 
Respiratory epithelial lesions 31 Malignant surface epithelial tumours 81 
Respiratory epithelial adenomatoid hamartoma 31 Conventional squamous cell carcinoma 81 
Seromucinous hamartoma 32 Verrucous squamous cell carcinoma 84 
Salivary gland tumours 33 Basaloid squamous cell carcinoma 85 
Pleomorphic adenoma 33 Papillary squamous cell carcinoma 87 
Malignant soft tissue tumours 34 Spindle cell squamous cell carcinoma 87 
Fibrosarcoma 34Adenosquamous carcinoma 89 
Undifferentiated pleomorphic sarcoma 35 Lymphoepithelial carcinoma 90 
Leiomyosarcoma 35 Precursor lesions 91 
Rhabdomyosarcoma 36 Dysplasia 91 
Angiosarcoma 38 Squamous cell papilloma & squamous cell papillomatosis 93 
Malignant peripheral nerve sheath tumour 39 Neuroendocrine tumours 95 
Biphenotypic sínonasal sarcoma 40 Well-differentiated neuroendocrine carcinoma 95 
Synovial sarcoma 41 Moderately differentiated neuroendocrine carcinoma 96 
Borderline / low-grade malignant soft tissue tumours 43 Poorly differentiated neuroendocrine carcinoma 97 
Desmoid-type fibromatosis 43 Salivary gland tumours 99 
Sinonasal glomangiopericytoma 44 Adenoid cystic carcinoma 99 
Solitary fibrous tumour 45 Pleomorphic adenoma 99 
Epithelioid haemangioendothelioma 46 Oncocytic papillary cystadenoma 99 
Benign soft tissue tumours 47 Soft tissue tumours 100 
Leíomyoma 47 Granular cell tumour 100 
Haemangioma 47 Liposarcoma 100 
Schwannoma 48 lnflammatory myofibroblastic tumour 101 
Neurofibroma 49 Cartilage tumours 102 
Other tumours 50 Chondroma and chondrosarcoma 102 
Meningioma 50 Haematolymphoid tumours 104 
Sinonasal ameloblastoma 51 
Chondromesenchymal hamartoma 51 4 Tumours of the oral cavity and mobile tengue 105 
Haematolymphoid tumours 52 WHO and TNM classifications 106 
Overview 52 lntroduction 108 
Extranodal NK/T-cell lymphoma 52 Malignant surface epithelial tumours 109 
Extraosseous plasmacytoma 54 Squamous cell carcinoma 109 
Neuroectodermal /melanocytic tumours 56 Oral p9tentially malignant disorders & oral epithelial dysplasia 112 
Ewing sarcoma/primitive neuroectodermal tumours 56 Oral potentially malignant disorders 112 
Olfactory neuroblastoma 57 Oral epithelial dysplasia 112 
Mucosa! melanoma 60 Proliferative verrucous leukoplakia 113 
Papillomas 115 
2 Tumours of the nasopharynx 63 Squamous cell papilloma 115 
WHO and TNM classifications 64 Condyloma acuminatum 116 
Verruca vulgaris 117 lntroduction 162 
Multifocal epithelial hyperplasia 117 Malignant tumours 163 
Tumours of uncertain histogenesis 119 Mucoepidermoid carcinoma 163 
Congenital granular cell epulis 119 Adenoid cystic carcinoma 164 
Ectomesenchymal chondromyxoid tumour 119 Acinic cell carcinoma 166 
Soft tissue and neural tumours 121 Polymorphous adenocarcinoma 167 
Granular cell tumour 121 Clear cell carcinoma 168 
Rhabdomyoma 122 Basal cell adenocarcinoma 169 
Lymphangioma 122 lntraductal carcinoma 170 
Haemangioma 123 Adenocarcinoma, NOS 171 
Schwannoma and neurofibroma 123 Salivary duct carcinoma 173 
Kaposi sarcoma 124 Myoepithelial carcinoma 174 
Myofibroblastic sarcoma 125 Epithelial-myoepithelial carcinoma 175 
Oral mucosa! melanoma 126 Carcinoma ex pleomorphic adenoma 176 
Salivary type tumours 127 Secretory carcinoma 177 
Mucoepidermoid carcinoma 127 Sebaceous adenocarcinoma 178 
Pleomorphic adenoma 127 Carcinosarcoma 179 
Haematolymphoid tumours 128 Poorly differentiated carcinoma 180 
Overview 128 Lymphoepithelial carcinoma 181 
CD30-positive T-cell lymphoproliferative disorder 129 Squamous cell carcinoma 182 
Plasmablastic lymphoma 129 Oncocytic carcinoma 182 
Langerhans cell histiocytosis 130 Sialoblastoma 183 
Extramedullary myeloid sarcoma 131 Benign tumours 185 
Pleomorphic adenoma 185 
5 Tumours of the oropharynx 133 Myoepithelioma 186 
(base of tangue, tonsils, adenoids) Basal cell adenoma 187 
WHO and TNM classifications 134 Warthin tumour 188 
lntroduction 136 Oncocytoma 189 
Squamous cell carcinoma 136 Lymphadenoma 190 
Squamous cell carcinoma, HPV-positive 136 Cystadenoma 191 
Squamous cell carcinoma, HPV-negative 138 Sialadenoma papilliferum 192 
Salivary gland tumours 139 Ductal papillomas 192 
Pleomorphic adenoma 139 Sebaceous adenoma 193 
Adenoid cystic carcinoma 139 Canalicular adenoma and other ductal adenomas 194 
Polymorphous adenocarcinoma 140 Non-neoplastic epithelial lesions 195 
Haematolymphoid tumours 141 Sclerosing polycystic adenosis 195 
lntroduction 141 Nodular oncocytic hyperplasia 195 
Hodgkin lymphoma 141 L1/mphoepithelial sialadenitis 196 
Burkitt lymphoma 142 lntercalated duct hyperplasia 197 
Follicular lymphoma 143 Benign soft tissue lesions 198 
Mantle cell lymphoma 144 Haemangioma 198 
T-lymphoblastic leukaemia/lymphoma 144 Lipoma/sialolipoma 198 
Follicular dendritic cell sarcoma 145 Nodular fasciitis 199 
Haematolymphoid tumours 200 
6 Tumours and tumour~like lesions 147 Extranodal marginal zone lymphoma of mucosa-
of the neck and lymph nodes associated tymphoid tissue (MALT lymphoma) 201 
WHO classification 148 
lntroduction 148 8 Odontogenic and maxillofacial bone tumours 203 
Tumours of unknown origin 150 WHO classification 204 
Carcinoma of unknown primary 150 lntroduction 205 
Merkel cell carcinoma 151 Odontogenic carcinomas 206 
Heterotopia-associated carcinoma 152 Ameloblastic carcinoma 206 
Haematolymphoid tumours 154 Primary intraosseous carcinoma, NOS 207 
Cysts and cyst-like lesions 155 Sclerosing odontogenic carcinoma 209 
Branchial cleft cyst 155 CJear cell odontogenic carcinoma 210 
Thyroglossal duct cyst 156 Ghost cell odontogenic carcinoma 211 
Ranula 156 Odontogenic carcinosarcoma 213 
Dermoid and teratoid cysts 157 Odontogenic sarcomas 214 
Benign epithelial odontogenic tumours 215 
7 Tumours of salivary glands 159 Ameloblastoma 215 
WHO and TNM classifications 160 Ameloblastoma, unicystic type 217 
Ameloblastoma, extraosseous/peripheral type 218 
Metastasizing ameloblastoma 218 
Squamous odontogenic tumour 219 
Calcifying epithelial odontogenic tumour 220 
Adenomatoid odontogenic tumour 221 
Benign mixed epithelial & mesenchymal odontogenic tumours 222 
Ameloblastic fibroma 222 
Primordial odontogenic tumour 223 
Odontoma 224 
Dentinogenic ghost cell tumour 226 
Benign mesenchymal odontogenic tumours 228 
Odontogenic fibroma 228 
Odontogenic myxoma/myxofibroma 229 
Cementoblastoma 230 
Cemento-ossifying fibroma 231 
Odontogenic cysts of inflammatory origin 232 
Radicular cyst 
lnflammatory collateral cysts 
Odontogenic and non-odontogenic developmental cysts 
Dentigerous cyst 
Odontogenic keratocyst 
Lateral periodontal cyst and botryoid odontogenic cyst 
Gingival cysts 
Glandular odontogenic cyst 
Calcifying odontogenic cyst 
Orthokeratinized odontogenic cyst 
Nasopalatine duct cyst 
Malignant maxillofacial bone and cartilage tumours 
Chondrosarcoma 
Mesenchymal chondrosarcoma 
Osteosarcoma 
Benign maxillofacial bone and cartilage tumours 
Chondroma 
Osteoma 
Melanotic neuroectodermal tumour of infancy 
Chondroblastoma 
Chondromyxoid fibroma 
Osteoid osteoma 
Osteoblastoma 
Desmoplastic fibroma 
Fibro-osseous and osteochondromatous lesions 
Ossifying fibroma 
Familia! gigantiform cementoma 
Fibrous dysplasia 
Cemento-osseous dysplasia 
Osteochondroma 
Giant cell lesions and simple bone cyst 
Central giant cell granuloma 
Peripheral giant cell granuloma 
Cherubism 
Aneurysmal bone cyst 
Simple bone cyst 
Haematolymphoid tumours 
Solitary plasmacytoma of bone 
232 
233 
234 
234 
235 
236 
238 
238 
239 
241 
241 
243 
243 
244 
244 
246 
246 
246 
247 
248 
249 
249 
249 
250 
251 
251 
253 
253 
254 
255 
256 
256 
257 
257 
258 
259 
260 
260 
9 Tumours of the ear 
WHO classification 
lntroduction 
Tumours of the external auditory canal 
Squamous cell carcinoma 
Ceruminous adenocarcinoma 
Ceruminous adenoma 
Tumours of the middle and inner ear 
Squamous cell carcinoma 
Aggressive papillary tumour 
Endolymphatic sac tumour 
Otosclerosis 
Cholesteatoma 
Vestibular schwannoma 
Meningioma 
Middle ear adenoma 
10 Paraganglion tumours 
WHO classification 
lntroduction 
Carotid body paraganglioma 
Laryngeal paraganglioma 
Middle ear paraganglioma 
Vagal paraganglioma 
Contributors 
Declaration of interests 
IARC/WHO Committee for ICD-0 
Sources of figures 
Sources of tables 
References 
Subject index 
List of abbreviations 
261 
262 
263 
263 
263 
264_ 
265 
266 
266 
266 
267 
268 
269 
270 
271 
272 
275 
276 
276 
277 
281 
282 
283 
285 
292 
293 
294 
297 
298 
340 
347CHAPTER 1 
Tumours of the nasal cavity, paranasal 
sinuses and skull base 
Squamous cell carcinomas 
Lymphoepithelial carcinoma 
NUT carcinoma 
Neuroendocrina carcinomas 
Adenocarcinomas 
Teratocarcinosarcoma 
Sinonasal papillomas 
Respiratory epithelial lesions 
Salivary gland tumours 
Malignant soft tissue tumours 
Borderline / low-grade malignant 
soft tissue tumours 
Benign soft tissue tumours 
Haematolymphoid tumours 
Neuroectodermal / melanocytic tumours 
WHO classification of tumours of the nasal cavity, 
paranasal sinuses and skull base 
Carcinomas 
Keratinizing squamous cell carcinoma 
Non-keratinizing squamous cell carcinoma 
Spindle cell squamous cel l carcinoma 
Lymphoepithelial carcinoma 
Sinonasal undifferentiated carcinoma 
NUT carcinoma 
Neuroendocrine carcinomas 
Small cell neuroendocrine carcinoma 
Large cell neuroendocrine carcinoma 
Adenocarcinomas 
lntestinal-type adenocarcinoma 
Non-intestinal-type adenocarcinoma 
Teratocarcinosarcoma 
Sinonasal papillomas 
Sinonasal papi lloma, inverted type 
Sinonasal papilloma, oncocytic type 
Sinonasal papi lloma, exophytic type 
Respiratory epithelial lesions 
Respiratory epithelial adenomatoid hamartoma 
Seromucinous hamartoma 
Salivary gland tumours 
Pleomorphic adenoma 
Malignant soft tissue tumours 
Fibrosarcoma 
Undifferentiated pleomorphic sarcoma 
Leiomyosarcoma 
Rhabdomyosarcoma, NOS 
Embryonal rhabdomyosarcoma 
Alveolar rhabdomyosarcoma 
Pleomorphic rhabdomyosarcoma, adult type 
Spindle cell rhabdomyosarcoma 
Angiosarcoma 
Malignan! peripheral nerve sheath tumour 
Biphenotypic sinonasal sarcoma 
Synovial sarcoma 
8071/3 
8072/3 
8074/3 
8082/3 
8020/3 
8023/3* 
8041/3 
8013/3 
8144/3 
8140/3 
9081/3 
8121 /1 
8121 /1 
8121/0 
8940/0 
8810/3 
8802/3 
8890/3 
8900/3 
8910/3 
8920/3 
8901/3 
8912/3 
9120/3 
9540/3 
9045/3* 
9040/3 
Borderline/low-grade malignant soft tissue tumours 
Desmoid-type fibromatosis 8821 /1 
Sinonasal glomangiopericytoma 9150/1 
Solitary fibrous tumour 8815/1 
Epithelioid haemangioendothelioma 9133/3 
Benign soft tissue tumours 
Leiomyoma 
Haemangioma 
Schwannoma 
Neurofibroma 
Other tumours 
Meningioma 
Sinonasal ameloblastoma 
Chondromesenchymal hamartoma 
Haematolymphoid tumours 
Extranodal NK/T-cell lymphoma 
Extraosseous plasmacytoma 
Neuroectodermal / melanocytic tumours 
Ewing sarcoma/ primitive neuroectodermal 
tumour 
Olfactory neuroblastoma 
Mucosa! melanoma 
8890/0 
9120/0 
9560/0 
9540/0 
9530/0 
9310/0 
9719/3 
9734/3 
9364/3 
9522/3 
8720/3 
The morphology codes are from the lnternational Classification of Diseases 
for Oncology (ICD-0) 1776AJ. Behaviour is coded /O for benign tumours; 
/1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in 
situ and grade 111 intraepithelial neoplasia; and /3 for malignan! tumours. 
The classification is modified from the previous WHO classification , taking 
into account changes in our understanding of these lesions. 
'These new codes were approved by the IARC/WHO Committee for ICD-0. 
12 Tumours of the nasal cavity, paranasal sinuses and skull base 
TNM classification of carcinomas of the nasal cavity and 
paranasal sinuses 
TNM classificationª·" 
T - Primary tumour 
TX Primary tumour cannot be assessed 
TO No evidence of primary tumour 
Tis Carcinoma in situ 
Maxillary sinus 
T1 Tumour limited to the antral mucosa. with no erosion or 
destruction of bone 
T2 Tumour causing bone erosion or destruction, including 
extension into hard palate and/or middle nasal meatus, 
except extension to posterior wall of maxillary sinus and 
pterygoid plates 
T3 Tumour invades any of the following: bone of posterior 
wall of maxillary sinus, subcutaneous tissues, !loor or 
medial wall of orbit, pterygoid fossa, ethmoid sinuses 
T4a Tumour invades any ot the following: anterior orbital 
contents, skin of cheek, pterygoid plates, infratemporal 
fossa, cribriform plate, sphenoid or frontal sinuses 
T4b Tumour invades any of the following: orbital apex, dura, 
brain, middle cranial fossa, cranial nerves other than max-
illary division of trigeminal nerve (V2), nasopharynx, clivus 
Nasal cavity and ethmoid sinus 
T1 Tumour limited to one subsite of nasal cavity or ethmoid 
sinus, with or without bony invasion 
T2 Tumour involves two subsites in a single site or extends to 
involve an adjacent site within the nasoethmoidal 
complex, with or without bony invasion 
T3 Tumour extends to invade the medial wall or !loor of the 
orbit, maxillary sinus, palate, or cribriform plate 
T4a Tumour invades any of the following: anterior orbital 
contents, skin of nose or cheek, minimal extension to 
anterior cranial fossa, pterygoid plates, sphenoid or 
frontal sinuses 
T4b Tumour invades any of the following: orbital apex, dura, 
brain, middle cranial fossa, cranial nerves other than V2, 
nasopharynx, clivus 
N - Regional lymph nodes (i.e. the cervical nodes) 
NX Regional lymph nades cannot be assessed 
NO No regional lymph node metastasis 
N1 Metastasis in a single ipsilateral lymph node, s; 3 cm in 
greatest dimension 
N2 Metastasis as specified in N2a, N2b, or N2c below 
N2a Metastasis in a single ipsilateral lymph nade, > 3 cm but 
s; 6 cm in greatest dimension 
N2b Metastasis in multiple ipsilateral lymph nodes, all s; 6 cm 
in greatest dimension 
N2c Metastasis in bilateral or contralateral lymph nades, ali 
s; 6 cm in greatest dimension 
N3 Metastasis in a lymph nade > 6 cm in greatest dimension 
Note: Midline nodes are considered ipsilateral nodes. 
M - Distant metastasis 
MO No distan! metastasis 
M1 Distan! metastasis 
Stage grouping 
Stage O Tis NO MO 
Stage 1 T1 NO MO 
Stage 11 T2 NO MO 
Stage 111 T1- 2 N1 MO 
T3 N0-1 MO 
Stage IVA T1- 3 N2 MO 
T4a N0-2 MO 
Stage IVB T4b Any N MO 
AnyT N3 MO 
Stage IVC AnyT Any N M1 
ªAdapted from Edge et al. [625AI - used with permission of the American 
Joint Committee on Cancer (AJCC), Chicago, lllinois; the original and prima-
ry source for this information is the AJCC Cancer Staging Manual, Seventh 
Edition (2010) published by Springer Science+Business Media - and Sobin 
et al. [2228A) . 
ºA help desk for specific questions about TNM classification is available at 
http://www.uicc.org/resources/tnm/helpdesk. 
TNM classification of carcinomas of the nasal cavity and paranasal sinuses 13 
Tumours of the nasal cavity, paranasal 
sinuses and skull base 
lntroduction 
Slootweg P.J . 
Chan J.K.C. 
Stelow E.B. 
Thompson L.D.R. 
The sinonasal tract (i.e. the nasal cav-
ity and associated paranasal sinuses) 
is the site of origin for a wide variety of 
neoplasms. The entities included in th is 
chapter meet one of three inclusion crite-
ria: (1) they occur exclusively in the sino-
nasal tract , (2) they occur at other head 
and neck sites but show a predilection 
for the sinonasal tract, or (3) they are im-
portant in the sinonasal tract for differen-
tial diagnostic reasons. The first group is 
discussed extensively and the other two 
more concisely, with the reader referred 
to other chapters for additional informa-
tion. This edition includes NUT carcino-
ma and biphenotypic sinonasal sarcoma 
as well-defined new entities. HPV-related 
Carcinomas 
Keratinizing squamous ce// 
carcinoma 
Bishop J.A. 
Bell D. 
Westra W.H .. 
Detinition 
Sinonasal keratinizing squamous cell 
carcinoma (KSCC) is a malignant epi-
thelial neoplasm arising from the surface 
epithelium lining the nasal cavity and 
paranasal sinuses and exhibiting squa-
mous differentiation. 
ICD-0 code 8071/3 
carcinoma with adenoid cystic-like fea-
tures is provisional ly listed as a subtype 
of non-keratinizing squamous cell carci-
noma, with additional data needed to jus-
tify ful l recognition as a unique entity. Tu-
mours of bone and carti lage, which were 
included in both the jaw and sinonasal 
tract chapters in the previous edition, are 
in this edition discussed exclusively in 
Chapter 8 (Odontogenic and maxillofacial 
bone tumours, p. 203) - a more appropri-
ate approachgiven their morphological 
overlap with sorne odontogenic tumours. 
The role of immunohistochemical and 
genetic features in tumour characteriza-
tion is reported with a balance between 
worldwide global application and the use 
of more expensive diagnostic methods 
not everywhere available, in an effort to 
ensure a more universal applicability of 
the classification . 
lt is noted that sorne tumours may consti-
tute a spectrum of entities, such as high-
grade non-intestinal-type adenocar-
cinoma and sinonasal undifferentiated 
Synonym 
Epidermoid carcinoma 
Epidemiology 
Sinonasal KSCCs are rare, and the sino-
nasal tract is the least common head and 
neck subsite involved by squamous cell 
carcinoma (SCC) {82}. KSCC most often 
affects patients in their sixth to seventh 
decades of life, and men are affected 
twice as often as women (82,2065,.2438}. 
Etiology 
Cigarette smoking increases risk, al -
though less dramatically than in other 
head and neck sites {271,960,1458, 
2688}. Wood dust, leather dust, and other 
14 Tumours of the nasal cavity, paranasal sinuses and skull base 
carcinoma, and that there may be sorne 
overlap between tumours, such as be-
tween sorne sinonasal undifferentiated 
carcinomas and high-grade neuroendo-
crine carcinomas. More data are needed 
befare recommendations can be made 
on how best to classify tumours within 
these categories. In the meantime, we 
have tried to remain consistent with pre-
vious classification systems of tumours 
both at this site and at others (e.g. the 
classification of high-grade neuroendo-
crine carcinomas of the lung). 
Within the sinonasal trae!, CT is primarily 
used to evaluate mass effect on adjacent 
osseous structures, whereas MRI is bet-
ter for disti nguishing mucosa! thickening 
and fluid resulting from a pathological 
mass process. Thus, these imaging mo-
dalities are complementary techniques. 
However, in general, cross-sectional im-
aging findings are not unique or tumour-
specific; therefore, information regarding 
imaging findings is included only when it 
is of specific diagnostic value. 
industrial exposures are linked to sinona-
sal KSCC, although the association is 
not as strong as with intestinal-type ade-
nocarcinoma {940,1490,1627). High-risk 
HPV is most frequently associated with 
non-keratinizing squamous cel l carci-
noma (see Non-keratínizing squamous 
ce// carcinoma, p. 15) (199,636,1335}. 
Sorne sinonasal papillomas (2-10%) un-
dergo malignant transformation, usually 
into KSCC and less frequently into non-
keratinizing squamous cel l carcinoma 
(1 750}. 
Localization 
The maxillary sinus is most frequently af-
fected, followed by the nasal cavity and 
ethmoid sinus. Primary carcinomas of the 
sphenoid and frontal sinuses are rare {82, 
1999, 2065, 2342, 2438}. 
Cl inical features 
Presenting symptoms are generally non-
specific and include nasal obstruction, 
epistaxis, and rhinorrhoea. Facial pain 
and/or paralysis, diplopía, and proptosis 
are indicative of more-advanced tumour 
growth {1458}. lmaging determines ex-
tent of disease. 
Macroscopy 
The tumour is exophytic or endophytic, 
with various degrees of ulceration, ne-
crosis, and haemorrhage. 
Cytology 
Aspirates of metastases are cellular, with 
sheets and small clusters of malignant 
squamous cells with intracellular and 
extracellular keratinization. Mixed inflam-
mation and necrosis can be present. 
Histopathology 
KSCC exhibits histological features iden-
tical to those of conventional squamous 
cell carcinoma of other head and neck 
sites, with irregular nests and cords of 
eosinophi lic cel ls demonstrating kerati-
nization . and inducing a desmoplastic 
stromal reaction. Grades include well, 
moderately, and poorly differentiated. 
See Chapter 3 ( Tumours of the hypophar-
ynx, /arynx, trachea and parapharyngeal 
space, p. 77) for further detail. 
Genetic profile 
The genetic profile is similar to that of 
KSCC of other upper aerodigestive tract 
sites, whereas the genetic profile of non-
keratinizing squamous cell carcinoma is 
~ 
Fig. 1.02 Sinonasal non-keratinizing squamous cell carcinoma. A lnterconnecting squamous ribbons invading the 
stroma with a broad, pushing border. B lnvasion takes the form of thick, anastomosing ribbons of tumour cells with 
a smooth stromal interface and no desmoplastic reaction. C Non-keratinizing squamoid cells with nuclear atypia, 
numerous mitotic figures, and peripheral palisading of tumour nuclei. 
similar to that of its counterpart in the oro-
pharynx (447,1458,1474}. 
Prognosis and predictive factors 
The 5-year overall survival rate for sino-
nasal squamous cell carcinoma is approx-
imately 50-60%, and is stage-depend-
ent (2065,2397,2438) Carcinomas of 
the nasal cavity have a better prognosis 
than carcinomas arising in the paranasal 
sinuses {82,617,2397,2438]. This differ-
ence is likely in part because sinus carci-
nomas present later and at higher stage; 
it is unclear whether there is a stage-for-
stage survival difference. Regional lymph 
node metastasis is uncommon (1458). 
Non-keratinizing squamous 
ce// carcinoma 
Bishop J.A. 
Brandwein-Gensler M. 
Nicolai P. 
Steens S. 
Syrjanen S. 
Westra W.H. 
Definition 
Non-keratinizing squamous cell carcino-
ma (NKSCC) is a squamous cell carcino-
ma (SCC) characterized by a distinctive 
ribbon-like growth pattern with absent to 
limited maturation. 
Carcinomas 15 
ICD-0 code 8072/3 
Synonyms 
Schneiderian carcinoma; transitional cell 
carcinoma; cylindrical cell carcinoma 
Epidemiology 
NKSCC accounts for approximately 10-
27% of sinonasal SCC. lt affects adults in 
their sixth to seventh decades of lite, and 
men more frequently than women {199, 
636,1784,1999}. 
Etiology 
In general, NKSCC has similar risk fac-
tors to keratinizing squamous cel l car-
cinoma, but 30-50% of cases harbour 
transcriptionally active high-risk HPV 
{199,636,1335). Sorne sinonasal papil-
lomas (2-10%) undergo malignan! trans-
formation. usually into keratin izing squa-
mous cell carcinoma and less frequently 
into NKSCC {1750). 
Localization 
NKSCC arises most frequently from the 
maxillary sinus or nasal cavity {82,1402, 
2065,24381. 
Clinical features 
Presenting signs and symptoms include 
nasal obstruction, discharge, epistaxis, 
facial pain or fullness, nasal mass or 
ulcer, and eye-related symptoms in ad-
vanced cases {1 458). Patients with para-
nasal sinus neoplasms present later and 
at a higher stage than do patients with 
nasal cavity carcinomas {82,2438). lm-
aging determines extent of disease. 
Macroscopy 
The tumours are variably exophytic and/ 
or inverted in growth, and often friable, 
with necrosis and/or haemorrhage. 
Cytology 
Aspirates of metastases are cellular, with 
clusters of basaloid cells showing cyto-
logical features typical of malignancy, 
with nuclear atypia and increased mitotic 
figures . Mixed inflammation and necrosis 
can be present. • 
Histopathology 
NKSCC characteristically grows as ex-
panding nests or anastomosing ribbons 
of cells in the submucosa, with a smooth 
stromal interface and a pushing border 
elic iting minimal or no desmoplasia. This 
16 Tumours of the nasal cavity, paranasal sinuses and skull base 
pattern is reminiscent of urothelial carci-
noma (hence the synonym "transitional 
cell carcinoma") and may be difficult 
to recognize as invasive, particularly in 
small biopsies. Papillary features can 
be seen within the tumour or at the mu-
cosa! surface. NKSCC has an immature 
appearance, with minimal or no kerati-
nization; tumour nuclei are oval and the 
N:C ratio is high. Basal/superfic ial cel-
lular polarity is often apparent: basal-
type cells often demonstrate peripheral 
palisading, whereas superficial cells are 
more flattened. Scattered mucinous cells 
are occasionally present. The degree of 
nuclear atypia varíes, but mitotic figures 
are typically numerous, and necrosis is 
common. There is no established role for 
tumour grading in this variant. 
There is a broad differentialdiagnosis·; 
the growth pattern of NKSCC can mimic 
that of a sinonasal papilloma with malig-
nant transformation. However, this would 
require confirmation of metachronous 
or synchronous sinonasal papilloma. 
Sinonasal undifferentiated carcinoma, 
neuroendocrine carcinoma, the salid 
variant of adenoid cystic carcinoma, 
and SMARCB1-def icient carcinomas 
should be considered in the differential 
diagnosis. The presence of so-called 
abrupt keratinization should raise the 
possibility of NUT carcinoma. 
NKSCC is diffusely positive for cytokerat-
ins (including high-molecular-weight 
forms such as CK5/6) and for p63 and 
p40. lt retains nuclear expression of 
SMARCB1 (INl1) and is negative for neu-
roendocrine markers, S100, and NUT1. 
HPV-related SCCs are diffusely p16-
positive by immunohistochemistry and 
positive for HPV by in situ hybridization 
and PCR. 
Genetic profile 
The distinctive mutational profiles of 
HPV-positive and HPV-negative sinona-
sal SCC are similar to those of their coun-
terparts in other head and neck sites, 
such as the oropharynx [447,1458,1474). 
Prognosis and predictive factors 
The 5-year overall survival rate of sino-
nasal SCCs as a group is approximately 
60%; it is unclear whether the survival rate 
of NKSee differs from that of keratiniz-
ing squamous cell carcinoma {82,1999, 
2065,2397,2438). HPV positivity may be 
associated with improved survival, al-
though the prognostic signif icance is not 
as clearly defined as it is in the oropha-
rynx {199,1335). Sorne studies have dem-
onstrated improved survival in sinonasal 
sce harbouring high-risk HPV or overex-
pressing EGFR [199,1335,2342}. 
The newly recognized sinonasal tract 
HPV-related carcinoma with adenoid 
cystic-like features is a distinctive HPV-
related carcinoma of the sinonasal tract, 
with histological and immunophenotypic 
features of both surface-derived and sali-
vary gland carcinoma - the latter show-
ing the appearance of a high -grade ad-
enoid cystic carcinoma. Among the few 
cases of HPV-related carcinoma with ad-
enoid cystic- like features that have been 
reported to date, the female-to-male ratio 
is 7:2 and the patient age range is 40-
75 years {199,202,1065). The presence 
of a high-risk HPV type suggests a viral 
etiology [202,1065). Most cases present 
with nasal obstruction and/or epistaxis, 
with a tan-white, fleshy mass undermin-
ing normal-looking mucosa. The tumour 
consists of highly cellular prol iferations of 
basaloid cells growing in various sizes, 
separated by th in collagenized fibrous 
bands. The growth pattern is predomi-
nantly salid, but cribriform structures are 
frequently encountered . The basaloid 
cells align around cylindromatous micro-
cystic spaces and have hyperchromatic 
and slightly angu lated nuclei with a high 
N:e ratio. In contrast to typical NKSCe, 
true ductal cel ls are also present (al-
though less conspicuous), often sur-
rounded by a peripheral layer of basaloid 
to clear myoepithelial cells. When this 
bilayered pattern is well developed, it im-
parts an appearance like that of epithe-
lial-myoepithelial carcinoma. Although 
overt squamous differentiation is not typi-
cally present in the invasive component, 
the surface epithelium may show various 
degrees of dysplasia. Mitotic rates are 
usually high, and necrosis may be seen. 
The basaloid cells show myoepithelial 
differentiation (e.g. S100, calponin , p63, 
and actin), and the ductal cel ls are KIT-
positive. Cytokeratins tend to be more 
strongly expressed in the ductal rather 
than myoepithelial cells . Both cell types 
are p16-positive and harbour high-risk 
HPV as detected by in situ hybridization. 
No MYB translocations (typically seen in 
about 50% of adenoid cystic carcinomas) 
have been identified [202} . To date, with 
only a limited number of cases reported, 
local recurrence has been seen, but no 
regional or distant metastases or tumour-
related deaths {202). 
Spmdmcell(sarcomawid) 
squamous cell carcinoma 
Bishop J.A. 
Lewis J.S. 
Definition 
Spindle cell squamous cell carcinoma 
(SCSCe) is a variant of squamous cell 
carcinoma characterized by predomi-
nan\ malignan! spind le and/or pleomor-
phic cells. 
ICD-0 code 
Synonym 
Sarcomatoid carcinoma 
Epidemiology 
8074/3 
sesee presents most commr;mly in el-
derly men {156,1330,2396}. This variant 
is rare in the sinonasal tract, accounting 
for < 5% of sinonasal squamous cell car-
cinomas {199,787,896,912,1032,1035}. 
Etiology 
sesee is associated with smoking and 
radiation exposure {1398 ,2396}. HPV has 
been negative in the few cases tested 
{199). 
Localization 
sesee arises in the nasal cavity and/ 
or maxillary or frontal sinuses [787,912, 
1032,1035). 
Clinical features 
Patients present with nasal obstruction, 
epistaxis, and/or facial swell ing, with 
masses apparent on eT or MRI {787,896, 
912,1032,1035}. 
Macroscopy 
Sorne SCSCCs grow as a polypoid mass 
with an ulcerated surface, similar to the 
more common laryngeal examples {896, 
912). 
Cytology 
See Spindle ce!/ squamous ce!/ carcino-
ma section (p. 87) in Chapter 3. 
Histopathology 
For histology and differential diagnosis, 
see Spindle ce// squamous ce!! carcino-
ma section (p. 87) in Chapter 3. 
Prognosis and predictiva factors 
No specific features are described for 
the sinonasal tract regían. 
Carcinomas 17 
Lymphoepithelial carcinoma 
Bishop J.A. 
Gaulard P. 
Gillison M. 
Definition 
Lymphoepithelial carcinoma (LEC) is a 
squamous cell carcinoma morphologi-
cally similar to non-keratinizing naso-
pharyngeal carcinoma, undifferentiated 
subtype. 
!CD-O code 8082/3 
Synonym 
Lymphoepithelioma-like carcinoma 
Epidemiology 
Sinonasal LEC is rare, with only about 40 
reported cases {1125,2034,2584,2733). 
lt most frequently affects men in their 
fifth to seventh decades of life (median 
patient age: 58 years) {381 ,1125,2034, 
2584,2733). Most reported cases have 
been in patients from Asia, where EBV-
related malignancies are endemic. 
Etiology 
In the sinonasal tract, most cases 
(> 90%) of LEC harbour EBV {1125,1392, 
2034,2584,2733}. 
Localization 
Sinonasal LEC arises in the nasal cav-
ity more frequently than in the paranasal 
sinuses (2034,2584,2733}. For an LEC 
to be considered truly primary to the 
sinonasal region, spread from a nearby 
nasopharyngeal carcinoma must be ex-
cluded on clinical, radiographical, and/or 
pathological grounds. 
Clinical features 
Patients present with nasal obstruction, 
nasal discharge, and/or epistaxis. Pa-
tients may also have eye symptoms or 
cranial nerve palsies as a result of local 
tumour invasion {1125,2034,2584,2733}. 
Macroscopy 
The tumours are irregular or polypoid, 
tan-white, bulky masses that may be 
haemorrhagic {1155,2034,2347). 
Cytology 
The cytological findings are the same as 
those far non-keratinizing nasopharyn-
geal carcinoma, undifferentiated subtype 
(see Nasopharyngeal carcinoma, p. 65.) 
H istopathology 
LEC is defined by its resemblañce to 
non-keratinizing nasopharyngeal carci-
noma, undifferentiated subtype (see Na-
sopharyngeal carcinoma, p. 65). 
By immunohistochemistry, LEC is dif-
fusely positive far pancytokeratin, CK5/6, 
p63, and p40, and is negative for lym-
phoid and melanocytic markers. Sino-
nasal LEC is usually positive far EBV-
encoded small RNA (EBER) by in situ 
hybridization. 
Sinonasal LEC must be distinguished 
from lymphoma and melanoma (potential 
mimics), as well as from sinonasal undif-
ferentiated carcinoma, a neoplasm that 
lacks the syncytial growth pattern of LEC, 
is consistently EBER-negative, and lacks 
CK5/6, with limited to absent p63 . 
Prognosis and predictive factors 
According to the SEER database, sinon-
asal LEC has a 5-year disease-specific 
survival rate of approximately 50%; 
patients with localized disease, aged 
18 Tumours of the nasal cavity, paranasal sinuses and skull base 
< 60 years, and of White ethnicity have 
significantly improved survival {381). 
Sinonasal LEC metastasizes to regional 
lymph nadesless frequently than does 
nasopharyngeal carcinoma, and tends 
to be radiosensitive even in the presence 
of nada! disease {381,1125,2034,2584, 
2733). 
Sinonasal undifferentiated 
carcinoma 
Lewis J.S. 
Bishop J.A 
Gill ison M. 
Westra W.H. 
Yarbrough W.G. 
Definition 
Sinonasal undifferentiated carcinoma 
(SNUC) is undifferentiated carcinoma of 
the sinonasal tract without glandular or 
squamous features and not otherwise 
classifiable . 
Table 1.01 Differential diagnosis of sinonasal 
undifferentiated carcinoma 
Lymphoma 
Non-keratinizing squamous cell carcinoma (including 
HPV-related carcinoma with adenoid cystic- like 
features) 
Basaloid squamous ce!! carcinoma 
High-grade neuroendocrina carcinoma 
Olfactory neuroblastoma 
NUT carcinoma 
Alveolar rhabdomyosarcoma 
Ewing sarcoma / primitiva neuroectodermal tumour 
Adenoid cystic carcinoma, solld-type (grade 111) 
Melanoma 
ICD-0 code 8020/3 
Epidemiology 
SNUC is rare, with about 0.02 cases 
per 100 000 people, accounting for only 
about 3-5% of ali sinonasal carcinomas 
(1458}. lt occurs in patients of a wide 
range of ages, from teenagers to the el-
derly (average patient age: 50-60 years). 
Approximately 60- 70% of patients are 
Caucasian males {371,1974}. 
Etiology 
No consistent etiology of SNUC has been 
identified. Sorne patients are smokers 
but many are not {365). lf EBV or HPV is 
detected, the diagnosis of SNUC should 
be questioned {199,365,885,2518}. 
Localization 
Tumours arise most frequently in the na-
sal cavity and ethmoid sin uses, and most 
present as very large masses involving 
multiple sites. As many as 60% of cases 
have spread beyond the sinonasal trae! 
to adjacent sites such as the orbital apex, 
skull base, and brain {1974). Nodal me-
tastases are relatively uncommon (occur-
ring in 10-15% of cases) despite large 
primary tumour size {416,885,1974}. 
Clinical features 
Patients present with nasal obstruction, 
epistaxis, headache, and diplopía or 
other visual symptoms (2656). Proptosis 
and periorbital swelling can be seen as 
well, features reflecting frequent orbital 
involvement. 
Macroscopy 
Tumours are usually large (> 4 cm) at 
presentation, with a fungating endoscop-
ic appearance and poorly defined mar-
gins radiographically {1883). 
Cytology 
Aspirates of metastatic SNUC are cel-
lular, with cohesive groups, single large 
malignant cells, and background necrotic 
debris. Numerous mitotic figures and ap-
optotic bodies can be seen. Neuroendo-
crine features are typically not prominent, 
and squamous or glandular features are 
not seen. 
Histopathology 
SNUC consists of sheets, lobules, and 
trabeculae of overtly malignant cells with 
moderately large round nuclei, varying 
amounts of cytoplasm, and wel l-defined 
cell borders. Nuclei vary from hyperchro-
matic to vesicular, but most tumours have 
open chromatin with prominent nucleoli. 
Apoptosis, mitoses, and necrosis are 
frequent. Despite their high-grade ap-
pearance, SNUCs characteristically have 
tumour nuclei of relatively consisten! size 
and lack of pleomorphism. By definition, 
there is no squamous or glandular differ-
entiation, although adjacent carcinoma in 
situ has been described. 
By immunohistochemistry, the tumour 
is positive for pancytokeratin (AE1/AE3) 
and simple cytokeratins such as CK7, 
CK8, and CK18, but is negative for 
CK5/6. The tumour cells are variably pos-
itive for p63, but consistently negative for 
its more squamous-specifi c isoform, p40 
{2186}. The cells are consistently positive 
for neuron-specific enolase. Very focal, 
patchy staining for chromogranin and 
synaptophysin may be seen {365,416}, 
but does not qualify a tumour as a neu-
roendocrine carcinoma in the absence 
of supporting histological features. The 
tumours are negative for carcinoembry-
onic antigen, S100, CD45, and calretinin 
{2635). The tumours are consistently 
p16-positive, regardless of HPV status 
{885,2518}. 
The differential diagnosis is lengthy 
(Table 1.1), but most importantly includes 
lymphoma, non-keratinizing squamous 
cell carcinoma, basaloid squamous cell 
Carcinomas 19 
carcinoma, and neuroendocrine carcino-
ma. Squamous cell carcinoma has areas 
of histological squamous differentiation 
and is consistently positive for CK5/6, 
p63, and p40. Neuroendocrine carcino-
mas have speckled chromatin and other 
histological features such as rosette 
formation and palisading, and are con-
sistently reactive with neuroendocrine 
marl<ers. NUT carcinoma has evidence 
of squamous differentiation (at least fo-
cally), is consistently diffusely positive 
for p63 and p40, and strongly expresses 
the NUT protein by immunohistochemis-
try. Recently, a subset of undifferentiated 
carcinomas with rhabdoid features and a 
lack of SMARCB1 (INl1) protein by immu-
nohistochemistry has been reported. lt is 
unclear whether these tumours constitute 
a distinct entity {198). 
Genetic profile 
No specif ic genetic alterations have been 
identified in SNUC {819). The S0X2gene is 
amplified in one third of tumours {2102}. KIT 
(CD117) is frequently strongly expressed, 
but no activating mutations or gene amplifi-
cations have been identified {416). 
Prognosis and predictive factors 
The prognosis of SNUC is poor, although 
it seems to have improved in recent 
years, likely dueto the use of aggressive 
trimodality therapy {371}. Systemic che-
motherapy is associated with particularly 
high response rates (243}. A large analy-
sis of SEER data showed a median over-
all survival of 22.1 months and 3-, 5-, and 
10-year survival rates of 44.3%, 34.9%, 
and 31.3%, respectively (371 ]. A recent 
meta-analysis had similarfindings {1974). 
Patient survival is significantly better with 
primary surgical resection [1974,2685) . 
NUT carcinoma 
French C.A. 
Bishop J.A. 
Lewis J.S. 
Muller S. 
Westra W.H. 
Definition 
NUT carcinoma is a poorly differentiated 
carcinoma (often with evidence of squa-
mous differentiation) defined by the pres-
ence of nuclear protein in testis (NUT) 
gene (NUTM1) rearrangement. 
- -
Fig. 1.09 NUT carcinoma. A Sheets of moderate-sized monomorphic poorly differentiated epithelioid cells have pale 
to clear glycogenated cytoplasm; the intervening stroma is sean!, and necrosis and mitoses are invariably present. 
B Abrupt keratinization can appear as a discrete island within a sea of poorly differentiated cells. C FISH demonstrates 
NUT rearrangement when red and green probes flanking the NUT Jocus are split apart; the red and green signals 
together are the normal NUT allele. D Diffuse, nuclear immunohistochemical staining with the NUT antibody is 
diagnostic of NUT carcinoma; the speckled pattern is characteristic but not always this distinct. 
ICD-0 code 8023/3 Clinical features 
Synonyms 
NUT midline carcinoma; t(15;19) carci -
noma; midline carcinoma of children and 
young adults with NUT rearrangement 
Epidemiology 
NUT carcinoma is a rare tumour in the 
upper aerodigestive tract {t59,393, 
2234}. Dueto its rarity, the true incidence 
is unknown. In the largest series report-
ed (n = 40), the median patient age was 
21 .9 years, but people of all ages were 
affected (range: 0.1- 82 years). A slight 
predominance of females was seen, with 
55% of the cases occurring in females 
{393). 
Etiology 
The etiology is unknown. There is no as-
sociation with HPV, EBV, other viral in-
fection; smoking; or other environmental 
factors . 
Localization 
Most cases (65%) in the head and neck 
are in the nasal cavity and paranasal si-
nuses, but rare cases involve the orbital 
region, nasopharynx, oropharynx, lar-
ynx, epiglottis, and majar salivary glands 
{159,508,763,2032}. The tumours are 
generally midline. 
NUT carcinoma presents with non-
specific symptoms caused by a rapidly 
growing mass. In the sinonasal tract, 
this manifests as nasal obstruction, pain, 
epistaxis, nasal discharge, and frequent-
ly eye-related symptoms such as prop-
tosis {205,692). lmag ing studies reveal 
extensive local invasion intoneighbour-
ing structures such as the orbit or brain 
(205 ,692}. In approximately 50% of cas-
es, NUT carcinoma presents with lymph 
nade involvement or distant metastatic 
disease {159}. 
Macroscopy 
Few tumours are resected, due to early 
disease spread. No consistent macro-
scopic features have been described . 
Cytology 
Aspirates of metastases are cellular, with 
variably sized clusters of malignant cells 
and single malignant cells. Mitotic figu res 
and apoptotic bodies are seen. Squa-
mous differentiation may be observed. 
Histopathology 
The diagnosis of NUT carcinoma is es-
tablished by demonstration of NUT re-
arrangement, rather than by histology. 
An unequivocal diagnosis can be made 
by demonstration of diffuse (> 50%) 
20 Tumours of the nasal cavity, paranasal sinuses and skul l base 
BRD4 N ..,_¡--............... --L.IJ.i._,¡,__i _____ _ 
Chromosome 15q14 
Chromosome 19pl3. l 
Chromosome 9q34.2 f 
BRD3 N ¡_,¡--..... =---'--L.1Ji.... _ _. 
Chromosome Bpll.23 
NSD3°NUT N .__.-....--~:::a:::::::.J• l.:;~=:;¡¡¡¡¡¡¡¡¡¡....¡.1u;;.:,•.;;:¡¡ 
PWWP 
1 PHD 
- SET 1 C/H rlch 
- Ac!dlc domainl 
Acidic doma in 2 
NLS 
1111 NES 
- Bromo 
ET 
Fig. 1.10 NUT carcinoma. Schematic illustration of the various translocations that occur in NUT carcinoma between 
NUTgenes and BRD4, BRD3, and WHSC1L1 (also called NSD3); the arrows indicate breakpoints. Nearly the entire 
NUT transcript is preserved in every known translocation. PWWP, PWWP domain; PHD, plant homeodomain; SET, 
SET domain; C/H rich, Cys/His-rich domain; NLS, nuclear Jocalization signal sequence; NES, nuclear export signal 
sequence; Bromo, bromodomain; ET, extraterminal domain. 
nuclear staining with the NUT monoclo-
nal antibody C52, which has a sensitiv-
ity of 87% (916}. Other diagnostic tools 
include FISH, RT-PCR, conventional cy-
togenetics, and targeted next-generation 
sequencing approaches . 
The histology is that of an undifferenti-
ated carcinoma or poorly differentiated 
squamous cell carcinoma. NUT carcino-
ma consists of sheets of cells with mod-
erately large, round to oval nuclei. The 
chromatin is vesicular with distinct nucle-
oli. Cytoplasm varíes from scant to mod-
erate, and can be clear. Mitotic activity is 
brisk and necrosis is often present. Hall-
mark features include monomorphism 
and the presence of so-called abrupt 
foci of keratinization. Occasional tumours 
have more extensive squamous differen-
tiation (764). lntratumoural acute inflam-
mation can be brisk and is frequently 
present. Glandular and mesenchymal 
differentiation, although described, is in-
frequent (566) . Markers other !han NUT 
that are commonly positive include p63, 
p40, and cytokeratins (2265). NUT carci-
noma occasionally (in 55% of cases) ex-
presses CD34 {764). Occasional positiv-
ity for neuroendocrine markers, p16, and 
TTF1 has also been described. 
Due to the non-specific, poorly differenti-
ated nature of NUT carcinoma, it is often 
confused with poorly differentiated squa-
mous cel l carcinoma, Ewing sarcoma, 
sinonasal undifferentiated carcinoma, 
leukaemia, germ cell tumour, and even 
olfactory neuroblastoma (763). A provi-
sionally defined entity included in the dif-
ferential diagnosis is SMARCB1-deficient 
carcinoma. However, unlike NUT carci -
nomas, SMARCB1-deficient sinonasal 
carc inomas do not exhibit focal kerati-
nization. lnstead, the basaloid cells 
demonstrate various degrees of rhab-
doid or plasmacytoid features. Be-
cause SMARCB1-deficient sinonasal 
carcinomas have biallelic inactivation of 
SMARCB1 (IN/1), immunohistochemi-
cal staining for SMARCB1 consistently 
demonstrates loss of nuclear expres-
sion, an importan! finding for distinguish-
ing SMARCB1-deficient carcinoma from 
NUT carcinoma. 
Genetic profile 
NUT carcinoma is genetically defined by 
rearrangements of the nuclear protein 
in testis (NUTJ gene (NUTM1). In most 
NUT carcinomas, most of the coding 
sequence of NUTM1 on chromosome 
15q14 is fused with BRD4 (in 70% of 
cases), BRD3 (in 6%), or WHSC1L1 (also 
called NS03), creating chimeric genes 
that encade NUT fusion proteins (159, 
764,765,766,767,2318}. In the remaining 
cases, referred to as NUT-variant carci-
noma, NUTM1 is fused toan unknown part-
ner gene. To date, no other oncogenic 
mutations have been identified in NUT 
carcinoma. 
Prognosis and predictive fact9rs 
Prognosis is poor, with a median overall 
survival of 9.8 months {393}. Sorne evi-
dence suggests that patients with NUT-
variant carc inoma may have a longer 
survival than do BRD-NUT carcinoma 
patients {159,763}. 
Neuroendocrine carcinomas 
Thompson L.D.R. 
Bell D. 
Bishop J .A. 
Definition 
Sinonasal neuroendocrine carcinoma is 
a high-grade carcinoma with morpholog-
ical and immunohistochemical features 
of neuroendocrine differentiation. 
ICD-0 codes 
Small cell neuroendocrine 
carcinoma (SmCC) 
Large cell neuroendocrine 
carcinoma (LCNEC) 
Synonyms 
8041/3 
8013/3 
Poorly differentiated neuroendocrine 
carcinoma; high-grade neuroendocrine 
carcinoma 
Epidemiology 
Sinonasal neuroendocrine carc inomas 
are rare, accounting for about 3% of 
sinonasal tumours, but are more com-
mon in middle-aged to older men. The 
mean patient ages are 49-65 years for 
LCNEC and 40-55 years for SmCC (370, 
1831,1853,2222}. 
Etiology 
There is rare association with transcrip-
tionally active high-risk HPV (199,1323} 
and previous irradiation (2535). but no 
strong smoking association {2296}. 
Localization 
The most common location is the ethmoid 
sinus, followed by the nasal cavity and 
the maxillary and sphenoid sinuses 
(1631,2222,2296}. 
Clinical features 
Many patients present with non-spe-
cific symptoms (e.g. nasal obstruction, 
discharge, and sinusitis) and have ad-
vanced local disease (pT3 or T4), with re-
gional or distan! metastases (to lung, liv-
er, or bone) (114,1428,1631,1853}. Rarely, 
paraneoplastic syndromes are reported 
{114,1207,2018,2482}. 
Macroscopy 
The tumours are large and destructive, 
with haemorrhage and necrosis. 
Carcinomas 21 
~ -- -Fig. 1.11 Sinonasal neuroendocrine carcinoma. A Coronal CT demonstrates a midline destructive mass. B Small cells with nuclear moulding, even chromatin distribution, and 
inconspicuous nucleoli are characteristic for a small cell neuroendocrine carcinoma; apoptotic figures and mitoses are apparent. C The neoplastic cells are large and have a high 
N:C ratio, with small nucleoli and salt-and-pepper nuclear chromatin distribution in a large cell neuroendocrine carcinoma. DA strong and diffuse, cytoplasmic dot-like (peri nuclear) 
reaction with pancytokeratin in a small cell neuroendocrine carcinoma. 
Cytology 
Aspirates of metastases are identical to 
those of SmCC and LCNEC sampled 
elsewhere. Malignant cel ls show less co-
hesion than seen in other epithelial malig-
nancies and are more fragile, displaying 
more crush artefact. Mitotic figures and 
apoptotic bodies are frequent. 
Histopathology 
Sinonasal neuroendocrine carcinoma is 
histologically identical to its counterparts 
in lung and other head and neck sites; 
for a detailed description, see Poorly dif-
ferentiated neuroendocrine carcinoma 
(p. 97). The tumours are highly infiltrative, 
with frequent perineural and lymphovas-
cular invasion (1853,2222). 
LCNEC contains large cells that show 
light microscopic neuroendocrine fea-
tures; for a detailed description of these 
features, see Poorly differentiated neuro-
endocrine carcinoma (p. 97). 
SmCC and LCNEC are strongly immu-
nopositive for cytokeratins (e.g. CAM5.2 
and AE1/AE3) and EMA, frequently 
showing a perinuclear or dot-like pattern 
(1587). Neuroendocrine differentiation 
can be confirmed by staining with at least 
one neuroendocrine marker, such as syn-
aptophysin (most sensitive and specific), 
chromogranin, neuron-specific enolase, 
or CD56 (least specific) {486}. although 
neuron-specific enolase is less common 
in LCNEC (114,2568}. In SmCC, S100 
protein staining (when positive) is diffuse 
rather than sustentacular{2222} . SmCC 
and LCNEC are positive far p16 (which 
is negative in sinonasal undifferentiated 
carcinoma); focally, they may be weakly 
positive for p63. The tumours are rarely 
reactive with calretinin and are consist-
ently negative far CK5/6, EBV-encoded 
small RNA (EBER), and CK20 {378,390, 
2635). ASCL1 (also called hASH1), which 
is a master gene for neuroendocrine dif-
ferentiation, shows a higher degree of 
expression in SmCC and LCNEC than 
in olfactory neuroblastoma or rhabdo-
myosarcoma (486,2331). Nuclear immu-
nohistochemistry for p53 correlates with 
TP53 mutations {758). 
Rare examples of sinonasal neuroendo-
crine carcinoma combined with either 
squamous cell carcinoma (in situ or in-
vasive) or adenocarcinoma ha'{e been 
reported (1 14,758;1320}. However, squa-
mous cell carcinoma or adenocarcinoma 
should not be regarded as sinonasal 
neuroendocrine carcinoma based solely 
on the presence of focal neuroendo-
crine immunoreactivity in the absence of 
22 Tumours of the nasal cavity, paranasal sinuses and skull base 
light-microscopic features of neuroendo-
crine differentiation. 
The differential diagnosis frequently in-
eludes olfactory neuroblastoma, sinona-
sal undifferentiated carcinoma, and NUT 
carcinoma. High-grade olfactory neu-
roblastoma may retain a focal lobular 
architecture with a variable presence of 
peripheral sustentacular cells demon-
strated by immunohistochemistry; cy-
tokeratins, if expressed, tend to be focal 
rather than diffuse. Sinonasal undifferen-
tiated carcinomas occasionally express 
neuroendocrine markers, but lack the 
morphological features of LCNEC [773, 
1034,2568}. NUT carcinoma does not 
show neuroendocrine differentiation, and 
typically shows diffuse expression of 
CK5/6 and p63 (692). 
Prognosis and predictiva factors 
The 5-year disease-free survival rate is 
about 50-65% overall, and is better for 
sphenoid sinus tumours (-80%) than 
for maxillary or ethmoid sinus tumours 
(-33%), in particular when managed by 
combination surgery and/or neoadjuvant, 
concurrent, or adjuvant chemoradiother-
apy, with neoadjuvant therapy possibly 
yielding a better outcome (especially 
for LCNEC) (770,1428,1631,1831,2462). 
Data are limited, but LCNECs tend to 
have a better prognosis than do SmCCs 
{1587, 1631, 2016 ,2462}. Advanced-stage 
disease is associated with poor progno-
sis {1831). 
Jntestinal-type adenocarcinoma 
Stelow E.B. 
Franchi A. 
Wenig B.M. 
Definition 
Sinonasal intestinal-type adenocarci-
noma (ITAC) is an adenocarcinoma of 
the sinonasal tract morphologically simi-
lar to adenocarcinomas primary to the 
intestines. 
ICD-0 code 8144/3 
Synonyms 
Colloid-type adenocarcinoma; colonic-
type adenocarcinoma; enteric-type 
adenocarcinoma 
- ;,. ... 
Epidemiology 
Sinonasal ITACs are uncommon, with 
an overall incidence of < 1 case per 
1 million person-years. However, inci-
dence varíes drastically across popula-
tions, and the tumours are as much as 
500 times as prevalent among people 
who work for prolonged periods in wood 
or leather-working industries as they are 
in the general population {9). Men are 
3 - 4 times as likely to develop these tu-
mours as women, which is thought to be 
due to differences in occupational ex-
posure rates (139,1238,2063}. Although 
the patient age range is reportedly wide, 
most patients are older, with mean and 
median reported patient ages at diagno-
sis in the sixth to seventh decades of lite. 
Etiology 
Many ITACs are secondary to wood dust 
or leather dust exposure {9,10,918,1238). 
Formaldehyde and texti le dust exposures 
may also increase the risk of these tu-
mours {1490). 
Localization 
ITACs typically develop near the lateral 
nasal wall , near the middle turbinate {139, 
2063). lt is estimated that 40% of cases 
develop in the ethmoid sinuses, 28% in the 
nasal cavity, and 23% in the maxillary sinus. 
Clinical features 
Patients with ITACs typically present with 
unilateral nasal obstruction, epistaxis, 
and/or rhinorrhoea {139,2063}. Less 
common symptoms include pain, facial 
contour changes, and diplopía. The tu-
mours present as soft tissue densities 
within the sinonasal tract {139}. Destruc-
tion of surrounding bone occurs in nearly 
half of ali patients. Patients most often 
present with multiple sites of involvement 
{139}. Osseous destruction with local 
spread into surrounding tissues, includ-
ing the orbit and brain, is frequently seen. 
Macroscopy 
In vivo, ITACs are polypoid, papillary, 
nodular, and fungating {139,2063). They 
are usually friable, sometimes ulcerated 
or haemorrhagic, and uncommonly ge-
latinous or mucoid. 
1
1 ,...1 
\ ,l ' - • 
Fig. 1.12 Sinonasal intestinal-type adenocarcinoma. A This well-differentíated tumour shows papillary growth with numerous goblet and Paneth cells. B This tumour is 
moderately differentiated, with cribriform growth and areas of necrosis. C This tumour is composed of abundan! extracellular mucus with occasional strips of malignan! epithelium. 
D Sorne tumours are composed of signet-ring cells. 
Carcinomas 23 
Cytology 
Aspirates of rare metastatic lesions show 
findings identical to those seen with colo-
rectal adenocarcinomas. 
Histopathology 
ITACs show a morphological spectrum 
similar to that of adenocarcinomas of 
the intestines {139,1238,2063}. They 
are often exophytic with a papillary and 
tubular growth (in approximately 75% 
of cases) or may be mucinous or com-
posed predominantly of signe! ring cells. 
The degree of differentiation varies from 
extremely well differentiated to poorly 
differentiated. Papillae and tubules are 
lined by a single !ayer of columnar epi-
thelial cells that show differentiation and 
cytological features similar to !hose seen 
in intestinal adenocarcinomas. Most cells 
appear columnar with eosinophilic, mu-
cinous cytoplasm. Paneth cells, goblet 
cells, and endocrine cells are typically 
also present in variable proportions. Al-
though atypia may be difficult to appreci-
ate, nuclear changes that appear at least 
adenomatous are the rule. Thus, nuctei 
are cigar-shaped, hyperchromatic, and 
enlarged, and lose basement membrane 
localization. Mitotic figures are frequent. 
Necrosis is usually present, typically 
within the tubular and folded spaces, 
similar to what is seen in intestinal adeno-
carcinomas. As these tumours become 
more poorly differentiated, tubular and 
papillary structures are replaced by nest-
ed, cribriform, and salid growth patterns. 
A minority of cases show abundan! mu-
cus production (139,1238). These cases 
are similar to sorne primary intestinal 
adenocarcinomas and consist of small 
to medium-sized cystic spaces (alveoli) 
partially lined by (and containing strips of) 
attenuated neoplastic epithelium rich in 
goblet cells. The strips often float like rib-
bons within mucus lakes and sometimes 
form small cribriform structures. The indi-
vidual neoplastic cells have atypical and 
hyperchromatic nuclei and abundant mu-
cinous cytoplasm. Less commonly, the 
neoplastic cells are mostly single , with 
a large amount of intracytoplasmic mu-
cus that compresses the nucleus (signet 
ring cells). Finally, sorne tumours have a 
mixed pattern of growth, appearing pap-
illary and tubular in sorne areas and more 
mucinous in others. 
ITACs are invasive (often extensively in-
filtrating the submucosa) and may show 
perineural and osseous invasion {139}. 
Stromal tissues are loase and fibrovas-
cular, often containing abundant chronic 
inflammatory cells. Histological similarity 
to primary gastrointestinal trae! tumours 
necessitates exclusion of a metastatic 
tumour. 
Proposed grading schemas are rather 
complicated, given the rarity of these tu-
mours {139,1238). Tumours that are pre-
dominately papillary can be graded as 
well, moderately, or poorly differentiated 
(papillary tubular cylinder cell 1, 11, and 
111; or papillary, colonic, and salid). Mu-
cinous tumours are either moderately dif-
ferentiated (alveolar) or poorly differenti-
ated (signet ringcell) . Mixed tumours are 
typically well to moderately differentiat-
ed. Overall survival rates at 3 years have 
been shown to vary depending on grade. 
Histochemical staining shows intracyto-
plasmic, intraluminal, and/or extracellu-
lar material that is mucicarmine-positive 
and gives a diastase-resistant positive 
periodic acid-Schiff (PAS) reaction 
{139}. Neoplastic cells express pancy-
tokeratins, are variably reactive with CK7 
and carcinoembryonic antigen, and are 
mostly CK20-positive {1213,1573}. Most 
tumours also express the markers CDX2, 
MUC2, and vi llin (358,1213}. There may 
be variable expression of neuroendo-
crine markers {1 573,1928}. 
Genetic profile 
KRAS mutations occur in 6-40% of cas-
es, whereas BRAF mutations occur in 
< 10% {755 ,1926,2037,2327). 1 umours 
are microsatellite-stable and do not lose 
expression of mismatch repair proteins 
{1 546,1854). EGFR mutations are infre-
quent and amplifications are uncommon 
{755,1926}. Expression of p53 is aber-
rant in more than half of ali cases, and 
41 % have been shown to have TP53 
mutations {757). CDKN2A (also called 
P16) is frequently altered, due either to 
promoter methylation or to loss of hete-
rozygosity at 9p21 {1857). Variable beta-
catenin expression has been reported, 
with sorne studies showing > 30% of 
cases with aberrant nuclear expression 
{757,1854}. 
Prognosis and predictive fact9rs 
The grading systems described above 
predict survival and recurrence, although 
results have not been universal {1 39,754, 
760,1238}. Low-grade papillary tumours 
have the best outcomes, with > 80% of 
patients surviving 3 years and > 60% of 
24 Tumours of the nasal cavity, paranasal sinuses and skull base 
patients being disease-free at 5 years. 
Grade 2 and 3 papillary tumours have 
3-year survival rates of 54% and 36%, 
respectively. Mucinous tumours with al-
veolar growth and mixed or transitional 
tumours have prognoses similar to that 
of grade 2 papillary tumours, whereas 
tumours showing signet ring morphology 
behave the most aggressively. Locally 
advanced tumours that invade into the 
orbit, skin, sphenoid or frontal sinuses, or 
brain have a significantly worse progno-
sis. Local disease is the most common 
cause of mortal ity. About 8% of patients 
have lymph nade metastases and 13% 
have distan! metastases {139}. 
Non-intestínal-type 
adenocarcínoma 
Stelow E.B. 
Brandwein-Gensler M. 
Franchi A. 
Nicolai P. 
Wenig B.M. 
Definition 
Sinonasal non-intestinal-type adeno-
carcinoma (non-lTAC) is an adenocar-
cinoma of the sinonasal tract that does 
not show the features of a salivary gland 
neoplasia and does not have an intesti-
nal phenotype. Although these tumours 
are morphologically heterogeneous, this 
category may include sorne specific enti-
ties that are morphologically unique (e.g. 
renal cell-l ike carcinoma). 
ICD-0 code 8140/3 
Synonyms 
Terminal tubulus adenocarcinoma; tubu-
lopapillary low-grade adenocarcinoma; 
low-grade adenocarcinoma; seromuci-
nous adenocarcinoma; renal cell- like 
carcinoma 
Epidemiology 
Sinonasal low-grade non-intestinal-type 
adenocarcinomas (LG non-lTACs) are 
very uncommon. There is no sex predi-
lection {967,1139,1721). Patients have 
ranged in age from 9 to 89 years, with 
a mean age at presentation in the sixth 
decade of life. High-grade non-intestinal-
type adenocarcinomas (HG non-lTACs) 
are rare, affect men more frequently, 
and occur over a wide age range, with a 
mean patient age at presentation in the 
sixth decade of lite {967,2266}. 
Etiology 
There is no known etiology for LG non-
lTACs or HG non-lTACs. Rare HG non-
lTACs have been associated with high-
risk HPV or sinonasal papillomas (2266). 
Localization 
Most LG non-lTACs (64%) arise in the 
nasal cavities (frequently the middle tur-
binate), and 20% arise in the ethmoid si-
nuses (967,1139). The remaining tumours 
involve the other sinuses or multiple lo-
cations throughout the sinonasal tract. 
Approximately half of ali HG non-lTAC 
cases are locally advanced at presenta-
tion and involve both the sinuses and the 
nasal cavity {967,2266}. Approximately 
one third involve the nasal cavity only. 
Clínica! features 
Most patients with LG non-lTACs present 
with obstruction (1721,2193}. Other symp-
toms include epistaxis and pain. Patients 
with HG non-lTACs present with obstruc-
tion, epistaxis, pain, deformity, and prop-
tosis {967}. On imaging, LG non-lTACs 
present as sol id masses, fi lling the nasal 
cavity or sinuses. HG non-lTACs show 
more destructive growth, with osseous 
involvement and invasion into surround-
ing structures (e.g . the orbit) . 
Macroscopy 
Low-grade non-lTACs may appear red 
and polypoid or raspberry-like and firm 
(1237). 
Histopathology 
Low-grade non-lTACs have predomi-
nately papillary and/or tubular (glandular) 
features with complex growth, including 
back-to-back glands (cribriform) with lit-
tle intervening stroma {967,1139,1237). A 
single layer of uniform mucinous cuboi-
dal to columnar epithelial cells lines the 
structures. These cells have eosinophilic 
cytoplasm and uniform, basally located 
nuclei. Mitotic figures are rare and necro-
sis is not seen. lnvasive growth, includ-
ing within the submucosa as well as into 
bone, may be present. Calcispherules 
are rarely seen (967). Occasional tu-
mours have more dilated glands (1237, 
1721). 
HG non-lTACs show much more diver-
sity in their histology {967,2266). Many 
have a predominately solid growth with 
Fig. 1.13 Sinonasal low-grade non-intestinal-type adenocarcinoma. Endoscopic view of the right nasal fossa (A) and 
coronal turbo spin echo T2-weighted MRI (B). The tumour (T) is centred on the superior meatus and laterally displaces 
the ethmoidal complex (asterisks); the point of origin was on the upper part of the septum. LW, lateral wall; MT, middle 
turbinate; NS, nasal septum. 
occasional glandular structures and/ 
or individual mucocytes. Sorne have a 
nested growth and are infiltrative. Numer-
ous mitotic figures are seen with necrosis 
(individual-cel l and confluent), as well as 
infiltrative growth with tissue destruction 
and osseous invasion. 
Occasional cases are composed pre-
dominately of c lear cells, reminiscent of 
metastatic renal cell carcinoma {2287) . 
These tumours have been referred to 
as sinonasal renal cell-like carcino-
mas. The tumours are composed of 
monomorphous cuboidal to columnar 
glycogen-rich clear cells that lack mucin 
production . The cellular cytoplasm may 
be crystal clear or slight ly eosinophilic. 
Perineural invasion, lymphovascular in-
vasion, necrosis, and severe pleomor-
phism are absent, and the overall histo-
logical impression is that of a low-grade 
neoplasm. 
In most LG non-lTACs and HG non-
lTACs, intraluminal mucin or material 
that gives a diastase-resistant positive 
reaction with periodic acid-Schiff (PAS) 
Carcinomas 25 
can be identif ied. In HG non-lTAC, cel ls 
with intracytoplasmic mucin or diastase-
resistant PAS positivity may be pres-
ent. The tumours express cytokeratins 
(typically CK7 and infrequently limited 
CK20) {2266}. Squamous antigens, such 
as p63, are typically not expressed orare 
expressed only focally (2193}. Markers of 
intestinal differentiation, such as CDX2 
and MUC2, are also not expressed or 
are expressed only focally {358,2266}. 
Sorne authors have reported expres-
sion of D0G1, SOX10, and S100 (1933). 
HG non- lTACs can focally express 
neuroendocrine antigens (2266). Renal 
cell- like carcinomas express CAIX and 
CD1 0, but do not express PAX8 or renal 
cell carcinoma marker (2156}. Beta-cat-
enin and mismatch repair protein expres-
sion is wildtype {2679). Overexpression 
of p53 may occur as well (2193}. 
Genetic profile 
Only rare LG non-lTACs have been stud-
ied for molecular abnormalities. RAS mu-
tations are not seen (755). Rare BRAF 
mutations have been found (755). 
Teratocarcinosarcoma 
Definition 
Sinonasal teratocarcinosarcoma is a 
malignant sinonasal neoplasm with com-
bined histologicalfeatures of teratoma 
and carcinosarcoma, lacking malignant 
germ cell components. 
ICD-0 code 9081/3 
Synonyms 
Malignant teratoma; blastoma; teratocar-
c inoma; teratoid carcinosarcoma 
Epidemiology 
Teratocarcinosarcoma is a rare tumour 
affecting adults (median patient age: 60 
years), with a strong male predilection. 
Localization 
The tumour most commonly involves the 
nasal cavity, fol lowed by the ethmoid si-
nus and the maxillary sinus {1628). lntrac-
ranial extension occurs in approximately 
20% of cases (1628). 
Clinical features 
The most common presenting symptoms 
are nasal obstruction and epistaxis. lm-
aging studies show a nasal cavity mass 
with opacification of paranasal sinuses 
and frequent bone destruction. 
Macroscopy 
Tumour tissue is firm to friable, with a 
variegated reddish-purple to browri appear-
ance. When present, the surface mucosa 
is often ulcerated, and areas of necrosis 
and haemorrhage are evident at the cut 
surface. 
26 Tumours of the nasal cavity, paranasal sinuses and skull base 
B This tumour is 
Prognosis and predictive factors 
Approximately 25% of LG non- lTACs 
recur, and only 6% of patients die from 
their tumours, usually as a result of loss 
of local control {967,1139,1721). Patients 
with HG non-lTAC tare much worse {967}; 
most die from the disease within 5 years 
of diagnosis. Occasional HG non-lTACs 
metastasize local ly and distally. The re-
ported cases of renal cell- like carcinoma 
have neither recurred nor metastasized 
(2156). 
Franchi A. 
Wenig B.M. 
Histopathology 
Teratocarcinosarcoma is composed of 
an admixture of epithelial, mesenchy-
mal, and neuroepithelial elements. The 
epithelial components include kerati-
nizing and non-keratinizing squamous 
epithelium, pseudostratified columnar 
ciliated epithelium, and glandular/duct-
al structures. An importan! diagnostic 
feature is the presence of nests of 
immature squamous epithelium with clear 
so-called fetal-appearing cells {966}. 
The most-represented mesenchymal ele-
ments are spindle cells with features of 
f ibroblasts or myofibroblasts, but areas 
with rhabdomyoblastic, cartilaginous, os-
teoblastic, smooth-muscle, or adipocytic 
differentiation can be seen, with appear-
ances ranging from benign to frankly ma-
lignant. The neuroepithelial component 
consists of a proliferation of immature 
round to oval cells either in solid nests 
or within a neurofibrillary background, 
sometimes with rosette formation. 
The immunohistochemical profile matches 
that of the tumour components, including 
epithelial, mesenchymal, and neuroepi-
thelial components. PLAP, alpha-fetopro-
tein, hCG, and CD30 are negative. 
Cell of origin 
The favoured hypothesis is origin from 
somatic pluripotent stem cells of the 
neuroepithelium related to the olfactory 
membrane {1801,2054). 
Genetic profile 
There are limited reports in the literature 
on the cytogenetic abnormalities. These 
abnormalities include extra copies of 
chromosome 12p in a subpopulation of 
neoplastic cells in a hybrid case that also 
exhibited foci of yolk sac elements {2380) 
in addition to teratocarcinosarcoma fea-
tures, thus not completely meeting the 
definition that excludes malignan! germ 
cell components, and the presence of tri-
somy 12 with a subclone of cells showing 
loss of 1p in one case {2516). In another 
study, no amplification of 12p was found 
in any of 3 cases {2054). 
Prognosis and predictive factors 
Teratocarcinosarcoma is an aggressive 
tumour, with frequent lymph node and 
distan! metastasis. Reported survival 
rates range from 50% to 70% in different 
series, with an average follow-up of 40 
months {1628). 
Teratocarcinosarcoma 27 
Sinonasal papillomas 
Sinonasal papilloma, 
inverted type 
Hunt JL 
Bell D. 
Sarioglu S. 
Definition 
Sinonasal inverted papilloma is a surface 
mucosa! lesion of the sinonasal tract that 
usually shows inverted growth and has 
multi layered epithelium with mucocytes 
and transmigrating neutrophils. 
ICD-0 code 8121/1 
Synonyms 
lnverting papilloma; inverted Schneide-
rian papil loma; Schneiderian papil loma, 
inverted type 
Epidemiology 
lnverted papillomas are the most fre-
quent papillomas of the sinonasal region, 
arising from the sinonasal epithelial lin-
ing. An estimated 0.74- 2.3 new cases 
may be expected per 100 000 population 
annually (294,1750). The tumour is most 
frequent in the fifth and sixth decades of 
lite (patient age range: 6- 84 years) and is 
2.5-3 times as common in males as in fe-
males {141,1224,251 1). Recurrences are 
frequent and malignant transformation 
has been reported in 1.9- 27% of cases 
in different series; most malignancies 
were synchronous tumours (1750). 
Etiology 
Exposure to organic solvents seems to be 
a risk factor for inverted papilloma devel-
opment {505), whereas no such associa-
tion far smoking or alcohol consumption 
has been shown. Varying rates of HPV 
detection have been reported. In a meta-
analysis including 760 inverted papilloma 
cases, 38.5% of the cases were HPV-
positive by either in situ hybridization or 
PCR {2323). Low-risk HPV (HPV 6 and 
11) is 2.8 times as frequent as high-risk 
HPV (HPV 16 and 18) in inverted papil-
loma. However, high-risk HPV is more 
frequent in cases with high-grade dys-
plasia and carcinoma (1352). E6 and E7 
mRNAs, associated with transcriptionally 
active high-risk HPV infection, were de-
tected in ali cases in a series of 19 in-
verted papillomas; however, this expres-
sion was seen in only 1% of the tumour 
cells in 58% of the cases, and HPV DNA 
was positive in only 2 cases. Expression 
of p16, which is an accepted surrogate 
biomarker for high-risk HPV infection in 
oropharyngeal carcinoma, is controver-
sia! in inverted papilloma; in sorne series, 
no correlation between p16 and HPV was 
seen {420,2283}. 
28 Tumours of the nasal cavi ty, paranasal sinuses and skul l base 
Localization 
The nasal cavity and the maxillary sinus 
are the most common locations of invert-
ed papilloma, with the medial wall being 
the most common site of origin in the 
maxillary sinus. Other locations as site 
of primary origin are more rare, includ-
ing the ethmoid sinus, frontal sinus, and 
nasal septum. About 30% of cases origi-
nate from multiple sites. lnverted papil-
loma may rarely be bilateral and may 
originate from multiple extrasinonasal 
siles, including the nasopharynx, phar-
ynx, lacrimal sac, middle ear, temporal 
bone, and neck (75,1224,2147). 
Clinical features 
Patients may present with non-specific 
symptoms such as nasal obstruction, 
polyps, epistaxis, rhinorrhoea, hyposmia, 
and headache of long duration . Rarely, 
sensorineural and auditory symptoms 
are described. Both CT and MRI are val-
uable; CT may provide information about 
the site of origin of the tumour, and MRI 
shows the extent of the disease. On MRI, 
the lesion characteristically has a septate 
striated appearance (75). Several staging 
systems have been proposed for invert-
ed papil loma (75,1224). One commonly 
used staging system {1283} depends 
on the extent of disease, considering 
both radiological and endoscopic find-
ings. The American Joint Committee on 
Cancer (AJCC) staging system is also 
commonly used. 
Macroscopy 
lnverted papilloma is covered with a grey, 
undulating surface resembling a mulber-
ry. Because of their cellular density, the 
lesions do not transilluminate. 
Histopathology 
Multiple inversions of the surface epi-
thelium into the underlying stroma, com-
posed of squamous and/or respiratory 
cells and lined by a distinct and intact, 
continuous basement membrane, is the 
typical morphology of inverted papilloma. 
Non-keratinizing squamous or transition-
al epithelium, 5-30 cells thick, frequently 
predominates, and is covered by a layer 
of ci liated columnar cells. lnfiltration of 
the epithelium by neutrophils (so-called 
transmigrating neutrophils) is frequently 
seen. Mitoses are sparse and confined 
to the basal layers {141,2002,2075). 
There is usuallya loss of underlying se-
romucinous glands (2075}. The stroma 
may be either loase or dense, and may 
be inflamed. Cells showing squamous 
and columnar differentiation are positive 
far cytokeratins (e.g. CK10, CK10/13, and 
CK1/2/10/11) {2106}. 
Premalignant and malignant features, 
dysplasia, carcinoma in situ, and inva-
sive carcinoma can be seen arising in 
inverted papilloma. Sampling should be 
thorough, and evidence of malignan! 
transformation should be sought during 
histopathological evaluation. There is no 
consensus about the grading of dyspla-
sia in inverted papilloma, and the diag-
nosis of malignan! transformation may be 
challenging. Keratinizing squamous cell 
carcinoma, non-keratinizing squamous 
cell carcinoma, mucoepidermoid car-
cinoma, sinonasal undifferentiated car-
cinoma, and verrucous squamous cell 
carcinoma can ali be seen in malignan! 
transformation. Lymphovascular inva-
sion, atypical mitoses, desmoplasia, 
bone invasion, decreased transmigrating 
neutrophils, paradoxical maturation, dys-
keratosis, increased Ki-67 expression, 
and p53 expression in > 25% of cells are 
among the most importan! features of 
malignancy (1750}. 
Genetic profile 
lnverted papillomas are neoplastic and 
monoclonal proliferations, as shown by 
X chromosome analysis. However, the 
chromosomal LOHs at arms 3p, 9p21, 
11q13, 13q11, and 17p13 that occur fre-
quently during neoplastic transformation 
of the upper respiratory tract have not 
been detected {315). In one small series 
of 7 cases, at least one epigenetic event 
of aberrant DNA hypermethylation was 
observed, suggesting a role of epigenet-
ics in inverted papilloma development 
(2276). Furthermore, from a small num-
ber of cases studied, it appears that acti-
vating mutations in the EGFR gene have 
a high prevalence in inverted papillomas 
and in concurrent squamous cell carci-
nomas arising from inverted papilloma 
{2442A). 
Prognosis and predictive factors 
In one large series, cases originating from 
the nasal cavity had a significantly lower 
recurrence rate {1224). The ratio of low-
risk HPV (HPV 6 and 11) to high-risk HPV 
(HPV 16 and 18) was 1.1:1 in inverted pap-
illoma with high-grade dysplasia, versus 
4.8:1 in the rest of the cases, suggesting 
an association between high-risk HPV and 
malignan! transformation {1352). However, 
no correlation was found between E6/E7 
transcriptional activity and progression, 
recurrence, or malignan! transformation 
(2283). In one series, malignant transfor-
mation in inverted papilloma was identified 
more frequently in smokers (in 24.6% of 
cases) !han in non-smokers (in 2.8%), and 
the odds ratio of malignancy for smoking 
was 12.7 (1020). Type of surger.y is also an 
importan! prognostic factor for recurrence 
{962). 
Sinonasal papilloma, 
oncocytic type 
Hunt J.L. 
Chiosea S. 
Sarioglu S. 
Definition 
Sinonasal oncocytic papilloma is a papil-
loma derived from the sinonasal epithe-
lium composed of both exophytic fronds 
and endophytic invaginations lined by 
multiple layers of columnar cells with 
oncocytic features. lntraepithelial micro-
cysts containing mucin and neutrophils 
are characteristic. 
ICD-0 code 8121/1 
Synonyms 
Oncocytic Schneiderian papilloma; cylin-
drical cell papilloma; columnar cell papil-
loma 
Epidemiology 
Oncocytic papilloma is equally distribut-
ed between the sexes, and most patients 
are aged > 50 years (2511 ). 
Sinonasal papillomas 29 
Etiology 
Unlike in exophytic and inverted papi llo-
mas, HPV has not been identified in on-
cocytic papillomas (792}. 
Localization 
Oncocytic papilloma almost always oc-
curs unilaterally on the lateral nasal wall 
or in the paranasal sinuses (usually the 
maxillary or ethmoid). lt may remain lo-
calized, involve both areas, or (if neglect-
ed) extend into contiguous areas. 
Clinical features 
Patients present with nasal obstruction 
and/or intermittent epistaxis. 
Macroscopy 
Oncocytic papilloma is a fleshy, pink, 
tan, or reddish-brown polypoid growth. 
Histopathology 
Oncocytic pap liorna exhibits both exo-
phytic and endophytic growth. The epi-
thelium is multilayered, 2-8 cells thick, 
and composed of columnar cells with 
swollen, finely granular cytoplasm. The 
high content of cytochrome c oxidase 
and ultrastructural presence of numerous 
mitochondria establish the papilloma's 
oncocytic nature { 145). The nuclei are 
either small, dark, and uniform or slightly 
vesicular with barely discernible nucleoli . 
Cilia in various stages of regression may 
be observed in the outermost cells. The 
epithelium usually contains small cysts 
til led with mucin or neutrophils (microab-
scesses). These cysts are not present in 
the stroma, which helps distinguish this 
lesion from rhinosporidiosis. The stroma 
varíes from oedematous to fibrous, and 
may contain modest numbers of lympho-
cytes, plasma cells, and neutrophils, but 
few eosinophils. Seromucinous glands 
are sparse to absent. Oncocytic pap-
illoma may rarely undergo malignant 
transformation. lt is also occasionally 
confused with low-grade papi llary ade-
nocarcinoma {1403). The presence of in-
tact basement membranes and absence 
of infiltrative growth are features that in-
dicate a benign lesion. In addition, the 
presence of intraepithelial mucin-filled 
cysts and microabscesses and the strati-
fied oncocytic epithelium of a papilloma 
are rarely seen in low-grade adenocarci-
noma. 
Prognosis and predictive factors 
The clinical behaviour parallels that of 
inverted papilloma. lf inadequately ex-
c ised, especial ly using mucosa! strip-
ping, at least 25- 35% of cases recur, 
usually within 5 years {962). Smaller tu-
mours can be resected endoscopically. 
About 4-17% of all oncocytic papil lomas 
harbour a carcinoma {1201,1441,2511). 
Most of these are squamous, but mu-
coepidermoid, small cell, and sinonasal 
undifferentiated carcinomas have also 
been described {2370,2511}. Prognosis 
depends on the histological type, the 
degree of invasion, and the extent of tu-
mour. In sorne instances, the carcinoma 
is in situ and of little consequence to the 
patient, whereas other cases are locally 
aggressive and may metastasize. 
Sinonasal papilloma, 
exophytic type 
Hunt J.L. 
Lewis J.S. 
Richardson M. 
Sarioglu S. 
Syrjanen S. 
Definition 
Sinonasal exophytic papilloma is a papil-
loma derived from the sinonasal mucosa, 
composed of papillary fronds with deli-
cate fibrovascular cores covered by mul-
tilayered epithelium. 
ICD-0 code 8121/0 
Synonyms 
Schneiderian papilloma, exophytic type; 
fungiform papi lloma; everted papil loma; 
transitional cell papil loma; septal papil-
loma; Ringertz tumour 
Epidemiology 
Exophytic papillomas are 2-1 O times as 
common in men as in women, and typi-
cally occur in individuals aged 20- 50 
years (reported range: 2-87 years) (441}. 
Etiology 
Theré is increasing evidence to suggest 
that exophytic papil lomas may be etio-
logically related to HPV. In a large meta-
analysis, exophytic papil lomas were as-
sociated with HPV in 63.5% of cases, 
predominantly with the low-risk types 6 
and 11 , and rarely with types 16 and 57b 
{2323). 
Localization 
Exophytic papil lomas usually arise on 
the lower anterior nasal septum. As they 
enlarge, they may secondarily involve the 
lateral nasal wall, but only intrequently 
originate from this location . lnvolvement 
of the paranasal sinuses is practically 
non-existent. Bilateral lesions are ex-
ceptional. Benign keratinizing cutaneous 
tumours of nasal vestibule origin do not 
constitute sinonasal exophytic papilloma. 
Clinical features 
The typical presenting symptoms are 
epistaxis, unilateral nasal obstruction, 
and the presence of an asymptomatic 
mass. 
Macroscopy 
The lesions present as papillary or 
warty; grey, pink, or tan; non-translucent 
growths attached to the nasal septum by 
a relatively broad base. 
Histopathology 
Exophytic papillomas are typically as 
large as about 2.0 cm. Microscopically, 
Exophytic growth pattern with thickened epitheliumand focal mucocytes. 
30 Tumours of the nasal cavity, paranasal sinuses and skull base 
they are composed ot papillary fronds 
with fibrovascular cores covered by 
a multilayered epithelium that is 5-20 
cells thick. The epithelium varíes trom 
squamous to ciliated pseudostrati-
fied columnar (respiratory), or may be 
transitional between the two. Scat-
tered mucocytes are common. Surface 
keratinization is absent or scant, unless 
the lesion has been irritated by trauma 
or exposure to the drying effects ot air. 
Mitoses are rare and are not usually 
atypical. Unless infected or irritated, the 
stroma contains few inflammatory cells. 
Malignant change in exophytic papillo-
ma is extremely rare {157,441}. Exophytic 
papillomas must be distinguished from 
keratinizing cutaneous squamous cell 
papi llomas, which are much more com-
mon in the nasal vestibule. The absence 
ot extensive surface keratinization, pres-
ence of mucocytes, and presence ot cil i-
ated and/or transitional epithelium help 
to contirm the diagnosis ot exophytic 
papilloma. The presence ot seromuci-
nous glands and septal cartilage turther 
indicate that the lesion is ot mucosa! 
rather than cutaneous origin. 
Respiratory epithelial lesions 
Respiratory epithelial 
adenomatoid hamartoma 
Wenig B.M. 
Franchi A. 
Ro JY. 
Definition 
Sinonasal respiratory epithelial adenom-
atoid hamartoma (REAH) is a benign ac-
quired overgrowth ot indigenous glands 
of the sinonasal tract arising trom the sur-
tace epithelium. 
Synonym 
Glandular hamartoma 
Epidemiology 
The lesions predominantly occur in adult 
patients, with a distinct male predomi-
nance {1367,2588}. Patients range in 
age from the third to ninth decades ot 
lite, with a median patient age in the sixth 
decade !1367,2588). 
Localization 
The majority occur in the nasal cavity, 
in particular the posterior nasal septum 
{2588} . lnvolvement of other intranasal 
sites occurs less often, and may be iden-
tified along the lateral nasal wall, middle 
meatus, and inferior turbinate. Uncom-
monly, the lesions may occur in the na-
sopharynx, ethmoid sinus, and frontal si-
nus. Most lesions are unilateral but sorne 
are bilateral {2588) . 
Clinical features 
Patients present with nasal obstruction, 
stuffiness, epistaxis, and chronic (recur-
rent) rhinosinusitis occurring over the 
course of months to years {2588}. 
Prognosis and predictive factors 
Complete surgical excision is the treat-
ment of choice. lnadequate excision 
(rather than multiplicity of lesions) proba-
bly accounts for the local recurrence rate 
of 22- 50% {441}. Exceptionally, carcino-
mas have been seen arising in exophytic 
papillomas, with reported cases including 
squamous cell carcinoma; mucoepider-
moid carcinoma (1750}; and low-grade 
non-intestinal, non-salivary gland ad-
enocarcinoma {220). HPV status has not 
been clearly shown to correlate with re-
currence risk or carcinoma development. 
Macroscopy 
REAHs are polypoid or exophytic lesions 
with a rubbery consistency. They are tan-
white to reddish-brown and measure as 
much as 6 cm in greatest dimension. 
Histopathology 
Histopathology shows a glandular pro-
liferation composed of widely spaced, 
small to medium-sized glands separated 
by stromal tissue. The glands arise in 
direct continuity with the surface epithe-
lium, which invaginates downwards into 
the submucosa {1 852,2588}. The glands 
are round to oval and composed of multi-
layered c iliated respiratory epithelium, of-
ten with admixed mucin-secreting (gob-
let) cells; glandular dilatation distended 
with mucus can be seen. A characteristic 
finding is the presence of envelopment of 
the glands by a thickened, eosinophil ic 
basement membrane {2588). Atrophic 
Respiratory epithelial lesions 31 
glandular alterations may be present, 
lined by a single !ayer of flattened to 
cuboidal-appearing epithelium. Small re-
active-appearing seromucinous glands 
are present among the glandular prolif-
eration. Addítíonal coexisting findings 
may include sinonasal inflammatory pol-
yps, surface epithelial hyperplasia and/ 
or squamous metaplasia, and osseous 
and/or chondroid metaplasia. Rarely, the 
lesions may be associated with sinona-
sal inverted papilloma or solitary fibrous 
tumour {2588}. The occasional pres-
ence of both REAH and seromucinous 
hamartoma suggests a spectrum from 
pure REAH to seromucinous hamartoma 
{1218). 
The glands are immunoreactive for cy-
tokeratins such as AE1/AE3, CAM5.2, 
and CK7 but negative for CK20 and 
CDX2. Myoepithelial/basal cell markers 
(including p63) are typically present but 
may be absent; the absence of markers 
for myoepithelial/basal cells does not 
confer a diagnosis of adenocarcinoma 
{1 794). 
Genetic profile 
The reported increased fractional allelic 
loss of 31 % is unusually high for a non-
neoplastic entity, raising the possibility 
that REAH may in fact be a benign neo-
plasm rather than a hamartoma {1796}. 
Prognosis and predictive factors 
Complete surgical excision is curative. 
Seromucinous hamsrtoms 
Ro J.Y. 
Franchi A. 
Definition 
Sinonasal seromucinous hamartoma 
(SH) is a benign overgrowth of indige-
nous seromucinous glands of the nasal 
cavity and paranasal sinuses. 
Synonyms 
Epithelial hamartoma; glandular hamarto-
ma; microglandular adenosis of nose {445) 
Epidemiology 
SHs are extremely rare (1218). They oc-
cur predominantly in adults, with a male-
to-female ratio 3:2. The patient age range 
is 14-85 years (mean: 56 years). 
Etiology 
SH has no association with any specific 
etiological agent, but it often arises in the 
setting of inflammatory polyps. 
Localization 
SH usually occurs at the posterior nasal 
septum or nasopharynx, and is rarely de-
scribed on the lateral nasal wall or in the 
paranasal sinuses (2567). 
Clinical features 
The typical symptoms are nasal obstruc-
tion and epistaxis. The lesions are often 
found incidentally, and are sometimes 
associated with other medica! condi-
tions, such as rheumatoid arthritis, Par-
kinson disease, and chronic sinl!sitis. 
Physical examination reveals a polypoid 
mass without other aggressive features. 
Macroscopy 
SHs are typically polypoid or exophytic, 
typical ly with a rubbery consistency and 
32 Tumours of the nasal cavity, paranasal sínuses and skull base 
a tan-white to reddish-brown appear-
ance. They measure 0.6-6 cm in grea-
WWtest dimension. 
Histopathology 
SH is a polypoid mass covered by respira-
tory epithelium, and contains small to large 
glands and ducts lined by a single layer of 
cuboidal or flattened epithelíal cells with 
bland, oval to round nuclei and ampho-
philic to eosinophílíc cytoplasm. Mitoses 
are absent. The surrounding fibrous stro-
ma often contains a lymphoplasmacytic 
infiltrate (125,1044). Eosinophilic secretion 
can be seen in the lumen, and goblet or 
clear cells may be observed. The tubular 
glands may be encircled by thick base-
ment membrane material. The proliferat-
ing tubules intermíngle with the pre-ex-
isting seromucínous acini or invaginated 
respiratory epithelium forming glands or 
cysts, similar to features of respiratory epi-
thelial adenomatoid hamartoma, support-
ing the possibility that SH and respiratory 
epithelial adenomatoid hamartoma con-
stitute a spectrum of lesíons, often seen 
together {2565,2567). 
lmmunohistochemistry shows positiv-
ity for CK17, CK19, EMA, lysozyme, and 
S100, with an absence of myoepíthe-
lial (basal) cells around the seromuci-
nous glands (731). The stroma around 
tubules is posítive for calponín, SMA, 
and desmín, indicating myofibroblastíc / 
smooth muscle differentiatíon {1564}. 
Prognosis and predictiva factors 
Conservative but complete surgical ex-
c isíon is curative. With follow-up avail-
able from 4 months to 10 years (mean: 6 
years), ali patients are alive and well after 
surgical removal, with no documented 
cases of metastasis and only one report 
of recurrence (731}. 
Salivary gland tumours 
P/eomorphic adenoma 
Definition 
Pleomorphic adenoma(PA) is a benign 
tumour with variable cytomorphological 
and architectural manifestations. The 
identification of epithelial and myoepithe-
lial/stromal components is essential for 
the diagnosis of PA. 
See also the Pleomorphic adenoma 
section (p. 185) in Chapter 7 (Tumours of 
sa/ivary glands). 
ICD-0 code 
Synonym 
Benign mixed tumour 
Epidemiology 
8940/0 
Most intranasal PAs present in the third to 
sixth decades of lite, with a slight female 
preponderance (8,477,2109,2257f. 
Localization 
The tumour generally (in about 80% of 
cases) arises in the nasal septal mucosa, 
despite the fact that the seromucinous 
glands are mainly located in the lateral 
wall and turbinates (8,1286,2109}. 
Clinical features 
The most common presenting symptom 
is unilateral nasal obstruction. Epistaxis 
and sinusitis can occur secondary to 
extension into the maxillary sinus {2109}. 
Affected patients present within 1 year of 
the onset of symptoms {2109}. 
Macroscopy 
The range of tumour size is 0.5- 7 cm, 
and the tumours are descri bed as exo-
phytic or polypoid (with a broad base), 
oval, dome-shaped, firm, and grey 
(8,2109}. No destruction of surrounding 
tissue is seen. 
. ; . ' 
~" . . • •• " • • • • . f' : ,, 
>. I ,, ~- . t ~ ..... \ ' . ,. .- . ··"' . .. . . 
• • "\.,1 ~. ~·. ~ ' 
'.· - . • ... " t i .. .. ... -
, 
• 
• 
13 , . 
' ,. ..... .... 
• 
-.. j • • 
Histopathology 
In the nasal cavity, these neoplasms 
display a more dominant epithelial com-
ponen! (vs stromal components) than is 
seen in PAs of the major salivary glands 
{8,2109}. 
Bell D. 
Bullerdiek J. 
Gnepp D.R. 
Hunt J.L. 
Prognosis and predictive factors 
Complete surgical excision is the treat-
ment of choice. The recurrence rate is 
lower than that of parotid PA. Malignan! 
transformation of PA of the nasal cavity 
has been reported in 2.4-10% of cases 
{8,451,2109). 
Salivary gland tumours 33 
Malignant soft tissue tumours 
Fibrosarcoma 
Franchi A. 
Flucke U. 
Thompson L.D.R. 
Definition 
Fibrosarcoma is a malignant spindle 
cell tumour with fascicular architecture 
and variable collagen matrix production, 
showing fibroblastic/myofibroblastic dif-
ferentiation. lt is a diagnosis of exclusion. 
ICD-Ocode 
Synonym 
Adult-type fibrosarcoma 
Epidemiology 
8810/3 
Sinonasal fibrosarcoma is a rare tumour 
(accounting for < 3% of ali non-epithelial 
tumours), but is the second most com-
mon head and neck sarcoma. lt affects 
adults (mean age: 55 years), with no sig-
nifican! sex predilection {1829). 
Etiology 
The etiology is uncertain, but sinonasal 
radiation-induced fibrosarcomas have 
been reported {314}. 
Localization 
The maxillary sinus is the most common 
site of involvement, followed by the nasal 
cavity {1829). 
Clinical features 
The most common presentations are na-
sal obstruction, epistaxis, and a nasal 
mass, usually with short symptom dura-
tion {780}. 
Macroscopy 
The tumour presents as a polypoid, poor-
ly circumscribed, white, firm, and pedun-
culated or fungating mass projecting into 
the lumen, with frequent infiltration of the 
adjacent bone. Haemorrhage and necro-
sis are present in high-grade examples. 
Histopathology 
Fibrosarcomas are moderately to highly 
cellular proliferations of spindle cells, 
arranged in intersecting fascicles, often 
with a herringbone or chevron pattern, 
and with a variable amount of co llagen 
production. There is moderate cel lular 
atypia, but profound pleomorphism is 
usually lacking. Tumours with signifi-
can! pleomorphism and storiform areas 
are better categorized as undifferentiat-
ed pleomorph ic sarcoma. Mitotic a.ctiv-
ity is variable. The tumour borders are 
poorly defined and there is invasion of 
the sinonasal mucosa and bone. Histo-
logical grading, with distinction of low-
grade and high-grade tumours, is per-
formed on the basis of cellularity, atypia, 
mitotic activity, and tumour necrosis. 
Because the histological appearance 
of the tumour is non-specif ic, diagno-
sis requ ires the exclusion of other enti-
ties, including sarcomatoid carcinoma, 
synovial sarcoma, leiomyosarcoma, 
spindle cell rhabdomyosarcoma, spin-
dle cel l melanoma, malignan! periph-
eral nerve sheath tumour, biphenotypic 
sinonasal sarcoma, glomangiopericy-
toma, desmoid f ibromatosis, and fibro-
blastic osteosarcoma. An appropriate 
immunohistochemical panel is neces-
sary to rule out these other neoplasms, 
with the addition of selected molecular 
studies as necessary. By convention, 
the tumour is reactive with vimentin and 
34 Tumours of the nasal cavity, paranasal sinuses and skull base 
occasionally with actins, but negative 
for epithelial markers, S100 protein, 
S0X10, HMB45, beta-catenin, desmin, 
myogenin, and CD34. Electron mi-
croscopy can confirm the fibroblastic 
differentiation of the tumour, demon-
strating the presence of abundant cy-
toplasmic rough endoplasmic reticulum 
cisternae and excluding the presence 
of epithel ial, muscle, and melanocytic 
differentiation. 
Genetic profile 
The genetic profile of sinonasal fibrosar-
coma has not been specifical ly investi-
gated, but soft tissue fibrosarcomas in 
general show a complex karyotype, with 
several numerical and structural chromo-
somal abnormalities. 
Prognosis and predictive factors 
The disease-specific survival rate is 
about 75%, with better survival among 
patients treated with surgery (with or 
without adjuvant radiotherapy) than 
among those treated with radiotherapy 
alone {1829). The rate of recurrence is 
high (-60%), and recurrence is usually 
identified befare metastatic disease (to 
lung or bone), which occurs in about 
15% of patients. The prognosis is worse 
far male patients, and in cases of large 
tumours, multisite involvement, high his-
tological grade, and positive margins 
{156,780,965,1263}. 
Undifferentiated 
pleomorphic sarcoma 
Flucke U. 
Franchi A. 
Thompson L.D.R. 
Definition 
Undifferentiated pleomorphic sarcoma is 
a high-grade soft tissue sarcoma with no 
line of differentiation. lt is a d iagnosis of 
exclusion . 
ICD-0 code 
Synonym 
Malignant fibrous histiocytoma 
Epidemiology 
8802/3 
This sarcoma occurs in adults, and 
sinonasal examples are rare. However, 
undifferentiated pleomorphic sarcoma is 
the third most frequently reported histo-
type in !he sinonasal tract, after rhabdo-
myosarcomas and fibrosarcomas (2326, 
2534). 
Etiology 
Radiation therapy contributes to the risk 
of developing an undifferentiated pleo-
morphic sarcoma {2294,2534). 
Localization 
Lesions are generally evenly distributed 
among the sinonasal tract (i.e. maxillary 
sinus, nasopharynx, and nasal cavity), 
upper aerodigestive system, and parotid 
reg ion (2294,2326,2534}. The mass is 
usually subcutaneous or submucosal in 
location, regardless of the affected site, 
but may also arise in bone (2294). 
Clinical features 
There are non-specific signs and symp-
toms, including a painless mass, nasal 
obstruction, proptosis, diplopía, and 
epistaxis. Very rarely, undifferentiated 
p leomorphic sarcoma presents with re-
gional or d istan! metastasis {2294). 
Macroscopy 
The tumours consist of a multilobulated 
greyish-white fl eshy mass. Cut surface 
often shows haemorrhagic, myxoid, and/ 
or necrotic changes. Most neoplasms 
appear circumscribed. but extension into 
adjacent structures may be seen {2578). 
Histopathology 
The tumour is composed of an admixture 
of spindle and pleomorphic cells set in a 
variably collagenized extracellular matrix. 
Cel lularity varíes. Pleomorphism, numer-
ous mitoses, atypical mitoses. areas of 
tumour necrosis, histiocyte-like cells, and 
foamy cells, as well as giant tumour cells 
with enlarged, polylobulated nuclei are 
commonly observed. 
lmmunohistochemically, there are sorne 
limited foci of SMA reactivity, whereas 
h-caldesmon, desmin, S100 protein, and 
epithel ial markers are usually not ex-
pressed. Histiocytic antigens are of no 
uti lity. 
Ultrastructural ly, many tumour cells show 
features of f ibroblasts, myofibroblasts,or 
histiocytes. 
Undifferentiated pleomorphic sarcoma is 
a diagnosis of exclusion. Other potential 
mimics must be ru led out, including car-
cinomas, melanoma, lymphoma, and sar-
comas (including rhabdomyosarcoma, 
leiomyosarcoma, malignan! peripheral 
nerve sheath tumour, dedifferentiated 
and p leomorphic liposarcoma, and high-
grade myxofibrosarcoma) {902l. 
Genetic profile 
There are complex genetic aberrations 
{902). 
Prognosis and predictive factors 
The 5-year survival rate is 60-70% 
{2326,2529). Surgery seems to be es-
sential regardless of the margin status, 
and radiation therapy seems to be nec-
essary for local control {2326). Previous 
radiation has been reported as an ad-
verse prognostic factor for d isease-free 
survival {2534l. 
Leiomyosarcoma 
Flucke U. 
Franchi A. 
Definition 
Leiomyosarcoma is defined as sarcoma 
with smooth muscle d ifferentiation. 
ICD-Ocode 8890/3 
Epidemiology 
Smooth muscle tumours of the sinona-
sal tract are very rare. Most cases arise 
in adults. Children are rarely affected 
(538,606,902,1047). 
Etiology 
Radiation therapy contributes to the risk 
of developing a leiomyosarcoma {778). 
Localization 
The nasal cavities, nasopharynx, and 
paranasal sinuses may be involved 
{778,1312,2326). Tumours can also 
arise in the oral cavity or perioral reg ion 
(606,2104). 
Clinical features 
The tumours present as a polypoid soft 
tissue mass. Symptoms depend on the 
site of involvement and include pain, 
nasal obstruction, and epistaxis. The 
lesions can also affect the c raniofa-
cial bone, either primarily or secondar-
ily. Leiomyosarcomas metastasize to the 
lung, liver, brain, other soft tissue sites, or 
bone. Lymph nade metastases are rarely 
reported {606,778,1312,2326,2664}. Me-
tastasis from other siles (e.g . the uterus) 
should be excluded {606,2104l . 
Malignant soft tissue tumours 35 
Macroscopy 
The tumours are polypoid , fi rm, and ei-
ther poorly defined or well circumscribed 
but unencapsulated. On sectioning, they 
are whorled and whitish or tan-grey, with 
areas of haemorrhage, cystic degenera-
tion, and necrosis {538,778,1590). 
Histopathology 
The tumours show infiltrative growth or 
sharply demarcated borders. They are 
composed of spindle cells arranged in in-
terlacing fascicles. Storiform architecture 
can be focally present. The tumour cel l 
nuclei are oval to elongate and frequently 
blunt-ended. There is variable atypia, 
with enlarged nuclei and hyperchroma-
sia. Nucleoli are sometimes obvious. The 
eosinophil ic cytoplasm often shows small 
perinuclear vacuoles. Epithelioid cyto-
morphology is rarely seen . Osteoclastic 
and pleomorphic giant cells may occur. 
Tumours with a myxoid background must 
not be confused with spindle cell myoepi-
thelioma. Scattered inflammatory cells 
are seen in sorne cases. Rarely, dys-
trophic or psammomatous calcification 
has been reported . The French Fédéra-
tion Nationale des Centres de Lutte Con-
tre le Cancer (FNCLCC) grading criteria 
depend on mitotic activity, necrosis, and 
resemblance to normal tissue {467,538, 
606,902,1312,1590,1607}. 
lmmunohistochemically, smooth muscle 
differentiation is demonstrated by diffuse 
staining for desmin, h-caldesmon, SMA, 
and MSA, with positivity for at least two of 
these markers {467,1312,1607). 
Genetic profile 
There is a complex genomic profile, 
with a variety of genes involved in the 
pathobiology of leiomyosarcomas, inclu-
ding TP53, FANCA, ATM, RB1, CDK2NA. 
PTEN, MYOCO, ROR2, and MED12 
{902,1607,1961}. 
Prognosis and predictive factors 
Clinical behaviour depends mainly on 
tumour location, with sinonasal tumours 
being more aggressive dueto their clase 
proximity to both orbital and cerebral cav-
ities. Surgery is the treatment of choice, 
but wide resection is often impossible. 
Radiotherapy can be given. One third of 
ali patients d ie of their tumour, as a re-
sult of either distant metastases or un-
contro lled local recurrence involving vital 
head and neck structures. Complete sur-
gical excision seems to be an important 
predictor of disease-free survival. 'Mor-
phologically high-grade sarcomas seem 
to be more aggressive {467,606,778,902, 
1607,2294,2326}. 
Rhabdomyosarcoma 
Franchi A. 
Flucke U. 
Thompson L.D.R. 
Definition 
Rhabdomyosarcoma is a malignant mes-
enchymal tumour with skeletal muscle 
differentiation. Embryonal, alveolar, pleo-
morphic, and spindle-cell subtypes are 
recognized. 
ICD-0 codes 
Rhabdomyosarcoma, NOS 8900/3 
Embryonal rhabdomyosarcoma 8910/3 
Alveolar rhabdomyosarcoma 8920/3 
36 Tumours of the nasal cavity, paranasal sinuses and skull base 
Pleomorphic rhabdomyosarcoma, 
adult type 8901/3 
Spindle cel l rhabdomyosarcoma 8912/3 
Synonyms 
Rhabdosarcoma; myosarcoma; 
malignant rhabdomyoma 
Epidemiology 
Sinonasal rhabdomyosarcoma is a rare 
tumour, with an overal l annual incidence 
of 0.034 cases per 100 000 population 
{2066}. lt is the most common sinona-
sal sarcoma in both children and adults 
(317,983,2326}. The peak incidence is in 
patients in the first decade of life, with no 
significan! sex predilection (2066) . 
Etiology 
Rare examples of rad iation-induced 
sinonasal rhabdomyosarcoma have 
been reported {1191}. 
Localization 
The most commonly involved siles are 
the paranasal sinuses, followed by the 
nasal cavity (2066}. 
Clinical features 
Symptoms include nasal obstruction, 
pain, facial swelling, proptosis, and 
epistaxis (317,779}. 
Macroscopy 
Most lesions present as polypoid, poorly 
c ircumscribed masses with smooth sur-
faces, often extending into the adjacent 
structures . They are fleshy, gelatinous le-
sions with a tan to grey cut surface. Bot-
ryoid rhabdomyosarcoma presents with 
multiple grape-like polypoid masses. The 
spindle-cell variant is tan-white with a 
f irm consistency. 
Histopathology 
In the sinonasal tract. embryonal rhab-
domyosarcoma (including the botryoid 
variant) is the most frequent histological 
subtype in young patients. lt consists 
of primitive round to spindle cells, with 
scant cytoplasm and hyperchromatic 
nuclei. Scattered rhabdomyoblasts with 
brightly eosinophilic eccentric cytoplasm 
are observed. Their number increases 
in tumours treated with chemotherapy. 
Botryoid rhabdomyosarcoma typically 
has a polypoid arch itecture, and pre-
sents linear aggregates of tumour cells 
clase to the surface epithelium (cambium 
layer), yielding a gradient of cellularity. 
Sinonasal alveolar rhabdomyosarcoma 
is more frequent in the adult population 
(2326}, and typically presents f ibrovas-
cular septa separating nests of round, 
small to medium-sized neoplastic cel ls, 
which tend to coalesce in the centre 
with dyscohesion at the periphery. Giant 
cells with multiple peripheral nuclei may 
be present. The salid variant of alveolar 
rhabdomyosarcoma lacks the fibrovas-
cular septa, and the tumour cel ls grow in 
sheets. The spindle-cell subtype is very 
rarely observed in the sinonasal region 
{1707); it consists of a fasciculated pro-
liferation of spindle cells with elongated 
nuclei and pale indistinct cytoplasm, with 
interspersed spindled or polygonal rhab-
domyoblasts with abundan!, brightly eo-
sinophil ic cytoplasm. 
lmmunohistochemically, the most use-
fu l myogenic markers are desmin and 
MYF4 (myogenin), which are expressed 
in all tumours. Compared with alveolar 
rhabdomyosarcomas, in which there 
is MYF4 staining in almos! 100% of the 
nuclei, embryonal rhabdomyosarcomas 
stain for MYF4 in a more heterogeneous 
fashion, which provides a clue as to their 
subclassification (1819). MYOD1, tasi 
myosin, myoglobin, and MSA are also 
positive, but less specific. SMA is posi-
tive in about 10% of cases {983). Rhab-
domyosarcoma, in particular the alveolar 
subtype, may coexpress non-myogenic 
markers, including cytokeratins (in 5- 8% 
of cases), EMA, CD56, chromogranin, 
synaptophysin, CD20, and CD99, and 
this may be a source of diagnostic con-
fus ion with carcinomas, neuroendocrine 
tumours, and haematolymphoidtumours 
{1707,2671). 
Ultrastructurally, rudimentary sarcom-
eric structures, consisting of alternating 
thin and thick filaments with Z band-
like structures, are recognized in the 
cytoplasm. 
Genetic profile 
Most alveolar rhabdomyosarcomas (70-
80%) harbour a PAX3-FOX01 fusion, 
and the PAX7-FOX01 fusion is less fre-
quently detected. ldentification of these 
gene fusions is particularly useful for the 
diagnosis of tumours arising in unusual 
clinical settings (e.g. in older adults) and/ 
or with atypical morphology and immu-
nohistochemical profiles {2671). To date, 
no specific recurren! genetic abnormality 
has been identified in embryonal rhab-
domyosarcoma. Most of these tumours 
have allelic losses in various chromo-
some 11 loci. Paediatric spindle cell 
rhabdomyosarcoma shows a consisten! 
NCOA2 rearrangement (1661 ). 
Genetic susceptibility 
Rhabdomyosarcoma can arise in chil-
dren affected by genetic syndromes, 
including Li- Fraumeni syndrome (asso-
ciated with an inactivating mutation of 
TP53), Costello syndrome (also called 
fac iocutaneoskeletal syndrome; HRAS 
mutation), neurofibromatosis type 1 (in-
activating mutation of one allele of the 
NF1 gene), and Beckwith-Wiedemann 
syndrome (mutation or deletion of the 
11 p15.5 chromosomal region) {506). 
Prognosis and predictiva factors 
Overall , rhabdomyosarcoma carries a rel-
atively poor prognosis among sinonasal 
Malignan! soft tissue tumours 37 
sarcomas, with a 5-year survival rate of 
40-45% (2326,2645,2648}. Patient age 
< 18 years and female sex are associ-
ated with better survival (2066,2381). 
Patients with alveolar rhabdomyosarco-
mas present more often with regional and 
distant metastases and have a higher re-
currence rate and poorer survival {2381) 
than do patients with the embryonal or 
botryoid subtype. lnfiltration of the skull 
base and the presence of a residual tu-
mour after primary therapy have also 
been associated with an unfavourable 
clinical course (2648). 
Angiosarcoma 
Bullerdiek J. 
Flucke U. 
Franchi A. 
Thompson L.D.R. 
Definition 
Angiosarcoma is a malignant neoplasm 
of vascular origin. 
ICD-0 code 9120/3 
Synonyms 
Epithelioid haemangioendothelioma; ma-
lignant haemangioendothelioma; malig-
nant angioendothelioma; haemangiosar-
coma; haemangioblastoma 
The use of these synonyms is discour-
aged, particularly given that epithelioid 
haemangioendothelioma is a unique entity. 
Epidemiology 
Nearly 50% of cases develop in the skin 
and superficial soft tissues of the head 
and neck, but sinonasal angiosarcoma 
accounts for < 0.1 % of al i head and neck 
malignancies and < 1% of all sinona-
sal malignancies (107,1540,1706,1718}. 
Sinonasal angiosarcomas can develop 
in patients of any age (reported range: 
8-82 years), with peak incidence in 
the fifth decade of life (mean patient 
age: 47 years), younger than the cor-
responding age for skin and soft tissue 
angiosarcomas of the head and neck 
{107,1508,1540). There is a male predi-
lection, with a male-to-female ratio of 3:2 
(777,1718,2419,2613,2626}. 
Etiology 
Environmental exposure to radiation 
(1472,1508,1706}, vinyl chloride (2613), 
and coal dust are rarely reported risk 
factors. 
Localization 
A single site of involvement within the 
sinonasal tract is more common than 
multiple sites ; the nasal cavity and max-
illary sinus are most frequently affected 
(777,1718,241 9,2613,2626}. 
Clinical features 
The presenting signs and symptoms, 
which are non-specific and usually of 
short duration (mean: 9.8 months), are 
most commonly recurrent epistaxis and 
obstruction (1718} along with nasal dis-
charge, enlarging mass, sinusitis, epi-
phora, pain, diplopía, and headaches. 
Sinonasal angiosarcomas are infi ltrative 
tumours, often associated with bone 
erosion. The tumours show contrast 
enhancement or a bright signal on T2-
weighted MRI. Angiography reveals 
tumour extent and feeder vessel(s), 
38 Tumours of the nasal cavity, paranasal sinuses and skull base 
1 . 
'~' ' 6.. ·~ --.- ..... .._. ........... _ ' 
Fig. 1.29 Sinonasal angiosarcoma. Neolumen formation 
is seen within this angiosarcoma, where there is only mild 
nuclear pleomorphism; vascular channels are apparent 
throughout. 
facilitating pre-surgical embolization 
(1718,241 9}. Staging is not applied to 
sinonasal angiosarcoma, but lymph node 
and distant metastasis are not common 
at initial presentation. 
Macroscopy 
The tumours can be as large as 8 cm 
(mean: 3.9 cm); paranasal sinus tumours 
are typically larger than sinonasal cav-
ity tumours (6.8 vs 2.2 cm). The tumours 
are nodular to polypoid , soft, friable, 
purple to red, and often ulcerated, with 
associated haemorrhage and necrosis 
(777,1718,2419,2613,2626}. 
Histopathology 
The tumours develop below an intact, 
uninvolved epithelium, with vasoforma-
tive neoplastic cells expanding into soft 
tissue and bone, frequently accompa-
nied by necrosis and haemorrhage. The 
tortuous, irregular, freely anastomosing 
vascular channels create cleft-like spac-
es, rudimentary vessels, capillary-sized 
vessels, and/or large cavernous spaces 
filled with erythrocytes and lined by 
plump, enlarged, atypical, spindled or 
epithelioid endothelial cells protruding 
into the vascular spaces in multiple layers 
or papillae. lntracytoplasmic lumina (of-
ten containing erythrocytes) are patho-
gnomonic. Enlarged pleomorphic nuclei 
show coarse, heavy nuclear chromatin 
distribution, irregular nuclear contours, 
and prominent nucleoli. Mitotic figures, 
including atypical forms , are easily iden-
tified throughout (1718,2419,2613,2626). 
The tumours are diffusely immunoreac-
tive with vimentin, CD34, CD31, claudin 5, 
ERG, FLl1, 02-40, and factor Vlll-related 
antigen, and focally reactive with keratin 
(in particular the epithelioid variant) and 
actin {1609,1718,2626}. Grading is not 
applied to sinonasal angiosarcoma. 
Genetic profile 
There are no specific cytogenetic find-
ings {2626}. 
Prognosis and predictive factors 
Although recurrences are com-
mon (occurring in -40% of cases), 
the overall survival rate far angio-
sarcoma is still approximately 60% 
{7?7,1706,1718,2419,2613,2626}. Meta-
static disease occurs most commonly 
to the lung, liver, spleen, and bone 
(marrow) {1718} . Specific etiological fac-
tors are associated with shorter survival 
{2613,2675}. 
Malignant peripheral 
nerve sheath tumour 
Flucke U. 
Franchi A. 
Thompson L.D.R. 
Definition 
Malignant peripheral nerve sheath tu-
mours (MPNSTs) are malignant soft tis-
sue neoplasms that arise from peripheral 
nerves or benign nerve sheath tumours 
with variable differentiation towards one 
of the cellular components of the nerve 
sheath (i.e. Schwann cells, fibroblasts, or 
perineurial cells). 
ICD-0 code 9540/3 
Synonyms 
Malignant schwannoma; neurofibrosar-
coma; malignant neurilemmoma 
Epidemiology 
About 20% of all MPNSTs develop in the 
head and neck, with 25~30% of cases 
associated with neurofibromatosis type 
1 (NF1). MPNSTs occur mainly in adults, 
with a wide patient age range and a 
mean patient age in the fifth decade of 
life {965,972}. Cases associated with NF1 
tend to occur in younger patients, with a 
mean patient age in the third to fourth 
decade {613}. More rarely, MPNSTs de-
velop during childhood (2398). 
Etiology 
MPNST develops in the setting of NF1 
and infrequently in patients who have 
been irradiated (2005}. 
Fig. 1.30 Sinonasal malignan! peripheral nerve sheath 
tumour. Coronal T2-weighted MRI demonstrates a large, 
heterogeneously enhancing mass filling the maxillary 
sinus. 
Localization 
Cranial nerves are involved, with the 
vestibular and vagal nerves being most 
commonly atfected (613,1626). 
Clinical features 
The tumours arise de novo, commonly in 
a majar nerve trunk or from a pre-existing 
neurofibroma, and rarely from schwan-
noma. Patients may present with a painful 
and/or rapidly enlarging mass, with asso-
ciated neurological deficits {2398}. 
Macroscopy 
The tumours may be withinor attached to 
a nerve trunk or neurofibroma with a fusi-
form appearance. They tend to be white, 
sal id, and fleshy, sometimes with myxoid 
change and frequent necrosis and haem-
orrhage {965,2398}. 
Histopathology 
MPNSTs are usually unencapsulated, 
highly infiltrative tumours with a range 
of cell morphologies (including spin-
dle, epithelioid, pleomorphic, and small 
round cel l). Common growth patterns 
include a marbled effect with alternating 
cellular and myxoid areas, perivascular 
cuffs, poorly defined nuclear palisad-
ing, and neuroid whorls. A rosette-like 
appearance with hyaline bands is less 
common . Tumours often show multiple 
patterns with in the same lesion , including 
pleomorphic or small-cel l areas. Spindle 
cell MPNSTs are often arranged in long 
fascicles or a herringbone pattern. The 
cells have elongated , tapered, buckled, 
or wavy nuclei and scant amphophilic cy-
toplasm. The nuclei may be hyperchro-
matic or may be vesicular with coarse 
chromatin. Mitoses, haemorrhage, and 
necrosis are frequent. Heterologous (e.g. 
osteoid, cartilage, striated muscle, oran-
giosarcoma) elements are seen in about 
15% of cases {613,965,2005,2398}. Ma-
lignan! triton tumour shows MPNST with 
rhabdomyosarcoma {965}. Glandular 
MPNST may have goblet cells, with be-
nign or malignant glands present. The 
tumours are c lassified as low-grade or 
high-grade on the basis of mitotic index, 
atypical mitoses, pleomorphism, and ne-
crosis {2005,2398}. 
There is no diagnostic immunoprofile, 
but neoplastic cells show nuclear and 
cytoplasmic S100 protein and nuclear 
S0X10 immunoreactivity {1608}. Epithe-
lioid MPNSTs show strong S100 protein 
expression and loss of SMARCB1 (INl1) 
(in 70% of c ases), whereas only scat-
tered cells are reactive with S100 protein 
Malignant soft tissue tumours 39 
in spindle cell MPNSTs in which INl1 is 
retained. Nestin shows strong cytoplas-
mic staining and is useful in combination 
with other markers. Cytokeratins, EMA, 
and C034 may be positive, but their ex-
pression has not been described in the 
epithelio id variant (1138,2398}. 
Genetic profile 
The most frequent gene alterations in-
elude loss of NF1 on 17q11 and of TP53on 
17q13. lnactivation of the NF1 tumour sup-
pressor gene can occur both in sporadic 
cases and in patients with NF1 {2398}. 
Genetic susceptibility 
The tumours are associated with NF1. 
Prognosis and predictive factors 
MPNSTs are aggressive tumours. Worse 
prognosis is associated with large tu-
mours (> 5 cm), NF1 association, high tu-
mour grade, trunca! location, high mitotic 
index (> 6 mitoses per 1 O high-power 
fields), and incomplete resection. The 
recurrence rate is as high as 40%, and 
approximately two thi rd of cases metas-
tasize, usually haematogenously to the 
lungs and bone {965,972,2398}. 
Biphenotypic sinonasal 
sarcoma 
Lewis J.E. 
Oliveira A. M. 
Definition 
Biphenotypic sinonasal sarcoma (BSNS) 
is a low-grade spindle cell sarcoma with 
distinctive histological, immunohisto-
chemical, and molecular features . lt is 
most frequently characterized by a recur-
rent PAX3-MAML3 gene fusion. 
ICD-0 code 9045/3 
Synonym 
Low-grade sinonasal sarcoma with neu-
ral and myogenic features 
Epidemiology 
BSNS predominantly affects females, 
with a female-to-male ratio of 2:1. The re-
ported patient age range is 24-85 years 
(mean: 52 years) {1051,1409,1913}. 
Localization 
BSNS typically involves multiple siles 
in the sinonasal tract, in particu lar the 
40 Tumours of the nasal cavity, paranasal sinuses and skull base 
superior aspect of the nasal cavity and 
ethmoid sinus. Tumour may also extend 
to the orbit or cribrifo rm plate. 
Clinical features 
The symptoms, whic h are relatively non-
specific and reflect the presence of a 
sinonasal mass, include difficulty breath-
ing through the nose, facial pressure, 
and congestion. 
Macroscopy 
The gross specimen usually presents as 
multiple polypoid fragments of somewhat 
firm, reddish-pink to tan or grey tissue, as 
large as approximately 4 cm in greatest 
aggregate dimension. 
Histopathology 
The tumour is characterized by a cel-
lular submucosal spindle-cell prolifera-
tion, composed of elongated spindle 
cells arranged in medium-length to long 
intersecting fascicles. A herringbone 
pattern, which resembles the histology 
of synovial sarcoma, is frequently seen. 
Tumours are unencapsulated and infi l-
trative, including into bone. There is a 
scant. delicate col lagen matrix. Nuclei 
are slender and relatively uniform in ap-
pearance, without significant pleomor-
phism or hyperchromasia. Mitotic activity 
is sparse (1051 ,1409,1913}. Most tumours 
show a striking concomitant proliferation 
of the covering epithelium, the invagi-
nations of which are intimately admixed 
with neoplastic spindle cells. Squamous 
or oncocytic metaplasia of the epithe-
lial proliferation can resemble that seen 
in sinonasal papillomas. Other frequent 
findings include haemangiopericytoma-
tous vascular pattern and the presence 
of scattered small lymphocytes. A minor-
ity of cases (11%) show focal rhabdo-
myoblastic differentiation, a histological 
feature that may be associated with an 
alternate fusion partner {1051). 
lmmunohistochemical features are also 
distinctive. Ali tumours show at least fo-
cal positivity for S100 and most (96%) 
also stain with either SMA or MSA. S100 
zand actin staining patterns may be fo-
cal, patchy, or diffuse. Focal and/or weak 
reactivity for CD34, desmin, MYOD1 , my-
ogenin, EMA, and cytokeratin has been 
noted in severa! cases (1051,1409}. 
Genetic profile 
At the cytogenetic and molecular levels, 
BSNS is characterized by the chromo-
somal translocation t(2;4)(q35;q31.1), 
which results in an in-trame fusion of 
exon 7 of the transcription factor PAX3 
to exon 2 of MAML3, a coactivator of 
the Notch signalling pathway. The fu-
sion transcript is highly expressed and 
may contribute to the unusual phenotype 
of this tumour {2545}. PAX3-MAML3 is 
found in most examples, but a subset of 
cases harbour alternate PAX3 or MAML3 
fusion genes, including PAX3-FOX01 
and PAX3-NCOA 1, the same fusion tran-
scripts found in alveolar rhabdomyosar-
coma (1051,2305,2628}. 
Prognosis and predictive factors 
The natural history of BSNS is character-
ized by slowly progressive growth with 
A B 
PAX3 
MAML3 
• • 1 1 1 1 1 1i 1 1 • • 
1 l l • • 1 1 j 1 1 N 
PAX3 ! 
PAX3-MAML3 •-1._._I •-.l_.1.__ _____ .1-, 
''-111\111-Hj ••,H!-lJ---•• 
MA~L3 j 60 
' " ! ! ! ! ,1. ! ! 
PAXJ-MAML:J f 
" e D g -' 40 ¡ 
~ 
e 
~ 20 
1 u 
~ 
Control PAX3· PAX3 PAX3-
MAML3 FOX01 
Fig. 1.34 Biphenotypic sinonasal sarcoma. Structure and transactivation potential of the PAX3-MAML3 fusion protein. 
A,B The t(2;4) translocation /uses exons 1-7 of PAX3 to exons 2-5 of MAML3 to create a novel PAX3-MAML3 fusion 
protein that retains the DNA-binding domains of PAX3 but lacks the Notch-binding site of MAML3; the arrows along the 
chromosomes indicate the transcription orientation of PAX3, MAML3, and PAX3-MAML3. C Fusion-signal FISH shows 
the juxtaposition of the 5' PAX3 (red) locus to the 3' MAML3 (green) locus; the location of these probes is shown in 
panel A. D Transient transcription assays demonstrate the poten! transactivation potential of PAX3-MAML3. PD, paired 
domain; HD, homeodomain; TAO, transactivation domain. Reprinted from Wang X et al. {2545}. 
invasion of local structures. Nearly 50% 
of patients with follow-up in the original 
series experienced local recurrence, as 
long as 9 years after initial treatment. 
Neither metastatic disease nor death 
from disease has been reported {1409}. 
Specific predictive factors have not been 
defined. 
Synovial sarcoma 
Bullerdiek J. 
Bell D. 
Definition 
Synovial sarcoma is a mesenchymal tu-
mour that displays a variable degree of 
epithelial differentiation, including gland 
formation, and has a specific chromo-
somal translocation t(X;1 B)(p11 ;q11) that 
leads to formation of an SS18-SSX fusion 
gene (735).ICD-0 code 
Synonyms 
Synovial cell sarcoma; synovioma 
Epidemiology 
9040/3 
Synovial sarcomas are the most com-
mon non-rhabdomyosarcoma soft tissue 
sarcomas in children, adolescents, and 
young adults, with a mean patient age at 
first diagnosis in the third to fourth dec-
ade of life {121 5). 
Etiology 
Synovial sarcomas 
ally associated with 
{568 ,629,2459). 
Localization 
are exception-
prior radiotherapy 
The sinonasal tract and skull are rare 
localizations. 
Clinical features 
There are palpable, deep-seated swell-
ings, with or without associated pain or 
tenderness. 
Macroscopy 
Lesions are yellow or grey to white, and 
well circumscribed when slow-growing. 
Histopathology 
Severa! monophasic subtypes (i.e. spin-
dle-cell, calcifying/ossifying, myxoid, 
and poorly differentiated) and biphasic 
subtypes with glandular or solid epithe-
lial cells can be distinguished. Poorly 
differentiated tumours may contain ar-
eas with frequent mitoses and necrosis 
{726,2399}. There is TLE1 nuclear immu-
noreactivity in as many as 95% of cases; 
Malignant soft tissue tumours 41 
variable positivity for CD99, BCL2, and 
CD56; and patchy to focal reactivity with 
epithelial markers (EMA), cytokeratins 
(CK7), and BerEP4. The tumours are usu-
ally negative for S100 and WT1. 
Genetic profile 
The chromosomal translocation t(X;18) 
(p11 ;q11), likely acting as driver mutation, 
is a specific genetic alteration in synovial 
sarcomas (2436), and is also described 
among skull base and sinonasal tract tu-
mours {181,450,835,2299}. lt results in a 
gene fusion between SS18 (also cal led 
SYT) and one of three SSX genes (454). 
The fusion can be detected by classic 
cytogenetics, quantitative RT-PCR {903}, 
or FISH {827) . Variant translocations ex-
ist, and a considerable percentage of 
synovial sarcomas do not show these 
aberrations. 
Prognosis and predictive factors 
The prognosis varíes depending on stag-
ing, grading, resectability, use of radia-
tion therapy, site of primary tumour, and 
presence of metastases {2507). Clinically 
aggressive behaviour, apparently deter-
mined early during tumorigenesis, is as-
sociated with more-complex genomes 
and upregulation of AURKA and KIF18A 
{1930). 
Fig. 1.36 Biphasic synovial sarcoma. A lmmunoreactivity with a pancytokeratin cocktail. B Nuclear immunoreactivity 
with TLE1 . 
42 Tumours of the nasal cavity, paranasal sinuses and skull base 
Borderline / low-grade malignant 
soft tissue tumours 
Desmoid-type fibromatosis 
Wenig B.M. 
Flucke U. 
Thompson L.D. R. 
Definition 
Oesmoid-type fibromatosis is a locally in-
filtrative, non-metastasizing, cytologically 
bland (myo)fibroblastic neoplasm. 
ICD-0 code 8821/1 
Synonyms 
Desmoid tumour; aggressive fibroma-
tosis; infantile fibromatosis (desmoid 
variant) 
Epidemiology 
About 10-15% of cases occur in the 
head and neck {528,1556,2532). As 
many as 30% of cases occur in children 
(551,738,1018,1847). There is no sex 
predilection. 
Etiology 
There is an association with Gardner 
syndrome (familia! colorectal polyposis) 
{463), including familia! adenomatous 
polyposis (472,2094). Surgery-related 
trauma may be a contributory factor. 
Localization 
Soft tissues of the neck are most com-
monly affected {155,551}. whereas 
the maxillary sinus, nasopharynx, and 
oral cavity are infrequently involved 
{753,780,856}. Multifocality may be seen 
in syndromic cases. 
Clinical features 
Symptoms include an enlarging painless 
neck mass, as well as nasal obstruction 
and epistaxis in the sinonasal tract. Fa-
cial deformity, proptosís, and dysphagia 
may occur with disease progression. 
Macroscopy 
Desmoid-type fíbromatosis presents as 
a fí rm , tan-white, poorly delineated or 
infiltratíng lesíon of variable size, wíth a 
trabecu lar or whorled appearance on cut 
section. 
Histopathology 
Histopathology shows a poorly circum-
scribed, infiltrative (to muscle and/or 
bone), fascicular growth of moderate 
cellularity composed of spindle-shaped 
cells with tapering to plump _vesicular 
nuclei, small nucleoli, and indistinct cyto-
plasm, separated by abundant collagen. 
Mild nuclear pleomorphism and rare mi-
totic figures may be identified; atypical 
mítoses and necrosis are absent. The 
stroma is variably collagenized, may 
focally be myxoid or mucoid-appearing, 
and may be characterized by keloid-like 
collagen. Vascularity varies, consisting 
of compressed vessels that tend to be 
evenly spaced. Lesiona! cells are reac-
tive for vimentín, nuclear beta-caten in (in 
70-75% of cases), actins, and occasion-
ally desmin {184,335,1818,2400). 
Genetic profile 
Cytogenetic abnormalities on chromo-
somes 8 and 20 support a monoclonal 
neoplastic nature (269). Germline mu-
tations of the APC gene are primarily 
identified in the setting of Gardner-type 
familia! adenomatous polyposis, where-
as mutations in the beta-catenin gene 
(CTNNB1) are identified in as many as 
85% of sporadic cases (738,1059,1355). 
with T41A, S45F, and S45P mutations be-
ing the most frequent {1 059,1355). 
Genetic susceptibility 
Patients with Gardner syndrome {463} or 
Gardner-type famil ia! adenomatous poly-
posis are at increased rísk {472,2094). 
Prognosis and predictiva factors 
In general, the prognosis is good (1193}, 
with positíve surgical margins associated 
with recurrence, usually < 2 years after 
surgery (1050}. Young patient age and 
CTNNB1 S45F mutatíon may be indepen-
dent risk factors for recurrence (473,2457). 
Borderline/low-grade malignan! soft tíssue tumours 43 
Sinonasal 
glomangiopericytoma 
Thompson L.O.R. 
Flucke U. 
Wenig B.M. 
Definition 
Sinonasal glomangiopericytoma is a 
sinonasal tumour demonstrating a perivas-
cular myoid phenotype. 
ICD-Ocode 9150/1 
Synonym 
Sinonasal haemangiopericytoma- like 
tumour 
Epidemiology 
Glomangiopericytomas account for 
< 0.5% of all sinonasal tract neoplasms 
{356,476,2389). with a slight female pre-
dilection and a peak incidence in the sev-
enth decade of lite, although individuals 
of any age may be affected. 
Localization 
The tumour is nearly always unilateral 
(only 5% are bilateral), affecting the na-
sal cavity alone and frequently extending 
into paranasal sinuses. lsolated parana-
sal sinus involvement has also been re-
ported {189,356,476,640,2389]. 
Clinical features 
Most patients present with nasal obstruc-
tion and epistaxis, with other non-specific 
findings present for an average duration 
of < 1 year {2389}. Associated severe on-
cogenic osteomalacia has been reported 
{257,356). 
Macroscopy 
The tumours are generally polypoid, non-
translucent, beefy red to pink, soft, and 
fleshy to friable, with an average size of 
3.0cm. 
Histopathology 
The unencapsulated tumour is identified 
below an intact epithelium, although fric-
tion surface erosion may be seen in large 
tumours. There is a so-called patternless 
diffuse architecture, frequently effacing or 
enveloping normal tissue. The cells may 
be arranged in short fascicles; in stori-
form, whorled, meningothelial, or reticu-
lar arrangements; or in short palisades 
of closely packed cells. The cells are 
separated by a vascular plexus ranging 
from capillaries to large patulous spaces. 
Prominent, thick, acellular, perithelioma-
tous hyalinization is a characteristic fea-
ture. There is a syncytial architecture to 
the c losely packed, uniform, oval to elon-
gate cells, with indistinct cell borders. The 
nuclei are oval to spindle-shaped, vesic-
ular to hyperchromatic, and surrounded 
by nondescript cytoplasm. Mitoses are 
limited (< 3 per 10 high-power fields), 
and nuclear pleomorphism is absent to 
mild. Mast cells, eosinophils, and extrav-
asated erythrocytes are variably present. 
Tumour giant cells are rarely identified, 
but an aggregation of degenerating tu-
mour cells, similar to those of symplas-
tic glomus tumour, may be seen {657). 
lnfrequently, fibrosis or myxoid change 
may be identified . Rarely, glom·angio-
pericytoma may contain mature adipose 
tissue(lipomatous) or extramedullary 
haematopoiesis {742,904,1732,2389}. 
Concurrent coll ision tumours, most 
often solitary fibrous tumours, have 
been reported {17,822,2389). Malignant 
glomangiopericytomas show pro-
found pleomorphism, necrosis, and 
increased mitoses {2389). By immuno-
histochemical analysis, glomangiopericy-
tomas usually show diffuse reactivity with 
actins (SMA > MSA), nuclear beta-
catenin, cycl in 01 , factor Xllla, 1 and vi-
mentin, and lack significan! expression 
of CD34, CD31, CD11 7, STAT6, BCL2, 
cytokeratin, EMA, desmin, or S100 pro-
tein {17,356,630,1274,1339,2389}. 
Genetic profile 
Somatic, single-nucleotide-substitution, 
heterozygous mutations in the beta-
catenin gene (CTNNB1), specifically in 
the GSK3beta region (codons 32, 33, 
37, 41 , and 45 encoded by exon 3) have 
been identified in glomangiopericytoma 
{923,1339]. Accumulation of beta-catenin 
results in nuclear translocation, which 
has been shown to upregulate cyclin 01 
and lead to its oncogenic activation. Ac-
tivation of beta-catenin and the resulting 
cyclin 01 overexpression are important 
pathogenetic events {1339}. In the dif-
ferential diagnosis it is importan! to note 
that NAB2-STAT6 gene fusion in solitary 
fibrous tumours {603}. MIR143-NOTCH 
fusion in glomus tumours {1 660} and 
t..._. , I a ..a,Ullll- .:.lll.- _ _.L ____ ,._ 
Fig. 1.38 Nasal glomangiopericytoma. A The surface respiratory epithelium is uninvolved by !he patternless proliferation of spindled neoplastic cells; there is well-developed 
peritheliomatous hyalinízation. B Spindled cells with ovoid nuclei in a syncytial arrangement; numerous eosínophils and mast cells are apparent. 
44 Tumours of the nasal cavity, paranasal sinuses and skull base 
ACTB-GL/1 fusion in pericytoma (514} 
are not seen in glomangiopericytoma. 
Prognosis and predictiva factors 
Glomangiopericytoma is an indolent tu-
mour with an excellent survival rate. Re-
currence (which occurs in as many as 40% 
of cases) is usually a result of inadequate 
surgery {356,640,2389}. Aggressive (ma-
lignan!) behaviour is suggested by tumour 
size > 5 cm, bone invasion, profound 
nuclear pleomorphism, high mitotic rate 
(> 4 mitoses per 10 high-power fields), 
and necrosis {356,476,1274,2389}. 
Solitsry fibrous tumour 
Flucke U. 
Thompson L.D.R. 
Wenig B.M. 
Definition 
Solitary fibrous tumour is a fusion gene-
associated tumour of fibroblastic pheno-
type, with a branching vasculature. 
ICD-0 code 
Synonyms 
Haemangiopericytoma; giant cell 
angiofibroma 
Epidemiology 
8815/1 
Solitary fibrous tumours are rare, account-
ing for < 0.1% of ali sinonasal neoplasms 
(151). Adults are mainly affected, with no 
sex predilection (17,564,861,2620,2735}. 
Localization 
Tumours affect the nasal cavity (2620, 
2735}. 
Clinical features 
Patients experience nasal obstruction 
and epistaxis, among other non-specific 
findings (1 51,2620,2735}. 
Macroscopy 
Tumours are polypoid, firm, and 
white, and are usually small due to the 
confined space of the sinonasal tract 
(151,2620,2735}. 
Fig. 1.40 Solitary fibrous tumour. A Note the pattemless architecture of the fibroblastic cells; there is a collagenous 
background, and sinonasal mucosa is seen in the upper part of the field. B Nuclear STAT6 expression is !he most 
specific immunohistochemical marker. 
Histopathology 
Tumours are submucosal, pseudoen-
capsulated, and variably cellular, con-
sisting of bland spindle-shaped cells 
arranged in a haphazard architecture. 
Multinucleated giant cells may be pre-
sent. The vessels are stellate to stag-
horn-like in shape. There is a variable 
collagenous background that includes 
ropey, keloidal, or amianthoid collagen 
bundles. lmmunohistochemically, the 
cells show a specific reaction with STAT6 
(nuclear) and CD34, but are non-reactive 
with desmin, S100 protein, actins, and 
nuclear beta-catenin (489,563,603,923, 
2620,2683,2735}. 
Genetic profile 
NAB2-STAT6 gene fusion seems to be 
specific {33,511,565,1634]. 
Prognosis and predictive factors 
Complete surgical resection is usu-
ally curative. Patient age > 55 years, 
tumour size > 15 cm, necrosis, and > 4 
mitoses per 10 high-power fields prob-
ably suggest more aggressive behaviour 
{564,1297,2659). 
Borderl ine/low-grade malignan! soft tissue tumours 45 
Epithelioid 
haemangioendothelioma 
Flucke U. 
Franchi A. 
Definition 
A malignant neoplasm of low- to inter-
mediate-grade, composed of neoplastic 
cells that have an endothelial phenotype, 
epithelioid morphology, and a hyalinized, 
chondroid, or basophilic stroma. 
ICD-0 code 9133/3 
Epidemiology 
There is a wide patient age distribu-
tion, with children rarely being affected 
(280,2579). 
Localization 
Occurrence in the head and neck is rare. 
Epithelioid haemangioendothelioma may 
arise in soft tissue, skin, and bone. The 
neck, oral cavity, salivary glands, and 
jawbones may be affected . Very rarely, 
a lymph node may be the primary site 
(422,662,739,1886}. 
Clinical features 
Epithelioid haemangioendotheliomas 
are classically slow-growing, infiltrative, 
and (rarely) metastasizing lesions (280). 
Symptoms are mostly non-specific. 
Pain and tenderness may be present 
{1589,2579). There is a propensity for 
lymph node metastasis (739). 
Macroscopy 
The (multi)nodular mass typical ly shows 
a pale, solid cut surface, sometimes with 
sorne haemorrhage {280}. 
Histopathology 
The epithelioid- and histiocytoid-ap-
pearing endothelial cells are arranged in 
short cords and strands in a myxohyaline 
stroma. They show subtle intracytoplas-
mic lumina and an abundant hyaline cy-
toplasm. Striking nuclear atypia is seen in 
approximately 30% of cases. Mitotic ac-
tivity is usually low. Multicellular vascular 
channels are present in individual cases 
{574,739,1589,2579}. 
Endothelial markers are expressed, with 
CD31, ERG, and FLl1 being the most 
sensitive. Cytokeratin expression is seen 
in about 30% of cases, which may as a 
result be confused with carcinomas or 
myoepithel ial tumours (739,1589}. There 
is nuclear positivity for CAMTA1 in cases 
with WWTR1-CAMTA1 fusion . There is 
nuclear expression of TFE3 in cases with 
YAP1-TFE3 fusion, but this marker should 
be used with caution due to the possibil-
ity of unspecific staining (662,739,2161). 
Genetic profile 
WWTR1-CAMTA1 fusion is present in 
most of the cases. A small subset of 
tumours harbour a YAP1-TFE:J fusion 
(85,662,739,2351}. 
46 Tumours of the nasal cavity, paranasal sinuses and skull base 
Prognosis and predictive factors 
Most cases behave in an indolent man-
ner. A progressive clinical course with tu-
mour-related fatality has been document-
ed in sorne instances {574,1589,2579). 
A proposal for ri sk stratification showed 
that > 3 mitoses per 50 high-power fields 
and tumour size > 3 cm are associated 
with higher mortality, irrespective of local-
ization , atypia, cell spindling, or necrosis 
(574). 
Benign soft tissue tumours 
Leiomyoma 
Definition 
Leiomyomas are benign tumours with 
smooth muscle differentiation (and 
vascular differentiation in the case of 
angioleiomyoma). 
ICD-0 code 8890/0 
Epidemiology 
Leiomyomas are extremely rare in the 
head and neck region, accounting for 
< 1% of all leiomyomas (2488}. Adults are 
rnost commonly affected, with an equal 
sex distribution {1047,2488). lt seems that 
most sinonasal tract examples are angio-
leiomyomas {20,1047,1607}. 
Localization 
The most common site of leiomyoma 
in the head and neck region is the lips, 
followed by the tangue, cheeks, pal-
ate, gingiva, and mandible (2488}. The 
tumours are extraordinarily rare in the 
sinonasal tract, with involvement of the 
nasal cavity in most of the cases and 
more rarely of the paranasal sinuses (20, 
778,1047). 
Clinical features 
The tumours are clinically indistinct 
and present as longstanding polypoid 
rnasses with nasal obstruction, epistaxis, 
and pain (20,778,1047,2488). 
Macroscopy 
Lesions are polypoid, nodular, and usual-
ly sharply demarcated,with a white to tan 
trabecular cut surface {20,1047,2488). 
Histopathology 
Tumours are subepithelial with infre-
quent mucosa! ulceration. Spindled tu-
mour cells are arranged in intersecting 
fascicles. The nuclei are oval to elongate 
and cigar-shaped, without atypia. There 
is eosinophilic fibrillary cytoplasm. Un-
like in leiomyosarcoma, mitotic figures 
are absent. Angioleiomyoma, the most 
common smooth muscle tumour in this 
region, shows a prominent vasculature 
surrounded by smooth muscle cells with 
which the vessels are intimately associat-
ed. Calcification, ossification, fatty meta-
plasia, or myxohyaline degeneration may 
be seen and may suggest regression in 
longstanding lesions {20,606,778,1047, 
1606). A fatty componen! is more com-
mon in males and older patients {20). 
lmmunohistochemically, lesions express 
smooth muscle markers (alpha-SMA, 
MSA, desmin, and caldesmon) but are 
negative far HMB45, S0X10, and S100 
(20,1047,1606}. 
Genetic profile 
Angioleiomyomas show loss of 22q1 1.2 
and low-level amplification of Xq {1741). 
Prognosis and predictive factors 
The prognosis is excellent {20,1047}. 
Thompson L.D.R. 
Bullerdiek J . 
Flucke U. 
Franchi A. 
Haemangioma 
Definition 
Haemangioma is a benign neoplasm of 
vascular phenotype. 
ICD-0 code 9120/0 
Synonyms 
Lobular capillary haemangioma; pyogen-
ic granuloma; capillary haemangioma; 
cavernous haemangioma 
Epidemiology 
Mucosa! haemangiomas account for 
about 10% of head and neck haeman-
giomas and about 25% of non-epithelial 
sinonasal tract neoplasms {777,1620, 
1936,2221). Haemangiomas occur in 
patients of all ages (median: 40 years). 
There are incidence peaks among boys 
and adolescent males and among preg-
nant women, with an equal sex distribu-
tion in patients aged > 40 years {644, 
777,963,1174, 1620,2221 J. 
Etiology 
Lobular capillary haernangioma is associ-
ated with injury, hormonal factors (pregnan-
cy and oral contraceptive use) (559,1292, 
1936). and drugs (vemurafenib) {2061). 
Localization 
The anterior septum is most frequently 
affected, followed by turbinates and 
sinuses (644,1620,1936,2221}. 
Benign soft tissue tumours 47 
A 
Fig. 1.43 Lobular capillary haemangioma. 
surrounding a central penetraling vessel. 
Clinical features 
Presenting symptoms include epistaxis 
and obstruction, usually of short duration 
(559,1620,1936,2221). lmaging studies 
show an intensely enhancing tumour sur-
rounded by a hypoattenuated peripheral 
rim, often with bony remodell ing (1174, 
1360,2669}. 
Macroscopy 
The mean size is < 1.0 cm, but examples 
as large as 8 cm have been reported 
{1936,2221). The gross appearance 
ranges from that of a diffuse, flat mass 
to that of a bulging, polypoid nodule. The 
lesions are soft and usually have surface 
epithelial ulceration {644,777,963,1174, 
1620). 
Histopathology 
Haemangiomas in the sinonasal tract 
are divided primarily into capillary and 
cavernous types {1174,1620,1936,1956, 
2221}. Other variants are reported rarely. 
Lobular capillary haemangioma is a cir-
cumscribed proliferation of capillaries 
with plump endothelial cells surrounded 
by pericytes in a fibromyxoid stroma, ar-
ranged in one or more lobules (which may 
show high cellularity). Each lobule has a 
large central vein surrounded by small 
capillaries, with an overlying collarette of 
epithelium (often ulcerated or atrophic). 
Mitoses are often identified, without atyp-
ical forms. Cavernous haemangiomas 
are composed of multiple, large, cystic, 
thin-walled, blood-fil led spaces lined by 
endothelial cells and separated by scant 
connective tissue stroma. The neoplastic 
cells react with FLl1, CD34, CD31, and 
factor Vl ll-related antigen, with variable 
expression of estrogen and progesterone 
receptors. 
Genetic profile 
A single case had a clonal del(21) 
(q21.2q22.12) {2425¡. 
Genetic susceptibility 
Associations with Sturge- Weber syn-
drome (encephalotrigeminal angiomato-
sis) and von Hippel-Lindau disease have 
been reported. 
Prognosis and predictive factors 
Recurrences, which occur in as many 
as 42% of cases, are usually identified 
in older patients. Pregnancy-related re-
gression occurs after parturiti<5n {134, 
559,1936,2221). Angiosarcomas arise de 
novo {1718). 
Schwannoma 
Definition 
Schwannoma is a benign tumour of 
Schwann-cell phenotype. 
ICD-0 code 9560/0 
Synonyms 
Neurilemmoma; benign peripheral nerve 
sheath tumour 
Epidemiology 
Less than 4% of schwannomas involve the 
nasal cavity and paranasal sinuses (929, 
952,994,2170). developing in middle-
aged adults (mean patient age: 50 years; 
range: 17-81 years) with an equal sex dis-
tribution {747,1594,2170,2314). 
48 Tumours of the nasal cavity, paranasal sinuses and skull base 
Localization 
Sinonasal schwannomas arise from the 
branches of the cranial nerves (V and IX-
XI I) and autonomic nervous system, af-
fecting (in descending arder of frequen-
cy) the ethmoid and maxillary sinuses, 
nasal cavity, and sphenoid and frontal 
sinuses {952,994,1866,2170,2314). 
Clinical features 
The most common presenting symp-
toms are headache, nasal obstruction, 
facial pain, and Horner syndrome (ocu-
losympathetic palsy), followed by other 
non-specific findings {929,1866,2170, 
2314). lmaging shows an inhomogene-
ous, low-density soft tissue mass, with 
bone erosion occasionally noted {1230, 
1866,2170,2314). Tumours may expand 
into the orbit, nasopharynx, and cranial 
cavity (1866,2170). 
Macroscopy 
Sinonasal schwannomas can reach 7 cm 
in size (mean: 2.5 cm). They are well-
circumscribed , globular, firm to rubbery, 
yellowish-tan tumours with a solid to myx-
oid and cystic cut su rface, frequently with 
haemorrhage. 
Histopathology 
Schwannomas are unencapsulated tu-
mours composed of Antoni A cel lular 
areas with nuclear palisad ing alternating 
with hypocellular, myxoid Antoni B areas. 
The tumour cel ls are fusiform with elon-
gated cytoplasmic extensions imparting a 
wavy to spindled appearance. The nuclei 
are wavy and tapered , with heterochro-
matin. In Antoni B areas, a perivascular 
hyalinization is characteristic. Mitoses are 
scant and necrosis is absent. Extensive 
degeneration may result in a narrow rim 
of recognizable tumour at the periphery 
(300,952}. Epithelioid variants and hybrid 
tumours (i.e . neurofibroma and perineuri-
oma) are rare in the sinonasal tract {109). 
Jmmunophenotype 
The neoplastic cells are strongly and 
diffusely reactive with S100 protein and 
SOX10, with CD34-positive fibroblasts 
in the Antoni B areas. Focal GFAP and 
AE1/AE3 immunoreactivity has been de-
scribed, but neurofilament protein (NFP) 
and actin are negative {1608}. 
Prognosis and predictive factors 
Schwannomas exceptionally undergo 
malignan! transformation {972,1575,1626, 
2422). but otherwise have a very low re-
currence potential. 
Neurofibroma 
Definition 
Neurofibroma is a benign peripheral 
nerve sheath tumour composed of mixed 
Schwann cells, perineural-like cells, and 
intraneural fibroblasts. 
ICD-0 code 
Synonym 
Fibroneuroma 
Epidemiology 
9540/0 
Neurofibromas are exceptional in the 
sinonasal tract. They show no sex pre-
dilection. The mean patient age is in the 
fifth decade of life overall, and ·35 years 
among patients with neurofibromatosis 
type 1 {109}. 
Localization 
Sinonasal neurofibromas arise most com-
monly at the nasal vestibule, followed by 
the maxillary sinus {1 09,281); the majority 
are unilateral {211 ,1308}. 
Clinical features 
Non-specific symptoms include a mass, 
obstruction, epistaxis, and pain {81,109, 
1866). 
Macroscopy 
Tumours are firm, glistening, fusiform , 
and sometimes polypoid, with a mean 
size of 3.1 cm (81,109,998). 
Histopathology 
Neurofibromas are unencapsulated 
tumours intimately associated with nerve 
twigs. Lesiona! cells (modified Schwann 
cells, intraneural fibroblasts, and perineu-
rial hybrid cells) intermix with coarse col-
lagen bundles and mast cel ls within a mu-
copolysaccharide-rich stroma. There are 
ovoidto spindled cells with undulating, 
pointy nuclei with thin cytoplasmic pro-
cesses extending into the stroma, often 
e: ~ ,':::r;~\½;. , :, ,•, . t ~ ~ ;::.:' ;;_:Jf }1{j 1g;:J/\f :{f :;;;;{( 
· .. ·· , . • ··" , IP' ',· • ' • ' ·' .. ·. lit~~ ,, . .,,., -. ..,-.,•" .v, ·,,-, ' . ' ,. • , . . " · ' . 
1•' ... •..,..--: ~ -'- ~~...: ., '- ~\ ~ .. \. ~ • ._ ~'°V~ _. .,d,-!1 ,• .,; "• ,,.,- t.:,, . 
~ .. .: ... :.-:., .. :.:.!-·. ,. , ,· 't~ , ,\ ,_ ..... .. --:.- ~, .. , ·'.. ·· . .1 ,·, ~·.''., ·; .. ª~ n 
. ;/': .... ~ ~:;: i~ : .. ~·i._)l~.::~1~<--:.~\"!'::.:' :._;~- -: ... _~ ·~~~~;'~_.; /~/~ .;_ .'f:-i~~ .~ .. ~ ~ 
Fig. 1.45 Nasal neurofibroma. A An intact squamous mucosa overlies a proliferation of Schwann cells, perineurial cells, and fibroblasts blended with collagen libres. B Nerve fibre 
twigs are interspersed among Schwann cells, perineurial cells, and collagen fibres; mast cells are also present. 
Benign soft tissue tumours 49 
with a centripetal gradient of cellularity. 
lncreased cellularity, a storiform growth 
pattern, and pleomorphism may be seen, 
but fascicular growth or increased mi-
toses (in particular atypical mitoses) sug-
gest malignan! change {109,994,1866). 
Plexiform neurofibroma and composite 
tumours (i.e. schwannoma and perineu-
rioma) are exceptional {109,1026,1308), 
and the diffuse type has not been report-
ed. The subpopulations of neurofibroma 
Other tumours 
Meningioma 
Ro J.Y. 
Bell D. 
Nicolai P. 
Thompson L.D.R. 
Definition 
Meningioma is a neoplasm composed of 
meningothelial cel ls. 
ICD-0 code 
Synonym 
Sinonasal trae! meningioma 
Epidemiology 
9530/0 
Primary extracranial (i.e. ectopic or ext-
racalvarial) meningiomas of the sinona-
sal tract are rare, accounting for 0 .1 % of 
primary sinonasal neoplasms, 2% of all 
meningiomas, and 24% of al l primary ex-
tracranial meningiomas. Direct extension 
are highlighted with S100 protein, GFAP, 
CD34, and BCL2, with S0X10, NFP, and 
calretinin highlighting the axons specifi-
cally (109,719}. 
Genetic profile 
Neurofibromatosis type 1- related neu-
rofibromas have associated biallel ic inac-
tivation by germline mutations of the NF1 
gene (17q11 .2) {6,1836). 
is much more common, with 20% of men-
ingiomas showing extracranial extension 
{772,1867,2029,2388). By consensus, a 
diagnosis of primary sinonasal menin-
gioma should not be rendered when a 
detectable intracranial mass is present 
{1666,2029). Sinonasal mening iomas af-
fect women and men equally (with a ra-
tio of 1:1), and have a mean patient age 
of 48 years (range: 13- 88 years) {2160, 
2388). 
Etiology 
Radiation exposure and sex hormones 
are unproven etiological factors {772, 
1006,1039). 
Localization 
Sinonasal meningiomas involve the nasal 
cavity most commonly, followed by the 
paranasal sinuses (most commonly the 
frontal sinus), with multiple siles frequent-
ly affected. Most tumours are left-sided 
{772,1006,1867,2029,2388}. 
50 Tumours of the nasal cavity, paranasal sinuses and skull base 
Genetic susceptibility 
About 10% of sinonasal neurofibromas 
arise within neurofibromatosis type 1 
{109,2001,2453). 
Prognosis and predictive factors 
Neurofibromas are benign, with a 5% re-
currence rate due to incomplete excision 
{1866,2001 }. Malignan! transformation is 
exceptional {1866). 
Clinical features 
Symptoms are non-specific, present for a 
long duration (mean: 4 years), and most 
commonly include a mass or polyp and 
nasal obstruction {772,823,1006,1867, 
2388). The imag ing findings are non-
specific, revealing opacification, sorne-
times with bone erosion or hyperosto-
sis . In most cases, direct extension by 
permeative growth from an intracranial 
primary can be documented; the intrac-
ranial primary may be a small en plaque 
meningioma \1666,2388). 
Macroscopy 
The tumours are often polypoid , covered 
by an intact epithelium, and expanding 
into bone. They can reach 8.0 cm in size 
(mean: 3 cm). 
Histopathology 
Sinonasal meningiomas, often blended 
with surface squamous or respiratory 
epithelium, are arranged in lobules of 
whorled syncytial meningothelial cells. 
Nuclei are bland and round to oval, with 
small nucleoli and occasional intranu-
clear cytoplasmic inclusions {2388}. 
Psammoma bodies are occasionally 
present. 
ot the i 5 histological types of menin-
gioma, the most common in the sinona-
sal trae! are meningothelial , transitional, 
metaplastic, and psammomatous, and 
most are grade i tumours {i858,i859}. 
Grade 2 and 3 meningiomas are rare 
{2388}. 
Meningiomas typically react with EMA, 
CK18, and vimentin. Rare tumours may 
react with pancytokeratin and CK? (in a 
pre-psammomatous pattern), CD34 (fi-
brous and atypical types), and SiOO pro-
tein (fibrous type), whereas GFAP, STAT6, 
and SMA are non-reactive {2160). Pro-
gesterone and estrogen receptor reactiv-
ity is present {2388l. 
Genetic susceptibility 
Neurofibromatosis type 2 association is 
not significan! in sinonasal meningiomas. 
Prognosis and predictive factors 
The prognosis of sinonasal meningiomas 
is good. Although recurrences develop 
in about 30% of cases (due to incom-
pletely excised tumours), metastasis and 
malignan! transformation have not been 
reported [i006,i858,1867,2388). 
Sinonasal ame/oblastoma 
Wenig B.M. 
Definition 
Sinonasal ameloblastoma is a locally ag-
gressive, primarily gnathic (jaw) tumour 
with a high propensity for recurrence. 
lt originales wholly within the sinonasal 
trae!, without connection to gnathic siles, 
arising from sinonasal epithelium and 
showing histological features identical to 
!hose of its counterpart originating in the 
jaw. 
ICD-0 code 93i0/0 
Epidemiology 
Sinonasal ameloblastomas are un-
common tumours. There is a decided 
male predilection and the mean palien! 
age at presentation is 59.7 years (ap-
proximately 15-25 years older than far 
ameloblastoma occurring in the jaws) 
{2090}. 
Localization 
The tumours may involve the nasal cav-
ity only, the paranasal sinuses only, or 
both the nasal cavity and the paranasal 
sinuses {2090}. 
Clinical features 
Patients usually present with a mass le-
sion and nasal obstruction; symptom 
duration ranges from 1 month to severa! 
years {2090}. Unlike gnathic ameloblas-
tomas, which have a characteristic mul-
tilocular and radiolucent presentation, 
sinonasal ameloblastomas are described 
radiographically as salid ma:sses or 
opacifications {2090l. Bone destruction, 
erosion , and remodelling (with remnant 
of bony shell delimiting the lesion as it 
grows) may be present {2090). 
Histopathology 
Histologically, sinonasal ameloblastomas 
are similar in appearance to their gnath-
ic counterparts. In the sinonasal trae!, 
ameloblastomatous proliferation can be 
seen arising in direct continuity with the 
intact sinonasal surface mucosa! epithe-
lium, a finding that in conjunction with the 
absence of continuity with gnathic sites 
confirms primary sinonasal origin. 
Prognosis and predictive factors 
Overal l treatment success correiates with 
complete surgical eradication performed 
in conjunction with thoroughly detailed 
radiographical imaging. 
The tumour may recur, which generally 
happens within 1-2 years of the initial 
procedure but may occur years after the 
surgery {2090}. No tumour deaths, me-
tastases, or instances of malignan! trans-
tormation have been reported. 
Chondromesenchymal 
hamartoma 
Toner M. 
Hunt J.L. 
Definition 
Chondromesenchymal hamartoma is a be-
nign, locally destructive, tumour-like growth 
containing mixed mesenchymal elements. 
Synonyms 
Nasal chondromesenchymal hamarto-
ma; mesenchymoma 
Epidemiology 
This rare lesion occurs predominantly in 
infants, but occasionally in older children 
and adults, with amale predominance. 
Localization 
The most common sites are the parana-
sal sinuses, nasal cavity, and orbit. lntra-
cranial and skull base extension may oc-
cur [1568}. 
Clinical features 
This is a slow-growing expansile lesion 
that can be locally destructive. Patients 
maypresent with nasal congestion or 
symptoms related to a polypoid mass. 
Radiological tindings may appear de-
ceptively aggressive, with bone erosion 
and intracranial extension. 
Other tumours 5i 
Macroscopy 
The tissue is typically firm and white, re-
sembling cartilage. 
H istopathology 
Histopathology shows a fabular prol ifera-
tion of mature and immature hyaline car-
tilage in a variably ce llular fibrous back-
ground {1568). The stromal component 
may be highly cellular, and mitoses may 
be present. The stromal and carti laginous 
elements may be admixed with bony tra-
beculae or may surround bony islands 
{1795). The cartilaginous areas are S100-
positive; the stromal cells are SMA-posi-
tive and cytokeratin-negative {1795). 
Genetic susceptibility 
There is an association with the pleuro-
pulmonary blastoma-associated O!CER1 
familia! tumour susceptibi lity syndrome, 
.. 
Fig. 1.48 Chondromesenchymal hamartoma. Fibrovascular stroma with cellular lobules of cartilage that surround bony 
trabeculae. 
in which chondromesenchymal hamar-
toma may be the presenting lesion 
(2281). 
Prognosis and predictive factors 
After surgical removal, the recurrence 
rate is generally low (1554). 
Haematolymphoid tumours 
Overview 
Chuang S.-S. 
Ferry J.A. 
Definition 
Nearly ali haematolymphoid tumours 
arising from the nasal cavity or paranasal 
sinuses are non-Hodgkin lymphomas, 
although extramedullary plasmacytomas 
and rare myeloid and histiocytic neo-
plasms also occur {116,1027,1830,1888}. 
Epidemiology 
Sinonasal lymphoma accounts for 12-
15% of ali head and neck cancers. lt is 
the third most common sinonasal malig-
nancy, after squamous cell carcinoma 
and adenocarcinoma {484,1012}. In the 
USA, the frequency decreased in the 
early 21st century, probably reflecting 
a reduction in HIV-associated lympho-
mas due to antiretroviral therapy {484). 
However, extranodal NK/T-cell lym-
phoma, nasal-type (ENKTL), which has 
a predilection for East Asians and Latín 
Americans {86,446,607,1349), is increas-
ing in the USA, with an average annual 
increase in incidence of approximately 
9% between 2000 and 2011 (607}. 
Localization 
ENKTL has a predilection for the nasal 
cavity and may also arise from paranasal 
sinuses (86,446,607,1349}. Diffuse large 
B-cell lymphoma (DLBCL) most • com-
monly arises from the paranasal sinuses 
but may arise from the nasal cavity (1169). 
Clinical features 
Patients with nasal tumours present with 
nasal obstruction, epistaxis, and/or a de-
structive mass involving nose, nasal sep-
tum, palate, orbit, or facial skin. Patients 
with paranasal tumours present with 
symptoms of chronic paranasal sinusitis 
and soft tissue or bony destruction. B 
symptoms (e.g. fever, night sweats, and 
weight loss) occur in about 20% and 10% 
of patients, respectively, with sinonasal 
ENKTL and DLBCL. 
Histopathology 
In addition to DLBCL and ENKTL" there 
have been rare cases of other sinona-
sal haematolymphoid tumours , such as 
sinonasal Burkitt lymphoma, peripheral 
T-cell lymphoma, MALT lymphoma, extra-
osseous plasmacytoma, extramedullary 
52 Tumours of the nasal cavity, paranasal sinuses and skull base 
myeloid sarcoma, and histiocytic neo-
plasm (484,500,1012). 
Prognosis and predictive factors 
Modern therapies have significantly 
improved the prog nosis of sinonasal 
DLBCL. lnvolvement of multiple sinuses 
is a negative prognostic indicator (11 69). 
Extranoda/NK/T-celllymphoma 
Chuang S.-S. 
Gaulard P. 
Jaffe E.S. 
Ko Y. -H. 
Definition 
Extranodal NK/T-cell lymphoma, nasal-
type (ENKTL) is an extranodal lymphoma 
with a cytotoxic phenotype and a univer-
sal association with EBV. 
ICD-0 code 9719/3 
Synonyms 
Angiocentric lymphoma; lethal midline 
granuloma; malignan! midline reticu losis; 
polymorphic reticulosis 
fig. 1.49 Extranodal NK/T-cell lymphoma, nasal-type. A Right nasal tumour with obstruction, ecchymosis of the nasal 
side wall and facial skin, and invasion to the right nasal ala with tumour formation. B Postcontrast CT of the same case 
shows a homogeneously enhancing soft tissue mass in !he right nasal cavity involving the right nostril, nasal ala, and 
perinasal facial skin, and destruction of !he anterior lower aspee! of the nasal septum. 
Epidemiology 
Extranodal NK/T-cell lymphoma is more 
prevalent among East Asians and the 
indigenous populations of Mexico and 
Central and South America than in other 
populations {86,446,1349,19401. 
Etiology 
The precise etiology is unknown, al-
though EBV is crucial in pathogenesis. 
Lifestyle and environmental factors such 
as being a farmer, pesticide use, and liv-
ing near incinerators might be risk factors 
(2657). 
Localization 
ENKTL occurs most commonly in the 
upper aerodigestive tract (in 70- 85% of 
cases), mainly in the nasal cavity, para-
nasal sinuses, and Waldeyer ring (pha-
ryngeal lymphoid ring), with sorne cases 
occurring in the skin, gastrointestinal 
tract, soft tissue, and other extranodal 
siles {1132,1229,1909,2317}. 
Clinical features 
Patients with nasal tumours present with 
nasal obstruction and/or epistaxis. Nasal 
tumours may cause perforation of the 
nasal septum or palate and may spread 
to the skin or orbit with ecchymosis or 
ulcerative tumours. Paranasal tumours 
may mimic chronic paranasal sinusitis. 
Most cases present with stage I or 11 dis-
ease, with as many as 10- 20% of cases 
spreading to skin, gastrointestinal tract, 
testis, or distan! nodal regions. 
Histopathology 
ENKTL infi ltrates nasal tissue in a diffuse 
pattern, frequently with an angiocentric/ 
angioinvasive growth pattern, leading to 
geographical tumour necrosis. In rare 
instances, multiple biopsies might be 
needed to identify tumours showing ex-
tensive necrosis with few viable cells. The 
neoplastic cel ls vary in size and have ir-
regularly folded nuclei, granular chroma-
tin, and small nucleoli. Small cells might 
mimic a benign infiltrate but exh ibit cel-
lular atypia such as irregular nuclear con-
tours and mitoses. 
lmmunohistochemical ly, the tumour cells 
express CD3, cytotoxic markers (i .e. TIA1, 
granzyme B, or perforin), and frequently 
CD56 (1132,19091. They rarely express 
CD4,·CD5, or CDS. Examples with large-
cell morphology often express CD30. 
CD57 is nearly always negative (1132}. 
The tumours are mainly derived from 
NK cells, with a minority (10-40%) hav-
ing T-cell lineage (gamma delta or more 
rarely alpha beta) {102,1132,1418,19091. 
CD56 is more frequently expressed in 
tumours of NK-cell origin, whereas CD5 
expression usually indicates a T-cel l lin-
eage {1132,19091. ENKTL is positive for 
EBV-encoded small RNA (EBER) in the 
majority of cells by in situ hybridization 
{443,444,2322) . LMP1 is usually weak or 
negative. Cases showing a similar phe-
notype but EBV negativity are consid-
ered peripheral T-cel l lymphoma, NOS 
{1108,2322). 
Genetic profile 
ENKTL shows complex genetic alter-
ations, with numerous chromosomal 
gains and losses {1695). The commonly 
deleted chromosomal region at 6q21-23 
contains severa! candidate tumour sup-
pressor genes, including PRDM1, ATG5, 
AIM1, HACE1, and FOX03 {1091,1189, 
1289}. ENKTL has a distinctive genetic 
signature shared by cases with NK-cell 
and T-cell origin (1053). The JAK/STAT 
pathway is activated in most cases, by 
genetic alterations of JAK3, STAT3, or 
PTPRK {406,485,1053,1272,1370}. Re-
current mutations are frequent in tumour 
suppressor genes, including TP53 (in 
20- 60% of cases) {1941) and DDX3X 
(in 20% of cases) (1134). EBV infection 
Haematolymphoid tumours 53 
severely deregulates host microRNA pro-
fi les; downregulation of miR-146a and 
miR-15a promotes cell prol iferation and 
predicts poor prognosis in ENKTL {1266, 
1802]. 
Genetic susceptibility 
The strong EBV association and ethnic 
predisposition suggest a genetic defect 
in the host immune response to EBV in-
fection [534,535}. The lymphotoxin alpha 
gene (LTA) +252 (AG) polymorphism is 
associated with increased risk of ENKTL(409}. 
Prognosis and predictiva factors 
Prognostication of ENKTL traditionally 
depends on clinicopathological param-
eters, including stage (1364,2431). How-
ever, the amount of EBV DNA in plasma 
is a surrogate biomarker of lymphoma 
load, with diagnostic and prognostic 
significance (1221,1319,2431). EBV DNA 
and PET findings have been integrated 
into prognostic algorithms {1226). With 
curren! regimens, durable remission can 
be achieved in 70-80% of stage 1/11 cas-
es, and as many as 50% of stage 111/IV 
cases (1318,2431 }. 
Extraosseous plasmacytoma 
Feldman A.L. 
Ott G. 
Definition 
Extraosseous plasmacytoma is a mass-
forming proliferation of monoclonal plas-
ma cells with extraosseous (extramed-
ullary) presentation, in the absence of 
underlying multiple myeloma. Extraosse-
ous plasmacytomas in the nasopharynx 
54 Tumours of the nasal cavity, paranasal sinuses and skull base 
and other soft tissues in the head and 
neck must be distinguished from 8-cell 
lymphomas with plasmacytic/plasmab-
lastic differentiation, in particular MALT 
lymphoma and plasmablastic lymphoma. 
ICD-0 code 
Synonyms 
Extramedullary plasmacytoma; 
plasmacytoma 
Epidemiology 
9734/3 
The median patient age is 60 years and 
there is a male predominance, with a 
male-to-female ratio of 3- 4:1 [46,1 617). 
Localization 
About 80% of extraosseous plasmacyto-
mas involve the upper respiratory tract, 
most commonly the nasal cavity and 
paranasal sinuses, followed by the na-
sopharynx, oropharynx, and larynx (46, 
1617). Less common primary sites in the 
head and neck include the hypophar-
ynx, salivary and thyroid glands, cervical 
lymph nodes, !rachea, and oesophagus. 
Cervical lymph nades are involved sec-
ondarily in about 15% of cases [1586). 
Clinical features 
Extraosseous plasmacytomas are typi-
cally solitary, and examples occurring in 
the head and neck most commonly (in 
80% of cases) presentas a mass {1617). 
Additional findings at presentation in-
elude airway obstruction, epistaxis, lo-
cal pain, proptosis, rhinorrhoea, cervical 
lymphadenopathy, and cranial nerve pal-
sies. A minority of patients (< 25%) have 
a monoclonal serum paraprotein (M pro-
tein), typically of lgA type {2245). By defi-
nition, diagnostic features of plasma cell 
myeloma are absent {1476). 
H istopathology 
Microscopic evaluation typical ly shows 
diffuse infiltration by sheets of plasma 
cells, which may be well, moderately, or 
poorly differentiated {1617,2316}. Amy-
loid deposits may be present {2316, 
2616). Moderately and well-differentiated 
extraosseous plasmacytomas mus! be 
distinguished from B-cell Jymphoma, in 
particular from MALT lymphoma with ex-
tensive plasmacytic differentiation (584, 
1062). Poorly differentiated extraosseous 
plasmacytomas must be distinguished 
from plasmablastic lymphoma (2316}; 
sorne cases may be anaplastic to the 
point that plasma-cell differentiation is 
not apparent, prompting consideration of 
poorly differentiated non-haematological 
neoplasms {1172). 
lmmunophenotype 
The neoplastic cells often express mark-
ers of plasmacytic differentiation, such 
as C0138, C038, VS38, and MUM1/IRF4 
{232} . They variably express C079a, 
only rarely express C020, and are typi-
cally negative for PAX5. Extraosseous 
plasmacytomas may express EMA. Cyc-
lin 0 1 has been reported to be negative. 
C056 is expressed less frequently than 
in plasma cell myeloma, and the Ki-67 in-
dex is lower !han in plasma cell myeloma 
j¡ 
Fig. 1.54 Plasmacytoma. Monotonous infiltrate of 
plasma cells. 
(1278). Monotypic immunoglobulin light 
chains can typically be demonstrated by 
immunohistochemistry or in situ hybridi-
zation. Staining for heavy chains may 
reveal expression of lgA or lgG, whereas 
staining for lgM should raise suspicion 
for B-cell lymphoma. EBV has been re-
ported to be positive in 15% of cases 
{26), but the presence of EBV should also 
prompt consideration of plasmablastic 
lymphoma. 
Genetic profile 
Sorne genetic features are similar to 
!hose of plasma cell myeloma (232}, 
but differences have been reported, in 
particular different IGH translocation 
partners {1 93}. 
Prognosis and predictive factors 
The prognosis of extraosseous plasma-
cytoma is much better than that of plas-
ma cell myeloma, and most patients are 
treated with local radiation therapy {504, 
583). Regional recurrence or spread to 
other extraosseous siles may occur, and 
about 15% of patients develop multiple 
myeloma {46}. 
Haematolymphoid tumours 55 
Neuroectodermal / melanocytic tumours 
Ewing sarcoma/primitive 
neuroectodermaltumour 
Wenig B.M. 
Flucke U. 
Thompson L.D.R. 
Definition 
Ewing sarcoma / primitive (peripheral) 
neuroectodermal tumours are high-grade 
primitive small round cell sarcomas with 
variable neuroectodermal differentiation, 
characterized by the presence of trans-
locations between the EWSR1 gene on 
chromosome 22 and a member of the 
ETS family of transcription factors. 
ICD-0 code 9364/3 
Synonyms 
Peripheral neuroectodermal tumour; pe-
ripheral neuroepithelioma; peripheral 
neuroblastoma; adult neuroblastoma 
Epidemiology 
Ewing sarcoma and primitive neuroec-
todermal tumour primari ly occur in non-
head and neck sites, with only 2-10% 
developing in the head and neck {49). 
The tumours are slightly more common in 
males {49,921}, and occur predominant-
ly (but not exclusively) in children and 
young adults {921,1017,1036,1331,2601, 
2617l; older patients may occasionally 
be affected {921,2617}. 
Localization 
The most common head and neck sites 
include the skull and jaws (49,2601}; less 
common siles include the sinonasal trae\ 
(most commonly the maxillary sinus or 
nasal fossa) {921,1036,1331,2617}, orbit, 
and various mucosa! sites . Extension to 
dura, orbit, or brain may be present (921). 
Clinical features 
Symptoms include pain, mass lesion, 
and nasal obstruction, which often de-
velop rapidly (within months) (261 7). 
Macroscopy 
Sinonasal tract tumours may appear 
polypoid or multilobular, greyish-white, 
and glistening, with associated haemor-
rhage; ulceration is often present. 
Histopathology 
The tumour is markedly cellular with dif-
fuse (sheet-like) or lobular growth; the ap-
pearance may occasionally be trabecu-
lar or cord- like. The tumour is composed 
of uniform small cells with round to oval 
nuclei, fine-appearing (powdery) nuclear 
chromatin , a distinct nuclear membrane, 
inconspicuous to small nucleoli, sean\ 
pale to vacuolated (clear) cytoplasm, and 
indistinct cell borders. Mitotic activity is 
variable, with 5-10 mitoses per 10 high-
power f ields. Prominent intratumoural 
thin-walled vessels are present, which 
may be compressed and obscured by 
the cellular proliferation . A minimal stro-
mal componen! is present, which may 
include thin fibrous strands separating 
tumour lobules. Pseudorosettes (Hom-
er Wright rosettes) are present in most 
cases; less often, true neural rosettes 
(Flexner-Wintersteiner rosettes) may be 
identified . Histological variants include 
atypical or large-cell, clear-cel l, haeman-
gioendothelioma-like, adamantinoma-
like, spindled , and sclerosing forms (197, 
743}. 
lntracytoplasmic material that gives a 
diastase-sensitive positive reaction with 
periodic acid-Schiff (PAS) is present. 
Neoplastic cells strongly and diffusely 
express membranous C099 in nearly ali 
cases. Nuclear FLl1 is seen in a large 
percentage of cases; those with EWSR1-
FL/1 fusion show strong nuclear reactions 
with the C-terminus of FL/1 (1506,2411, 
2544). Vimentin is positive. Cytokeratins 
show strong, focal to diffuse staining with 
a dot-like pattern in as many as one third 
of cases, and in particular in adamanti-
noma-like tumours {197,894,921}. There 
is reactivity for at least one neural marker 
(e.g. neuron-specific enolase, S100 pro-
tein, synaptophysin, chromogranin, NFP, 
or GFAP). KIT (CD 117) expression is 
A.. . ...t::~ :Mlllla:-.J.:aá:'l.i¡:.• - ~ ,. ... •• ....,,-.;~ • '.!:l ..... _.;..:...; ~.lii--J.::!ll~-Eo,,;,;~olCL-:=...,.,;¡¡=1--
Fig. 1.56 Sinonasal Ewing sarcoma / primitive neuroectodermal tumour. A Hypercellular neoplasm with diffuse growth composed of uniform small cells with round to oval nuclei, 
fine-appearing nuclear chromatin, and pale to vacuolated cytoplasm. B Neoplastic cells show diffuse and strong membranous CD99 staining in nearly all cases; CD99 is sensitive bul 
not specific for the diagnosis of Ewing sarcoma I primitive neuroectodermal tumour. 
56 Tumours of the nasal cavity, paranasal sinuses and skull base 
Fig. 1.57 Ewing sarcoma/ primitive neuroectodermal tumour. On EWSR1 dual-colour break-apart FISH, Ewing 
sarcoma cells that have the chromosomal rearrangement show a red signa! distanced from a green signa!, indicating 
a translocation involving one EWSR1 allele, whereas the second allele is intact, as shown by red and green signals 
that overlap. 
present in approximately 25% of cases 
(743). Rarely, desmin staining is present, 
but myogenic and haematolymphoid 
markers are typical ly absent. 
Genetic profile 
There is consisten! rec iproca! translo-
cation between chromosome 11 and 
chromosome 22 (present in 90- 95% of 
cases). The most common translocation 
involves the EWSR1 gene (on chromo-
some 22) and the FL/1 gene (on chromo-
some 11), resulting in an EWSR1-FLl1 fu-
sion transcript. C/C-DUX4 fusion, a result 
of a t(4;19) or t(10;19) translocation, may 
be identified in EWSR1 fusion- negative 
cases (1101}. CIC-DUX4 fusion-positive 
tumours occur mainly in young adult 
men, most frequently in the soft tissues of 
extremities. They show a higher degree 
of heterogeneity in nuclear morphol-
ogy and have variable CD99 expres-
sion (membranous, not diffuse) than do 
EWSR1 fusion-positive cases, raising the 
possibil ity that CIC-DUX4 fusion tumour 
may be outside the scope of Ewing sar-
coma (2246). 
Genetic susceptibility 
Heritable retinoblastoma may predispose 
patients to Ewing sarcoma and perhaps 
to a subset of poorly differentiated neu-
roectodermal tumours in the sinonasal 
region that may be re lated to olfactory 
neuroblastoma (1236). 
Prognosis and predictive factors 
The 5-year survival rate for sinonasal Ew-
ing sarcoma/ primitive neuroectodermal 
tumour is 50-75%, reflecting a better 
overall prognosis at this site compared 
with cases at other siles (49,921}. The 
5-year survival rate for patients with ad-
vanced disease is < 25% (2617}. Local 
recurrence and distan! metastases may 
occur within 2 years, even in patients with 
localized disease. When metastases oc-
cur, the most common sites include the 
lungs and bone; lymph nade metastasis 
is less common, occurring in approxi-
mately 20% of cases. 
Prognosis has been found to be linked 
to tumour stage as determinea by the 
lntergroup Rhabdomyosarcoma Study 
Group (IRSG) staging system (126}. tu-
mour size (with size > 8 cm associated 
with adverse behaviour) (127,2601}, TP53 
alteration (which appears to define a cli n-
ical subset with a markedly poorer out-
come) {1592}, the presence of the type 1 
EWSR1 -FLl1 fusion transcript (thought 
to suggest a better prognosis !han other 
fusion transcripts) (542}, and poor his-
tological or radiological response at the 
site of primary tumour and incomplete 
radiological remission of lung metasta-
ses alter primary chemotherapy (associ-
ated with adverse behaviour) (31,49,127}. 
There is an increased incidence of radia-
tion-induced sarcomas later in life among 
surviving patients (1838} . 
0/fsctory neuroblastoma 
Bell D. 
Franchi A. 
Gil lison M. 
Thompson L.D.R. 
Wenig B.M. 
Definition 
Olfactory neuroblastoma (ONB) is a ma-
lignan! neuroectodermal neoplasm with 
neuroblastic differentiation, most often 
localized in the superior nasal cavity. 
ICD-0 code 9522/3 
Synonyms 
Aesthesioneuroblastoma; aesthesioneu-
rocytoma; aesthesioneuroepithelioma; 
olfactory placode tumour 
Epidemiology 
ONB has an estimated annual incidence 
of 4 cases per 10 mil lion population, and 
accounts for approximately 3% of all 
sinonasal tumours (273). Patients range 
in age from 2 to 90 years. Although a 
bimodal age distribution was initially re-
ported, recen! data support an even dis-
tribution across ali ages, with a peak in 
the fifth and sixth decades of life (273 , 
1130,1903}. Males are affected slightly 
more often than females (male-to-female 
ratio: 1.2:1 ). There is no reported ethnic or 
fami lia! predilection. 
Localization 
The anatomical distribution of ONB is 
confined to the cribriform plate, the su-
perior turbinate (nasal concha), and the 
superior half of the nasal septum. The 
vomeronasal organ (also called Jacob-
son's organ), sphenopalatine ganglion, 
olfactory placode, and the terminal nerve 
(also called the ganglion of Loci) are in-
cluded in the areas of proposed origin. 
Ectopic tumours within the paranasal si-
nuses (other than the ethmoid sinuses) 
are vanishingly rare (except in recurrent 
cases), and the diagnosis of ONB with no 
involvement of the cribriform plate is a di-
agnosis of exclusion (1619,2383}. 
Neuroectodermal / melanocytic tumours 57 
Fig. 1.58 Olfactory neuroblastoma. lmaging studies 
show a dumbbell-shaped tumour. 
Fig. 1.59 Olfactory neuroblastoma. The gross 
appearance is that of a polypoid reddish-grey mass, with 
hypervascular cut surface. 
Clinical features 
Clinically, ONBs often have a subtle pre-
sentation mimicking that of benign inflam-
matory/infectious diseases, and delay in 
diagnosis is frequent. Nasal obstruction 
and epistaxis are typical early manifes-
tations; headaches, pain, excessive lac-
rimation, rhinorrhoea, and visual distur-
bances are uncommon. Anosmia occurs 
in < 5% of patients. Paraneoplastic syn-
dromes (i.e. ectopic adrenocorticotropic 
hormone syndrome or syndrome of in-
appropriate antidiuretic hormone secre-
tion) are detected in about 2% of patients 
(789}. Physical examination and flexible 
fibre-optic endoscopic evaluation, com-
plemented with CT and MRI, are useful in 
the diagnostic work-up. 
The classic imaging findings include 
a dumbbell-shaped mass extending 
across the cribriform plate, with the waist 
at the cribritorm plate. MRI better deline-
ates sinonasal and intraorbital or intracer-
ebral extension . ONB is T1-hypointense 
and T2-isointense or T2-hyperintense to 
grey matter, with avid homogeneous en-
hancement with contrast. Bone erosion 
is better demonstrated by CT, with care-
ful evaluation for erosion of the lamina 
papyracea, cribritorm plate, and fovea 
ethmoidalis. Peripheral tumour cysts and 
speckled calc ifications are characteristic 
of ONB. 
Severa! staging systems have been 
proposed, with no single system univer-
sally accepted. The first staging system 
proposed, and the one most commonly 
applied, is that of Kadish (1162), which 
stages local disease only; it distinguish-
es tumours that involve the nasal cav-
ity only (Kadish stage A), from those 
that extend into the paranasal sinuses 
(Kadish stage B), and those that extend 
beyond the paranasal sinuses (Kadish 
stage C) {11 62}. Morita (1650} modified 
the Kadish system by adding a stage D, 
defined by the presence of metastases 
(either regional nodal disease or distan! 
metastasis). The TNM staging system for 
paranasal sinus tumours can potentially 
be applied (626}; however, the Kadish 
system and Morita modification are more 
applicable, due to the biologically unique 
behaviour of ONB compared with other 
sinonasal tumours. 
Macroscopy 
The tumours are usua\ly unilateral, poly-
poid, glistening, soft, reddish-grey mass-
es with an intact mucosa; the cut surface 
appears greyish-tan to pinkish-red and 
hypervascularized. The tumours range 
from < 1 cm in size to large masses in-
volving the nasal cavity and intracrar1ial 
region. They frequently expand into the 
adjacent paranasal sinuses, orbit, and 
cranial vault (2383). 
Cytology 
Aspirates of metastatic lesions show cy-
tological findings most similar to those 
seen in low-grade neuroendocrine car-
c inomaaspirates, with nests of some-
what monomorphic, fragile epithelioid 
cells with delicate chromatin and cyto-
plasm. Aspirates of high-grade tumours 
may show features similar to !hose seen 
58 Tumours of t11e nasal cavity, paranasal sinuses and skull base 
Table 1.02 Olfactory neuroblastoma staging systems 
proposed by Kadish and Merita; reprinted from Ow TJ 
et al. {1789) 
Kadish stage 
A 
B 
e 
T umour confined to the nasal cavity 
Tumour involvement of the nasal 
cavity and paranasal sinuses 
Tumour extends beyond the nasal 
cavity and paranasal sinuses 
Morlta modiflcatlon 
A 
B 
e 
D 
Tumour confined to the nasal cavity 
Tumour involvement of the nasal 
cavity and paranasal sinuses 
Tumour extends beyond the nasal 
cavity and paranasal sinuses 
Presence of metastases (regional 
or distan!) 
in small cell neuroendocrine carcinoma 
aspira tes. 
Histopathology 
Low-grade ONBs form submucosal, 
sharply demarcated nests, lobules, or 
sheets ot cells, often separated by richly 
vascular or hyalinized fibrous stroma. 
Pseudorosettes (Homer Wright rosettes), 
with neoplastic cells palisading or cuffed 
around the central delicate fibri llar neu-
ral matrix, may be seen. The cells are 
often uniform, with sparse cytoplasm 
and round or ovoid nuclei with punctate 
salt-and-pepper chromatin and nucleoli 
that are either small or absent. ONB is 
characterized by fibrillary cytoplasm and 
interdigitating neuronal processes (neu-
ropil ), created by a syncytium ot cells. 
Higher-grade tumours show tumour 
necrosis, pleomorphism, increased mi-
toses, decreased to absent neuropil, and 
a less overt lobular growth pattern. The 
cells can be arranged in gland-like rings 
or tight annular formations with a true 
lumen (Flexner-Wintersteiner rosettes). 
Table 1.03 Olfactory neuroblastoma staging systems. Key features and criteria for Hyams grades 1-IV and corresponding hístopathological H&E slides 
Key feature/crlterlon 
Architecture 
Mitotic activity - ---
Nuclear polymorphism 
Lobular 
Absent 
Absent 
11 
Lobular 
Present 
Moderate 
Hyams grade 
111 
Variable 
Prominent 
Prominent ----t----------+----------t--
F i brillar y matrix Prominent ______ _._ ___ _ Present Minimal 
Rosettes Homer Wright rosettes Homer Wright reselles Flexner-Wintersteiner rosettes 
Necrosis Absent Absent 
IV 
Variable 
Marked 
Marked 
Absent 
Flexner-Wintersteiner rosettes 
- ----- -1----------+-----------1-----------1--- ---------j 
+/- present Common 
H&E 
Rosettes alone are not diagnostic of 
ONB, although the Homer Wright rosettes 
are nearly pathognomonic in the nasal 
cavity when containing true neuropil. 
Perivascular pseudorosettes (like those 
seen in ependymomas) are non-specific. 
The mitotic rate is variable, but is usually 
low, especially in lower-grade tumours. 
Calcifications (concretion-like or psam-
momatous) may be seen, less frequently 
as the grade increases. Melanin pig-
ment, ganglion cel ls, rhabdomyoblasts, 
divergen! differentiation as islands of true 
epithelium (squamous pearls or gland 
formation), and clear-cell change may 
occasionally be encountered in ONB 
[149,694,1457,1632}. 
The most widely used grading system 
for ONB was developed by Hyams et 
al. {950). This system divides the spec-
trum of ONB maturation into tour grades, 
ranging from most differentiated (grade 1) 
to least differentiated (grade IV), on the 
basis of tumour architecture, mitotic ac-
tivity, nuclear pleomorphism, fibril lary 
matrix and rosettes, necrosis, gland pro-
liferation, and calc ifications. This grading 
scheme has been independently val i-
dated in relation to prognosis {802,1203, 
2036,2336}. 
The typical immunohistochemical pro-
file includes diffuse staining for neuron-
specific enolase [2424}, synaptophysin, 
chromogranin A, CD56 (NCAM) and 
beta-tubulin, as well as variable S100 
protein reactivity, which is typically in a 
sustentacular cell pattern highlighting 
only cells at the periphery of the nests, 
often limited in higher-grade tumours. 
Sustentacular cells may also be posi-
tive for GFAP. Calretinin staining (nuclear 
and cytoplasmic) has been reported 
in ONB {2635) but can also be seen in 
other sinonasal tumours. As many as one 
third of ONBs may also stain focally far 
cytokeratin (CAM5.2, CK18) {1014,1619). 
Negative markers include C045RB, 
CD99, p63, and FLl1. Prol iferation mark-
er studies reveal a variable Ki: 67 prolif-
eration index (2- 50%) {1619,2383}, and 
BCL2 expression increases with tumour 
grade. Rare desmin or myogenin reactiv-
ity is seen in ONB with rhabdomyoblastic 
differentiation (203). 
Genetic protile 
ONB demonstrates numerous chromo-
somal aberrations, deletions, and gains, 
but with no consistent pattern {221,907, 
1015,1983}. In one study, a specific dele-
tion on chromosome 11 and gain on chro-
mosome 1 p were associated with metas-
tasis anda worse prognosis {221 }. Gains 
have been shown to be more frequent 
than losses, and high-stage ONBs show 
more alterations than low-stage_tumours. 
Gains in 20q and 13q may be impor-
tan! in the progression of this neoplasm; 
these regions may harbour genes with 
functional relevance in ONB. The detec-
tion of PTCH1, GL/1, and GL/2 in 70%, 
70%, and 65%, respectively, of human 
ONB specimens suggests that the SHH 
signalling pathway may be involved in the 
pathogenesis of this neoplasm {1534}. 
The OMP and RICBB genes have been 
found to be expressed in ONBs {875}. 
Prognosis and predictive factors 
In addition to staging, histological grade 
is usefu l in prognostication and manage-
ment of ONB {174,1203,1519,2468}. High-
grade tumours tend to have a poorer 
outcome {174,616,1130,1 519}. A single in-
stitutional retrospective review found that 
high tumour grade was signif icantly asso-
ciated with poor outcome, but advanced 
stage was not {174). Metastatic ONB is 
associated with significantly worse over-
all survival, and high-grade ONB with 
significantly worse disease-free survival. 
High Hyams grade (111/IV) is associated 
with more aggressive locoregional dis-
ease {1519} and is a predictor of worse 
disease-free survival (174). lt is yet to be 
determined whether histopathological 
grading alone is a sufficient stratifica-
tion tool and an independent predictor 
of overall survival {616,802,1203,2036, 
2336,2468). 
Neuroectodermal / melanocytic tumours 59 
Mucosa/ melanoma 
Williams M.O. 
Speight P. 
Wenig B.M. 
Definition 
Mucosal melanoma is a malignant neo-
plasm arising from melanocytes in the 
mucosa. 
ICD-0 code 8720/3 
Epidemiology 
Sinonasal mucosal melanomas con-
stitute 1% of all melanomas and about 
4% of ali sinonasal tumours (796,1645). 
There is a wide patient age range, with 
an incidence peak in the seventh decade 
of lite (2395). There is no sex predilection 
(2395}. 
Etiology 
Mucosal melanomas are biologically dis-
tinct from cutaneous melanomas. Etio-
logical factors, including melanocytosis, 
remain speculative. 
Fig. 1.61 Sinonasal mucosa! melanoma. T2-weighted 
axial MRI of sinonasal mucosa! melanoma of the nasal 
septum (arrow). 
Localization 
Sinonasal mucosa! melanomas most fre-
quently arise in the nasal cavity or sep-
tum, and rarely in the nasopharynx or 
maxillary sinuses (1645,2395). 
Clinical features 
Patients may present with non-specif-
ic symptoms of epistaxis or sinonasal 
congestion. 
Macroscopy 
Sinonasal mucosal melanomas are 
often polypoid, and range from deeply 
'> 
Fig. 1.62 Sinonasal mucosa! melanoma. A polypoid 
slightly pigmentad mass distends the submucosa. 
pigmented (black) and friable to tan or 
grey and firm. 
Cytology 
Aspirates of metastatic lesions show the 
diversity of features discussed within the 
histopathology section below, similar to 
the features seen in aspirates of meta-
static dermal melanoma. The diagnosis 
must be considered within the differential 
for any aspirate showing a malignancy 
that is not obviously epithelial. 
Histopathology 
Solid sheets or nests of epithelioid cel ls 
.:J. '' . 
Fig. 1.63 Sinonasal mucosa! melanoma. The histological features vary from (A) clear, non-pigmented, slightly spindled cells to (B) pigmented epithelioid cells with prominent nucleoli. 
The histological spectrum of melanoma includes (C) spindled, fasciculated growth pattern and (D) rhabdoid proli feration. 
60 Tumours of the nasal cavity, paranasal sinuses and skull base 
with variable N:C ratios infiltrate the sub-
mucosa. Surface ulceration is often pre-
sent, but with intact surface epithelium, 
pagetoid and/or surface spread may 
be present. Variable cellular morphol-
ogy is present from case to case and 
within individual cases, ranging from 
epithelioid/undifferentiated cells to spin-
dled, plasmacytoid, and rhabdoid cells, 
with or without prominent nucleol i. In 
neoplasms with a prominent spindle-
cell componen!, fascicu lar to storiform 
growth can be seen. Mitoses are read-
ily identified and atypical forms are often 
present. Discohesion leads to cuffing of 
endothelial cells (resulting in a pseudo-
papillary or peritheliomatous pattern). As 
many as 50% of lesions are amelanotic, 
resulting in a broader differential diagno-
sis at th is site, including small blue cell 
tumours (olfactory neuroblastoma and 
rhabdomyosarcoma), high-grade carci-
nomas (sinonasal undifferentiated car-
cinoma, poorly differentiated squamous 
cell carcinoma, NUT carcinoma, and 
SMARCB1 -deficient carcinoma), neu-
roendocrine carcinomas, diffuse large 
8-cell lymphoma, and Ewing sarcoma/ 
primitive neuroectodermal tumour. 
lmmunohistochemical evaluation is 
necessary, particularly in amelanotic 
tumours. S100 protein and melanocytic 
markers (HMB45, tyrosinase, melan-A, 
MITF, and S0X10) show variable sensi-
tivity depending on morphological type. 
S100 protein highlights > 95% of epithe-
lioid/undifferentiated melanomas, versus 
85% of spindled mucosal melanomas 
(1917,2395). Similar variability has been 
noted far melanocytic markers, which 
highlight 75- 80% of melanomas with epi-
thelioid morphology versus 65-70% of 
spindle cell melanomas (2395). 
Genetic profile 
The molecular profile is distinct from those 
of cutaneous and uveal melanomas, with 
higher rates of K/Tmutations, followed by 
Table 1.04 Molecular alterations in melanomas vary by site of origin 
Frequency by site of orlgln 
Molecular alteration Mucosa! {2708} Cutaneous {1} Ocular (uveal) {2467} 
BRAF mutationsª <6% 
NRAS 15-20% 
K/Tmutationl 
amplificationb 
25% (10-37%) 
BAP1 mutation Unknown 
GNAQ 0% 
GNA11 Rare 
50% 
30% 
6- 8% 
3% 
2% 
4% 
0% 
<5% 
< 1% 
50% (metastases) 
50% 
36°/.o 
Monosomy of chromosome 
Treatment and clinical trials are on-golng for: 
ªBRAF inhibitors (cutaneous) and 
blmatinib (mucosa!; most patients develop resistance). 
lmmunotherapy trials are also underway; evaluation in all subsites will be cri tica! for determining efficacy. 
NRAS mutations and rare BRAF muta-
tions (Table 1.04) (1,2467,2708}. 
Genetic susceptibility 
Sinonasal mucosal melanomas have a 
possible association with melanocytosis, 
which is strongly associated with uveal 
melanomas. 
Prognosis and predictive factors 
Distinguishing mucosa! from cutaneous 
origin and excluding metastasis to the 
sinonasal region are importan! for stag-
ing and prognosis. The seventh edition of 
the American Joint Committee on Cancer 
(AJCC) cancer staging manual added 
head and neck mucosa! melanoma stag -
ing: ali tumours are T3- 4, associated 
with poor overall survival (< 30%) at 5 
years {1 17,530,1495}. Metastatic disease 
(stage IV) and advanced patient age 
are the most importan! prognostic fac-
tors. K/T-mutant tumours have shown re-
sponse to KIT inhibitor therapy; however, 
the response is not durable (1009,2439}. 
Future therapeutic development requires 
trials specifically evaluating mucosa! 
melanomas; findings in cutaneous mela-
nomas may not be applicable, due to the 
different genetic profile {1354). Cutane-
ous melanoma prognostic factors (e.g. 
Clark level of invasion and Breslow tu-
mour thickness) do not apply. 
Neuroectodermal/melanocytic tumours 61 
CHAPTER 2 
Tumours of the nasopharynx 
Nasopharyngeal carcinoma 
Nasopharyngeal papillary adenocarcinoma 
Salivary gland tumours 
Benign and borderline lesions 
Soft tissue tumours 
Haematolymphoid turnours 
Notochordal tumours 
WHO classification of tumours of the nasopharynx 
Carcinomas 
Nasopharyngeal carcinoma 
Non-keratinizing squamous cell carcinoma 
Keratinizing squamous cell carcinoma 
Basaloid squamous cell carcinoma 
Nasopharyngeal papillary adenocarcinoma 
Salivary gland tumours 
Adenoid cystic carcinoma 
Salivary gland anlage tumour 
Benign and borderline lesions 
Hairy polyp 
Ectopic pituitary adenoma 
Craniopharyngioma 
8072/3 
8071/3 
8083/3 
8260/3 
8200/3 
8272/0 
9350/1 
Soft tissue tumours 
Nasopharyngeal angiofibroma 9160/0 
Haematolymphoid tumours 
Diffuse large B-cell lymphoma 9680/3 
Extraosseous plasmacytoma 9734/3 
Extramedullary myeloid sarcoma 9930/3 
Notochordal tumours 
Chordoma 9370/3 
The morphology codes are from the lnternational Classification of Diseases 
for Oncology (ICD-0) 1776A}. Behaviour is coded /0 for benign tumours: 
/1 for unspecified, borderline, or uncertain behaviour; /2 far carcinoma in 
situ and grade 111 intraepithelial neoplasia; and /3 for malignant tumours. 
The classification is modilied from the previous WHO classification, taking 
into account changes in our understanding of these lesions. 
TNM classification of carcinomas of the nasopharynx 
TNM classification•,b 
T - Primary tumour 
TX Primary tumour cannot be assessed 
TO No evidence of primary tumour 
Tis Carcinoma in situ 
T1 Tumour confined to nasopharynx, or extends to 
oropharynx and/or nasal cavity 
T2 Tumour with parapharyngeal extension (which denotes 
posterolateral infiltration of tumour) 
T3 Tumour invades bony structures of skull base and/or 
paranasal sinuses 
T4 Tumour with intracranial extension and/or involvement of 
cranial nerves, infratemporal fossa, hypopharynx, orbit, or 
masticator space 
N - Regional lymph nodes (i.e. the cervical nodes) 
NX Regional lymph nades cannot be assessed 
NO No regional lymph nade metastasis 
N1 Unilateral metastasis in cervical lymph node(s), and/ 
or unilateral or bilateral metastasis in retropharyngeal 
lymph nades, s: 6 cm in greatest dimension, above the 
supraclavicular fossa 
N2 Bilateral metastasis in cervical lymph node(s), s: 6 cm in 
greatest dimension, above the supraclavicular fossa 
N3 Metastasis in cervical lymph node(s), > 6 cm and/or in the 
supraclavicular fossa 
N3a > 6 cm in greatest dimension 
N3b In the supraclavicular fossaº 
Note: Midline nades are considered ipsilateral nades. 
M - Distant metastasis 
MO No distan! metastasis 
M1 Distan! metastasis 
Stage grouping 
Stage O Tis NO MD 
Stage 1 T1 NO MD 
Stage 11 T1 N1 MO 
12 N0-1 MD 
Stage 111 T1-2 N2 MO 
T3 N0-2 MO 
Stage IVA T4 N0-2 MO 
Stage IVB AnyT N3 MO 
Stage IVC AnyT Any N M1 
'Adapted from Edge et al. {625A} - used with permission of the American 
Joint Committee on Cancer (AJCC), Chicago, lllinois; the original and prima­
ry source for this information is the AJCC Cancer Staging Manual, Seventh 
Edition {2010) published by Springer Science+Business Media - and Sobin 
et al. {2228A). 
"A help desk for specific questions about TNM classification is available at 
http://www.uicc.org/resources/tnm/helpdesk. 
ºThe supraclavicular fossa is !he triangular region defined by three points: 
(1) !he superior margin of the sternal end of the clavicle, (2) the superior mar­
gin of the lateral end of the clavicle, and (3) !he point where the neck meets 
the shoulder; this includes caudal portions of levels IV and V. 
64 WHO and TNM classification of tumours of the nasopharynx 
lntroduction 
A broad range of neoplasms can arise 
in tl1e nasopharynx, from epithelial to 
mesenchymal, lymphoid, and neuro-
ectodermal. The most common is na-
sopharyngealcarcinoma, which shows 
remarkable geographical differences in 
incidence. In this chapter, only the more 
common tumour types and site-specific 
tumour types are described in detail. 
Other tumour types that can occur in the 
nasopharynx are covered in other chap-
ters, including Chapter 1 (Tumours of 
the nasal cavity, paranasal sinuses and 
sku/1 base, p. 11), Chapter 3 (Tumours 
Nasopharyngeal carcinoma 
Definition 
Nasopharyngeal carcinoma (NPC) is a 
carcinoma arising in the nasopharyngeal 
mucosa that shows light microscopic or 
ultrastructural evidence of squamous dif-
ferentiation . The term encompasses non-
keratinizing, keratinizing, and basaloid 
squamous cell carcinoma. 
ICD-0 codes 
Non-keratinizing squamous cell 
carcinoma 
Keratinizing squamous cell 
carcinoma 
Basaloid squamous cell 
carcinoma 
Synonyms 
8072/3 
8071/3 
8083/3 
Lymphoepithelial carcinoma; undiffer-
entiated carcinoma with lymphoid stro -
ma; squamous cell carcinoma (WHO 
grade 1); non-keratinizing carcinoma 
(WHO grade 2); undifferentiated carci-
noma (WHO grade 3) 
Epidemiology 
NPC is an uncommon tumour among 
Caucasians, with an age-adjusted an-
nual incidence of less than 1 case per 
100 000 population. The annual inci-
dence in North America is 0.3-0.7 cases 
per 100 000 population {1 124). NPC is 
common among sorne ethnic groups, 
including the lnuit, Northern Africans, 
and Chinese from south-eastern Asia. 
Sorne of the highest incidences of NPC 
have been observed in Hong Kong SAR, 
China, with 2012 age-standardized inci-
dences of 12.5 cases and 4.1 cases per 
100 000 males and females, respective-
ly {363}. The annual incidence of NPC 
in southern China is 15-50 cases per 
100 000 population {1004}. The rates in 
menare commonly double or trip le those 
in women. NPC affects predominantly 
adults, but rare cases are seen in the 
paediatric population . In high-risk popu-
lations, NPC incidence rises alter the age 
of 30 years, peaks at 40- 60 years, and 
then declines {1822} In Chinese who mi-
grate to North America, the incidence of 
NPC declines, but remains significantly 
higher than in the general North Ameri-
can population {296}. 
The age-standardized incidences of 
NPC have decreased over the past dec-
ades, particularly among Ch inese in 
Hong Kong SAR {826,2693). 
Etiology 
Causative carcinogens have not yet 
been definitively identified, but tobacco 
smoking and alcohol consumption are 
likely contributing factors for keratiniz-
ing NPC (K-NPC); and a high consump-
tion of salted and fermented foods with 
Chan J.K.C. 
Slootweg P.J. 
of the hypopharynx, /arynx, trachea and 
parapharyngea/ space, p. 77), Chapter 4 
(Tumours of the oral cavity and mobile 
tangue, p. 105), and Chapter 5 (Tumours 
of the oropharynx, p. 133). 
Petersson B.F. 
Bel! D. 
EI-Mofty S.K. 
Gill ison M. 
Lewis J .S. 
Nadal A. 
Nicolai P. 
Wenig B.M. 
Table 2.01 Structures involved by local infiltration of 
nasopharyngeal carcinoma; MRI data of 308 patients , 
Pamela Youde Nethersole Eastern Hospital, Hong Kong. 
Structures involved 
Adjacent soft tissues 
Nasal cavity 
Oropharyngeal wall, soft palate 
Parapharyngeal space, carotid space 
Pterygoid muscle (medial, lateral) 
Prevertebral muscle 
Bony erosion / paranasal sinus 
Nasal septum 
Pterygoid plate(s), pterygomaxillary 
fissure, pterygopalatine fossa 
Maxillary antrum 
Ethmoid sinus 
Sphenoid sinus; sphenoid bone; 
foramina lacerum, ovale, and rotundum 
Clivus 
Petrous bone, petro-occipital fissure 
Jugular foramen, hypoglossal canal 
Pituitary fossa/gland 
Extensive/intracraniat extension 
Cavernous sinus 
Cerebrum, meninges, cisterns 
lnfratemporal fossa 
Orbit, orbital fissure(s) 
Hypopharynx 
Frequency 
87% 
21% 
68% 
48% 
19% 
3% 
27% 
4% 
6% 
38% 
41% 
19% 
4% 
3% 
16% 
4% 
9% 
4% 
2% 
Nasopharyngeal carcinoma 65 
1984 l9S6 l98S 1990 1992 199~ 1996 199S 2000 
Year 
Fig. 2.01 Age-standardized incidence rates (per 100 000 population} of malignan! neoplasm of nasopharynx by sex in 
Hong Kong SAR, China, 1983-2000; compiled based on the World Standard Population specified by Ahmad 08 et al. 
{29). Note: Data from 1996 onwards are based on population estimates using the resident population approach rather 
than the extended de facto approach. The Hong Kong Population Census conducted in June to August 2011 provides 
a benchmark for revising population figures compiled since the 2006 Hong Kong Population By-census. Classification 
of diseases and causes of death is based on the lnternational Statistical Classification of Diseases and Related Health 
Problems, 10th Revision (ICD-1 O) from 2001 onwards; figures from 2001 onwards may not be comparable with figures 
for previous years, which were compilad based on ICD-9. Reprinted from Hong Kong Cancer Registry {363). 
Table 2.02 Common presenting symptoms and signs of 
nasopharyngeal carcinoma; data from 722 consecutiva 
patients treated at Pamela Youde Nethersole Eastern 
Hospital, Hong Kong SAR, China, in 1994-2001. 
Presenting features Frequency 
Symptoms 
Neck mass 42% 
Nasal (postnasal drip, discharge, 46% 
bleeding, obstruction) 
Aura! (tinnitus, discharge, earache, 42% 
deafness) 
Headache 16% 
Double vision, squint, blindness 6% 
Facial numbness 5% 
Speech/swallowing problem 2% 
Weight loss 4% 
Physical signs 
Enlarged neck node(s} 72% 
Bilateral neck nades 35% 
Neck nodes extending to supraclavicular 12% 
fossa 
Cranial nerve palsy 10% 
Deafness 3% 
Dermatomyositis 1% 
66 Tumours of the nasopharynx 
high nitrosamine content has been im-
pl icated in non-keratinizing NPC (NK-
NPC) in populations where that histologi-
cal subtype is endemic. NK-NPC has a 
multifactorial etiology, including genetic 
susceptibility, EBV infection, and pos-
sibly consumption of salted fish {96,97, 
1003, 1005,1740,2693,2694,2695,2696). 
Salted fish contains volatile carcinogenic 
nitrosamines or their precursors, as well 
as EBV-activating substances [1045, 
1046,2144,2734}. The importance of ex-
posure in early life is indicated by studies 
showing that low-risk ethnic groups born 
in high-risk areas have higher risk of NPC 
{1120,1121). In low-incidence regions 
like northern China, the consumption of 
salted fish still carries an adjusted rela-
tive risk as high as 5.6 {295}. Other envi-
ronmental factors, such as occupational 
exposure to wood dust, formaldehyde, 
heat, smoke, dust, and chemica[ fumes 
have also been proposed as possible 
contributing or causative factors {98, 
1740,2693). 
Most studies show that NK-NPC has a 
strong association with EBV, especially 
in endemic regions; conversely, EBV is 
generally absent in K-NPC, especially in 
non-endemic regions (1542,1731). EBV 
infection is necessary but not sufficient 
for tumorigenesis. 
Oncogenic (h igh-risk) HPV types may 
play a role in a subset of NPCs, espe-
cially in non-endemic regions. Like in the 
oropharynx, HPV-related NPCs most fre-
quently show non-keratinizing histology 
{2000,2273). 
Localization 
The pharyngeal recess (fossa of Rosen-
müller) is the most common site of ori-
gin {1010,1011). The next most common 
site is the superior posterior wall of the 
nasopharynx. 
Clinical features 
Most patients present with locoregionally 
advanced disease, commonly with cervi-
cal lymph node metastases (1040,2508) 
The presenting symptoms are related 
to the presence of a mass in the naso-
pharynx (e.g. epistaxis, obstruction, and 
blood-stained postnasal drip), Eustachi-
an tube dysfunction (e.g. hearing impair-
ment, tinnitus, and serous otitis media), 
skull base involvement with impairment 
of the fifth and sixth cranial nerves (e.g. 
headache, diplopía, facial pain, numb-
ness, and paraesthesia), and painless 
neck mass dueto lymph node metastasis 
(1358). Distant metastasis at presentation 
has been reported in approximately 5% of 
patients {2368}, and 10% of patients with 
NPC are asymptomatic . In endemic are-
as, 12% of patients with dermatomyositis 
Fig. 2.02 MRIof nasopharyngeal carcinoma (NPC}. A 
40-year-old woman presented wilh a 2-month history 
of tinnitus, followed by neck masses, nasal symptoms, 
headache, and diplopia. Physical examination revealed 
left sixth nerve palsy and bilateral upper-middle cervical 
lymph nades. Endoscopy revealed tumour in the 
nasopharynx extending to the posterior nasal cavity. 
Biopsy confirmad undifferentiated carcinoma. MRI 
showed NPC with extensiva local infiltration of adjacent 
soft tissues, erosion of skull base/ paranasal sinuses, 
and intracranial extension, together with bilateral 
retropharyngeal and cervical nodes. 
have NPC as an underlying malignancy 
[1848). whereas only 1% of patients with 
NPC have dermatomyositis (2367). 
Tumour spread 
NPC is notorious for its highly malignan! 
behaviour, with extensive locoregional in-
filtration and early lymphatic spread, ero-
sion of skull base and paranasal sinuses, 
intracranial spread, infiltration of cranial 
nerves, and extension to adjacent struc-
tures (e.g. infratemporal fossa, orbit, and 
hypopharynx). Given the rich lymphatic 
plexus in the nasopharynx, lymphatic 
spread occurs early in the course of dis-
ease. In cases staged by imaging, about 
20% of patients have no enlarged nodes, 
and about half have retropharyngeal 
node involvement {21 40}. The jugulodi-
gastric node is the most commonly pal-
pable node at presentation, and involve-
ment of the posterior cervical chain is 
more frequent than with other head and 
neck cancers. The most common sites of 
distan! metastasis (in descending arder 
of frequency) are bone, lung, liver, and 
distan! nades {2369). 
TNMstaging 
The main differences between the sixth 
and seventh editions of the AJCC can-
cer staging manual are that (1) tumours 
classified in the sixth edition as T2a (i.e. 
tumour extending to oropharynx and/or 
nasal cavity without parapharyngeal ex-
tension) are classified in the seventh edi-
tion as T1 and (2) retropharyngeal lymph 
node(s). regardless of unilateral or bilat-
eral location, are considered N1 in the 
seventh edition. 
Serology 
EBV serology is positive in most patients 
with NK-NPC (917). lgA antibody against 
EBV viral capsid antigen and lgG/ lgA 
against EBV early antigens are the most 
extensively used diagnostic tools, with 
detection rates of 69-93% {383,525). 
Another approach is to test for elevated 
levels of circulating EBV DNA or RNA, 
using techniques for detecting the 
BamHI-W region of the EBV genome, 
EBV-encoded small RNAs (EBERs), or 
EBNA1 in the plasma or serum, with re-
ported sensitivity in NPC as high as 96% 
{382,1433,1463,2168). 
Macroscopy 
The tumour can present as a smooth 
bulge in the mucosa, a discrete raised 
nodule with or without surface ulceration, 
or a frankly infiltrative fungating mass. In 
sorne cases, there is no grossly visible le-
sion (1468}. 
Cytology 
Aspirates of metastatic K-NPCs and NK-
NPCs show findings similar to those at 
other sites. Aspirates often show a back-
ground of lymphocytes and plasma cells, 
with irregular clusters of large cells with 
overlapping vesicular nuclei and large 
nucleoli (384,1265). The cytoplasm of 
these cells is often frag ile and barely 
visib le. There are commonly many na-
ked nuclei (1636} The diagnosis can be 
readily confirmed by immunostaining for 
cytokeratin and in situ hybridization for 
EBER. 
Histopathology 
Non-keratinizing squamous ce// 
carcinoma 
NK-NPC exhibits a variety of architec-
tural patterns, frequently mixed within the 
Nasopharyngeal carcinoma 67 
same tumour mass, ranging from solid 
sheets to irregular islands, trabeculae, 
and discohesive sheets of malignant 
cells intimately intermingled with variable 
numbers of lymphocytes and plasma 
cel ls. 
The undifferentiated subtype, which is 
more common, is characterized by large 
tumour cells with a syncytial appearance, 
round to oval vesicular nuclei, and large 
central nucleoli. The nuclei can be chro-
matin-rich rather than vesicular and the 
neoplastic cells generally have scant am-
phophilic or eosinophil ic cytoplasm. The 
malignant cells can assume spindle-cell 
features in fascicular arrangements. 
The differentiated subtype exhibits cel-
lular stratification and pavementing, o/-
ten with plexiform growth; occasional 
keratinized cells may be present. Com-
pared with those in the undifferentiated 
subtype, the neoplastic cells are often 
slightly smaller, the N:C ratio is lower, 
the nuclei are o/ten more chromatin-rich, 
and the nucleoli are usually less promi-
nent. Focally, intercellular bridges may 
be present. 
However, subclassification into undiffer-
entiated and differentiated subtypes has 
no clinical or prognostic value. 
The density of lymphocytes and plasma 
cells within the tumour cell aggregates is 
68 Tumours of the nasopharynx 
highly variable. When abundant, the in-
flammatory cells break up the tumour into 
tiny clusters or single cells, making it dif-
ficult to recognize the epithelial nature of 
the neoplasm. Sorne cases may demon-
strate abundant eosinophils, neutrophils, 
or epithelioid granulomas {399,781,1379, 
1471). A desmoplastic stromal reaction is 
uncommon. 
lsolated or scattered groups of tu-
mour cells may appear shrunken, with 
smudged nuclei and dense amphophilic 
or eosinophilic cytoplasm. In as many as 
10% of cases, there are interspersed in-
tra- or extracellular small spherical amy-
loid globules {1919]. Uncommon features 
include papillary frond formation, clear-
cell change, accumulation of extracellular 
oedema fluid or mucosubstances, and 
presence of intracytoplasmic mucin in 
very rare cells {1109,1302). 
In cervical lymph node metastases, 
malignant cells within the lymph nodes 
may be arranged in various patterns. In 
particular, neoplastic cells may display 
Reed- Sternberg cell-like features in a 
mixed inflammatory background, mim-
icking Hodgkin lymphoma (329,1384). 
Epithelioid granulomas (sometimes ne-
crotizing) are present in approximately 
20% of cases (1384). A cystic appear-
ance of NK-NPC metastases to lymph 
nodes may simulate a metastasis from 
the oropharynx. 
Keratinizing squamous ce// carcinoma 
K-NPCs are a group of invasive carci-
nomas showing obvious squamous dif-
ferentiation at the light microscopic leve!, 
in the form of intercellular bridges and/or 
various degrees of keratinization, accom-
panied by a desmoplastic stroma, akin to 
that seen in squamous cel l carcinoma at 
other head and neck sites. K-NPC can 
arise de novo or (more rarely) secondary 
to radiotherapy {398). 
Basaloid squamous ce// carcinoma 
This tumour is morph0logically identical 
to analogous tumours more commonlY 
occurring in other head and neck sites, 
and has infrequently been reported to 
occur as a primary tumour of the naso-
pharynx (132,133,1672,1839,2528}. EBV 
may be positive, especially in high-inci-
dence ethnic groups (1672,2528}. 
/mmunohistochemistry 
NPC stains strongly far p63, pancy-
tokeratin, and high-molecular-weight cy-
tokeratins, with often patchy expression 
of low-molecular-weight cytokeratins and 
EMA. CK7 and CK20 are negative (756}. 
EBV detection 
NK-NPC is associated with EBV in almost 
ali cases. The most reliable way to dem-
onstrate EBV is in situ hybridization far 
EBER {1037,1066,1085,1904,2428}. This 
test is helpful in the evaluation of cervi-
cal lymph nades harbouring undifferen-
tiated ar poorly differentiated squamous 
cell carcinoma of unknown arigin, with 
a positive result strongly suggesting the 
possibility of NPC. 
lmmunostaining for LMP1 is not a sensi-
tive ar reliable method far demonstrating 
lhe presence of EBV {908,1833,1904). 
PCR far EBV is not rel iable either, be-
cause even a few bystander EBV-positive 
lymphocytes can give rise to a positive 
result {2428). 
Genetic profile 
Deletions on 3p and 9p are early events 
in NPC (442), and the chromosomal re-
gions that most frequent show gain and 
loss are on chromosome 12 and 3p. Ar-
ray comparative genomic hybridization 
studies have identifiedfrequent copy-
number gains of MYCL (1p34.3), TERC 
(3q26.3), ESR1 (6q25.1), and PIK3CA 
(1056). Genomic sequencing reveals a 
distinctive mutational signature, with nine 
significantly mutated genes (1431}. The 
significance of these genes in pathogen-
esis, prognosis, and response to therapy 
has yet to be determined. 
Genetic susceptibility 
The risk of developing NPC is linked to 
genes coding far certain tissue antigens 
(i.e. HLA genes). In Chinese populat ions, 
HLA-A*02 alleles and HLA-8*46 alleles 
are associated with a high risk of NPC 
(864,1042). High-resolution genotyping 
has shown a consisten! association be-
tween NPC and the HLA-A*0207 allele, 
which is common in Chinese popu lations 
{990]. Genetic polymorph isms in genes 
coding for metabolic enzymes· (CYP2E1 
and GSTM1) and DNA repai r enzymes 
(OGG1 and XRCC1) have also been as-
sociated with increased risk of NPC {989, 
991 ). Linkage studies have suggested 
that susceptibility loci for NPC are pres-
ent on chromosomes 3, 4, and 14 {700, 
2654). Familia! clustering of NPC is well 
reported (1003,1 133,1157,2609}. The 
relative risk in fi rst-degree relatives of 
patients with NPC varíes from 6.3 to 21.3 
{397,1362,2692,2722} . There are no clini-
cal characteristics that separate sporadic 
from fami lia! cases. 
Prognosis and predictive factors 
The most powerful prognostic factor of 
NPC is stage at presentation. A study us-
ing the 2002 TNM staging system found 
that the 5-year disease-specific survival 
rate for stage I disease was 98%; for 
stage IIA- B, 95%; far stage 111, 86%; and 
for stage IVA-B, 73%. lncreasing tumour 
volume is a negative prognostic factor, 
with an estimated 1% increase in risk of 
local failure per 1 cm3 increase in vol-
ume (386,2330). Circulating plasma/se-
rum levels of EBV DNA are substantially 
elevated in patients with active disease 
(in particular distan! metastasis); drop to 
very low l itres upan remission (374,1462, 
1728,2168}; and correlate with advanced 
stage {1463} and survival {374,1462}. 
Other unfavourable prognostic factors 
are fixation of involved neck nades, male 
sex, patient age > 40 years, cranial nerve 
palsy, and ear symptoms at presentation 
(1851,2139,2368). 
The issue of histopathological type 
(keratin izing vs non-keratinizing) in rela-
tion to prognosis is complex. Compared 
with NK-NPC, K-NPC shows a greater 
propensity far locally advanced tumour 
growth (which occurs in 76% vs 55% of 
cases, respectively) (1966} and a lower 
propensity for lymph nade metastasis 
(which occurs in 29% vs 70% of cases, 
respectively) (1715). Sorne studies have 
suggested that K-NPC is less respon-
sive to radiation therapy and has a worse 
prognosis than NK-NPC {1023,1715, 
1966,2142}, but other studies have not 
found any differences in biological be-
haviour (375,737}. 
The significance of the presence of high-
risk HPV is not wel l established. Severa! 
studies have suggested that HPV-related 
tumours have a worse prognosis than do 
EBV-related cases, but perhaps a bet-
ter outcome than do cases negative far 
both viruses {592,1435,1460,1561,2000, 
2273}. 
With improved treatment protocols, the 
development of a second malignan! tu-
mour becomes significan!. Squamous 
cell carcinoma and various sarcomas 
Nasopharyngeal carcinoma 69 
are most common. The annual incidence 
of postradiation squamous cell carci-
noma has been reported to be 0.55-1 % 
{1270,2531}; in one study, the mean la-
tency period was 10.5 years (range: 
6.4- 15.8 years) {380). Postradiation 
squamous cell carcinoma may occur at 
uncommon siles, such as the externa! 
auditory canal, middle ear, and temporal 
bone {1430,1461,1752,2364}. 
Nasopharyngeal papillary 
adenocarcinoma 
Definition 
Nasopharyngeal papil lary adenocarci-
noma is a low-grade adenocarcinoma 
with predominately papi llary architecture, 
found in the nasopharynx. 
ICD-0 code 8260/3 
Synonym 
Thyroid-like low-grade nasopharyngeal 
papillary adenocarcinoma 
Epidemiology 
Nasopharyngeal papil lary adenocarcino-
mas account tor < 1% of nasopharyngeal 
malignancies. They can occur in patients 
of any age (reported range: 9- 64 years) 
{1894,2590). No sex predilection has 
been shown. 
Localization 
Nasopharyngeal papillary adenocarci-
nomas can involve any part of the naso-
pharynx {2590). 
Clinical features 
Patients typically present with nasal ob-
struction (1894,2590}. Subsets of pa-
tients present with rhinorrhoea, epistaxis, 
otitis media, or hearing problems. 
70 Tumours of the nasopharynx 
Macroscopy 
Nasopharyngeal papil lary adenocarcino-
mas are exophytic and appear papillary, 
polypoid, or nodular. They may be soft or 
gritty (2590}. 
Histopathology 
Nasopharyngeal papillary adenocarcino-
mas are composed of complex, arboriz-
ing papil lae with hyalinized fibrovascular 
cores and glands {1894,2590] . The le-
sions are invasive and typically involve 
the surface epithelium, tocally merging 
with non-neoplastic epithelium. Papillae 
are lined by a single layer of cuboidal 
to columnar cells that have a moder-
ate amount of eosinophilic cytoplasm. 
Similar to those seen in papillary thyroid 
carcinomas, the nuclei vary trom round 
to oval and have moderate membrane 
irregularity with vesicular to clear chro-
matin. Psammomatoid calcifications are 
seen in about one third of cases. Mitotic 
figures are uncommon and necrosis is 
rare. Perineural and angiolymphatic inva-
sion are not seen. 
The tumours express EMA, CK5/6, and 
often CK7 {1894,2590}. The subset of 
cases positive for CK19 and TTF1 {342} 
has been referred to as thyroid-like 
Many prognostic molecular and immuno-
histochemical markers have been stud-
ied, but only that of p lasma/serum levels 
of EBV DNA {2717} has been incorporat-
ed into cl inical practice. 
Stelow E.B. 
Bell O. 
Wenig B.M. 
low-grade nasopharyngeal papillary ad-
enocarcinoma, but thyroglobul in is nega-
tive. S100 protein expression is seen fo-
cally in many cases. 
Genetic profile 
BRAF mutations have not been identified 
(1768,1870). 
Prognosis and predictiva factors 
Most patients with nasopharyngeal papil-
lary adenocarcinoma have been treated 
with surgery alone, although sorne have 
also received radiation therapy {1894, 
2590}. No patients have developed re-
currences or metastases. 
Salivary gland tumours 
Adenoid cystic carcinoma 
Stelow E.B. 
Bell D. 
Seethala R. 
Stenman G. 
Definition 
Adenoid cystic carcinoma is a slow-
growing and relentless sal ivary gland 
malignancy composed of epithelial and 
myoepithelial neoplastic cells that form 
various patterns, including tubular, c ribri-
form , and solid forms. 
ICD-0 code 8200/3 
Epidemiology 
Approximately 2-8% of adenoid cystic 
carcinomas involve the nasopharynx 
(1709,1864). The tumours are the most 
common salivary gland malignancy af-
fecting the area and account for almos! 
one quarter of ali adenocarcinomas found 
at the site {1894). The mean patient age 
at presentation is 45 years, and men and 
women are equally affected {1894,2391). 
Localization 
Adenoid cystic carcinoma can involve 
the nasopharynx either in isolation or 
through spread from !he sinonasal trae!. 
Clinical features 
Patients most often present with epistax-
is, nasal obstruction, and tinnitus {1447). 
Most patients present with advanced-
stage disease {325,2391). 
Histopathology 
The histological and immunohistochemical 
Fig. 2.1 O Salivary gland anlage tumour. 
"stroma". 
findings 'are similar to those for adenoid 
cystic carcinomas found elsewhere 
(2391). They are described in detail in 
the Adenoid cystic carcinoma section 
in Chapter 7, p. 164. The tumours are 
mostly submucosal, but sorne may show 
mucosa! extension. 
Genetic profile 
The adenoid cystic carcinoma- specific 
1(6;9) chromosomal translocation, result-
ing in a MYB-NF/8 gene fusion, has been 
detected in tumours at this site (987,1862, 
2391). 
Prognosis and predictiva factors 
The reported 5-year disease-free and 
overall survival rates are 30-65% and 
54-70%,respectively {325,1447). 
Salivary g/and anlage tumour 
Chiosea S. 
Seethala R. 
Skálová A. 
Definition 
Salivary gland anlage tumour is a mid-
line nasopharyngeal lesion with biphasic 
epithelial and myoepithel ial components 
(979). 
Synonym 
Congenital pleomorphic adenoma {554, 
937) 
Epidemiology 
Approximately 35 examples of salivary 
gland anlage tumour have been reported 
{554,816,978,979, 1537, 1633, 1945,2282, 
2406,2516). The affected patients are 
infants (diagnosed by 3 months of age), 
and there is a male predi lection. A case 
suspected to have developed in utero 
has been reported {1945). 
Localization 
Salivary gland anlage tumours occur in 
the posterior nasal septum or the poste-
rior nasopharyngeal wall. 
Clinical features 
Patients present with respiratory distress 
due to nasal airway obstruction {979). Be-
fore birth, salivary gland anlage tumour may 
be associated with polyhydramnios {1945). 
Macroscopy 
The typical appearance is that of a poly-
poid to peduncu lated smooth tan-brown 
mass with solid to microcystic cut sur-
tace (979). 
Histopathology 
Salivary gland anlage tumours display 
a complex polypoid configuration, with 
a submucosal network of tu bules and 
ducts with variable keratinization that are 
continuous with the surface squamous 
epithelium. The spindle cell componen! 
varíes from hypocellular to more cellu lar 
myoepithelial nodules in the centre of the 
polyp. Cellular atypia and mitoses are 
absent {979). The epithelial components 
are positive for cytokeratins and EMA, 
and the myoepithelial nodules express 
SMA and cytokeratins . 
Prognosis and predictive factors 
No recurrences alter excision have been 
reported. 
Salivary gland tumours 71 
Dani
Realce
Benign and borderline lesions 
Hairypolyp 
Definition 
Hairy polyp is a benign polypoid lesion 
with a suspected developmental orígin, 
composed of ectoderm and mesoderm. 
Synonyms 
Teratoid polyp; dermoid polyp 
Epidemiology 
Haíry polyp occurs primaríly in neonates 
and older ínfants, and extremely rarely in 
adults {364,888}. There is a femare pre-
dominance, wíth a female-to-male ratio of 
6:1 (89,622,1210). 
Localization 
The most common locatíon is the lateral wall 
of the nasopharynx (accounting for 60% ot 
cases), but hairy polyp may also occur in 
the oropharynx, palate, tonsil, tangue, lip, 
and middle ear (622,1210,1223]. 
Clinical features 
The presentatíon includes a peduncu-
lated mass that may be assocíated wíth 
cough , dyspnoea, vomiting, and difficulty 
in swallowing. Rarely, it is associated with 
other congenital malformations, such as 
cleft palate or Dandy- Walker syndrome 
{106,2359}. 
Macroscopy 
The polyp has a skin-like surface and 
can be as large as 6 cm in greatest di-
mension, with an attachment to the lateral 
wall of the nasopharynx {1623}. 
Histopathology 
The polyp is covered by keratinized 
squamous epithelium containing pi-
losebaceous units. The core consists 
of fibroadipose tissue. Skeletal muscle, 
carti lage, and bone may be present. 
Meningothelial remnants have been iden-
tified {1770). Hairy polyp is differentiated 
from teratoma by a lack of endodermal 
components. 
Prognosis and predictive factors 
Surgical excision is curative {23591. 
72 Tumours of the nasopharynx 
Ectopic pituitary adenoma 
Definition 
Ectopic pituitary adenoma is a benign 
anterior pituitary gland neoplasm that 
does not involve the sel la turcica. 
ICD-0 code 8272/0 
Synonyms 
Extrasellar pituitary adenoma; extracra-
nial pituitary adenoma 
Epidemiology 
Pituitary adenomas account for < 3% ot 
tumours ot the sphenoid sinus or naso-
pharynx (683,1782,2392} . Palien! age 
at presentation varíes widely (range: 
2-84 years; mean: 54 years). 
Females are affected slightly more than 
males, with a female-to-male ratio of 1.3:1 
(2392} . 
Localization 
Ectopic pítuitary adenomas occur most 
trequently in the sphenoid sinus/bone 
{301,1459,1959,2392,2417). followed by 
the nasopharynx, with rare cases re-
ported in the nasal cavity, ethmoid sinus, 
temporal bone, and nasal bridge (87, 
1959). 
Clinical features 
Symptoms include obstruction, sinusi-
tis, rhinorrhoea, discharge, headache, 
and pain. Visual disturbances and 
nerve changes are uncommon (2392) . 
Sorne patients present with endocrino-
pathic manifestations, such as Cush-
ing syndrome (hypercortisolism), acro-
megaly, amenorrhoea, or galactorrhoea 
(468,483,1030,1932,2175). 
Asymptomatic presentation occurs in 
about 10% of cases. lmaging studies are 
required to exclude direct extension from 
the sella. Bone destruction is often pres-
ent (873,958,2207,2668). 
Macroscopy 
Macroscopically, ectopic pituitary ade-
nomas are polypoid tumours measuring 
0.8-8 cm (mean: 3.4 cm) (1459,21661. 
Katabi N. 
Hunt J.L. 
Thompson L.D.R. 
Wenig B.M. 
H istopathology 
Ectopic pituitary adenoma is a submu-
cosal epithelioid neoplasm with solid, or-
ganoid, and trabecular growth patterns. 
The epithelioid cells have round nuclei, 
with a dispersed chromatin pattern and 
granular eosinophilic cytoplasm. Plas-
macytoid-appearing cells may be pres-
ent. Gland-like spaces may be seen, 
but there is no squamous differentiation. 
There is mild to moderate nuclear varia-
tion (so-called endocrine atypia). Scat-
tered mitotic figures may be present, but 
not atypical mitoses or necrosis. Cai-
cifications and psammoma-like bodies 
may be identified [1459,1493,2166). The 
stroma is usually richly vascularized and 
often heavíly collagenized. 
The tumour cel ls express cytokeratins 
(often in a perinuclear dot-li ke pattern) 
and neuroendocrine markers (e.g . syn-
aptophysin, CD56, and chromogranin). 
S100 protein may be positive, but the 
sustentacular pattern of oltactory neuro-
blastoma ís absent. Reactivity with two 
or more pi tuitary hormones is seen in as 
many as 50% of cases. About one third 
of ali cases express a single hormone, 
most commonly prolactin. Approximately 
20% of ectopic pituitary adenomas are 
null cell adenomas - lacking expression 
of any hormone marker. The diagnosis 
of null cell adenoma is preferably sup-
ported by the demonstration of pituitary 
transcription factors (e.g. PIT1 , TPIT, SF1, 
ER-alpha, GATA2, and alpha subunits) 
. 
Fig. 2.11 Ectopic pituitary adenoma. Strong and diffuse 
granular cytoplasmic immunoreactivity for prolaclin, one 
of the peptides mas! commonly identified in ectopic 
pituitary adenoma. 
.,. _,, \ 
Fig. 2.1 2 Ectopic pituitary adenoma. A Organoid growth pattern with rich vascularity. B Marked sclerosing fibrosis associated with compressed neoplastic cells. e Rosettes and 
pseudorosettes. D Profound nuclear pleomorphism can frequently be seen in pituitary adenoma; there is a spicule of bone noted, as bone destruction may be seen. 
[87,1459). Ectopic pituitary 
must be distinguished from 
roendocrine neoplasms. 
adenoma 
other neu-
Prognosis and predictive factors 
Surgical resection can be curative, but 
recurrences are not uncommon. 
Craniopharyngioma 
Definition 
Craniopharyngioma is a benign epithelial 
tumour thought to derive from the Rathke 
cleft. 
ICD-0 code 9350/1 
Synonym 
Pituitary adamantinoma 
Localization 
Craniopharyngioma can occur extra-
cranially in the nasopharynx 11622). and 
exceptionally in the sinonasal tract 11064, 
1748,2716). 
Clinical features 
Nasopharyngeal involvement is associ-
ated with headache, impaired vision, and 
nasal obstruction. 
Macroscopy 
Most craniopharyngiomas have a cystic 
component containing brown (so called 
machine-oil) fluid {2697). 
H istopathology 
The adamantinomatous type shows 
cords of basaloid cells with peripheral 
palisading surrounding loose stellate-
type cells. In addition, so-called wet kera-
tin (composed of eosinophilic keratinized 
cells with ghost nuclei) and associated 
calcifi cation is present. The papillary 
type includes sheets of dyscohesive 
squamous epithelium that form pseudo-
papillae with anastomosing fibrovascular 
stroma {1 905,2333}. 
Genetic profile 
The adamantinomatoustype harbours 
CTNNB1 (beta-catenin) mutations and 
the papillary type harbours BRAFV600E 
mutations {263,1547). 
Prognosis and predictive factors 
Treatment includes surgery with or with-
out radiation 12697}. Craniopharyngioma 
may be associated with long-term mor-
bidity and recurrence {1948). 
Benign and borderline lesions 73 
Soft tissue tumours 
Nasopharyngeal angiofibroma 
Definition 
Nasopharyngeal angiofibroma is a locally 
aggressive, variably cellular fibrovascular 
neoplasm arising in the nasopharynx of 
young males. 
ICD-0 code 9160/0 
Synonyms 
Angiofibroma; juvenile angiofibroma; 
juvenile nasopharyngeal angiofibroma 
Epidemiology 
Nasopharyngeal angiofibroma is rare, 
constituting < 0.5% of ali head and neck 
tumours {230,2700). lts incidence is 
0.4 cases per million in the general popu­
lation and 3.7 per million in the at-risk 
population (i.e. 1 O- to 24-year-old males) 
{845). The tumour develops almost exclu­
sively in adolescent and young males (av­
erage patient age: 17 years) (230,1716, 
2621). Female patients should be evalu­
ated for underlying testicular feminization. 
Etiology 
There is evidence of hormonal depend­
ency of nasopharyngeal angiofibroma. 
Tumour growth is associated with pu­
berty in boys, and tumour cells frequently 
express androgen receptor (1063,1716, 
2621). 
. - ........ , .. . ,,,-.-;-:· - .. "'·i:; ./
\ }':-.-, - . - ' . - �-·1·-; 
\ ·� ' · ... 
'1'1 '1�: . . ···- �r. ' 
-.� , 
Fig. 2.13 Nasopharyngeal angiofibroma. 30 reconstruction 
of CT angiography of a 15-year-old boy with a hypervascular 
left nasal mass centred in the sphenopalatine foramen 
and extending into the pterygopalatine fossa, with 
supply from an enlarged left interna! maxillary artery 
(arrow), which is a branch of the externa! carotid artery 
(arrowhead). 
74 Tumours of the nasopharynx 
• 
• 
\: . • -:cr ' • I •�
- .. . , " 
. .,.•.:. \ 
Localization 
Nasopharyngeal angiofibroma arises in 
the nasopharynx or posterolateral nasal 
cavity wall (230,1716,2700}. 
Clínica! features 
Patients present with the classic triad 
of nasal obstruction, epistaxis, and na­
sopharyngeal mass (230,1222). Other 
symptoms include nasal discharge, si­
nusitis, facial deformity, deafness, otitis, 
diplopía, proptosis, headache, and pain 
{1716,2700}. Radiological imaging fre­
quently shows a tumour in the nasophar­
ynx and nasal cavity with sinus opacity 
and bone destruction. Anterior bowing of 
the posterior wall of the maxillary antrum 
(called the Holman-Miller sign or the an­
tral sign) is typical {1716,2700}. Large tu­
mours can extend into maxillary, ethmoid, 
and sphenoid sinuses; pterygopalatine 
and infratemporal fossa; and orbit. lntrac­
ranial extension (usually into the middle 
Prasad M.L. 
Franchi A. 
Thompson L.D.R. 
cranial fossa) is seen in 10-30% of cases 
{230,1388,1559,1716}. Angiography is 
diagnostic, identifies the feeding vessel 
(usually the interna! maxillary artery), and 
is essential for pre-surgical embolization 
{219). Due to the characteristic imaging 
appearance, diagnostic biopsy (which 
carries a risk of life-threatening haemor­
rhage) is often unnecessary. 
Macroscopy 
The average tumour size is 4 cm, but tu­
mours as large as 22 cm have been re­
ported. The neoplasm is polypoid and 
lobulated and often takes the shape of 
surrounding structures. 
Histopathology 
The tumour has two components: vascu­
lar and stromal. The blood vessels are of 
various sizes, shapes, and thicknesses, 
ranging from slit-like capillaries to ir­
regularly dilated and branching vessels. 
. .. . ' ,; 
• . • I ' . r.. , _..,.,,. ,, .. 
·,-~ ..¡,,, ·'-'·' 
, .D, .: ' ' ' .- - .J..:·· . . .. 
Fig. 2.14 Nasopharyngeal angiofibroma. A A richly vascular tumour underlying the nasopharyngeal respiratory-type 
mucosa, showing variously sized blood vessels in a cellular fibroblastic stroma. The vascular componen! ranges 
from capillaries to large dilated vessels. B The vascular componen! is variable, ranging from thin, slit-like branching 
capillaries supported only by endothelial cells to dilated vessels; the stroma shows dense collagen with spindled to 
stellate fibroblasts. C In this area, the stroma is loose and myxoid, and contains stellate fibroblasts. The blood vessel 
walls range from !hin (supported only by endothelium) to unevenly thick, due to !he variable mural smooth muscle 
content. D Nuclear localization of beta-catenin is seen in stromal cells only; in endothelial cells, the expression remains 
membranous and cytoplasmic. 
Scanned by CamScanner
The vessel walls may be thin (support-
ed only by endothelial cells) or may be 
ensheathed focally or continuously by 
smooth muscle of varying thickness. No 
elastic tissue is identified except in feed-
ing arteries. 
The stroma consists of bipolar or stellate 
fibroblastic cells with plump, vesicular, 
spindled nuclei, and the cells may ap-
pear to be arranged around the blood 
vessels. Nucleoli are indistinct and mi-
toses are usually absent. Scattered multi-
nucleated stellate stromal giant cells may 
be seen. The stroma varies from loose, 
oedematous, and cellular to densely col-
lagenous and paucicellular; mast cells 
are frequently present. Tumours treated 
with embolization show areas of necrosis 
and intravascular foreign material. Tu-
mours treated with the androgen recep-
tor blocker flutamide are hypocellular, 
with increased stromal collagen {815}. 
CD31 and CD34 immunohistochemistry 
highlights the endothelium of blood ves-
seis, and SMA highlights the smooth 
muscle in the vessels. The stromal cells 
show nuclear expression of androgen 
receptor and beta-catenin - the latter in 
> 90% of tumours 15,1063}. The stromal 
cells occasionally express SMA, espe-
cially at the periphery of the tumour, but 
are negative for desmin and S100 pro-
tein. Expression of estrogen receptor, 
progesterone receptor, and KIT (CD117) 
has been reported 11452,1641,1978}. 
Genetic profile 
Nasopharyngeal angiofibroma is charac-
terized by chromosomal gains 1282}. Loss 
of the Y chromosome with gain of the 
X chromosome is frequently document-
ed 12092}. Somatic mutation in exon 3 of 
the beta-catenin gene (CTNNB1) is seen 
in 75% of the tumours, although nuclear 
localization of beta-catenin is seen in 
> 90% of cases {5}. 
Haematolymphoid tumours 
Definltion 
Haematolymphoid tumours of the na-
sopharynx are neoplasms of lymphoid, 
plasma cell, or myeloid origin arising in 
the nasopharynx. 
ICD-0 codas 
Extraosseous plasmacytoma 9734/3 
Extramedullary myeloid sarcoma 9930/3 
Diffuse large B-cell lymphoma 9680/3 
Epidemiology 
Nasopharyngeal lymphomas account 
for about 15% {37,666,934} of all head 
and neck lymphomas and for 9% {1372} 
to 35% {682} of Waldeyer ring (pharyn-
geal lymphoid ring) lymphomas. Oiffuse 
large 8-cell lymphoma is the most com-
mon type {37,50,682,2652}. NK-cell and 
T-cell lymphomas occur more trequently 
in Asia than in western countries {1054}. 
Adults and (rarely) children are affected 
{50,432,1635}. The average patient age 
and male-to-female ratio vary by type of 
lymphoma. For example, extranodal NK/ 
T-cell lymphoma (see Extranodal NK!T-
ce/1 /ymphoma, p.52) {1108,23221 affects 
slightly younger patients, with a higher 
male-to-female ratio, than does diffuse 
large 8-cell lymphoma (see Diffuse large 
8-cell lymphoma) {2652}. Burkitt lym-
phoma is a common type among children 
12642}. 
Nasopharyngeal extraosseous plasma-
cytoma accounts for 10-16% of ali head 
and neck extraosseous plasmacyto-
mas {116,494,2078}. Nasopharyngeal 
myeloid sarcoma is rare {433,1957). 
Etiology 
Most lymphomas, plasmacytomas, and 
myeloid sarcomas arise sporadically. 
EBV contributes to the pathogenesis of 
NK/T-cell lymphoma. Sorne patients with 
high-grade 8-cell lymphoma or classical 
Hodgkin lymphoma are immunocompro-
mised {1939,2228}. 
Localization 
Lymphoma forms an often bulky, usually 
symmetrical lesion, commonly with inva-
sion of adjacent structures {432,2652). 
Stage at presentationvaríes by type of 
lymphoma, but most lymphomas involve 
Genetic susceptibility 
There have been isolated reports of na-
sopharyngeal angiof1broma arising in 
association with familial adenomatous 
polyposis 1712,832,2454). 
No germline mutations of APC, C TNN81, 
or any other gene have been reported in 
sporadic nasopharyngeal angiofibroma. 
Prognosis and predictiva factors 
One or more recurrences occur in 5- 25% 
of patients {230,1222,1388}. Prognosis 
depends on the size and extent of the 
tumour, the presence of multiple feeding 
vessels (including bilateral vascularity), 
and the completeness of surgical resec-
tion {1559,2227}. 
Sarcomatous transformation has been 
reported in association with radiotherapy, 
as has metastasis {2621 }. Spontaneous 
regression after puberty can rarely occur 
{2621}. 
Ferry J.A. 
Ko Y.-H. 
cervical lymph nodes at presentation, 
and more-distant spread is not uncom-
mon {37,50,432,1054,1635}. 
Clinical features 
Patients present with nasal obstruction, 
epistaxis, hearing loss, headache, dysp-
noea, and/or cervical lymphadenopathy. 
A minority have constitutional symptoms 
{50,1054,2228,2652}. 
Histopathology 
Diffuse large B-cell lymphoma is most 
common, followed by NK/T-cell lym-
phoma and peripheral T-cell lymphoma, 
NOS {50,432,1054,1372,2652}. Other 
lymphomas include MALT lymphoma 
{50,1372,2652). follicular lymphoma 
{50,432,1372). Burkitt lymphoma {2228, 
2652}, and mantle cell lymphoma 
{2652}, as well as the rare anaplastic 
large cell lymphoma {1054,2652), 8-
and T-lymphoblastic lymphomas {1054, 
1473), and classical Hodgkin lymphoma 
{1143,1939). 
Haematolymphoid tumours 75 
Notochordal tumours Baumhoer D. 
Bullerdiek J . 
Nicolai P. 
' •• .. '. ,, 
.. . .... -,, ' , .. -· -. . . . \ . . ··· - . 
.. 
!'~• 
• 
1 -~-r~.,, 
. . ' ,, ' . . . , : ... - -
. . 
. , ... . ' 
, .. :•., ... . ' ...... ... ;, . , · ~r . 
'.f. I .• / • l '' 
.. • ., • l, _.>:.~.r • .... 
., "-"' ' . .. .. 
, ... . ,. - : .. :. 
• _,.,. . ... • ..O ' -141,~ . 
Fig. 2.15 Chordoma. A Nests of epilhelioid cells with eosinophilic and vacuolated cytoplasm showing osteodestructive growth. B lmmunohistochemical double-stain with CK19 (red, 
staining of cytoplasm) and brachyury (brown, staining of nuclei). 
Chordoma 
Definition 
Chordoma is a malignant tumour with no-
tochordal differentiation. 
ICD-0 code 9370/3 
Epidemiology 
The annual incidence of chordoma is 
0.8 cases per 100 000 population, with 
32- 42% arising in cranial sites, mainly in 
the base of the skul l. 
There is a male predominance, with a 
male-to-female ratio of 1.6:1. lndividu-
als of any age can be affected, although 
chordoma is rare in chi ldhood (372, 
2224). 
Localization 
The clivus is most commonly involved. 
The nasopharynx and nasal cavity can 
be involved by local extension, but 
76 T umours of the nasopharynx 
primary occurrence at these sites is ex-
ceedingly rare {2665). 
Clinical features 
Chordomas present with headache, era-
nial nerve palsy, or brain stem compres-
sion, depending on the anatomical struc-
tures compromised. 
Macroscopy 
The tumours generally show bone-de-
structive growth; the cut surface is gelati-
nous or cartilage-like. 
Histopathology 
Chordomas consist of cords and lobules 
of cells in a myxoid stroma, separated 
by thin fibrous sepia. The characteristic 
cells are physaliphorous, with abundant 
and highly vacuolated (bubbly) cyto-
plasm, but many tumour cells are non-
descriptly epithelioid in appearance. 
The nuclei are uniform and round, with 
variable pleomorphism. Necrosis is fre-
quently present. Chordoma typically 
shows expression of cytokeratins, EMA, 
S100, and brachyury {1610,2517). Vari-
ants include chondroid chordoma, which 
shows matrix reminiscent of hyaline car-
tilage, and dedifferentiated chordoma, 
which is a biphasic tumour with classic 
chordoma juxtaposed to high-grade un-
diffe rentiated sarcoma. 
Genetic susceptibility 
In rare familia! cases, a duplication of 
the T (brachyury) gene can be found 
(2670}. 
Prognosis and predictive factors 
The most importan! prognostic factor is 
complete surgical resection, which can 
be achieved only rarely in cranial sites 
{2259}. The 3-, 5 -, and 10-year overall 
survival rates are 80.9%, 73 .5%, and 
58.7%, respectively {372}. 
CHAPTER 3 
Tumours of the hypopharynx, larynx, 
trachea and parapharyngeal space 
Malignant surface epithelial tumours 
Precursor lesions 
Neuroendocrine tumours 
Salivary gland tumours 
Soft tissue tumours 
Cartilage tumours 
Haematolymphoid tumours 
WHO classification of tumours of the hypopharynx, larynx, 
trachea and parapharyngeal space 
Malignant surface epithelial tumours 
Conventional squamous cell carcinoma 
Verrucous squamous cel l carcinoma 
Basaloid squamous cell carcinoma 
Papillary squamous cell carcinoma 
Spindle cell squamous cell carcinoma 
Adenosquamous carcinoma 
Lymphoepithelial carcinoma 
Precursor lesions 
Dysplasia, low grade 
Dysplasia, high grade 
Squamous cell papilloma 
Squamous cell papillomatosis 
Neuroendocrine tumours 
Well-differentiated neuroendocrine carcinoma 
Moderately differentiated neuroendocrine 
carcinoma 
Poorly differentiated neuroendocrine carcinoma 
Small cell neuroendocrine carcinoma 
Large cel l neuroendocrine carcinoma 
8070/3 
8051/3 
8083/3 
8052/3 
8074/3 
8560/3 
8082/3 
8077/0 
8077/2 
8052/0 
8060/0 
8240/3 
8249/3 
8041/3 
8013/3 
Salivary gland tumours 
Adenoid cystic carcinoma 
Pleomorphic adenoma 
Oncocytic papillary cystadenoma 
Soft tissue tumours 
Granular cel l tumour 
Liposarcoma 
lnflammatory myofibroblastic tumour 
Cartilage tumours 
Chondroma 
Chondrosarcoma 
Chondrosarcoma, grade 1 
Chondrosarcoma, grade 2/3 
Haematolymphoid tumours 
8200/3 
8940/0 
8290/0 
9580/0 
8850/3 
8825/1 
9220/0 
9220/3 
9222/1 
9220/3 
The morphology codes are from the lnternational Classification of Diseases 
for Oncology (ICD-0) {776A}. Behaviour is coded /O for benign tumours: 
/1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in 
situ and grade 111 intraepithelial neoplasia; and /3 for malignant tumours. 
The classification is modified from the previous WHO classification, taking 
into account changes in our understanding of these lesions. 
78 WHO classification of tumours of the hypopharynx, larynx, trachea and parapharyngeal space 
TNM classification of carcinomas of the larynx 
TNM classification•,b 
T - Primary tumour 
TX Primary tumour cannot be assessed 
TO No evidence of primary tumour 
Tis Carcinoma in situ 
Supraglottis 
T1 
T2 
T3 
T4a 
Tumour limited to one subsite of supraglottis, with normal 
vocal cord mobility 
Tumour invades mucosa of more than one adjacent 
subsite of supraglottis or glottis or region outside the 
supraglottis (e.g. mucosa of base of tongue, vallecula, or 
medial wall of pyriform sinus), without fixation of the larynx 
Tumour limited to larynx with vocal cord fixation and/or in-
vades any of the following: postcricoid area, pre-epiglottic 
space, paraglottic space, inner cortex of thyroid cartilage 
Tumour invades through the thyroid cartilage and/or 
invades tissues beyond the larynx; for example, !rachea, 
soft tissues of neck including deep/extrinsic muscle of 
tongue (genioglossus, hyoglossus, palatoglossus, and 
styloglossus), strap muscles, thyroid , oesophagus 
T4b Tumour invades prevertebral space or mediastinal struc-
Glottis 
T1 
T1a 
T1 b 
tures, or encases carotid artery 
Tumour limited to vocal cord(s) (may involve anterior or 
posterior commissure), with normal vocal cord mobility 
Tumour limited to one vocal cord 
Tumour involves both vocal cords 
T2 Tumour extends to supraglottis and/or subglottis, and/or 
with impaired vocal cord mobility 
T3 Tumour limited to larynx with vocal cord fixation and/or in-
vades paraglottic space and/or inner cortex of the thyroid 
cartilage 
T4a Tumour invades through the outer cortex of the thyroid 
cartilage and/or invades tissues beyond the larynx;for 
example, trachea, soft tissues of neck including deep/ 
extrinsic muscle of tongue (genioglossus, hyoglossus, 
palatoglossus, and styloglossus), strap muscles, thyroid, 
oesophagus 
T4b Tumour invades prevertebral space or mediastinal struc-
tures, or encases carotid artery 
Subglottis 
T1 Tumour limited to subglottis 
T2 Tumour extends to vocal cord(s), with normal or impaired 
mobility 
T3 
T4a 
Tumour limited to larynx, with vocal cord fixation 
T4b 
Tumour invades cricoid or thyroid cartilage and/or 
invades tissues beyond the larynx; for example, trachea, 
soft tissues of neck including deep/extrinsic muscle of 
tongue (genioglossus, hyoglossus, palatoglossus, and 
styloglossus), strap muscles, thyroid, oesophagus 
Tumour invades prevertebral space or mediastinal 
structures, or encases carotid artery 
N - Regional lymph nodes (i.e. the cervical nades) 
NX Regional lymph nades cannot be assessed 
NO No regional lymph node metastasis 
N1 Metastasis in a single ipsilateral lymph node,;::; 3 cm in 
greatest dimension 
N2 Metastasis as specified in N2a, N2b, or N2c below 
N2a Metastasis in a single ipsilateral lymph node, > 3 cm 
but ;::; 6 cm in greatest dimension 
N2b Metastasis in multiple ipsilateral lymph nodes, 
all ;::; 6 cm in greatest dimension 
N2c Metastasis in bilateral or contralateral lymph nodes, 
all;::; 6 cm in greatest dimension 
N3 Metastasis in a lymph node > 6 cm in greatest dimension 
Note: Midline nodes are considered ipsilateral nodes. 
M - Distant metastasis 
MO No distan! metastasis 
M1 Distan! metastasis 
Stage grouping 
StageO Tis NO MO 
Stage 1 T1 NO MO 
Stage 11 T2 NO MO 
Stage 11 1 T1-2 N1 MO 
T3 N0-1 MO 
Stage IVA T1-3 N2 MO 
T4a N0-2 MO 
Stage IVB T4b AnyN MO 
AnyT N3 MO 
Stage IVC AnyT AnyN M1 
'Adapted from Edge et al. (625A} - used with permission of the American 
Joint Committee on Cancer (AJCC), Chicago, lllinois; the original and prima-
ry source for this information is the AJCC Cancer Staging Manual, Seventh 
Edition (2010) published by Springer Science+Business Media - and Sobin 
et al. (2228A}. 
"A help desk for specific questions about TNM classification is available at 
http://www.uicc.org/resources/tnm/helpdesk. 
TNM c lassification of carcinomas of the larynx 79 
TNM classification of carcinomas of the hypopharynx 
TNM classification•,b 
T - Primary tumour 
TX Primary tumour cannot be assessed 
TO No evidence of primary tumour 
Tis Carcinoma in situ 
T1 Tumour limited to one subsite of hypopharynx and/or 
s 2 cm in greatest dimension 
T2 Tumour invades more than one subsite of hypopharynx or 
an adjacent site, or measures > 2 cm but s 4 cm in 
greatest dimension, without fixation of hemilarynx 
T3 Tumour > 4 cm in greatest dimension, or with tixation of 
hemilarynx or extension to oesophagus 
T4a Tumour invades any of the foliowing: thyroid/cricoid 
cartilage, hyoid bone, thyroid gland, oesophagus, central 
compartment soft tissue (which includes prelaryngeal 
strap muscles and subcutaneous fat) 
T4b Tumour invades prevertebral fascia, encases carotid 
artery, or invades mediastinal structures 
N - Regional lymph nodes (i.e. the cervical nodes) 
NX Regional lymph nades cannot be assessed 
NO No regional lymph node metastasis 
N1 Metastasis in a single ipsilateral lymph nade, s 3 cm in 
greatest dimension 
N2 Metastasis as specitied in N2a, N2b, or N2c below 
N2a Metastasis in a single ipsilateral lymph node, > 3 cm 
but s 6 cm in greatest dimension 
N2b Metastasis in multiple ipsilateral lymph nodes, 
ali s 6 cm in greatest dimension 
N2c Metastasis in bilateral or contralateral lymph nodes, 
ali s 6 cm in greatest dimension 
N3 Metastasis in a lymph nade > 6 cm in greatest dimension 
Note: Midline nades are considered ipsilateral nades. 
M - Distant metastasis 
MO No distan! metastasis 
M1 Distan! metastasis 
Stage grouping 
Stage O Tis NO MO 
Stage 1 T1 NO MO 
Stage 11 T2 NO MO 
Stage 111 T1-2 N1 MO 
T3 N0--1 MO 
Stage IVA T1-3 N2 MO 
T4a N0--2 MO 
Stage IVB T4b Any N MO 
AnyT N3 MO 
Stage IVC AnyT Any N M1 
ªAdapted from Edge et al. {625AJ - used with permission of the American 
Joint Committee on Cancer (AJCC), Chicago, lllinois; the original and prima-
ry source for this information is the AJCC Cancer Staging Manual , Sevent11 
Edition (201 O) published by Springer Science+Business Media - and Sobin 
et al. {2228AJ. 
bA help desk for specific questions about TNM classification is available at 
http://www.uicc.org/resources/tnm/helpdesk. 
80 Tumours of the hypopharynx, larynx, trachea and parapharyngeal space 
Tumours of the hypopharynx, larynx, 
trachea and parapharyngeal space 
Slootweg P.J. 
Grandis J.R. 
/ntroduction 
Laryngeal and hypopharyngeal pathol-
ogy mainly encompasses lesions of the 
covering mucous membrane, with un-
derlying soft tissues, salivary gland tis-
sue, and carti lage playing a minar role. 
Therefore, this chapter emphasizes le-
sions that arise from the mucosa! lining. 
The main difference from the previous 
edition is in the discussion of mucosa! 
premalignancies, about which the aim 
was to achieve a universally accepted 
consensus in arder to put an end to the 
confusion that can arise from the use of 
severa! difieren! classification systems. 
Currently, a two-t iered classification 
(consisting of low-grade and high-grade 
dysplasia) is recommended, to which 
guidelines have been added on how to 
recognize carcinoma in situ within the 
high-grade dysplasia group in case a 
three-tiered system is preferred. For 
neuroendocrine carcinomas, the widely 
accepted distinction between low-, inter-
mediate-, and high-grade carcinoma has 
been used, in line with the nomenclature 
for histologically similar lesions at other 
body siles. Discussion of soft tissue and 
salivary gland lesions, as well as haema-
tolymphoid tumours, has been limited to 
the specific entities that are often faund 
in the laryngohypopharynx or that have 
an importan! differential diagnostic role 
al this site. 
Malignant surface epithelial tumours 
Convenüonalsquamous 
ce// carcinoma 
Zidar N. 
Brandwein-Gensler M. 
Cardesa A. 
Helliwell T. 
Hille J. 
Nadal A. 
Definition 
Conventional squamous cell carcinoma 
(SCC) is a malignant epithel ial tumour with 
evidence of squamous differentiation. 
ICD-0 code 
Synonym 
Epidermoid carcinoma 
Epidemiology 
8070/3 
SCC of the larynx and hypopharynx is 
the second most common respiratory 
tract cancer, after lung cancer (359]. lt 
accounts for 1.6-2% of ali malignant tu-
mours in men and 0.2- 0.4% in women 
(238}. There is marked geographical 
variation in the frequency of SCC, both 
between countries and in different parts 
of the same country. 
lt occurs most frequently in the sixth and 
seventh decades of lite. Rare cases have 
Fig. 3.01 Macroscopic appearance of conventional squamous cell carcinoma. A Supraglottic carcinoma of the larynx: 
an ulcerated tumour with raised edges at the base of the epiglottis. B Subglottic carcinoma of the larynx: a partially 
flat and partially exophytic nodular tumour of the subglottis, extending to the anterior commissure. C Hypopharyngeal 
carcinoma of the piriform sinus: a large, ulcerated tumour with raised edges in the piriform sinus, extending to the 
aryepiglottic fo ld. 
been described in children (137,1766}. 
The tumours are more common in men 
(359,1947). although the male-to-female 
ratio is decreasing in sorne countries, 
possibly due to increased incidence of 
smoking among women over the past 
two decades (569). 
Tracheal carcinoma is rare, with ap-
proximately 1 tracheal carcin.oma far 
every 75 laryngeal cases; it accounts far 
< 0.1% of cancer deaths. SCC accounts 
far 55-73% of all tracheal carcinomas 
(143,820) . 
Etiology 
Cigarette smoking and (to a lesser ex-
tent) alcohol consumption are the most 
important risk factors far laryngeal and 
hypopharyngeal SCC (953). Eliminat-
ing smoking and alcohol consumption 
could prevent as many as 90% of laryn-
geal cancers {695). Other factors,such 
as gastro-oesophageal reflux, diet, nu-
tritional factors, and socioeconomic sta-
tus, have been linked to increased risk of 
laryngeal cancer, particularly in patients 
who lack the majar risk factors (480,665, 
762,1333}. 
Malignan! surface epithelial tumours 81 
HPVs play a limited role in the pathogen-
esis of SCC of the larynx. In recent stud-
ies, transcriptionally active HPVs were 
detected in 4-15% of cases {417,922, 
1408,2095). Unlike in the oropharynx, the 
morphology of laryngeal SCC does not 
predict viral etiology {1408). 
Localization 
There are geographical differences in the 
topographical distribution of laryngeal 
SCC. The most common location for la-
ryngeal SCC is the supraglottis in sorne 
countries (e.g. France, Spain , ltaly, Fin-
land, and the Netherlands) and the glot-
tis in others (e.g. the USA, Canada, the 
United Kingdom, and Sweden) [143). The 
rarest localization of laryngeal cancer is 
the subglottis {2067). 
Hypopharyngeal SCC occurs most fre-
quently in the piriform sinus (60-85% of 
cases) and rarely in other localizations, 
such as the posterior pharyngeal wall 
(10- 20%) and postcricoid area (5-15%) 
{971 ,2449). 
Tracheal SCC is usually located in the 
lower third of the trachea (> 50% of cas-
es) and less frequently in the upper or 
middle third {820). 
Clinical features 
The most common early symptoms of la-
ryngeal SCC are hoarseness (with glot-
tic and supraglottic SCC) and dyspnoea 
and stridor (with subglottic SCC). Other 
symptoms include dysphagia, change 
in the quality of voice, sensation of a for-
eign body in the throat, haemoptysis, and 
odynophagia {707,1949). 
The most frequent symptoms of hy-
popharyngeal SCC are odynophagia, 
dysphagia, and neck mass. Other symp-
toms include voice changes, otalgia, and 
constitutional symptoms {2449). 
Tracheal SCC usually presents with 
dyspnoea, wheezing or stridor, acute res-
piratory failure, cough, haemoptysis, and 
hoarseness {1970). 
Laryngeal, hypopharyngeal, and tra-
cheal SCCs can spread directly to con-
tiguous structures or via lymphatic and 
blood vessels, giving rise to lymph node 
and distant metastases. These tumours 
have a strong tendency to metastasize to 
the regional lymph nades. The localiza-
tion and frequency of lymph node metas-
tases depend on the site of the primary 
tumour. Haematogenous metastases are 
infrequent, but may occur in late stages 
of the disease, most frequently to the 
lung, liver, and bones (2248); intracra-
nial metastases have also been reported 
{544,2418). 
The TNM staging system is widely used 
for SCC. lt is presented in the text on 
pages 79 and 80. 
Macroscopy 
Laryngeal and hypopharyngeal SCC 
may present as an exophytic, flat, or 
nodular tumour with raised edges; as a 
polypoid lesion; or as a depressed, en-
dophytic lesion. Central ulceration is fre-
quently present. 
Tracheal SCC usually presents as a 
polypoid mass projecting into the lu-
men. Rarely, it grows as a circumferential 
mass. 
Cytology 
Aspirates of metastases are cellular, with 
sheets and small clusters of malignan! 
squamous cells with intracellular and 
extracellular keratinization. Mixed inflam-
mation and necrosis can be present. 
Histopathology 
The main histological features of SCC 
are squamous differentiation and inva-
sion. Squamous differentiation is charac-
terized by keratinization (with or without 
keratin pearl fo rmation) and/or intercel-
lular bridges. lnvasion manifests as in-
terruption of the basement membrane 
of the surface epithelium and the down-
wards growth of tumour islands, cords, 
or isolated tumour cells in the underly-
ing tissue. lnvasion is almost always ac-
companied by a desmoplastic stromal 
reaction, which consists of proliferation 
of myofibroblasts, excessive deposition 
of an extracellular matrix, and neovascu-
larization [2728,2729}. Tumour cells may 
invade the lymphatic and blood vessels 
or spread in the perineural plane or along 
nerves. 
SCCs are traditionally graded as well , 
moderately, or poorly differentiated, ac-
cording to the degree of differentiation, 
cellular pleomorphism, and mitotic ac-
tivity. Well-differentiated SCC c losely 
resembles normal squamous epithe-
lium and contains large, differentiated, 
keratinocyte-like squamous cells and 
small basal-type cells, which are usually 
located at the periphery of the tumour is-
lands. There are intercellular bridges and 
typically full keratinization; mitoses are 
scarce. Moderately differentiated SCC 
exhibits more nuclear pleomorphism and 
82 Tumours of the hypopharynx, larynx, !rachea and parapharyngeal space 
more mitoses, including abnormal mi-
toses; there is usually less keratinization. 
In poorly differentiated SCC, basal-type 
cells predominate, with frequent mitoses 
(including abnormal mitoses), barely 
discernible intercellular bridges, and 
minimal or no keratinization. Although 
keratinization is more likely to be present 
in well - or moderately differentiated SCC, 
it should not be considered an important 
histological criterion in grading SCC. Of-
ten, in the presence of an intact surface 
epithelium, intraepithelial dysplasia may 
be seen in direct continu ity with the SCC. 
Tumour growth at the invasive front can 
show an expansive or cohesive pattern 
(characterized by large tumour islands 
with well-defined pushing margins) and 
an infiltrative pattern (characterized by 
scattered small irregular cords or single 
tumour cells, with poorly defined infiltrat-
ing margins). 
lmmunophenotype 
SCC expresses various epithelial mark-
ers (e.g. cytokeratins, p63, and EMA). 
Well-differentiated SCC expresses me-
dium/high-molecular-weight cytokerat-
ins (e.g. CK5/6) but not low-molecular-
weight cytokeratins (e.g. CK8 and CK18), 
similar to normal squamous epithelium. 
Poorly differentiated SCC tends to lose 
expression of medium/high-molecular-
weight cytokeratins , and expresses low-
molecular-weight cytokeratins {1518} and 
vimentin {2474). 
Differentia/ diagnosis 
Well-differentiated SCC must be distin-
guished from verrucous and papillary 
carcinomas, as well as from benign con-
ditions such as pseudoepitheliomatous 
hyperplasia. Verrucous carcinoma lacks 
atypia, which is always present in SCC. 
Papillae formation and the absence of 
keratinization characterize papillary SCC, 
distinguishing it from SCC. Pseudoepi-
thel iomatous hyperplasia is a benign 
condition that consists of deep, irregular 
tangues of epithelium that lack the atypia 
and abnormal mitoses seen in SCC. 
Poorly differentiated SCC must be dif-
ferentiated from melanoma, lymphoma, 
and neuroendocrine carcinoma. The cor-
ree! diagnosis is best determined by the 
use of appropriate immunohistochem-
istry and special stains for demonstra-
tion of mucin production. Melanoma is 
distinguished from SCC by its expres-
sion of S100, HMB45, melan A and other 
melanocytic markers. 
Neuroendocrine carcinoma expresses 
neuroendocrine markers (e.g. synapto-
physin and chromogranin) but typically 
lacks p63 expression and does not show 
significant squamous differentiation. 
whereas SCC does not express neu-
roendocrine markers. Lymphoma is dis-
tinguished from SCC by the presence of 
CD45 (leukocyte common antigen) and 
markers of 8 -cell or T-cell differentiation. 
Genetic profile 
Laryngeal and hypopharyngeal SCCs 
develop as a result of multiple genetic 
abnormalities and the development of 
aneuploidy {478,846). LOH and com-
parative genomic hybridization studies 
have shown gains of 3q, 5p, 8q, 11q13, 
and 18p with losses at 3p, 5q, 8p, 9p, 
11q23-24, 13q, and 18q {1117,2100, 
2310). Loss of multiple tumour suppres-
sors is common. with the most commonly 
affected genes including CDKN2A and 
TP53. Amplified and mutated oncogenes 
include EGFR, VEGFA (previously called 
VEGF), PTGS2, PIK3CA, and matrix 
metalloproteinases {360,1515). Specific 
tumour suppressor microRNAs (the let-7 
family, miR-7, and miR-206) are down-
regulated {2627). 
Prognosis and predictive factors 
The overall5-year survival rate is 80-
85% for glottic SCC, 65- 75% for supra-
glottic SCC, about 40% for subglottic 
SCC {1431, 62.5% for hypopharyngeal 
SCC {2247). and 25- 47% for tracheal 
scc {820,1970}. 
Clinical prognostic factors 
Stage remains the most significan! pre-
dictor of survival, and is discussed in 
detai l elsewhere. Depth of invasion and 
the presence of regional and distant me-
tastases are independent predictors of 
survival. 
Localization is an important prognos-
tic factor {143}. The best prognosis has 
been reported for glottic SCC, and the 
worst prognosis for subglottic and tra-
cheal SCC. 
Other factors that may have a significan! 
impact on the outcome of SCC include 
patient age at presentation {425,2184), 
comorbidity (concurrent diseases) {395}, 
and performance status (425). 
Histopatho/ogical prognostic factors 
Differentiation. The reports on the prog-
nostic significance of traditional grading 
into well-, moderately, and poorly dif-
ferentiated SCC are conflicting. Sorne 
investigators have suggested that the 
grading system has a significan! asso-
ciation with survival {1896,2134,2607}. 
whereas others have not confirmed this 
observation {425,1113). The main criti-
cism of this widely used system of grad-
ing is related to its subjective nature and 
lack of objective criteria. 
Invasiva front. lt has been shown that 
the histological features at the invasive 
front are prognostically much more im-
portant than those in the central and su-
perficial parts of the tumour {284,285, 
2677). A simple grading system has 
Malignan! surface epithelial tumours 83 
been proposed for evaluation of the in-
vasive front, which correlates closely with 
prognosis. Four histological features are 
evaluated: degree of keratinization, nu-
clear polymorphism, pattern of growth, 
and inflammatory response. The score 
for each parameter is summarized as a 
total malignancy score, with a high score 
indicating poor prognosis {284,285}. Pat-
tern of invasion also features prominently 
in a multiparameter risk model for see 
{258}. 
Vascular and perineural invasion. The 
penetration of tumour cells in the lym-
phatic and/or blood vessels is associat-
ed with a high probability of lymph node 
and/or distant metastases. Vascular inva-
sion tends to occur in aggressive see 
and is associated with recurrence and 
poor survival (2678}. Similarly, perineural 
invasion is associated with an increased 
risk of local recurrence, regional lymph 
node metastases, and poorer survival 
{258,684,2134,2241,2678}. 
Extracapsular spread in lymph node 
metastases. Metastases in the lymph 
nodes are the single most adverse prog-
nostic factor in head and neck see (710, 
1353}. The presence of extracapsular 
spread in lymph nodes is also prognos-
tically important and is strongly associ-
ated with both regional recurrence and 
the development of distant metastases, 
resulting in poorer survival (262,710,996, 
2315). However, sorne studies have failed 
to conf irm the independent prognostic 
significance of extracapsular spread 
(1520,1896}. 
Resection margins. Resection margins 
clear of tumour are associated with a 
lower recurrence rate and better surviv-
al (1148,2211}. Margins are considered 
clear if there is no invasive see, see 
in situ, or dysplasia. An adequate mar-
gin of resection has not been precisely 
defined, but a margin of 5 mm is gener-
ally believed to be adequate (995}. Sorne 
studies have shown that even margins 
of 1-2 mm are adequate, particularly in 
glottic cancer (1698). 
Molecular factors. A systematic review 
failed to show any prognostic value of 
p53 expression in laryngeal carcinomas 
(1679,2353}. 
Verrucous squamous 
ce// carcinoma 
Zidar N. 
Cardesa A. 
Gil lison M. 
Helliwell T. 
Hille J. 
Nadal A. 
Definition 
Verrucous squamous cell carcinoma 
(VC) is a variant of wel l-differentiated 
squamous cell carcinoma (SeC) that 
lacks the cytological features of malig-
nancy, grows slowly, and is locally inva-
sive but does not metastasize. 
ICD-0 code 
Synonym 
Ackerman tumour (453} 
Epidemiology 
8051/3 
ve is a rare tumour; in the USA, the in-
cidence between 2000 and 201 1 was 
0.024 cases per 100 000 population . 
Most cases present in older males, in 
their sixth or seventh decades of life (610, 
1565}. 
Fig. 3.03 Laryngeal verrucous carcinoma. A broad-
based exophytic tumour with a warty surface. 
Etiology 
ve has been etiologically linked to to-
bacco smoking (1255,1565,1783,2252}. 
Recent studies using highly sensitive and 
specific molecular methods suggest that 
ve is not associated with HPV infection 
(557,1760,1825). 
Localization 
The larynx is the second most common 
site of occurrence of ve in the head and 
neck, after the oral cavity (1255}. Most 
cases arise from the true vocal cords, but 
ve may also occur in the supraglottis and 
subglottis (610,1 255,1565}, hypopharynx 
{1255}, and !rachea {2278). 
Fig. 3.04 Verrucous carcinoma. Fu\1-thickness view showing hyperkeratotic surface and projections and invaginations 
of well-differentiated squamous epithelium, invading the stroma with well-defined pushing margins. 
84 Tumours of the hypopharynx, larynx, trachea and parapharyngeal space 
Clinical features 
The symptoms and signs of ve are simi-
lar to those of conventional sce, with 
hoarseness as the most common pre-
senting symptom. Other symptoms in-
elude airway obstruction, weight loss, 
dysphagia, and throat pain {1565,1783}. 
Macroscopy 
ve presents as a large, tan to white, 
broad-based exophytic tumour with a 
warty surface. On cut surface, it is usu-
ally firm, with sharply defined margins. 
Histopathology 
VC consists of thickened, club-shaped 
projections and invaginations of well-dif-
terentiated squamous epithelium, com-
posed of one to several layers of basal 
cells and an expanded layer of spinous 
cells that lack cytological atypia . There is 
marked surface keratinization (so-called 
church-spire keratosis). Mitoses are rare 
and contined to the basal ce ll layer, and 
there are no abnormal mitoses. VC in-
vades the stroma with a well-defined 
pushing border, and invasion below the 
level of adjacent epithelium may be dif-
ficult to demonstrate in small biopsies 
unless the edge of the carcinoma is in-
cluded. Lymphoplasmacytic inflamma-
tion is common. lntraepithelial microab-
scesses may be present in association 
with Gandida species superinfection. 
Ves that contain foci of conventional 
see are considered hybrid (mixed) 
tumours {158}. 
The diagnosis of ve requires careful c lini-
cal and pathological correlation because 
the histological features have a wide dif-
ferential diagnosis, including epithelial 
hyperplasia, squamous cell papilloma, 
well-differentiated conventional see, 
papillary see, and hybrid carcinoma (in-
vasive see and VC). lnvasion below the 
basal cell layer of the neighbouring nor-
mal epithelium differentiates VG from ver-
rucous hyperplasia, but these diseases 
may occur concurrently, with a confluent 
interface. Squamous cell papilloma has 
thin, well-formed papillary fronds and is 
less keratinized. The lack of cytological 
atypia in ve distinguishes it from con-
ventional see, papillary see, and hybrid 
carcinoma {330}. An apparent discrep-
ancy between the clinical impression of 
malignancy and benign-looking mor-
phology should raise the suspicion of ve. 
There is no specific immunohistochemi-
cal marker for ve {1759,1761}. 
Genetic profile 
Molecular studies on ve are limited, and 
the genetic profile of laryngeal ve is 
largely unknown. The pattern of expres-
sion of microRNAs in ve differs from that 
in conventional see; the importance of 
this finding in the pathogenesis and di-
agnosis of ve remains to be determined 
(1 758,1759}. 
Prognosis and predictive factors 
ve is locally invasive and can cause 
extensive destruction if left untreated. lt 
does not metastasize to regional lymph 
nades or distant organs. lt has a better 
prognosis than does conventional see; 
the reported5-year survival rate far la-
ryngeal ve is 85-95% [610,1255}. The 
most important prognostic factor is stage 
at diagnosis; treatment is by surgery or 
radiotherapy (1052). Hybrid carcinoma 
has the potential for metastasis and 
should be treated as conventional see 
(1783}. 
Basa/oíd squamous 
ce// carcinoma 
Lewis J.S. 
Gillison M. 
Westra W.H . 
Zidar N. 
Definition 
Basaloid squamous cell carcinoma 
(BSee) is a clinically unfavourable vari-
ant of squamous cell carcinoma (SeC) 
composed of a prominent basaloid com-
ponent and with evidence of squamous 
cell differentiation. 
ICD-0 code 8083/3 
Malignant surface epithelial tumours 85 
Epidemiology 
Approximately 80% of patients with 
BSCC are White men in their mid-60s. 
Etiology 
Laryngeal and hypopharyngeal BSCC is 
strongly linked to tobacco use (reported 
in 80-90% of patients) and alcohol con-
sumption {658]. Transcriptionally active 
high-risk HPV, an established etiological 
factor at other sites, is consistently ab-
sent in BSCC arising at these anatomical 
subsites {171,415}. 
Localization 
The larynx is a common site for BSCC, 
with a predilection far the supraglottis . 
The tumours also occur in the hypophar-
ynx (piriform sinus) {658,775) and rarely 
in the trachea (1152). 
Clinical features 
The symptoms and signs vary according 
to the site of origin, but usually include 
dysphagia, hoarseness, weight loss, 
sore throat, cough, haemoptysis, and 
neck mass. BSCC usually presents at an 
advanced stage at the time of initial diag-
nosis, with lymph node metastases and 
occasionally distant metastases {658). 
Macroscopy 
There is no characteristic gross appear-
ance. The tumour usually appears as a 
flat or slightly elevated lesion with central 
ulceration and poorly defined borders. 
Rarely, it presents as a polypoid tumour 
{658). 
Cytology 
Aspirates of metastatic BSCC are cellu-
lar, with variably sized basaloid clusters 
of malignant cells exhibiting numerous 
mitotic figures and apoptotic bodies. 
Keratinization and definitive squamous 
differentiation may be rare and difficult to 
discern. Necrosis and mixed inflamma-
tion are often present. 
Histopathology 
BSCC consists of basaloid and conven-
tional squamous components {2521). The 
tumours are submucosal, with rounded 
nests with smooth borders and peripheral 
palisading. They tend to be closely ap-
posed, with thin lines of hyalin ized stroma 
between them, as if they are moulding to-
gether in a jigsaw-puzzle pattern. There 
is frequent comedonecrosis, and the tu-
mour cells are round to oval and hyper-
chromatic. Nucleoli are usually lacking 
but occasionally prominent. Gland-like 
foci with basophilic myxoid or mucoid ma-
terial are common and mimic true gland 
formation. A variable degree of nuclear 
pleomorphism is present, and high mitotic 
activity, apoptosis, and necrosis are com-
mon. Stromal hyalinization is characteris-
tic; it can be linear between and around 
nests and nodular within nests. The con-
ventional componen! may include abrupt 
keratin ization adjacent to basaloid cells , 
dysplastic changes in the squamous epi-
thelium, and conventional SCC. 
lmmunohistochemistry is strongly posi-
tive for high-molecular-weight cytokerat-
ins, p63, and p40 (in a diffuse pattern). 
BSCC is negative for synaptophysin and 
chromogranin {1649,2129}. The differ-
ential diagnosis includes adenoid cystic 
carcinoma - which lacks squamous 
differentiation and shows partial p63 
reactivity {655) - and small cell 
neuroendocrine carcinoma - which has 
angulated nuclei with speckled chromatin, 
is positive for neuroendocrine markers, 
shows punctate perinuclear reactivity for 
cytokeratin (CAM5.2), and usually lacks 
reactivity for high-molecular-weight cy-
tokeratins {2129}. The diagnosis of BSCC 
can still be made for tumours with all of 
the basaloid features even if they lack any 
86 Tumours of the hypopharynx, larynx, !rachea and parapharyngeal space 
overt histological evidence of squamous 
differentiation. However, there must be 
definitive immunohistochemical evidence 
of squamous differentiation, and adenoid 
cystic carcinoma and neuroendocrine 
carcinoma must be ruled out. 
Prognosis and predictive factors 
lt has been debated whether BSCC has 
a worse prognosis than conventional 
SCC. Most investigators have found la-
ryngeal/hypopharyngeal BSCC to be 
more aggressive than conventional SCC 
{776) . Patients with laryngeal BSCC have 
higher rates of nodal metastasis (-50-
70%) (658), significantly higher rates of 
distant metastasis, and poorer progno-
sis than do patients with conventional 
SCC {133,776,1439,2618). Active smok-
ers and patients with nodal metastases 
at presentation have worse prognosis. 
Given the relative rarity of laryngeal and 
hypopharyngeal BSCC, no predictive 
markers of proven clinical significance 
have been developed. Because HPV-
related oropharyngeal basaloid carcino-
mas can be otherwise indistinguishable 
from laryngeal/hypopharyngeal BSCC, 
any tumour that appears to arise in the 
larynx/hypopharynx but involves the oro-
pharynx should be tested for p16 and/ 
or high-risk HPV. This allows far the dis-
t inction of aggressive BSCC from more 
prognostically favourable HPV-related 
oropharyngeal carcinomas that are histo-
logically similar. 
Papil/ary squamous ce// 
carcinoma 
EI-Mofty S.K. 
Cardesa A . 
Helliwell T. 
HilleJ . 
Nada! A. 
Definition 
Papillary squamous cell carcinoma 
(PSCC) is characterized by a papillary 
growth pattern, with thin fibrovascular 
cores covered by severely dysplastic 
epithelial cells or immature basaloid cells 
with minimal or no maturation. 
ICD-0 code 8052/3 
Epidemiology 
PSCC is uncommon; its exact prevalence 
in the head and neck is unknown. lt is 
more common in male patients, with a 
male-to-female ratio of 2-3:1 (623,1140, 
2030,2298,2394). In one study, PSCC 
constituted 0.5% of all laryngeal cancers 
(623). The average patient age is report-
ed as mid-60s, with a slightly older aver-
age age among patients with oral PSCC 
{587,728,2030,2298). 
Etiology 
Etiological factors inc lude tobacco use 
and alcohol consumption {728,2030, 
2394), and HPV has recently been 
shown to be an etiological agent in a 
subset of PSCCs, particularly in the oro-
pharynx and sinonasal tract {1140 ,1580, 
2298). 
Localization 
PSCC has been reported in almost every 
site in the upper aerodigestive tract {587, 
1140,1 580,2030,2298,2394). 
Clinical features 
The lesions are described as exophytic 
growths that may be painless or painful. 
They can be pink, white, or both pink and 
white. Laryngeal tumours are associated 
with hoarseness and airway obstruction. 
Nodal metastasis is uncommon, and dis-
tan! metastasis is rare (587,623,2030, 
2298,2394). 
Macroscopy 
Grossly, the lesion is papillary, friable, 
and soft, with a pinkish-grey colour. 
Tumour size ranges from 0.2 to 4.0 cm 
{2298,2394). 
Cytology 
Aspirates of metastatic lesions show fea-
tures of keratin izing or non-keratinizing 
squamous cell carcinoma. 
Histopathology 
A signif ican! componen! of PSCC is 
composed of papillary projections with 
central fibrovascular cores. lnvasion 
may be difficult to establish morpho-
logically, but is implied by metastatic 
potential. The papillae are covered with 
malignant epithelial cells with little ar 
no keratinization. Two types of surface 
epithelium are described: one resem-
bles high-grade keratinizing epithelial 
dysplasia, and in the other, the epithelial 
cells are immature and basaloid, with no 
evidence of maturation or keratinization. 
Laryngeal tumours are not frequently 
HPV-associated, whereas oropharyn-
geal tumours are typically strongly posi-
tive for p16 and are HPV-related [1580, 
2298). 
Prognosis and predictive factors 
PSCC has a better prognosis than con-
ventional squamous cel l carcinoma, 
primarily due to low-stage presentation, 
with a low metastatic potential {587,623, 
1580,2030,2394). HPV-related PSCCs 
of the oropharynx show a trend towards 
betterpatient survival than is associated 
with HPV-negative PSCC {1580). 
Spindle ce// squamous 
ce// carcinoma 
Bishop J.A. 
Cardesa A. 
Helliwell T. 
Hille J. 
Nada! A. 
Definition 
Spindle cell squamous cell carcinoma (SC-
SCC) is a variant of squamous cell carci-
noma (SCC) characterized by predominan! 
malignan! spindle and/or pleomorphic cells. 
ICD-0 code 8074/3 
Fig. 3.08 Laryngeal spindle cell squamous cell carcinoma. 
A polypoid mass involving the larynx. 
Malignan! surface epithelial tumours 87 
Synonyms 
Sarcomatoid carcinoma; carcinosarcoma 
Epidemiology 
sesee is rare, accounting for < 1% of 
all laryngeal malignancies {608,2396). 
lt generally affects elderly patients, and 
has a male predilection {608,2396,2506). 
Etiology 
sesee is linked to cigarette smok-
ing and alcohol consumption. A subset 
of sesees may be radiation-induced. 
sesees of the larynx and hypopharynx 
are almost always negative for HPV {201, 
2396,2555). 
Localization 
The larynx, especially the glottis, is the 
most frequently involved site. The hy-
popharynx is infrequently affected {608, 
1398,1749,2396). 
Clinical features 
Patients present with airway obstruction 
and/or hoarseness (1398,2396) . 
Macroscopy 
sesee is usually a polypoid mass pro-
truding into the airway, often with an ul-
cerated surface mucosa {1398,2396, 
2506). 
Cytology 
Aspirates of metastatic sesee often 
show at leas! focal keratinizing see, but 
a malignan! spindle cel l componen! 'Tlay 
be all that is observed in sorne cases. 
Histopathology 
sesee is derived from the squamous 
epithelium and demonstrates divergen! 
differentiation by epithelial- mesenchy-
mal transition {437,1259,1749,27271. lt 
characteristically grows as an exophytic 
mass with a predominantly ulcerated sur-
face, sometimes containing remnants of 
dysplastic squamous epithelium and fre-
quently showing areas of transition toma-
lignant spindled or pleomorphic tumour 
cells. Most sesees demonstrate a hap-
hazard growth pattern of the spindled 
cells, and 7- 15% of cases exhibit hetera-
88 Tumours of the hypopharynx, larynx, trachea and parapharyngeal space 
logous mesenchymal differentiation in 
the form of malignan! bone, cartilage, 
or skeletal muscle {1398,2396,2702). 
sesee is usually overtly malignant, 
with hypercellularity, necrosis, atypi-
cal mitotic figures, and hyperchromatic 
nuclei demonstrating marked nuclear 
pleomorphism. However, a subset of 
sesees are deceptively bland in areas, 
with or without prominent areas of hya-
linization, mimicking reactive myofibro-
blastic proliferation or granulation tissue. 
The d iagnosis of sesee rests Oíl dem-
onstrating epithelial differentiation, either 
on routine morphology (i.e. squamous 
dysplasia of residual surface epithelium 
or foci of conventional see mixed with 
sarcomatoid tumour) or by immunohisto-
chemistry for cytokeratins (e.g. AE1/AE3), 
EMA, p63, or p40 {1406,1749). Howev-
er, as many as one third of sesees are 
purely spindled , and a significant subset 
is negative for epithelial markers {1398, 
1749,2396,2506). True sarcomas of the 
larynx/hypopharynx are rare, and a ma-
lignant spindle cell neoplasm arising at 
these sites is best considered an sesee 
until proven otherwise. 
Genetic profile 
sesee harbours complex genetic al-
terations, similar to poorly differentiated 
sees {436,437). 
Prognosis and predictive factors 
Despite its poorly differentiated appear-
ance, sesee of the larynx/hypopharynx 
(in particular the true vocal cord) tends 
to present at a low stage and, stage-for-
stage, has a prognosis similar to that of 
conventional see {187,608,1398,2396, 
2506}. Exophytic sesees are more eas-
ily resected and have the best prognosis 
(2396). 
Adenosquamous carcinoma 
Prasad M.L. 
Cardesa A. 
Helliwell T. 
HilleJ. 
Nadal A. 
Definition 
Adenosquamous carcinoma (ASC) is 
a malignan! tumour that arises from the 
surface epithelium and shows both squa-
mous and glandular differentiation. 
ICD-0 code 8560/3 
Epidemiology 
ASC is rare. lt has a male predisposition 
and usually develops in the sixth or sev-
enth decade of life (patient age range: 
34- 81 years) /1209). 
Etiology 
As with squamous cell carcinoma (SCC), 
smoking and alcohol consumption are like-
ly predisposing factors {1209). No associa-
tion with HPV has been reported in ASC 
from the larynx and hypopharynx /1553). 
Localization 
The larynx is a frequently affected site in 
the head and neck /60,1194,1209). A few 
cases in the hypopharynx have been re-
ported /1314,1548,1553,2093}. 
Clinical features 
Patients may present with hoarseness, 
sore throat, dysphagia, haemoptysis, or 
neck mass (1209). 
Macroscopy 
ASC may present as an exophytic or 
polypoid mass (median size: 4 cm) or as 
mucosal induration or ulceration, similar 
to SCC /825,1209}. 
Cytology 
Aspirates of metastases show features 
of keratinizing SCC. Malignan! glandular 
components, including cells with intracy-
toplasmic mucin, can be seen. 
Histopathology 
ASC has a biphasic morphology, with 
squamous and glandular differentiation. 
Origin from surface epithelium is support-
ed by the presence of squamous dyspla-
sia. The squamous and adenocarcinoma-
tous components are distinct but located 
,.: .. .. 
Fig. 3.11 Laryngeal adenosquamous carcinoma. A blending of the squamous and glandular components. 
in close proximity, an important diagnostic 
feature. The adenocarcinoma consists of 
cribriform and tubuloglandular structures 
and tends to occur in the deeper parts of 
the tumour /1209). lntraluminal (or rarely, 
intracytoplasmic) mucin may be demon-
strated by special stains, such as peri-
odie acid-Schiff (PAS), Alcian blue, and 
mucicarmine. The tumour shows necrosis, 
mitoses, and vascular and perineural in-
vasion consisten! with its high-grade na-
ture. Metastatic ASC may display only one 
componen!. 
lmmunohistochemistry shows the expres-
sion of p63 in the squamous componen!; 
carc inoembryonic antigen, low-molecu-
lar-weight cytokeratin (CAM5.2), and CK7 
in the adenocarcinomatous componen!; 
and high-molecular-weight cytokeratin in 
both components /1314,1548}. • CK20 is 
usually negative {1509}. 
The differential d iagnosis includes mu-
coepidermoid carcinoma, adenoid SCC, 
and conventional SCC invading the se-
romucinous glands. Distinction from mu-
coepidermoid carcinoma is importan! be-
cause ASC has a worse prognosis (Table 
3.01). Demonstration of mucin and carci-
noembryonic antigen helps to distinguish 
ASC from adenoid SCC. Conventional 
SCC invading or entrapping seromuci-
nous glands is d ifferentiated by its lobular 
architecture and the benign cytomorphol-
ogy of its g landular cells /1209). Necrotiz-
ing sialometaplasia, which is rare in the 
larynx, is characterized by the retention 
of the lobular architecture of the seromu-
cous glands (despite being replaced by 
squamous metaplasia), ischaemic necro-
sis of the acini, chronic inflammation, and 
pseudoepitheliomatous hyperplasia of the 
overlying squamous epithelium (1962}. 
Prognosis and predictiva factors 
ASC is more aggressive than convention-
al SCC, with a propensity far recurrence 
and dissemination {60,703}. Regional 
lymph node metastases occur in about 
75% of patients, and nearly 25% of pa-
tients develop distant metastases, most 
commonly to lung /1 209}. Clinical stage 
al presentation seems to correlate with 
prognosis. The 5-year survival rate is ap-
proximately 13- 50% {1194,1209,2093}. 
Table 3.01 Differences between adenosquamous and mucoepidermoid carcinoma 
Adenosquamous carcinoma Mucoepidermoid carcinoma 
Evidence of origin from overlying squamous epithelium 
(e.g. dysplasia) 
Keratinization in squamous cells, keratin pearls 
lnfiltrative glands al deeper parts 
Squamous and adenocarcinoma adjacent to each other 
Secondary invasion of submucosal glands· 
No intermediate cells 
No MAML2 translocation 
No evidence of origin from overlying squamous 
epithelium 
No keratinization or keratin pearls 
Glands widespread withlobular arrangement 
Epidermoid and glandular cells closely intermingled 
within lobules of tumour 
Arising from submucosal glands 
lntermediate cells present 
Usually associated with MAML2 translocationª 
8The presence of MAML2 lranslocalíon rules out adenosquamous carcinoma, bul MAML2 lranslocalíon is sorne-
limes absenl in mucoepidermoíd carcinoma {1194}. 
Malignan! surface epithelial tumours 89 
Lymphoepithelial carcinoma 
Bishop J.A. 
Gaulard P. 
Gill ison M. 
Definition 
Lymphoepithelial carcinoma (LEC) is a 
squamous cell carcinoma morphological-
ly similar to non-keratinizing nasopharyn-
geal carcinoma, undifferentiated subtype. 
ICD-0 code 8082/3 
Synonym 
Lymphoepithelioma-like carcinoma 
Epidemiology 
LEC of the larynx, hypopharynx, and !ra-
chea is rare, with only about 40 reported 
cases. lt affects older patients (mean pa-
l ien! age: 62 years), and there is a male 
predominance. Unlike nasopharyngeal 
carcinoma, which most frequently affects 
Asían patients, LEC in the larynx usually 
occurs in White patients {381,1507,2584, 
2706}. 
Etiology 
There is an association with smoking and 
alcohol consumption {604,1507,25841. 
There is also an association with EBV, 
although not as strong an association as in 
nasopharyngeal cases (1214,2584,2706). 
Localization 
LEC occurs more frequently in the lar-
ynx than in the hypopharynx. Rare cases 
have arisen in the !rachea (1363,1777, 
2340). 
Clinical features 
Patients present with hoarseness, neck 
mass, dysphonia, dysphagia, neck pain, 
and/or haemoptysis (604,1507,2584}. 
Cytology 
Aspirates of metastases show findings 
similar to those seen in aspirates of non-
keratinizing undifferentiated nasopharyn-
geal carcinoma. 
90 Tumours of the hypopharynx, larynx. !rachea and parapharyngeal space 
Histopathology 
LEC is defined by its resemblance to 
non-keratinizing und ifferentiated naso-
pharyngeal carcinoma (see Nasopharyn-
geal carcinoma, p. 65, Chapter 2). Unlike 
in the nasopharynx, LEC uncommonly 
harbours EBV in the larynx. 
Prognosis and predictiva factors 
According to SEER data, laryngeal LEC 
has a 5-year disease-specific survival 
rate of approximately 60% (381 }. Re-
gional lymph node metastasis occurs in 
approximately 75% of cases, with dis-
tan! metastasis in approximately 25% 
(1507). 
Precursor lesions 
Dysplasia 
Gale N. 
Hil le J. 
Jordan R.C. 
Nadal A. 
Williams M.O. 
Definition 
Dysplasia at this body site constitutes a 
spectrum of architectural and cytological 
epithelial changes of the upper aerodi-
gestive tract, caused by an accumulation 
of genetic changes that can be associ-
ated with an increased likelihood of pro-
gression to squamous cell carcinoma. 
ICD-0 codes 
Dysplasia, low grade 
Dysplasia, high grade 
Synonyms 
8077/0 
8077/2 
Squamous intraepithelial lesions; squa-
mous intraepithelial neoplasia 
Epidemiology 
Dysplasia is seen mostly in adults and af-
fects men more often than women, with a 
male-to-female ratio as high as 4.6:1 {799}. 
This disparity is especially evident alter 
the sixth decade of life. Epidemiological 
studies of laryngeal dysplasia are scarce. 
The annual incidence of laryngeal pre-
cancerous mucosal changes in the USA 
is 10.2 and 2.1 lesions per 100 000 males 
and females, respectively (245}. 
Etiology 
Cigarette smoking has been established 
as the princ ipal risk factor in laryngeal 
carcinogenesis, especially in combina-
tion with alcohol abuse. The increased 
risk is linked to age at the start of smok-
ing, duration of smoking, and quality of 
tobacco (2039,2451 }. Gastro-oesoph-
ageal reflux disease is also considered 
to be a possible risk factor {1395,2128}. 
High-risk HPV infection plays a minor role 
in dysplasia development {62 1,803,1644, 
1799}. Only integrated and transcription-
ally active HPV can play a significan! role 
in carcinogenesis, and HPV 16 is the 
most freq uent genotype (922,1408}. The 
overall prevalence of HPV in dysplasia 
Table 3.02 Morphological critaria far tha classification of laryngeal precursor lesions {797) 
Low-grade dysplasia (including previous category of mild dysplasia): 
Low malignan! potantial; a spactrum of morphological changas ranging from squamous hyperplasia toan 
augmentation of basal and parabasal calls occupying as much as the lower half of the epithelium, while the upper 
portian ratains maturation 
Architectural criteria 
Cytological criteria 
Stratification is preserved: transition of basal cells ar augmented basal/parabasal 
cell layer with perpendicular orientation to tha basement membrane to prickle cells 
horizontally oriented in the upper part 
Spinous layer: spectrum of changes ranging from increased spinous layer in the 
whola thickness up to changas in which prickle cells are seen only in the upper 
epithalial hall 
Basal/parabasal layer: spectrum of changes, from 2-3 unchanged layers to 
augmentation of basal and parabasal cells in the lower half of the epithelium 
At most minimal cellular atypia 
Parabasal cells: slightly incraased cytoplasm comparad to basal cells, enlarged 
nuclai, uniformly distributed chromatin, no intercellular bridges 
Rare regular mitoses in or near basal layer 
Few dyskeratotic cells present 
High-grade dysplasia (including previous categories of moderate dysplasia, severe dysplasia, and 
carcinoma in situ): 
A premalignant lesion; a spectrum of changes including immature epithelial cells occupying al leas! the lower half of 
the epithelium and as much as the whole epithelial thickness 
Abnormal maturation 
Variable degrees of disordered stratification and polarity in as much as the whole 
epithelium 
Architectural criteriaª 
Altered epithelial cells usually occupying from half to the entire epithelial thickness 
Two subtypes: keratinizing (spinous-cell type) and non-keratinizing (basal-cell type) 
Variable degree of irregularly shaped rete (bulbous, downwardly extending), with an 
intact basement membrane 
No stromal alterations 
Easily identified to conspicuous cellular and nuclear atypia, including marked 
variation in size and shape, marked variation in staining intensity with fraquent 
hyperchromasia, nucleoli increased in number and size 
Cytological criteriaª lncreased N:C ratio 
lncreased mitoses at or above the suprabasal level, with or without atypical forms 
Dyskeratotic and apoptotic cells are frequent throughout the entire epithelium 
ªComplete loss of stratification and polarity and/or severe cytological atypia and atypical mitoses qualifies as 
carcinoma in situ if a three-liered system is used. 
studies published since 2005 is 12% 
(range: 0- 38%) (621,803,1644,1799}. 
Localization 
Dysplasia can occur anywhere in the lar-
ynx, but it occurs most frequently along 
one vocal cord and less frequently along 
both vocal cords. The commissures as 
well as hypopharyngeal and. tracheal 
regions are rarely involved {801,1158, 
2349). 
Clinical features 
The symptoms and signs vary accord-
ing to the location and size of the lesion. 
Voice change, hoarseness, sore throat, 
and chronic cough are most common. 
Macroscopy 
Dysplasias are clinically identified as leu-
koplakias (white patches), erythroplakias 
(red patches), erythroleukoplakias (red 
and white patches), or chronic laryngitis. 
They present as small or large patches 
that are localized or diffuse, or as flat or 
exophytic and papillary lesions. Macro-
scopic appearance does not have any 
specific connotations for microscopy, 
which must always be determined histo-
logically (247,801}. 
Precursor lesions 91 
Table 3.03 Terminology and grading systems used for dysplasia I squamous intraepithelial lesion (SIL) 
Level of 
abnormal 
maturation 
(WH02005) 
WH02005 
{146} 
SIN 
classification 
{850} 
Ljubljana 
classification 
{799} 
1 1 
Amended Ljubljana 
classificalion {797} 
WH02017 
Lower 113 
'¡ Squamous Í 
hyperplasia 1 
1 Mild 
dysplasia 
Squamous 
hyperplasia 
SIN 1 
l Squam~os hyperplasia 
Basal/parabasal 
hyperplasia 
Low-grade SILLow-grade 
dysplasia 
113 to 112 
Upper 112 to 314 
Full thickness 
Moderate I SIN 1 or SIN 2 
dysplasia 
Moderate 
dysplasia 
SIN 2 
Atypical 
hyperplasia 
High-grade SIL 
High-grade 
dysplasia* 
-
Í Severe l 
1 dysplasia ,___ 
Carcinoma 
in situ 
Carcinoma 
in situ 
Carcinoma in situ 
*lf a three-tiered system is used, carcinoma in situ is separated from high-grade dysplasia. 
SIN, squamous intraepithelial neoplasia. 
Fig. 3.13 Leukoplakia of the left vocal cord. The anterior 
part of the left vocal cord is irregularly thickened and 
covered by whitish plaques. 
Histopathology 
Several classification systems have been 
devised to represent the spectrum of his-
tological changes and their relation to bi-
ological behaviour, especially malignant 
progression {732,797,1291,2582). 
Fig. 3.14 Low-grade dysplasia. Hyperplastic squamous 
epithelium shows augmented parabasal cells extending 
up to one third of the epithelium thickness; the upper half 
of the epithelium is unchanged. 
Although the grading of upper aerodi-
gestive tract dysplasia is to a certain 
degree a subjective process, grade is 
the most important prognostic factor far 
the biological behaviour of disease, be-
cause clinicians need a descriptor of the 
92 Tumours of the hypopharynx, larynx, !rachea and parapharyngeal space 
epithelial changes in arder to determine 
the appropriate treatment {733,1574, 
2076). A review of the currently used 
histological grading systems and their 
approximate relationship is presented in 
Table 3.03 {2592). 
In an effort to harmonize the various 
concepts of the listed classifications, 
with their various morphological crite-
ria and different terminology, a unified, 
two-grade system is proposed, with 
c lear morphological criteria far defining 
the prognostic groups: low-grade (mild 
dysplasia) and high-grade (moderate 
and severe dysplasia / carcinoma in situ) 
{797). lf a three-tiered system is preferred 
far treatment purposes, the high-grade 
category can be further separated into 
high-grade dysplasia and carc inoma in 
situ {797}. Far a morphological descrip-
tion of each grade of dysplasia, see Ta-
ble 3.02. 
Ancil lary studies (e.g. p53, p16, Ki-67, 
and EGFR) are currently not recommend-
ed for dysplasia c lassification. 
Genetic profile 
Accumulation of genetic alterations 
produces aneuploidy in preneoplastic 
cel ls (2072,2680). Laryngeal dysplas-
tic lesions show freq uent chromosomal 
changes/LOH al 9p21, 17p13, 3p26, 
and 3p14, with alterations al 9p21 be-
ing the earliest and most frequent, sug-
gesting the implication of the CDKN2A 
gene in the early phases of neoplastic 
transfarmation. The most likely target of 
17p13 LOH is TP53 {1679). Other mo-
lecular alterations consistently detected 
in premalignant laryngeal lesions include 
cyclin D1 overexpression (1814) and tel-
omerase activity reactivation ( 1451 , 1496, 
"') 
Fig. 3.16 High-grade dysplasia / carcinoma in situ. Prominent architectural disorder; epithelial cells show severe 
cellular and nuclear atypia, mitoses are present, the basement membrana is intact, and a thick parakeratotic !ayer is 
evident on the surface (see Table 3.02, p. 91 ). 
1497). None of these find ings are cur-
rently of diagnostic or prognostic utility. 
Prognosis and predictive factors 
A retrospective follow-up study found a 
highly significan! difference in the risk 
of malignan! progression between low-
and high-grade lesions, at 1.6% and 
12.5%, respectively (797,1184). Certain 
high-grade dysplasias (i .e. carcinomas 
in situ) are associated with higher risk of 
progression to invasive growth (occurring 
in 40% of cases) and may require more 
extensive surgery or radiation therapy, 
depending on the specific site (e.g. an-
terior commissure) and contributing risk 
factors (e.g. alcohol consumption and to-
bacco use) {2710). 
Squamous ce// papílloma and 
squamous ce// papíllomatosís 
Richardson M. 
Gale N. 
HilleJ. 
Zidar N. 
Definition 
Squamous cell papilloma and squamous 
cell papi llomatosis are benign exophytic 
squamous epithelial tumours cbmposed 
of branching fibrovascular cores, usu-
ally associated with HPV infection (geno-
types 6 and 11). 
ICD-0 codes 
Squamous cell papilloma 
Squamous cell papil lomatosis 
Synonyms 
8052/0 
8060/0 
Recurrent respiratory papil lomatosis; la-
ryngeal papillomatosis; juvenile papillo-
matosis; adult papillomatosis 
Epidemiology 
Squamous cell papilloma is the most 
common benign epithelial tumour of the 
larynx. Recurren! respiratory papilloma-
tosis (RRP) is characterized by multiple 
contiguous, locally recurren! squamous 
cell papillomas, although solitary lesions 
present infrequently. RRP is a rare dis-
ease involving the respi ratory tract that 
occurs in both children and adults. The 
true incidence and prevalence of RRP 
are uncertain. The best projected esti-
mates of annual incidence are 4.3 cases 
per 100 000 children and approximately 
1.8 cases per 100 000 adults {331 ,570}. 
The bimodal age distribution demon-
strates the first peak in children aged 
< 5 years (juvenile cases) and the sec-
ond peak in patients aged 20-40 years 
(adult cases) {331,1257). RRP is more 
common in children and is the most ag-
gressive form of the disease, with 25% of 
cases presenting during infancy {1969, 
2604). There is no sex predominance 
in children, but in adult patients there is 
a male-to-female ratio of 3:2 {570,602, 
1774). Although the disease is rare, mor-
bidity is notoriously high, compromising 
functions such as vocalization, swallow-
ing, and breathing {821,2605). 
Etiology 
HPV 6 and 11 are the most frequent 
genotypes (seen in 90% of cases) asso-
ciated with RRP as well as solitary pap-
illomas {800,2605). A minority of cases 
(4- 5%) have coinfection with genotypes 
HPV 6 and 11, and fewer cases (3- 4%) 
with other HPV genotypes (e.g. 16, 31, 
33, 35, and 39) (2605). 
The modes of HPV transmission include 
sexual contact, non-sexual contact, 
and maternal contact (direct or indirect) 
(1324). Most neonatal HPV infection oc-
curs by vertical transmission at birth 
{2325). A triad of factors (first-born 
child, vaginal delivery, and maternal age 
< 20 years) has been noted to correlate 
with RRP in children {1192). Caesarean 
section provides a lower risk of trans-
mission but is not completely protective 
against infection. In contras!, active ma-
ternal genital HPV infection at the time of 
delivery increases exposure to a signifi-
can! vi ral load, with a high risk for trans-
mitting infection {1324,2325). In adults, 
the mode of viral transmission remains 
unclear; transmission during sexual con-
tact and reactivation of a slow-progress-
ing latent infection from childhood have 
been suggested (1 199,1775,2028}. The 
unpredictable c linical course of RRP 
suggests possible host-specific genetic 
and immunological factors. Differences 
in HPV-specific immune response have 
been demonstrated between patients 
with RRP and controls {234,331,1742, 
2003}. 
Precursor lesions 93 
Localization 
The papillomas usually involve the vo-
cal cords and ventricles, followed by 
transmission to the false cords, epig lot-
tis, subglottic area, hypopharynx, and 
nasopharynx. Rarely (in 1-3% of cases), 
the papillomas may extend to the lower 
respiratory trae!, which is associated with 
high mortality {821 ,1742,2325}. The d istri-
bution of RRP follows a predictable pat-
tern, with the tumours occurring at siles 
where c iliated and squamous epithelium 
is juxtaposed. 
Clinical features 
The presentation includes progressive 
hoarseness and stridor associated with 
growths of exophytic lesions within the 
larynx. 
Macroscopy 
The proliferative luminal growths are exo-
phytic, sessile, or pedunculated masses 
with bosselated surfaces. The papil la-
mas often g row as a friable cluster and 
bleed easily w ith minar trauma. 
H istopathology 
Squamous cell papillomas have a core 
composed of an arborizing fibrovascular 
network covered by squamous epithe-
lium.Parabasal cell hyperplasia is often 
seen involving the lower half of the epi-
thelium. Pronounced to subtle koi locytic 
Fig. 3.17 Laryngeal papillomatosis. A Recurren! res-
piratory papillomatosis fills the endolaryngeal space. 
B Endoscopic view of multicoated clusters of papillomas 
within a larynx. 
~ili---~..;...:;.-..i. 
Fig. 3.18 Laryngeal papillomatosis. Florid papillomas line the endolarynx in this case of recurren! respiratory 
papillomatosis. 
94 Tumours of the hypopharynx, larynx , !rachea and parapharyngeal space 
features are seen in the upper layers of 
the epithelium. Mitotic features are seen 
along the basal to medial aspee! of the 
epithelium. Premature keratinization of 
individual epithelial cells contributes to 
a disorganized appearance. Surface 
keratinization is mínima!. Premalignant 
features are infrequent but should be re-
ported if present. 
HPV genotype and variants can be de-
termined using sensitive conventional or 
real-time PCR (1774}. A lthough far less 
sensitive, and unable to detect HPV vari-
ants, in situ hybridization has also been 
used. Failure to detect HPV by in situ hy-
bridization is considered consistent with 
a low copy numb er of HPV, below the de-
tection sensitivity threshold of the in situ 
hybridization technique. However, spe-
cific patterns of in situ hybridization sig-
nals indicate that the viral status is either 
episomal (a diffuse signa! pattern) or in-
tegrated (a punctate signa! pattern). The 
mechanism of squamous cel l papi lloma 
recurrence in juveniles may be more al-
tributable to HPV integration (274} . 
Prognosis and predictiva factors 
The c li nical course of RRP is unpredicta-
ble and ranges from complete remission, 
to relatively stable lesions, to an aggres-
sive c linical course of rapid progressive 
recurrences requiring surg ical interven-
tion, and potentially life-threatening res-
piratory obstruction {570,1522,2325}. 
The clinical significance of variants of the 
HPV 6 and 11 genotypes in patients with 
RRP is unknown {1522}. 
Sorne studies have found the HPV 11 
genotype to be the most importan! risk 
factor for aggressive c linical course, but 
this finding has not been consistently rep-
licated (1774, 2605}. Other studies sug-
gest that patient age at onset is importan! 
(286}. Children diagnosed at < 3 years of 
age are 3.6 times as likely to have more 
than tour surgeries per year as are chil-
d ren diagnosed at an older age (1 774, 
1969}. HPV 11 is more closely associated 
with a younger age at diagnosis, and in 
sorne studies it is associated with an ag-
gressive clinical course (2605}. In adults, 
both HPV 11 and an observation time 
> 1 O years have been found to be as-
sociated with aggressive clinical course 
(1774). These data suggest that there are 
factors other !han HPV type and patient 
age that determine disease course (286). 
A retrospective sequence analysis of 
HPV in RRP showed no evidence of 
Scanned by CamScanner
Clinical features 
Patients present with hoarseness, dys-
phagia, and airway obstruction {639, 
2463). Rarely, a paraneoplastic syn-
drome (due to aberran! hormone pro-
duction by the tumour) may be identified 
(218 ,709,2463,2586]. 
Macroscopy 
The tumours present as submucosal 
fleshy polypoid or sessile masses, 
0.5~3 cm in size (2586). 
Histopathology 
The tum:Jur cells grow in nests, cords, 
sheets, rnd trabeculae of round to sl ight-
ly spindled cells with ample amphophilic 
to eosinophilic granular (sometimes on-
cocytic) cytoplasm. Gland-like structures 
or rosettes may be seen, exceptional ly 
containing mucin vacuoles. The tumour 
nuclei exhibit stippled, evenly dispersed 
chromatin in a salt-and-pepper pattern . 
Minimal nuclear atypia is seen, mitotic 
rates are low (< 2 mitoses per 2 mm? or 
10 high-power fields), and necrosis is ab-
sent. The tumour stroma is often fibrotic 
and highly vascular. 
The neoplastic cells are positive for cy-
tokeratins, EMA, and al least one neu-
roendocrine marker (e.g. synaptophysin, 
chromogranin, or CD56). Peptides (e.g. 
serotonin, calcitonin, and somatostatin) 
may be positive, and TTF1 is variably 
positive. Ki-67 immunohistochemistry is 
not used in the grading of neuroendo-
crine tumours. 
Prognosis and predictiva factors 
The prognosis is difficult to determine 
due to the rarity of this tumour, but seems 
to be good alter surgery or laser resec-
tion. Recurrence and metastasis rates as 
high as 30% have been reported : with 
a 5-year survival rate of approximately 
80% {639,2463). Older studies reported 
a more aggressive behaviour, due to the 
inclusion of moderately differentiated 
neuroendocrine carcinomas {2229,2230, 
2463). 
96 Tumours of the hypopharynx. larynx. !rachea and parapharyngeal space 
Moderately differentiated 
neuroendocrine carcinoma 
Perez-Ordonez B. 
Bishop J.A. 
Gnepp D.R. 
Hunt J.L. 
Thompson L.D. R. 
Definition 
Moderately differentiated neuroendocrine 
carcinoma is an epithelial neoplasm 
demonstrating neuroendocrine differen-
tiation with a histological grade between 
well-differentiated and poorly differenti-
ated neuroendocrine carcinoma. 
ICD-0 code 8249/3 
Synonyms 
Atypical carcinoid; neuroendocrine car-
cinoma, grade 11 
Epidemiology 
These are the most common neuroen-
docrine carcinomas of the larynx (2463, 
2586,2631). They occur more frequently 
in men, with a male-to-female ratio of 
2.4:1, and have a peak incidence in the 
sixth and seventh decades of life (mean 
patient age: 63 years) {2463,2586,2589). 
Etiology 
Most patients are heavy tobacco users 
(2463,2589}. 
Local ization 
More than 90% of cases occur in the su-
praglottic region {2463,2589). 
Clinical features 
Patients present with hoarseness, 
dysphagia, sore throat, and occasion-
ally haemoptysis {2586,2589}. Rarely, a 
paraneoplastic syndrome (due to aber-
ran! hormone production by the tumour) 
may be identified {709,2463). 
Macroscopy 
The tumours are tan-pink polypoid sub-
mucosal masses, 0.2- 4 cm in size, and 
often covered by an ulcerated surface 
mucosa (2586,2589}. 
Histopathology 
The tumour cells grow in nests, cords, 
sheets, and trabeculae of round to 
slightly spindled cells with ample ampho-
philic to eosinophilic granular cytoplasm. 
Gland-like structures or rosettes may be 
seen. The tumour nuclei may exhibit stip-
pled, evenly dispersed chromatin or may 
show more nuclear atypia with promi-
nent nucleoli. The defining features are 
necrosis and/or 2-1 O mitoses per 2 mm2 
or iO high-power fields. Sorne tumours 
demonstrate oncocytic cytoplasm or 
stromal amyloid deposition . 
The neoplastic cells are positive for cy-
tokeratins and at leas! one neuroendo-
crine marker (e .g. synaptophysin, chro-
mogranin, or CD56). TTF1 is variably 
expressed. These tumours are frequently 
positive for calcitonin, which creates a 
potential diagnostic pitfal l, particularly in 
a lymph nade metastasis, where the tu-
mour can be mistaken for medullary thy-
roid carcinoma. 
Prognosis and predictive factors 
Approximately 30% of patients present 
with advanced disease, with a recurrence 
rate of about 60% and a 5-year survival 
rate of 50% {2463,2589,2632). There are 
no specific histological features that pre-
dict outcome. 
Poorly differentiated 
neuroendocrine carcinoma 
Perez-Ordonez B. 
Bishop J.A. 
Gnepp D'.R. 
Hunt J.L. 
Thompson L.D.R. 
Definition 
Poorly differentiated neuroendocrine car-
cinoma is a high-grade malignan! epithe-
lial neoplasm with evidence of neuroen-
docrine differentiation. Two subtypes are 
recognized: small cell neuroendocrine 
carcinoma (SmCC) and large cell neu-
roendocrine carcinoma (LCNEC). 
!CD-O codes 
Small cell neuroendocrine carcinoma 
8041/3 
Large cell neuroendocrine carcinoma 
8013/3 
Synonyms 
Small cell carcinoma, neuroendocrine 
type; oat cell carcinoma; neuroendo-
crine carcinoma, grade 111 
Epidemiology 
lt is the second most common neuroen-
docrine carcinoma of the larynx, tends to 
arise in older men (median patient age: 
60 years), and has a male-to-femalera-
tio of 2.3-4.3:1 {848 ,855,"1407,2463). 
Etiology 
More than 90% of patients are cigarette 
smokers {"1407,2463). An association 
with HPV has been identified, but may 
not be as significan! as the association 
of HPV with oropharynx or sinonasal tract 
tumours {2382). 
Localization 
Within the larynx, there is a predilection 
for the supraglottic larynx, followed by 
the subglottis {848,855,2463). 
Clinical features 
Patients present with non-specific symp-
toms, including hoarseness and/or dys-
phagia {848,855,1407,2463}. Many pa-
tients have regional or distan! metastases 
al presentation ["1612). Rarely, paraneo-
plastic syndromes are reported {709). 
Macroscopy 
The tumour is a fleshy, ulcerated submu-
cosal mass {848,1404f. 
H istopathology 
SmCC grows in nests, sheets, and tra-
beculae of cells, with occasional nuclear 
palisading or rosette-like structures. lt is 
highly infiltrative, with frequent perineural 
and lymphovascular invasion. The tu-
mour is composed of small to medium-
sized cells with hyperchromatic nuclei, 
finely granular chromatin, and indistinct 
nucleoli with scant cytoplasm. Nuclear 
moulding, prominent crush artefact, ne-
crosis, apoptosis, and DNA coating of 
vessel walls (the Azzopardi phenome-
non) are classic features, accompanied 
by a high mitotic rate (> 1 O mitoses per 
2 mm2 or 10 high-power fields) 
LCNEC shows organoid nesting, pali-
sading, rosettes, and/or trabeculae. lt is 
composed of medium-sized to large cells 
with abundan! cytoplasm. The nuclei 
have coarse chromatin (sometimes with 
a speckled, salt-and-pepper quality) and 
usually have a single prominent nucleo-
lus. The tumour exhibits comedonecrosis 
and a high mitotic rate (> 10 mitoses per 
2 mm2 or 1 O high-power fields). 
Neuroendocrine tumours 97 
Rare examples of SmCC and LCNEC 
harbour a component of squamous cell 
carcinoma, either within the invasive tu-
mour or within the overlying mucosa (i .e. 
squamous cell carcinoma in situ). Com-
bined SmCC- LCNEC cases are rarely 
seen (2631). 
Both SmCC and LCNEC are positive for 
cytokeratins (in particular low-molecu-
lar-weight cytokeratins) by immunohis-
tochemistry, and SmCC may exhibit a 
perinuclear or dot-l ike pattern. Neuroen-
docrine differentiation is confirmed by 
staining with at least one neuroendocrine 
98 Tumours of the hypopharynx, larynx, !rachea and parapharyngeal space 
marker (e.g. synaptophysin, chromogra-
nin , or C056). TTF1 immunoexpression is 
variable. SmCC and LCNEC are negative 
or only weakly positive for p63 and are 
consistently negative for CK5/6. 
Prognosis and predictive factors 
These highly aggressive malignancies 
have high rates of regional and distan! 
metastasis, with about 70% of patients 
presenting with advanced disease, and 
5-year survival rates of 5- 20% (708,848, 
1170,2463}. 
Salivary gland tumours 
Adenoid cystic carcinoma 
Stenman G. 
Gnepp D.R. 
Wenig B.M. 
Definition 
Adenoid cystic carcinoma (ACC) is a 
slow-growing and relentless salivary 
gland mal ignancy composed of epithelial 
and myoepithelial neoplastic cel ls that 
form various patterns , including tubular, 
cribriform, and sol id forms. 
See also the Adenoid cystic carcinoma 
section (p. 164) in Chapter 7. 
ICD-0 code 8200/3 
Epidemiology 
ACC is uncommon at these siles, but is 
the most common salivary gland malig-
nancy in this location {318,426,609,704, 
795,1058,1734,2371,2557]. There is no 
sex predilection and the tumours occur 
over a wide patient age range, but are 
most common in the sixth to eighth dec-
ades of life. 
Localization 
Most laryngeal tumours are subglottic, 
with the supraglottis being the next most 
common location {609,1665,1734,2371, 
2699). 
Clinical features 
Symptoms include airway obstruction, 
dysphagia, dyspnoea, cough, hoarse-
ness, sore throat, haemoptysis, and pain 
{1058,2557,2673) . Tracheal tumours may 
present with specific and asthma-mim-
icking symptoms {1022) . 
Macroscopy 
The tumour is a submucosal mass with or 
without surface ulceration . 
H istopathology 
The histology is similar to that seen in 
ACCs found in the majar and other minar 
salivary gland siles; see the Adenoid cys-
tic carcinoma section (p .164). 
Prognosis and predictiva factors 
Tracheal ACC o/ten presents at an ad-
vanced stage (2300). More than 50% of 
patients have metastases, frequently to 
the lungs {631 ). The 10-year survival rate 
is influenced by margin status {2319). 
In one study, most patients with larynge-
al ACC had T4 lesions at initial diagnosis, 
although 87.9% had NO disease and only 
6.1% had distant metastasis. The 5-year 
disease specif ic survival rate was higher 
among patients with laryngeal ACC who 
underwent surgery versus !hose who did 
not {609). 
Pleomorphic adenoma 
Bel! O. 
Bullerdiek J. 
Hunt J.L. 
Definition 
Pleomorphic adenoma (PA) is a benign 
tumour with variable cytomorphological 
and architectural manifestations. The 
identification of epithelial and myoepithe-
lial/stromal components is essential far 
the diagnosis of PA. 
See also the P!eomorphic adenoma sec-
tion (p .185) in Chapter 7 (Tumours of sa!i-
vary glands) . 
ICD-0 code 
Synonym 
Benign mixed tumour 
Localization 
8940/0 
Only a few examples of PA in the larynx and 
hypopharynx have been reported in the 
literature (612,2085). They are typically lo-
cated in the epiglottis or aryepiglottic folds. 
Clinical features 
The common clinical presentatión of PA 
is that of a slow-growing, painless mass. 
Histopathology 
See the Pleomorphic adenoma section 
(p. 185) in Chapter 7. 
Prognosis and pred ictiva factors 
Complete resection is curative. Recurren! 
lesions are associated with an unfavour-
able clinical course. 
Oncocytic papillary 
cystadenoma 
Bloemena E. 
Bel! D. 
Hunt JL 
Defin ition 
Oncocytic papillary cystadenoma is a 
cystic lesion lined by oncocytic epithe-
lium, with occasional luminal papillary 
projections. 
ICD-0 code 8290/0 
Synonyms 
Oncocytic cyst; oncocytic papillary cys-
tadenomatosis; oncocytic adenomatous 
hyperplasia; oxyphi lic adenoma; onco-
cytoma; adenoma in laryngocoele 
Epidemiology 
The tumour affects elderly patients, in the 
sixth and seventh decades of life {253}. 
Localization 
The tumour occurs in the larynx, typically 
in the supraglottis {1382,2274). 
Clinical features 
The symptoms are hoarseness, dyspho-
nia, and rarely, airway obstruction {175, 
2274). 
Salivary gland tumours 99 
Histopathology 
The tumour consists of unilocular or mul-
tilocular cysts lined by oncocytic epitheli-
um, with occasional intraluminal papil lary 
projections. The lesion can be multifocal. 
Hyperplastic cellu lar formation may re-
sult in more-solid nests of oncocytic cells 
{1382,2274). 
Cell of origin 
The cell of origin is the minor salivary 
gland duct cell {1382,2274). 
Prognosis and predictive factors 
These lesions show benign behaviour 
but may recur. An association with squa-
mous cell carcinoma has been described 
in a case report (2274). 
Soft tissue tumours 
Granular ce// tumour 
Allen C.M. 
Gnepp D.R. 
Wenig B.M. 
Definition 
Granular cell tumour is an uncommon 
benign tumour of Schwann-cell differen-
tiation characterized by poorly demar-
cated accumulations of plump granular 
ce lls {2458). 
See also the Granular ce!! tumoursection 
(p. 121) in Chapter 4. 
ICD-0 code 9580/0 
Synonyms 
Granular cell myoblastoma; granular cell 
schwannoma; granular cell neurofibro-
ma; Abrikossoff tumour 
Epidemiology 
Granular cell tumours most trequently 
occur in the third to fifth decades of lite 
{1057). No sex predilection has been 
noted far laryngeal granular cell tumour, 
but tracheal granular cell tumour has a 
female predilection. Black populations 
appear to be disproportionately affected 
compared with other ethnic groups. 
Localization 
Laryngeal granular cell tumours most 
commonly involve the posterior third of 
the true vocal fold; tracheal granular cell 
tumours usually affect the cervical por-
tian {2602]. 
Clinical featuresLaryngeal granular cel l tumours usu-
ally present with hoarseness. ·Tracheal 
granular cell tumours may cause stridor, 
cough, or haemoptysis {11 53). Other 
symptoms include sensation of a mass 
and dysphagia. As many as 10% of cas-
es involve two or more tumours {2602). 
Macroscopy 
Granular ce ll tumours present as sessile 
nodules measuring < 2 cm in diameter 
(92). On cut surface, the tumours are 
pale tan to yellowish-white. 
Histopathology 
The tumour shows submucosal unen-
capsulated or poorly circumscribed cel-
lular proliferation with syncytial, trabecu-
lar, or nested growth, composed of cells 
with round to oval nuclei and abundant 
coarsely granular eosinophilic cyto-
plasm. There is usually minimal nuclear 
pleomorphism and mitotic activity. Pseu-
doepitheliomatous hyperplasia of the 
overlying epithelium may also be seen in 
100 Tumours of the hypopharynx, larynx, trachea and parapharyngeal space 
a substantial proportion of these lesions, 
and care should be taken when evaluat-
ing a superficial biopsy sample to pre-
vent an overdiagnosis of squamous cell 
carcinoma, because occasional tumours 
may be associated with mild to moderate 
cytological atypia in the pseudoepithe-
liomatous hyperplasic component. The 
granular cells are often intimately associ-
ated with nerves . The cytoplasmic gran-
ules give a diastase-resistant positive 
periodic acid-Schiff (PAS) reaction. The 
tumour cells express 8100 protein, CD57, 
and S0X10 {72}, as well as CD68. 
Prognosis and predictive factors 
Surgical excision is curative. The risk of 
recurrence is low (< 10%). 
Líposarcoma 
Flucke U. 
Franchi A. 
Thompson L.D.R. 
Definition 
Li posarcoma is a malignant neoplasrn 
recapitulating fat. Three b iologically dis-
tinct categories are recognized: well-
differentiated/dedifferentiated (the most 
common), myxoid, and pleomorphic. 
ICD-0 code 8850/3 
Synonym 
Well-differentiated liposarcoma: atypical 
lipomatous tumour 
Epidemiology 
These rare t1..1mours predominantly affect 
older males (mean patient age: 60 years) 
(691,867}. 
Localization 
The tumours occur in the pharynx, 
mouth, larynx, and neck. The tangue is a 
common intraoral location {55,691,867}. 
Clinical features 
The tumour is a slow-growing, painless 
mass causing dysphagia and airway ob-
struction {867,1708). 
Macroscopy 
The tumours present as submucosal, well-
circumscribed, fatty- fibrous nodules (1708). 
Histopathology 
The most common lipoma-like subtype 
shows variation in ad ipocyte size, with 
hyperchromatic, enlarged nuclei. The ir-
regular fibrous septa have atypical stro-
mal cells {1708). Dedifferentiated non-
lipogenic areas can exhibit a wide variety 
of growth patterns and cytomorphology 
(e.g. spindle-cell, pleomorphic, giant-
cell, round-cel l, and meningothel ial-like). 
Heterologous elements (e.g. cartilage 
and bone) are rare {1538). MDM2 and 
CDK4 are positive in > 90% of the tu-
mours {192,1538}. 
Genetic profile 
Well -differentiated/dedifferentiated lipo-
sarcoma shows 12q13-15 amplification, 
including MDM2 and COK4 {192). 
Prognosis and predictiva factors 
Multiple recurrences of lipoma-like/well-
differentiated lesions may occur alter 
surgical treatment, with late dedifferen-
tiation. Tumour site and grade seem to 
influence prognosis, with laryngeal lipo-
sarcoma having a better outcome than 
oral tumours, possibly due to earl ier rec-
ognition {867). 
lnflammatory 
myofibroblastic tumour 
Wenig B.M. 
Flucke U. 
Franchi A. 
Definition 
lnflammatory myofibroblastic tumour 
is a distinctive neoplasm composed of 
myofibroblastic and fibroblastic spindle 
cells accompanied by an inflammatory 
infiltrate of plasma cells, lymphocytes, 
and/or eosinophils. 
ICD-0 code 8825/1 
Synonyms 
lnflammatory pseudotumour; plasma cell 
granuloma 
Epidemiology 
lnflammatory myofibroblastic tumours of 
the head and neck tend to occur in men 
and are most common in adults, although 
they can occur in children {462,2004). 
Localization 
Laryngeal inflammatory myofibroblas-
tic tumours primarily arise in the glottic 
regían {194,2509,2585). Non-Jaryngeal 
sites include the oral cavity, sinonasal 
tract, pharynx, tonsils, parapharyngeal 
space, salivary glands, and trachea 
{404,405,573,961,1776). 
Clinical features 
Laryngeal inflammatory myofibroblastic 
tumours present with hoarseness, stridor, 
dysphonia, ora foreign body sensation in 
the throat (194,2509,2585). In other sites, 
symptoms include obstruction, epistaxis, 
headaches, and dysphagia. 
Macroscopy 
The tumour is a polypoid, pedunculated 
or nodular firm lesion with a smooth ap-
pearance and a fleshy to fi rm consist-
ency, measuring 0.4- 3 cm in greatest 
dimension. 
Histopathology 
The tumour is a submucosal storiform 
to fascicular loosely cellular proliferation 
composed of spindle-shaped, stellate, 
epithelioid, and/or axonal (spider- like) 
cells with enlarged round to oval nuclei, 
Soft tissue tumours 101 
inapparent to prominent nucleol i, and 
abundant fibrillar-looking cytoplasm. ln-
tranuclear inclusions may be present in 
epithel ioid cells. Mitotic figures may be 
numerous but atypical mitoses are not 
seen. There is a variable admixture of 
lymphocytes, plasma cells, and/or eo-
sinophils. lnflammatory myofibroblastic 
tumours are immunoreactive for actins 
(focally to diffusely). Staining for desmin 
and cytokeratin is reported in 33% {464) 
to 77% {1581) of cases . ALK expression 
is seen in 36-60% of cases {366,376, 
481). Distinction from spindle cell squa-
mous cell carcinoma is critica!; areas of 
squamous dysplasia or differentiation are 
helpful in this differential diagnosis (see 
Spind!e ce// squamous ce!/ carcinoma, 
p. 87) . 
Genetic profile 
About 50-70% of cases (mainly in chil-
dren) have clona! rearrangements involv-
ing chromosome band 2p23 that fuse the 
3' kinase region of the ALK gene {890). 
Fusion partners include TPM3, TPM4, 
CLTC, RANBP2, and ATIC/268,481,1351, 
1416,1808}. 
Prognosis and predictive factors 
For laryngeal inflammatory myofibro-
blastic tumour, surgical resection is usu-
ally curative {573,901 ,2004,2585), but 
recurrence can rarely occur {901 ,2004, 
2585). Rare examples of extrapulmonary 
Cartilage tumours 
Chondroma and 
chondrosarcoma 
Gale N. 
Hunt J.L. 
Lewis J.S. 
Thompson L.D.R. 
Definition 
Chondroma is a benign mesenchymal 
tumour of larynx hyaline carti lage. Chon-
drosarcoma is a malignan! mesenchymal 
tumour of larynx hyaline cartilage. 
ICD-0 codes 
Chondroma 
Chondrosarcoma 
9220/0 
9220/3 
... ' ~- .. ~ 
Fig. 3.30 lnfiammatory myofibroblastic tumour. A The myofibroblasts may also appear epithelioid or histiocytoid, 
characterized by round to oval nuclei, enlarged nucleoli, and ample basophillc to eosinophilic granular cytoplasm; 
an inflammatory cell infiltrate is present. B The myofibroblasts include spindle-shaped to stellate cells with enlarged 
round to oblong nuclei and abundan! basophilic-appearing fibrillar cytoplasm; cells with long cytoplasmic extensions are 
seen. C lmmunohistochemical expression of ALK, including cytoplasmic staining as well as staining of the intranuclear 
inclusions. 
(non-head and neck) inflammatory myo-
fibroblastic tumour metastasize and 
may be associated with the presence 
of RANBP2 and round cel l morphol-
ogy {402,1539}. ALK reactivity may be 
Chondrosarcoma, grade 1 
Chondrosarcoma, grade 2/3 
Epidemiology 
9222/1 
9220/3 
Carti laginous tumours account for 
< 0.2% of ali laryngeal tumours, but 
are the most common non-epithelial 
tumours, with chondrosarcomas being 
much more common than chondromas 
{347,460,711,1397}. Chondromas oc-
cur across a wide patient age range, 
of 24-79 years (mean: 56 years), with a 
male-to-female ratio of 2:1 {1397). • 
Chondrosarcomas tend to occur in 
slightly older patients, with a patient age 
range of 25- 91 years (mean: 63 years), 
and have a male-to-female ratio of 3.2:1 
{611,1397,2387). Chondrosarcomas are 
a favourable prognostic indicator {462). 
ALK-negative casesmay carry higher 
risk of metastasis and death from dis-
ease {462). 
Fig. 3.31 Laryngeal chondrosarcoma. Cut section of a 
chondrosarcoma arising from the cricoid cartilage and 
showing a solid, focally lobular and glistening greyish-
blue surface. 
102 Tumours of the hypopharynx, larynx, !rachea and parapharyngeal space 
significantly more common in Whites 
than in Blacks, al a ratio of 7:1 (112). 
Etiology 
The etiology remains unclear, although 
severa! hypotheses have been proposed. 
Disordered ossification, which is found 
only in hyaline cartilage (cricoid and rare-
ly thyroid cartilage) in older patients and 
whlch occurs in areas of muscle inser-
tion, may serve as a nidus for tumour de-
velopment (112). lschaemic changes in 
chondroma may be a predisposing fac-
tor (2387}. Other possible predisposing 
factors are radiotherapy, polytetraf luoro-
ethylene (Te/Ion) injection, and repeated 
laryngeal trauma (1773). 
Local ization 
The most common site for laryngeal 
chondromas is the cricoid carti lage (ac-
counting for -70% of cases), followed by 
the thyroid, arytenoid, and tracheal carti-
lages, in decreasing order of frequency 
{112,1361,1397}. Chondrosarcomas de-
velop in the same locations, specifically 
along the anterior surface of !he posterior 
lamina of the cricoid cartilage {112,1773, 
2387}. Rare tumours arise in the epiglot-
tis (2387}. 
Clinical features 
Both tumours grow slowly, commonly as 
endolaryngeal masses. The symptoms 
of chondroma and chondrosarcoma are 
similar and depend on tumour size and 
location. Slowly progressive hoarseness, 
dyspnoea, dysphagia, and stridor are 
usually present. lf the tumour is located 
in the thyroid cartilage, the palien! may 
present with a palpable neck mass {112, 
1773,2387). MRI may help in delineating 
• 
\ . 
•. ,1,- ,:-. ··\ ', 
~--" ... ., .., ' f 
Fig. 3.32 Chondroma. Well-circumscribed tumour 
composed of hyaline cartilage, with low cellularity, lack 
of nuclear atypia of chondrocytes, and a single nucleus 
within a lacuna. 
tumour extent (112) CT reveals a hy-
podense, well-defined tumour with inter-
na! calcifications, cartilage destruction, 
and structural distortion {166,2541 ,2619). 
FDG -PET may help with tumour grading, 
metastasis detection, and local recur-
rence assessment (1773). 
Macroscopy 
Both tumours present as smooth, lobulat-
ed, submucosal masses covered by nor-
mal mucosa. On cut surface, the lesions 
are glassy, firm, white, or grey. Chon-
dromas are usually < 2 cm in diameter, 
whereas chondrosarcomas can be as 
large as 12 cm (mean diameter: 3.5 cm. 
Dedifferentiated chondrosarcomas have 
foci with a fleshy appearance {347,809, 
1397,2387}. 
H istopathology 
Chondromas are composed of mature 
hyaline cartilage histologically resembling 
normal cartilage. Hypocellular areas con-
tain evenly distributed, bland-looking 
chondrocytes in an abundan! basophilic 
matrix. Chondrocytes have small, uniform, 
'P. 
single nuclei surrounded by eosinophilic 
cytoplasm and there is usually only one 
cell per !acuna. Cellular pleomorphism, 
mitoses, and binucleated chondrocytes 
are absent. Scattered foci of calcification 
and ossification may be seen. 
Chondrosarcomas show variably in-
creas.ed cellularity, pleomorphism, multi-
nucleation, and mitoses, features useful 
in tumour grading. Most laryngeal chon-
drosarcomas are low-grade (grade 1), 
showing a pattern of lobular disarray 
and destructive invasion o/ native carti -
lage and bone. Chondrosarcomas have 
higher cellularity !han chondromas, bi-
nucleation in !he !acunar spaces , slight 
nuclear pleomorphism, and nuclear hy-
perchromasia. Moderately differentiated 
(grade 2) tumours show a higher degree 
of cellularity and nuclear pleomorphism 
than do grade 1 tumours, and may have 
scattered mitoses. High-grade (grade 3) 
tumours have high cel lularity; significan! 
multinucleation, nuclear pleomorphism, 
and hyperchromasia; necrosis; and in-
creased mitoses. Ossification and calci -
fication can be seen in ali grades (112, 
1397,2387). 
Rare cases of laryngeal clear cell chon-
drosarcoma have also been described, 
characterized by a sharp transition of 
conventional chondrosarcoma to a pop-
ulation of large clear cells with distinct 
cellular membranes but lacking typical, 
dense chondroid matrix (45). High-grade 
chondrosarcomas are rare, accounting 
for only about 5% o/ ali laryngeal chon-
drosarcomas {2387). Dedifferentiated 
laryngeal chondrosarcomas are exceed-
ingly rare; they show a biphasic appear-
ance with well-differentiated chondro-
sarcoma juxtaposed with a high-grade 
, . B •, t r 
~ 'f ... ' • ,., - - - ..-.-
Fig. 3.33 Chondrosarcoma. A Neoplastic proliferation with increased cellularity, chondrocytes showing mild nuclear and cellular pleomorphism and hyperchromasia, and invasion 
of the ossified region of the cricoid cartilage. B Moderately differentiated chondrosarcoma, grade 2. Remarkable cellularity, frequent binucleation in the !acunar spaces, and more 
pronounced nuclear and cellular pleomorphism. 
Cartilage tumours 103 
1 -
Fig. 3.35 MALT lymphoma arising in the larynx. There is a dense, diffuse infiltrate of marginal zone cells; neoplastic 
cells invade a submucosal gland to form a lymphoepithelial lesion. 
non-cartilaginous sarcoma {809,2387). 
lmmunohistochemistry is rarely neces-
sary, but the chondroid cel ls are immu-
noreactive with S100 protein and D2-40. 
Prognosis and predictive factors 
The 1-year, 5-year, and 10-year disease-
specific survival rates for chondrosar-
coma are 96.5%, 88.6%, and 84.8%, re-
spectively, although the local recurrence 
rate is relatively high (18-50%), usually 
dueto incomplete resection (611,2387). 
Tumour grade and tumour subtype do not 
seem to influence outcome (other than 
possibly for dedifferentiated tumours) 
(1992), which encourages conservative, 
function-preserving surgery (including 
laser therapy) as primary treatment (347, 
2387]. Distant metastases are exceed-
ingly rare {460) . 
Haematolymphoid tumours 
Ferry J. A. 
Chuang S.-S. 
Definition 
Haematolymphoid tumours are primary 
malignan! neoplasms of lymphoid, plas-
ma cell, or myeloid origin . 
Epidemiology 
Lymphomas arising in the larynx and 
trachea are rare, accounting for < 1% 
of neoplasms at these sites {717,1028, 
1541]. Approximately 4% of head and 
neck lymphomas arise in the larynx; 
tracheal lymphomas are even less com-
mon (934). Lymphomas affect women 
more often than men. Laryngeal plas 
104 Tumours of the hypopharynx, larynx, trachea and parapharyngeal space 
Wmacytomas constitute 5- 6% of extra-
osseous plasmacytomas of the head 
and neck (116,2078); nearly ali patients 
are adults. Extramedullary myeloid sar-
coma and mast cell neoplasms are very 
rare (1028}. Among patients with wide-
spread lymphoma or leukaemia, subtle 
laryngeal involvement is common {1028). 
Localization 
Lymphoma and plasmacytoma involve 
the larynx more often than the trachea. 
Lymphoma involves the supraglottic lar-
ynx more often than the subglottic larynx. 
Primary parapharyngeal or hypopharyn-
geal origin of haematolymphoid neo-
plasms is very rare. Lymphomas (545, 
1028,1300,1444) and plasmacytomas 
{1483,2143,2304) are usually localized; 
sorne MALT lymphomas involve multi-
ple mucosa-associated lymphoid tissue 
siles (997). 
Clinical features 
Patients present with cough, dyspnoea, 
and hoarseness (1300,1 444,2304,2718]. 
Macroscopy 
Lymphomas and extraosseous plasma-
cytomas are usually smooth-surfaced, 
raised or polypoid lesions {1028,1300, 
2718). Lymphomas may be multinodular 
and/or circumferential (586,2701 }. 
Histopathology 
The most common primary lymphoma at 
this body site is MAL T lymphoma (586, 
1300,1 444,2343,2718], but rare cases 
of diffuse large B-cell lymphoma (1028), 
extranodal NK/T-cell lymphoma (1 637}, 
anaplastic large cell lymphoma (1220), 
and other lymphomas have also been 
reported. Laryngeal extraosseous plas-
macytoma is sometimes associated with 
laryngeal amyloidosis(1483). 
Prognosis and predictive factors 
The prognoses of lymphomas at this 
body site are similar to those of their 
counterparts in other sites. Extraosseous 
plasmacytoma has a favourable progno-
sis (1 028). al though patients may devel-
op recurrences and a minority of cases 
progress to plasma cell myeloma (116, 
2078). 
j 
• 
CHAPTER 4 
Tumours of the oral cavity and 
mobile tongue 
Malignant surface epithelial tumours 
Oral potentially malignant disorders and 
oral epithelial dysplasia 
Papillomas 
Tumours of uncertain histogenesis 
Soft tissue and neural tumours 
Oral mucosal melanóma 
Salivary type tumours 
Haematolymphoid tumours 
• 
• 
r 
WHO classification of tumours of the oral cavity and 
mobile tongue 
Epithelial tumours and lesions 
Squamous cel l carcinoma 
Oral epithelial dysplasia 
Low grade 
High grade 
Proliferative verrucous leukoplakia 
Papillomas 
Squamous cell papilloma 
Condyloma acuminatum 
Verruca vulgaris 
Multifocal epithelial hyperplasia 
Tumours of uncertain histogenesis 
Congenital granular cell epulis 
Ectomesenchymal chondromyxoid tumour 
Soft tissue and neural tumours 
Granular cell tumour 
Rhabdomyoma 
Lymphangioma 
Haemangioma 
Schwannoma 
8070/3 
8077/0 
8077/2 
8052/0 
8982/0 
9580/0 
8900/0 
9170/0 
9120/0 
9560/0 
106 Tumours of the oral cavity and mobile tongue 
Neurofibroma 
Kaposi sarcoma 
Myofibroblastic sarcoma 
Oral mucosa! melanoma 
Salivary type tumours 
Mucoepidermoid carcinoma 
Pleomorphic adenoma 
Haematolymphoid tumours 
CD30-positive T-cell lymphoproliferative 
disorder 
Plasmablastic lymphoma 
Langerhans cell histiocytosis 
Extramedullary myeloid sarcoma 
9540/0 
9140/3 
8825/3 
8720/3 
8430/3 
8940/0 
9718/3 
9735/3 
9751/3 
9930/3 
The morphology codes are lrom the lnternational Classilication ol Diseases lar 
Oncology (!CD-O) (776A}. Behaviour is coded /0 far benign tumours; 
/1 far unspecified, borderline, or uncertain behaviour; /2 far carcinoma in 
situ and grade 111 intraepithelial neoplasia; and /3 lar malignan! tumours. The 
classification is modified from the previous WHO classil ication, taking into 
account changes in our understanding of these lesions. 
TNM classification of carcinomas of the lip and oral cavity 
TNM classification of carcinomas of the lip and oral cavity•,b 
T - Primary tumour 
TX Primary tumour cannot be assessed 
TO No evidence of primary tumour 
Tis Carcinoma in situ 
T1 Tumour s 2 cm in greatest dimension 
T2 Tumour > 2 cm but s 4 cm in greatest dimension 
T3 Tumour > 4 cm in greatest dimension 
T4a (lip) 
Tumour invades through cortical bone, inferior alveolar 
nerve, !loor of mouth, or skin (of chin or nose) 
T4a (oral cavity) 
Tumour invades through cortical bone, into deep/extrinsic 
muscle of tangue (genioglossus, hyoglossus, palatoglos-
sus, and styloglossus), maxillary sinus, or skin of tace 
T4b (lip and oral cavity) 
Tumour invades masticator space, pterygoid platas, or 
skull base; or encases interna! carotid artery 
Note: Superficial erosion alone of bone / tooth socket by 
gingival primary is no! sufficient to classify a tumour as T4. 
N - Regional lymph nodes (i.e. the cervical nodes) 
NX Regional lymph nodes cannot be assessed 
NO No regional lymph node metastasis 
N1 Metastasis in a single ipsilateral lymph node, s 3 cm in 
greatest dimension 
N2 Metastasis as specified in N2a, N2b, or N2c below 
N2a Metastasis in a single ipsilateral lymph node, > 3 cm 
but s 6 cm in greatest dimension 
N2b Metastasis in multíple ipsilateral lymph nodes, 
ali s 6 cm in greatest dimension 
N2c Metastasis in bilateral or contralateral lymph nodes, 
ali s 6 cm in greatest dimension 
N3 Metastasis in a lymph node > 6 cm in greatest dimension 
Note: Midline nades are considered ipsilateral nodes. 
M - Distant metastasis 
MO No distan! metastasis 
M1 Distan! metastasis 
Stage grouping 
StageO Tis NO MO 
Stage 1 T1 NO MO 
Stage 11 T2 NO MO 
Stage 111 T1-2 N1 MO 
T3 N0-1 MO 
Stage IVA T1-3 N2 MO 
T4a N0-2 MO 
Stage IVB AnyT N3 MO 
T4b Any N MO 
Stage IVC AnyT Any N M1 
ªAdapted from Edge et al. (625A} - used with permission of the American 
Joint Committee on Cancer (AJCC), Chicago, lllinois; the original and prima-
ry source for this information is the AJCC Cancer Staging Manual, Seventh 
Edition {201 O) published by Springer Science+Business Media - and Sobin 
et al. (2228AI. 
hA help desk for specific questions about TNM classification is available at 
http://www.uicc.org/resources/tnm/helpdesk. 
TNM classification of carcinomas of the lip and oral cavity 107 
Tumours of the oral cavity and 
mobile tongue 
lntroductíon 
In the previous edition, tumours of the oral 
cavity and oropharynx were discussed 
together in one chapter. Now, diseases 
of these two anatomical regions are the 
subjects of two separate chapters; this 
chapter being devoted to the oral cavity 
and Chapter 5 (p. 133) to the oropharynx. 
Furthermore, as in other chapters, in an 
effort to minimize overlap, only selected 
non-epithelial and soft tissue tumours, 
sal ivary neoplasms and haematolym-
phoid tumours are highlighted. The out-
come of this approach is that the content 
of this chapter is much reduced in com-
parison with the previous edition. 
Lesions that deserve prime attention in 
this chapter are the mucosa! diseases. 
The most pivotal malignancy of the oral 
cavity and mobile tongue is squamous 
cell carcinoma (SCC) arising from the 
mucosa! epithelium. More than 90% of 
oral cancers are SCC. Most cases of oral 
SCC are moderately to well differenti-
ated. For more detailed information on 
subtypes of SCC, see the correspond-
ing sections in Chapter 3 (Tumours of the 
hypopharynx, /arynx, trachea and para-
pharyngeal space, p. 77). 
Oral potentially malignant disorders, 
cl inical presentations carrying a risk of 
cancer development. and oral epithelial 
dysplasia, a spectrum of histological and 
cytological changes with an increased 
risk of progression to SCC, are also im-
portan! lesions for secondary prevention 
of oral SCCs. There are difieren! kinds of 
grading systems for epithelial dysplasia. 
In this chapter, a traditional three-tiered 
108 Tumours of the oral cavity and mobile tongue 
Takata T. 
Slootweg P.J. 
grading system and a binary system are 
described . For other grading systems and 
related terminology used for dysplasia/ 
squamous intraep ithelial lesion, refer to 
the corresponding sections in Chapter 3 
(Tumours of the hypopharynx, larynx, tra-
chea and parapharyngeal space, p. 77). 
Although the cause of oral SCC is mul-
tifactorial, accumulated information on 
etiological and genetic factors in oral 
SCC and related precursor lesions sup-
ports targeted diagnosis and therapy 
of oral SCC. The content of th is chapter 
reflects the increase in knowledge on 
oral diseases and its practica! appl ica-
tion in diagnosis and treatment. Hitherto 
unrecognized new entities deserving to 
be listed as such in this chapter have not 
been identified. 
Malignant surface epithelial tumours Sloan P. 
Gale N. 
Hunter K. 
Lingen M. 
Nylander K 
Reibel J. 
Salo T. 
Zain R.B . 
Squamous ce// carcinoma 
oefinition 
oral squamous cell carcinoma (OSCC) is 
a carcinoma with squamous differentia-
tion arising from the mucosal epithelium. 
The proportion of cases that arise in clini -
cally evident oral potentially malignan! 
disorders is unknown. lt is most frequent 
in the fifth and sixth decades of lite and 
is typically associated with risk factors 
such as smoking, alcohol consumption, 
and betel-quid chewing. 
ICD-0 code 8070/3 
Epidemiology 
More than 90% of cancers in the oral 
cavity are OSCCs. With respect to the 
epidemiology of oral cancer, specific ge-
ographical regions must be considered 
separately, because there is marked vari-
ation in incidence. Overall, oral cancer 
(when oropharyngeal siles are included) 
is the sixth most common cancer in the 
world [2548). The GLOBOCAN project 
estimated 300 373 new cases in 2012, 
with aglobal age-standardized incidence 
rate of 4.0 cases per 100 000 population 
per year and a global mortal ity rate of 
1.9 deaths per 100 000 population per 
year [702). High incidence of oral can-
cer is found in southern Asia (e.g . India; 
Pakistan; Sri Lanka; and Taiwan, China), 
with age-standardized incidence rates of 
> 10 cases per 100 000 population per 
year in parts ot India and Pakistan (702). 
lncidence is also high in eastern and 
western Europe (e.g. Hungary, Slovakia, 
Slovenia, and France), Latin America 
and the Caribbean (e.g. Brazil , Uruguay, 
and Puerto Rico), and Melanesia (e.g. 
Papua New Guinea) (702). Worldwide, 
oral cancer incidence is higher among 
males (5.5 cases per 100 000 popula-
tion per year) than temales (2.5 cases 
per 100 000). However, the rat io is the 
reverse in India and Thailand, where the 
reported male-to-temale ratios are 1 :2 
and U .56, respectively (1 280). Most 
oral cancers occur in patients aged 50-
70 years. As smoking rates decline, the 
A 
B 
Boll'IHAH 
C•noe1 ofthf' 1/p and 01111»1ity 
- 5.1• 
- 3.8-5.1 
1:1 2.5-3.S 
D u -2_5 
D <1_9 
BOl~ H XU 
Csnc:e-r ol the lip 111'\d 0<a! cevity 
- 2 .2• 
- l.&-2.2 
• 1,1.1 .c 
C) 0 .07-1 .1 
D <Q.e1 
No Data 
.. 
Fig. 4.01 Worldwide age-standardized rate (ASR) of (A) incidence and (B) mortality per 100 000 population per year, 
both sexes, of lip and oral cavity cancer. Reprinted from GLOBOCAN 2012, Ferlay J et al. {702}. 
incidence of intraoral cancer is decreas-
ing in sorne countries, whereas slight 
increases among younger patients have 
been reported in other countries (1456, 
2159). 
Etiology 
Smoking is by far the most importan! 
cause ot oral cancer. There is a dose-
dependent increase in risk, and. risk de-
creases after smoking cessation {1071, 
2550). Alcohol consumption interacts 
synergistically with smoking, resulting in 
a more than additive risk [121,865,1073). 
Smokeless tobacco is used orally in most 
parts ot the world, by chewing (chewing 
tobacco) or dipping (snuff). Smokeless 
tobacco in chewing or dipping torms 
causes oral cancer; however, sorne 
studies (in particular studies ot Swedish 
snuft) show negligible risk {229,1072). 
Areca nut and/or tobacco can be mixed 
with other substances (e.g. slaked lime, 
betel inflorescence, condiments, sweet-
ening agents, and spices) to create be-
tel quid. Betel-quid chewing increases 
the risk of oral cancer whether or not to-
bacco is added (900). HPV, in particular 
type 16, is a recognized etiological factor 
in oropharyngeal cancer but is only seen 
in a small minority (3%) of osees (515, 
840,1438,2135). Exposure to sunlight is 
Malignan! surtace epithelial tumours 109 
an established risk factor for lip cancer. Table 4.01 Subtypes of squamous cell carcinoma (SCC) of the oral cavity and mobile tongue 
In Western Australia, lip cancer accounts 
for as many cases as ali intraoral sites to-
gether {7) . Poor oral health is associated 
with oral cancer {591,899) but has not 
been proven an independent risk factor 
{2547}. A diet rich in fruits and vegetables 
seems to have sorne protective effect 
against oral cancer {264,1503}. 
Localization 
Oral cancer can affect any area of the 
oral mucosa. The most common siles for 
intraoral cancer in many populations are 
the tongue, floor of the mouth, and gin-
giva, accounting for more than half of all 
oral cancers (1337,1544,2423}. However, 
site distribution varies depending on 
the prevai ling risk factors. Among many 
Asian populations, osee most common-
ly affects the buccal mucosa, due to to-
bacco chewing and betel-quid chewing. 
Clinical features 
Oral cancers can be detected by visual 
inspection and palpation followed by bi-
opsy and histopathological examination. 
Evaluation of the neck is also importan!. 
Small cancers may be asymptomatic, 
whereas advanced tumours give rise to 
various symptoms and signs such as 
discomfort, pain, reduced mobil ity of the 
tongue, and irritation from wearing den-
tures. The clinical presentation is that 
of variably white, erythematous, mixed, 
nodular, and ulcerated changes; when 
present, ulcerated changes often have 
raised margins {120}. Non-healing ulcer-
ation is a feature suggestive of malignan-
cy; however, in a recent study, ulceration 
in osee (including its variants) was seen 
in slightly less than hall of the cases (56). 
eancer of the lower lip typically presents 
as a crusting lesion, often preceded by 
actinic cheilitis. An essential part of the 
diagnostic procedure for oral cancer is 
palpation of the lesion, typical ly revealing 
induration. Untortunately, small cancers 
are often unapparent to both patients 
and health professionals, resulting in di-
agnostic delay (872). One reason is that 
small cancers can mimic other lesions 
commonly seen in the oral cavity. 
Macroscopy 
Squamous cell carcinomas are firm in-
fi ltrative tumours, with a tan or white cut 
surface. 
Oral SCC subtype Features References 
Basaloid SCC High-grade carcinoma, more-frequent metastasis but overall {774,2653) prognosis comparable to that of conventional SCC 
Worse prognosis than conventional SCC in oral cavity and mobile 
Spindle cell SCC tongue; typically occurs as postradiation recurrence or second 
primary 
{187,824} 
- ---
Adenosquamous Highly infiltrative and aggressive, frequent metastasis, worse 
(1194, 1553,2113) carcinoma prognosis than conventional SCC 
--
Carcinoma Well differentiated, usually on mucoperiosteum, locally destructive 
cuniculatum deep burrowing pattern, metastasis rare, recurs locally but rarely if (2312) ever metastasizes 
Well-differentiated non-metastatic variant with pushing superficial 
Verrucous SCC invasion, exophytic, lacks atypia, good prognosis; may progress to {1517, 1759,2060) 
invasiva conventional SCC 
Lymphoepithelial Rare, present at high stage, 70% associated with regional lymph 
(2034) carcinoma nade metastasis; not ali are EBV-positive 
Papillary SCC Keratinizing and non-keratinizing types, often arises on gingivae; {1517,2060} better prognosis than conventional SCC 
High-risk cutaneous variant that may occur on the lip; acantholysis 
Acantholytic SCC can result in an adenoid appearance in poorly differentiated intraoral {605,807,2730} 
scc 
Cytology 
lntraoral tumours are usually evaluated 
by surgical biopsy. Meta-analysis shows 
that adjunctive tests cannot replace scal-
pel biopsy and histological assessment 
for oral cancer diagnosis {1985}. Fine-
needle aspiration is useful for the detec-
tion of lymph node metastasis. Aspirates 
are cellu lar, with sheets and small clus-
ters of malignan! squamous cells with 
intracellular and extracellu lar keratiniza-
tion. Mixed inflammation and necrosis 
can be present. 
differentiated; poorly differentiated squa-
mous cell carc inoma is less frequent. 
Well-differentiated osee is characterized 
by nests, cords, and islands of large cells 
with pink cytoplasm, prominent intercellu-
lar bridges, and round nuclei, which may 
not be obviously hyperchromatic. Dys-
keratotic cells and squamous pearls are 
prominent. Cellular and nuclear pleomor-
phism, nuclear hyperchromasia, and mi-
totic figures (including atypical forms) in-
crease with tumour grade. Grading alone 
does not correlate well with prognosis. In 
poorly differentiated osee, features of 
squamous differentiation are minimal or 
absent, requiring immunohistochemical 
confirmation; AE1/AE3, e K5/6, p63, and 
H istopathology 
Most cancers of the oral cavity and 
mobile tangue are moderately or well 
,•. ,. 
Fig. 4.02 Conventional, moderately differentiated oral squamous cell carcinoma showing keratin pearl formation. 
110 Tumours of the oral cavity and mobile tongue 
;__... __ 
Fig. 4.03 Oral squamous cell carcinoma of mobile tongue showing an adverse pattern of infiltration. 
p40 are useful markers. Well-differentiat-
ed tumours tend to invade in large islands, 
whereas less-differentiated tumours tend 
to have jagged or finger-like projections 
or smallislands and dispersed ind ividual 
cel ls at the invasive front. Significan! des-
moplastic stroma with inflammatory host 
response can be found around nests 
of invading tumour cells. Adjacent mu-
cosa frequently shows various grades 
of epithel ial dysplasia. Perineural and 
lymphovascular invasion are seen, more 
frequently in poorly differentiated tumours 
{258,297,1424,2494). 
Genetic profile 
Most osees are genetically unstable 
(183,1885,2070). with chromosomal loss 
at 3p, 8p, 9p, 17p and gains at 3q and 
11q {396,2375}. These changes may ex-
tend for sorne distance from the clinical 
lesion, underpinning the clinical phe-
nomenon of f ield cancerization (249). 
Genes reported to have a role in osee 
(e.g. TP53, CDKN2A, PTEN, HRAS, and 
PIK3CA) are mutated with sufficient fre-
quency to support their potential role 
as drivers in cancer development {818, 
1492,1712,1885,2288,2375}. 
Genetic susceptibility 
The evidence of inherited genetic sus-
ceptibility for the development of osee 
is limited. osee may arise as part of a 
more general cancer syndrome, such as 
in patients with Li-Fraumeni syndrome 
(1924] or Fanconi anaemia (223} . 
Prognosis and predictiva factors 
eonventional osee is aggressive, with 
a propensity for local invasion and early 
lymph node metastasis. The most signifi-
can! prognostic factors are tumour size, 
nodal status, and distan! metastasis. 
eonventional histological grading corre-
lates poorly with clinical outcomes (259). 
Histological risk factors associated with a 
worse prognosis include a non-cohesive 
pattern of invasion {1424). perineural and 
lymphovascular invasion {2636,2640). 
bone invasion {625], and thickness 
> 4 mm {57}. Margins from the resec-
tion specimen predict local control better 
than margins from the tumour bed {1562}. 
High-grade dysplasia at a mucosa! mar-
gin correlates with local recurrence and 
second primary tumours (1424,2561). Ex-
tracapsular spread f rom metastasis in the 
neck, two or more positive nodes, and 
involvement of levels IV and V correlate 
with adverse outcome. 
Malignan! surface epithelial tumours 11 1 
Oral potentially malignant disorders 
and oral epithelial dysplasia 
Oral potentially malignant 
disorders 
Definition 
Oral potentially malignant d isorders 
(OPMDs) are c linical presentations that 
carry a risk of cancer development in the 
oral cavity, whether in a clinically defin-
able precursor lesion or in c linically nor-
mal oral mucosa. 
Epidemiology 
In western countries, the reported preva-
lence of leukoplakia general ly ranges 
from 1% to 4%. Higher prevalence rates 
are reported in parts of south-eastern 
Asia {1704}. The g lobal prevalence of leu-
koplakia is 2- 3% {1871}. In contras\, oral 
erythroplakia is a rare lesion, w ith preva-
lence between 0.02% and 0.83% {1972} . 
Men are affected much more commonly 
than women. Other OPMDs can be com-
mon, but have much lower transformation 
rates. 
Etiology 
OPMDs have different causes. Tobacco 
use (smoking and/or chewing) and al-
cohol consumption are associated with 
sorne leukoplakias {1704). The use of 
areca nut, w ith o r without tobacco, caus-
es oral submucous fibrosis {2404). For 
many cases of OPMDs, no etiological 
factors are known . High-risk HPV infec-
t ion is only very rarely present in OPMDs 
Table 4.02 Oral potentially malignan! disorders 
Erythroplakia 
Erythroleukoplakia 
Leukoplakia 
Oral submucous fibrosis 
Dyskeratosis congenita 
Smokeless tobacco keratosis 
Palatal lesions associated with reverse smoking 
Chronic candidiasis 
Lichen planus 
Discoid lupus erythematosus 
Syphilitic glossitis 
Actinic keratosis (lip only) 
{1567,2629), and whether it plays a role in 
transformation has yet to be determined. 
Localization 
OPMDs can involve any intraoral site. 
Their distribution varíes by specific d is-
order, with etiological factors, and to a 
certain extent patient age and sex {1704}. 
Erythrop lakia is most frequently seen on 
the soft palate, floor of the mouth, and 
bucea! mucosa {1972). 
Clinical features 
Most high-risk OPMDs form red, white, 
or sp eckled oral lesions. "Leukoplakia" 
is a clinical term used to describe white 
plaques of questionable risk, once other 
specific conditions and other OPMDs 
have been ruled out {2551}, which nor-
mally requ ires biopsy. Leukoplakias can 
be homogeneously white or predomi-
nantly white with nodular, verrucous, or 
red areas . Predominantly white examples 
with red areas are called erythroleuko-
plakias (speckled leukoplakias). Oral 
erythroplakia is defi ned equivalently, 
but as a red patch. Specifically defined 
OPMDs have characteristic presenta-
tions, and epithelial dysplasia may or 
may not be present. Other OPMDs have 
been reviewed elsewhere {2475). 
Genetic susceptibility 
OPMDs are seen in the rare disorders 
Fanconi anaemia {889) and dyskeratosis 
congenita {932), but no genetic predis-
position is present in most cases. 
Prognosis and predictive factors 
The transformation risk in many OPMDs 
is low, and many regress (1307}. For leu-
koplakia, a mean global transformation 
rate of 1- 2% has been estimated {1871}. 
A meta-analysis of cases with oral epithe-
lial dysplasia found a transformation rate 
of 12% (1579). Presence of oral epitrielial 
dysplasia is the most important prognos-
tic factor for malignant transformation, 
but c linical characteristics such as ap-
pearance (homogeneous vs. non-homo-
geneous), s ize, and site also have impli-
cations for clinical management {1704}. 
112 Tumours of the oral cavity and mobile tangue 
Reibel J . Tilakaratne W.M. 
Gale N. Westra W.H . 
HilleJ. Williams M.O. 
Hunt J .L. Vigneswaran N. 
U ngen M. Fatani HA 
Muller S. Odell E.W. 
Sloan P Zain R.B. 
Oral epithelial dysplasia 
Definition 
Oral epithelial dysplasia (OED) is a spec-
trum of architectural and cytological epi-
thelial changes caused by accumulation 
of genetic changes , associated w ith an 
increased risk of progression to squa-
mous cel l carcinoma. 
ICD-0 codes 
Low grade 
High grade 
Synonyms 
8077/0 
8077/2 
Epithelial precursor lesions; intraepithe-
lial neoplasia; squamous intraepithelial 
lesions 
H istopathology 
OED includes abnormal proliferation, matu-
ration , and differentiation of epithelial cells. 
The epithelium may be atrophic, acanthot-
ic, keratinized, or non-keratinized. Dyspla-
sia is present in a minority of leukoplakias 
but is a consisten! finding in erythroplakia 
and erythroleukoplakia. 
Table 4.03 lists the architectural and cyto-
logical disturbances that are used to diag-
nose OED. The number and combination 
of features vary between lesions. There is 
no good evidence to indicate how the pres-
ence of individual features could be trans-
lated into a grade of dysplasia. No specific 
combination of features reliably distinguish-
es hyperplasia from mild dysplasia. OED 
may be diagnosed on the basis of architec-
tural or cytological features alone. 
Traditionally, OED is divided into three 
grades of severity. Judging the number 
of thirds of the epithelium affected is one 
factor in defining a grade. Mild dysplasia 
can be defined by cytological atypia lim-
ited to the basal third, moderate dysplasia 
by extension into the middle third , and se-
vere dysplasia by extension into the upper 
third. However, architectural and cytologi-
cal atypia and the architecture of the con-
nective tissue interface should increase the 
grade. Marked atypia in the basal third of 
the epithelium may be suffic ient for a di-
agnosis of severe dysplasia. Carcinoma in 
Table 4.03 Diagnostic criteria for epithelial dysplasia; adapted from Barnes Letal. {146) 
Architectural changas _____ Cytological changes 
Irregular epithelíal stratification 
Loss of polarity of basal cells 
Drop-shaped rete ridges 
lncreased number of mitotic figures 
Abnormally superficial mitotic figures 
Premature keratinization in single cells 
Keratin pearls within rete ridges 
Loss of epit11elíal cell cohesion 
Table 4.04 Gradingsystems for epithelíal dysplasia 
WHO dysplasia grade 
Mild dysplasia 
Moderate dysplasia 
e--
Severe dysplasia 
Abnormal variation in nuclear size 
Abnormal variation in nuclear shape 
Abnormal variation in cell size 
Abnormal variation in cell shape 
lncreased N:C ratio 
Atypical mitotic figures 
lncreased number and size of nucleolí 
Hyperchromasia 
Binary system 
Low-grade dysplasia 
High-grade dysplasia 
- -
~ 
The cut-off point between low-grade and high-grade dysplasia, as suggested by Kujan O et al. {1291), is tour 
architectural and five cytological changes (see Table 4.03}, irrespective of the level within the epithelium. 
According to Nankivell P et al. {1702), a cut-off point of tour architectural and four cytological changes may improve 
prognostication. 
situ in the oral cavity is considered synony-
mous with severe dysplasia. 
Dysplasia grading is poorly reproducible 
between observers. Sorne studies show 
good prognostic value (2250). but others 
find a poor association with outcome {721, 
1505) . Consensus grading after review by 
more than one pathologist may enhance 
diagnostic reliabil ity (733,2249,2250). To 
improve reproducibility, sorne authors ad-
vocate a binary system (1291 ,1702,2553}, 
in line with proposals for laryngeal lesions 
(798), but binary scoring requires validation 
befare it can be routinely applied in the oral 
cavity. 
An unusual subset of OEDs positive for 
HPV has been described, histologically 
characterized by epithelial hyperplasia 
and marked karyorrhexis and apoptosis 
throughout the epithelium {2629). Accord-
ing to conventional criteria, these qualify 
as severe dysplasia, but the risk of trans-
formation has yet to be determined. lmmu-
nostaining far p16 alone cannot be used 
as a surrogate marker for HPV infection in 
OED. 
Genetic profile 
Prognostic genetic and molecular mark-
ers for malignan! transformation have 
been reported {1902,1971). most notably 
LOH at chromosomal arms 3p and 9p 
{316,2017) in combination with two addi-
tional markers at 4q and 17p {2712}. 
Prognosis and predictive factors 
Although the presence of dysplasia 
correlates with the development of 
squamous cell carcinoma, most OEDs 
never progress to carc inoma. A meta-
analysis of lesions with OED showed a 
transformation rate of 12% [1579). Gen-
erally, the more advanced the degree 
of dysplasia, the higher the likelihood of 
developing squamous cell carc inoma 
{1366,1579,2176,2552}. The 15-year 
mal ignan! transformation rates of mild, 
moderate, and severe dysplasia (as 
defined by the traditional three-grade 
system) are approximately 6%, 18%, 
and 39%, respectively, and the pres-
ence of dysplasia indicates long-term 
risk {2250) . The general problem of low 
reproducibility of curren! diagnostic c ri-
teria underlies the poor correlation with 
transformation found in sorne studies 
{276,601,1016). 
Prolíferative verrucous 
leukoplakia 
Definition 
Proliferative verrucous leukoplakia (PVL) 
is a distinct and aggressive form of oral 
potentially malignan\ disorder {2551). lt is 
multifocal, has a progressive course, and 
is associated with high recurrence and ma-
lignan! transformation rates {2,839,936). 
Epidemiology 
PVL is rare in comparison with conven-
tional oral leukoplakia. lt occurs in older 
Table 4.05 Selected recen! reports on malignan! transformation of oral leukoplakia; in part adapted from Warnakulasuriya S and Ariyawardana A {2549) 
Frequency 
Authors/year Country Cases Notes 
Observation period of malignan! 
(years) transforma-
tlon 
Saito T et al . 2001 {2046) Japan 142 a, b 4 (0.6-16) 6.3% 
~ lmstrup P et al. 2006 {1016) Denmark 254 a, b 6 (1.1-20.2) 6.7% --
Warnakulasuriya Set al. 2011 {2552); 
United Kingdom 335 a,b 9 6.9% 
Sperandio Metal. 2013 {2250) 
·-
Ho MW et al. 2012 {1007) 
1----
United Kingdom 83 a,c 5 24.1% 
Liu W et al. 2012 {1450) China 320 a, c 5.1 (1-20) 17.8% 
Brouns E et al. 2014 {276) Netherlands 144 a,b 4.7 (1-14.9) 11.0% -
Dos! F et al. 2013 {600) Auslralia 368 a,c,d Not available 7.1%· 
Mehanna HM et al. 2009 {1579) Meta-analysis 992 c, d Not applicable 12.1% 
>- -
"rreated and untreated cases. bWith and without dysplasia. coysplasias only. dlncludes clinical diagnoses other !han leukoplakia. "Annual transformation rate: 1%. 
Oral potentially malignan! disorders and oral epithelial dysplasia 113 
Fig. 4.04 Proliferative verrucous leukoplakia. A61-year-old woman presented with an advanced proliferative verrucous 
leukoplakia involving the dorsal (A) and ventral surfaces of the tongue and palate (B). The patient had undergone 
multiple biopsies and surgeries during the previous 4 years, which had resulted in diagnoses of invasive and in situ 
squamous cell carcinomas. 
patients (aged > 60 years), with a female-
to-male ratio of 4:1 {2,311}. 
Etiology 
The etiology is unknown. In Europe and 
North America, PVL is not associated 
with known risk factors of oral cancers 
(i.e. tobacco use and alcohol consump-
tion). Neither HPV nor any other virus is 
associated with the development of PVL 
(81 1). 
Localization 
PVL frequently involves gingiva, alveolar 
mucosa, and palate {839). The lateral 
and ventral surfaces of the tangue and 
floor of the mouth are rarely involved dur-
ing the early stages of PVL. 
Clinical features 
PVL exhibits varied clinical features in four 
clinical stages: (1) focal flat white kerato-
sis, (2) diffuse and multifocal white patch-
es, (3) slowly progressive horizontal and 
exophytic growth resulting in a warty (ver-
rucoid) surface with focal erythematous 
areas, and (4) development of verrucous 
or squamous cell carcinoma {839}. How-
ever, not every PVL goes through these 
cl inical stages, and development of car-
cinoma has been noted in PVL clinically 
presenting as multifocal flat patches. 
Histopathology 
Histopathology corresponds to the varied 
clinical features of PVL: localized flat or 
verrucous hyperorthokeratosis with mini-
mal or no dysplasia, resulting in the un-
derestimation of risk of malignan! trans-
formation of these lesions during their 
early stages. Dysplasia develops only 
during the late stages of PVL, before pro-
gressing into either verrucous or squa-
mous cell carcinoma (839). Definitive 
diagnosis of PVL requires clinical and his-
topathological correlation. PVL frequently 
shows interface mucositis characterized 
by a band-like, lymphohistiocytic infiltrate 
subjacent to the basal cells; therefore, it 
may be misdiagnosed as lichen planus 
in early stages {311,839}. However, the 
. • ~~·, 
f'l'\,~ ·fl::.~ 
~~!t 
Fig. 4.05 Oral epithelial dysplasia. A Hyperkeratosis with normal architecture and cytology. B Mild dysplasia: lack of polarization of basal cells, abnormal variation in nuclear size, 
shape, and stainability (hyperchromasia), and increased number of mitotic figures. Changes are confined to the basal third of the epithelium. C Moderate dysplasia: drop-shaped 
rete ridges, mild abnormal variation in nuclear size and stainability (hyperchromatism), increased nuclear/cytoplasmic ratio, and atypical mitotic figures in the basal/parabasal area. 
Changes extend to the mid-third of the epithelium. 
114 Tumours of the oral cavity and mobile tangue 
presence of any dysplasia precludes the 
diagnosis of lichen planus. Diagnosis 
also requires the distinction of PVL from 
other white oral lesions by correlating the 
clin ical and microscopic presentations 
both retrospectively and prospectively 
through clase surveillance. 
Genetic profile 
lnactivation (by homozygous deletion) 
of COKN2A (also called P16/NK4a and 
P14ARF), which codes for the tumour 
Papillomas 
Squamous ce// papilloma 
Muller S. 
Gale N. 
Odell E.W. 
Richardson M. 
Syrjanen S. 
Definition 
Squamous cell papilloma is a benign hy-
perplastic exophytic localized prolifera-
tion with a verrucous or cauliflower- like 
morphology [2284l. 
ICD-0 code 8052/0 
Epidemiology 
Squamous cell papillomas are common 
and can occur in patients of any age, 
althoughthey occur more frequently 
in the third to fifth decades of lite 
{1914,1925,2284) . There is an equal sex 
distribution. 
suppressor proteins p16 (p161NK4a) and 
p14ARF, is more frequent in PVL {1279} 
than in other oral potentially malignan! 
disorders. Like other oral potentially ma-
lignan! disorders, PVLs also develop 
chromosomal instability, and DNA an-
euploidy can predict their risk of devel-
oping into carcinoma {1234). 
Prognosis and predictiva factors 
As many as 70% of PVLs develop into 
invasive cancer, resulting in a mortality 
Etiology 
HPV infection has been reported, with 
the most common types being 6 and 11 
(886,1168,1668,2324}. Reported preva-
lence rates of HPV DNA in oral squa-
mous cell papillomas range from 0% to 
100% (average: 34%) {1168,1668). This 
considerable variation may be due to dif-
ferences in the HPV detection techniques 
used. 
Localization 
Any oral site can be involved, but the 
most common sites are the soft palate, 
tangue, lips, and gingiva (1914,1925, 
2284). 
Clinical features 
Squamous cell papillomas may" be pe-
dunculated or sessile. The pedunculated 
lesions are composed of a cluster of fin-
ger-like fronds and may be white or mu-
cosa! in colour, depending on the degree 
of keratinization. The sessile lesions are 
rate of 30-40% (2,311). Carcinomas aris-
ing from PVL have better prognosis and 
long -term survival !han do conventional 
oral cancers. The development of multi-
ple primaries at different locations is not 
uncommon in patients with PVL {36). 
dome-shaped and have a more nodular, 
papillary, ar verrucous surface (1925, 
2284). Most squamous cell papillomas 
are solitary and grow rapidly to about 
0.5 cm. Clinically distinguishing oral 
squamous cel l papilloma from verruca 
vulgaris, condyloma acuminatum, and 
multifocal epithelial hyperplasia is diffi-
cult [2325). Multiple papillomas can be 
seen in the setting of solid organ trans-
plant and HIV infection . 
Histopathology 
The lesions are exophytic, composed 
of papi llary proliferations of hyperplas-
tic stratified epithel ium that are either 
covered by a layer of parakeratin or or-
thokeratin of variable thickness or are 
non-keratinized (2284} . The finger-like 
epithel ial projections extend from a nar-
row base, supported by fibrovascular 
cores containing dilated capillaries. The 
stroma may be oedematous or hya-
linized. Koilocytes are infrequent and 
Papillomas 115 
mitotic activity unusual, except in the set-
ting of trauma or inflammation [2284). 
Prognosis and predictiva factors 
Treatment is simple excision, and recur-
rence is unusual {1914). There have been 
no reports of malignan! transformation or 
dissemination. 
Condyloma acuminatum 
Vigneswaran N. 
Lippman S. 
Muller S. 
Williams M.O. 
Definition 
Oral condyloma acuminatum (CA) is the 
oral equivalent to anogenital CA. 
Synonym 
Venereal condyloma 
Epidemiology 
Oral CAs are frequently transmitted 
sexually, with a peak incidence in young 
adults and a male predominance {1258, 
2284). Autoinoculation in patients with 
genital CA has been reported. Occur-
rence in children may be associated with 
sexual abuse {2284). Multiple CAs may 
indicate immunodeficiency. 
Etiology 
HPV type 6 or 11 is identified in most 
cases. Neither histological appearance 
nor HPV type is an accurate indicator of 
genital origin, and non-sexual transmis-
sion is possible {2325}. 
Localization 
CAs most o/ten occur on the labial mu-
cosa, soft palate, and frenulum {2284}. 
Clinical features 
Clinically, CA presents as a single or 
cluster of asymptomatic, painless ses-
sile masses with an exophytic growth 
pattern. The surface is finely nodular, 
pink to slightly red , and tlatter than that 
of verruca vulgaris. The lesions are larger 
than squamous cell papillomas; reaching 
15 mm in diameter {976,2284). 
Fig. 4.09 Condyloma acuminatum. Clinically, a sessile, 
flnely nodular, pink mass is identifled on the frenulum of 
the tangue. 
116 Tumours of the oral cavity and mobile tangue 
Histopathology 
Histopathology shows a hyperplastic 
squamous proliferation associated with 
fibrovascular cores, exophytic growth, 
and a broad base. Basilar nuclear en-
largement may be present, but keratino-
cyte maturation is maintairied, typically 
without the keratinization seen in verruca 
vulgaris. Compared with squamous cell 
papillomas, CAs have broader papil lae, 
which are o/ten blunted. The rete pro-
cesses are bulbous, short, and straighter 
than those seen in papillomas, and 
koilocytes are more readi ly identified 
[77). In situ DNA hybridization or PCR 
amplification studies may be required 
far detection and typing of HPV to distin-
guish these lesions from other exophytic 
growths, including verrucous squamous 
cell carcinoma. 
Prognosis and predictiva factors 
Recurrence after excision is common and 
more frequent than in squamous cell pap-
illomas. Malignant transformation has not 
been reported in oral CA. HPV vaccines 
that protect against types 6 and 11 could 
also help to prevent associated CA {993}. 
Verruca vulgaris 
Muller S. 
Lippman S. 
Wil liams M.O. 
Definition 
Verruca vulgaris (VV) is a benign virus-
induced hyperplastic localizad pro lifera-
tion with a verrucous or caulif lower-like 
morphology {2284). 
Epidemiology 
VV is the most common HPV-related le-
sion of the skin, but can also occur in the 
oral mucosa, perhaps as a result of au-
toinoculation {886,1925). Oral VV is most 
common in the third to fourth decade of 
life, with a slight male pred ilection. 
Etiology 
Commonly reported HPV types include 
2, 4, 40, and 57 {541,1455,2284). 
Localization 
The most commonly reported oral sites 
are the lips, hard palate, anterior tongue, 
and gingiva. 
Clinical features 
VV is asymptomatic. lt may be peduncu-
lated or sessi le with a rough pebbly or 
papi llary white surface {1455,1925,2284). 
VVs grow rapidly (to a maximum size 
of < 5 mm), and multiple or clustered 
lesions can occur. 
Histopathology 
VVs are exophytic, composed of papil-
lary proliferations of hyperplastic strati-
fied epithelium that are covered by a 
thick layer of orthokeratin ¡1925,2284). 
The elongated rete ridges converge to-
wards the centre. A prominent granular 
cell layer with keratohyalin granules often 
shows koilocytic changes. 
Prognosis and predictive factors 
Spontaneous regression is seen, par-
ticu larly in ch ildren. Treatment is simple 
excision, and recurrence can occur (886, 
1455,1925). 
Mulüfocalepfthellalhyperplasia 
Vigneswaran N. 
Carlos R. 
Lippman S. 
Mosqueda-Taylor A. 
Muller S. 
Will iams M.O. 
Definition 
Multifocal benign squamous epithe-
lial proliferation exclusively affecting oral 
mucosa, caused by human papil loma 
virus (HPV) {1965,2042). 
Synonyms 
Heck disease; focal epithelial hyperplasia 
Fig. 4.11 Multiple papules in the lower lip mucosa of a 
15-year-old boy. 
Epidemiology 
Multifocal epithelia l hyperplasia (MFEH) 
is more prevalen! in children and ado-
lescents with a female predominance as 
high as 5:1 {1965,2042). First reported in 
Native Americans and Eskimo peoples, 
it is panracial, documented in a lmost 
every ethnic group and geographical 
reg ion {2042). 
Etiology 
HPV types 13 and 32 are implicated. 
However, other genotypes such as 1, 6, 
11 , 16, 18 and 55 have also been detect-
ed {974,2042}. MFEH in o lder patients is 
mainly caused by HPV 32 (2042). Low 
socioeconomic status, malnutrition and 
c rowded living conditions are thought 
to be contributing factors. These prob-
ably explain the striking epidemio logi-
cal d ifferences between developed and 
developing countries . HIV patients have 
increased risk for MFEH (2042,1 233}. 
Localization 
The most common locations for MFEH 
are the lips, buccal mucosa, and bor-
ders of the tongue. Hard palate and g in-
giva are rare ly affected {2042}. The low-
er lip is characteristically more affected 
than the upper lip, and most lesions in 
the buccal mucosa are located along the 
occlusal plane. 
Clinicalfeatures 
MFEH presents as multiple papules sim-
ilar in colour to the adjacent mucosa, 
measuring up to 5-10 mm. They may 
coalesce, forming plaques that may be-
come secondarily keratinized. The most 
common appearance is a papulonodular 
form with a smooth surface that occurs in 
the non-keratinized mucosa. 
Papillomas 117 
Fig. 4.12 Focal epithelial hyperplasia, viral change and mitosoid body (inset). 
Histopathology 
MFEH shows mild hyperkeratosis and 
prominent acanthosis, with preserva-
tion of normal cell maturation {2042). 
Occasional koilocytes and "mitosoid" 
figures composed of cells with karyor-
rhectic nuclei that may mimic mitoses, 
representing a cytopathic nuclear viral 
damage, are noted within ali epithelial 
layers {2042). The mitosoid figures are 
the most importan! feature of this entity; 
they are not present or are extremely rare 
in other HPV-related lesions. HPV sub-
types implicated in MFEH do not cause 
118 Tumours of the oral cavity and mobile tangue 
functional inactivation of the RB gene 
and hence p16 immunohistochemistry 
has no diagnostic role. 
Genetic susceptibility 
Familia! transmission of MFEH is linked to 
the presence of HLA-DRB1*0404 (810). 
Prognosis and predictive factors 
Most lesions in chi ldren spontaneously 
disappear al puberty or with improved 
living conditions. 
Tumours of uncertain histogenesis 
congenital granular ce// epulis 
Allen C.M. 
Bullerdiek J. 
RoJY 
Definition 
Congenital granular cell epulis is a rare 
benign tumour that affects the alveo-
lar processes of newborns and is com-
posed of sheets and nests of cells with 
abundan! granular cytoplasm {479). 
Synonyms 
Congenital epulis; congenital epulis of 
the newborn; congenital gingival granu-
lar cell tumour; Neumann tumour 
Epidemiology 
Congenital granular cell epulis affects 
newborns. Most series identify a striking 
female predilection {2698). 
Localization 
Most cases develop on the maxillary 
anterior alveolar process, although the 
mandibular anterior alveolar process can 
also be affected {428}. 
Clinical features 
Congenital granular cell epulis typically 
presents as a pedunculated soft tissue 
mass of normal mucosa! colour, ranging 
... 
Fig. 4.14 Congenital granular cell epulis of the maxilla. 
Fig. 4.15 Congenital granular cell epulis. Lesiona! 
cells with small, uniform nuclei and abundan! granular 
cytoplasm. 
from < 1 cm to severa! centimetres in di-
ameter {1293). 
Histopathology 
Congenital granular cel l epulis is char-
acterized by sheets and nests of large 
polygonal cells with demarcated cell 
membranes and granular cytoplasm. The 
r ,.- J # /
141':,,~.,' .... ~ .... ,., .:~. >-#: .. . ,, • 
• - , - ;" ... "'. ~-~ ..11, ... ... ,. • .. :..;,.1,,.• .. ... . ' ·--:k ~. i·~'-li'i'¡'j ~ .. ~ 1:. ,{¡., ... , - --9: .. -~--: •; - ; ~ -..... • • • " ... .._ , 
'_,; - _,;.t~ .. .;' ~,.,,, ...-... ~~ .. ~ . ~. ~., ~ - ·~";. ... :. • .. • - , • . 
. , _-,. -:. ti ~-· .. ·~!J: .... a_ ,. • .. -.. ...>_~ ... .. .A ........... l.-.. .. t · . .,:a, • ':'Y-'~ • • J : ·>; # ... ... ~-- . . .,.. '"';. -- ~·.. ..... ,. 'IJ " "' - ~ . ... .. ~ ! • • ...,..,~ ¿ .. 
· ~ • # , ~ • :...::. ~ ~ -~ ' ··~~·w•,: ; .. -·· ,-~,.. ¡: "'~ -·-- -: , .. ... ~~ !...,, 
1, .,, • ,~' \ • , # , • • ' ., .... - , , ~ - ... .¡ t • ~ :,-. 
' . •.,f ,. • ._"t... - ., • ,._~. ' ··- -, ,. ~ -. · - •'le · ~-·,• , .. ,111~ ,.,. .. •••,,._."/ ,•. / / ~-.! •...,_~ ... -- .:~ , ., • ' f.•• _,.,• ' :, ' ,~~ 
'.ti ..:-- \ , ,•.: . ... - .. ., -.__.. ,, .. ',/ , ... '\ "'"' • • • .... /. ··- . , ~ . • , ,..- . ,. -..! "' ) ·- \""' ,, - 7 •: ; • ., ..... ,, - .. : .. -'~ . 
• , ,.~ ' .,,.,. .,.,. • •} "" , ,. .... f "' · # _, .,. .. . 
' r.tf, '· • ' · -; · ; • ... 'L , • J * · ~ "' ..,, . ... ., ~ 1~· 
· ,· • l -, ,~"· \ ~ """, .... ,, • . .,. .. , ,- • ',; . ,, .. . , ... • 61. 
\ ... ..._ • \ 'I ~ 1 .. / f'\ , • :" ,. • • f • r '/'' -. - •' 7 • 
• • I ' .. ~ ;. • • . • ..., ,, • .J. , • ~ .. •• • A. , 
~ - , .. "". 4 ,... • - • 
~ .... __ , "' " .... , ' ,, ,. ' ,.,, , ' ..... • • • . .. • • tlll!" 
1'4 , .,. ~·" .M ' ',, . ; _ ,., •• "' , • ' • , '• ... - .. . 1111! .. ~ 
~ 
. •• ~· !:' ~~ ., ~ . .. ..l.¡ t ., •. ,,, .. ..... t ~- ... t 
J, ..,. ' .,,, ~ 4 1' I • • 1 • ,. 
1
• • '¡ " L . . ~ ~ •, ~~ . .-, . ' . '1 ' . .. . 4(1' ., • " _.. • , ~ • ,# 
., - ' ~"i ..,,.._ • • , ..... . • •• . .,. • .. . 
~ ' ... ;~ .. ~ . , - . - ' .. .. " } ' 
~ . ~ ~·- .. - .... ~ ¿ .... ., . " . ' ' 
Fig. 4.13 Congenltal granular cell epulis. Bland, attenuated surface oral epithelium and underlying sheets of uniformly 
distributed lesiona! cells with scattered delicate blood vessels. 
overlying surface epithelium is usually at-
tenuated, and pseudoepitheliomatous 
hyperplasia is not a feature. The tumour 
nuclei are typically small, uniform, and 
pale-staining, with no evidence of mitotic 
activity {428). In most cases , numerous 
small, thin-walled blood vessels are uni-
formly distributed throughout the lesion . 
Unlike the lesiona! cells of granular cell 
tumour of the tangue, those of congenital 
granular cell epulis show no reactivity for 
S100 protein. 
Prognosis and predictiva factors 
Conservative excision is the treatment 
of choice, particularly if the lesion in-
terferes with eating or breathing !1304). 
Excisional biopsy may also be indicated 
if the cl inical diagnosis is uncertain. For 
smaller lesions, observation may be ap-
propriate, because spontaneous regres-
sion has been noted occasionally. Recur-
rence is not seen. 
Ectomesenchymal 
chondromyxoid tumour 
Bishop J. A. 
Gnepp D.R. 
Ro J.Y. 
Definition 
Ectomesenchymal chondromyxoid tu-
mour (EMCMT) is a benign mesenchy-
mal neoplasm composed of cells pheno-
typical ly resembling myoepithelial cells. 
ICD-0 code 
Synonym 
Myoepithelioma {1736,2630} 
Epidemiology 
8982/0 
About 60 cases of EMCMT have been 
reported, affecting a wide patient age 
range (7- 78 years), with a mean patient 
age of 37 years. No sex predilection is 
apparent (44,2218}. 
Tumours of uncertain histogenesis 119 
Localization 
In the oral cavity, EMCMT arises almos! ex-
clusively in the dorsum of the anterior tangue. 
Rare cases have been reported in the poste-
rior tangue and hard palate {44,1735). 
Clinical features 
EMCMT presents as a longstanding 
(present fo r months or even years), pain-
less, submucosal tangue mass without 
ulceration. 
Macroscopy 
EMCMTs are generally small (< 2 cm), 
circumscribed, tan-grey nodules with a 
gelatinous gross appearance. 
Cytology 
Cytology shows cellu lar smears with 
myxoid to thick fibrillary tissue fragments, 
with clusters of oval, polygonal, or spin-
dled cells with uniform nuclei [440). 
H istopathology 
EMCMT is an unencapsulated but 
generally well-circumscribed neoplasm 
within the tangue submucosa. Entrap-
ment of skeletal muscle fibres may be 
seen. At low power, EMCMT grows as 
lobules of cells separated by fibrous 
bands, with frequent slit-like clefts within 
the tumour. The tumour cells are round, 
fusiform, or spindled cells arranged in 
cords, sheets , or a reticulated pattern 
within a myxoid or chondromyxoid 
stroma. Tumour cells have moderate 
amounts of eosinophilic to amphophilic 
cytoplasm, indistinct cel l borders, and 
nuclei with irregular membranes (e.g. 
with indentations or pseudoinclusions). 
Hyperchromatic nuclei and nuclear 
enlargement or multinucleation may be 
encountered . Mitotic figures are rare. 
Plasmacytoid cells and ductal structures 
are not encountered. • 
120 Tumours of the oral cavity and mobile tangue 
EMCMT is consistently immunoreactive 
far GFAP and usually immunoreactive far 
S100 protein and CD57. lmmunostaining 
far cytokeratins, EMA, actin, and p63 is 
variable [44,2218). 
Cell of origin 
The cell of orig in is unknown. EMCMT 
may arise from undifferentiated ectomes-
enchymal cells from the embryonic neu-
ral crest mesenchyme of the first b ranchi-
al arch [2218). Minar salivary gland origin 
is less likely, given the inconsistent cy-tokeratin immunostaining and absence of 
minor salivary glands in the dorsal ante-
rior tangue {880}. 
Prognosis and predictive factors 
The prognosis is excellent, with a low risk 
of recurrence. 
Soft tissue and neural tumours 
Granular ce// tumour 
Allen C.M. 
Gnepp D.R. 
Ro J.Y. 
Definition 
Granular cel l tumour is an uncommon 
benign tumour of Schwann-cell differen-
tiation characterized by poorly demar-
cated accumulations of plump granular 
cells (2458). 
ICD-0 code 9580/0 
Synonyms 
Granular cell myoblastoma; granular cell 
schwannoma; granular cell neurofibro-
ma; Abrikossoff tumour (ali obsolete) 
Epidemiology 
Most granular cell tumours are diagnosed 
during the third to fifth decades of lite, 
although they may occur in patients 
of any age. Most reports describe a 
female-to-male ratio of 2:1, anda higher 
incidence in Black populations has been 
noted. 
Localization 
Although granular cell tumour can affect 
any subcutaneous ar submucosal site, 
approximately 30-40% of cases occur 
on the tangue. The buccal mucosa is the 
second most common intraoral site. 
Fig. 4.17 Granular cell tumour. Sessile nodule of the 
dorsal tangue showing intact surface mucosa that is 
stretched by the underlying tumour. 
Clinical features 
Granular cell tumour presents as a non-
tender, rubbery-firm, slow-growing, ses-
sile, submucosal mass. On palpation, the 
tumour often feels demarcated, but not 
encapsulated. lf the tumour is near the 
surface, a yellowish to creamy-white col-
our is afien apparent. Most granular cell 
tumours are solitary, but multiple tumours 
have infrequently been reported (2074). 
Macroscopy 
On cut surface, the tumour is a pale tan 
to yellowish-white submucosal nodule. 
Histopathology 
This unencapsulated submucosal tumour 
intermingles with the adjacent normal tis-
sue. The lesiona! cells usually appear po-
lygonal and exhibit abundan! eosinophil -
ic granular cytoplasm. The tumóur nuclei 
may be centrally or eccentrically located 
and are typically uniformly small, round, 
and pale-staining . The granular cells are 
often intimately associated with adja-
cent muscle fascicles or nerves. Sorne 
granular cell tumours have a significan! 
degree of background fibrosis, with rela-
tively few lesiona! cells. The cytoplasmic 
granules give a diastase-resistant posi-
tive periodic acid-Schiff (PAS) reaction. 
lmmunohistochemistry is positive for 
S100 protein, CD57, and SOX10 {72). 
CD68 antibodies also label the cytoplas-
mic granules . Pseudoepitheliomatous 
hyperp lasia overlies a substantial propor-
tion (30- 50%) of these lesions; therefore, 
care should be taken when evaluating a 
superficial biopsy sample to preven! an 
erroneous diagnosis of squamous cell 
carcinoma. Rare cases of granular cell 
tumour with concurren! squamous cell 
carcinoma have been reported, so care-
ful and thorough evaluation of sections is 
necessary {1 68l. Rare examples of ma-
lignant granular cell tumour (character-
ized by pleomorphism, mitotic activity, 
spindle-shaped lesiona! cells, and ne-
crosis) have also been described (2458). 
Soft tissue and neuml tumours 121 
Cell of origin 
lmmunohistochemical studies suggest 
differentiation consistent with an origin 
from Schwann cells {1976}. 
Prognosis and predictive factors 
Although recurrence is possible, the like-
lihood seems to be low, even when le-
siona! tissue appears to have been tran-
sected at the margins {2458}. 
Rhabdomyoms 
Bullerdiek J. 
Ro J .Y. 
Thompson L.D.R. 
Definition 
Rhabdomyoma is a benign tumour with 
skeletal muscle differentiation. 
ICD-0 code 8900/0 
Epidemiology 
Rhabdomyoma is divided into fetal , ju-
venile, and adult subtypes on the basis 
of histology rather than patient age. For 
adult rhabdomyoma, patient age var-
íes broadly (with a median age in the 
sixth decade of life {457)). Fetal rhabdo-
myoma usually occurs in newborns and 
during early childhood . There is a male 
predominan ce. 
Localization 
Rhabdomyomas occur predominantly 
in the head and neck. About 15% of pa-
tients with adult rhabdomyoma present 
with multifocal disease (1427}. Common 
localizations are the parapharyngeal 
space (affected in 36% of cases), larynx 
(15%), submandibular (14%), paratrache-
al region adjacent to the thyroid gland 
(12%), tangue (11 %), and floor of the 
mouth (9%) {540). 
Clinical features 
The tumours present as soft, painless 
and non-tender masses. 
Macroscopy 
Rhabdomyoma presents as a well-de-
lineated, rounded or coarsely lobulated, 
sessile or pedunculated smooth submu-
cosal mass that is greyish-yellow to red-
dish-brown on cut surface. The tumours 
can be 0.5-10 cm, with most examples 
measuring 1-3 cm. There is no haemor-
rhage or necrosis. 
Histopathology 
The adult type is composed of variably 
sized, deeply eosinophilic polygonal 
cells and cells with vacuolated cytoplasm 
(spider cells). Rod-shaped cytoplasmic 
crystals (so-called jackstraws) or cross 
striations may be seen. Necrosis and mi-
toses are absent. The fetal type is com-
posed of an intimate, haphazard-looking 
mixture of round or spindled mesen-
chymal cells and differentiated cells 
with myofibrils within an occasionally 
myxoid mucopolysaccharide-rich matrix . 
There is a gradient of cellularity or matu-
ration towards the periphery. Strap cells 
with eosinophilic cytoplasm, occasionally 
with cross striations, may be seen. 'íhere 
is immunopositivity for SMA, desmin, my-
oglobin, and MYOD1; fetal myosin may 
be seen in the fetal type. S100 protein 
and GFAP may be focally expressed. 
122 Tumours of the oral cavity and mobile tongue 
Genetic profile 
Aberrations of the PTCH1 locus have 
been reported in fetal rhabdomyomas 
{982\, which may be associated with 
naevoid basal cell carcinoma syndrome. 
Prognosis and predictive factors 
Recurrences are uncommon after surgi-
cal excision. Malignant transformation 
does not occur. 
Lymphangioma 
Bullerdiek J. 
Flucke U. 
Definition 
Lymphangioma is a congenital malfor-
mation of lymphatic vessels. 
ICD-0 code 9170/0 
Synonyms 
Lymphangioepithel ioma (obsolete); 
lymphangiomatous polyp 
Epidemiology 
Lymphangiomas are relatively uncom-
mon. They are usually diagnosed in in-
fancy or early childhood. 
Localization 
The skin and subcutaneous tissue of the 
head and neck region is the most com-
mon local ization far lymphangiomas, but 
they are only occasionally reported in 
the oral cavity. lntraoral lymphangiomas 
arise most commonly on the dorsum of 
the tangue, followed by the palate, buc-
ea! mucosa, gingiva, and lips {2450}. 
Clinical features 
Clinical behaviour varíes, with erratic 
growth, progression, or even spontaneous 
regression during the first two decades 
of lile. Symptoms are related to size and 
perturbation of structure {280,2450). The 
lesions can be pedunculated or sessile. 
Histopathology 
The malformations consist of variably 
sized, irregular, thin-walled fluid-fil led 
spaces lined by lymphatic endothe-
lium surrounded by a stroma of fibrous, 
smooth-muscle, and adipose tissue, 
along with lymphocytes {280}. The vas-
cular endothelial cells are immunoposi-
tive for CD31 or CD34 {1186), podoplanin 
(as recognized by 0 2-40), PROX1, and 
VEGFR3. Lymphatic endothelial cells 
stain for LYVE1 {280,1163,1536}. The 
wal ls of the lymphatic vessels stain posi-
tively for SMA (1186,1977}. 
Genetic susceptibility 
Like other vascular anomalies, malfor-
mations of lymphatic vessels are com-
mon in Proteus syndrome {465}, which is 
caused by a somatic activating mutation 
in AKT1 {1437). Other genetic disorders 
associated with lymphangioma include 
Turner syndrome {45,X syndrome) and 
trisomy 21 {280}. 
Prognosis and predictiva factors 
Recurrences may occur alter surgical 
resection {280}. 
Haemangioma 
Bullerdiek J. 
Flucke U. 
Definition 
Oral haemangiomas are benign vascular 
hamartomas affecting the mucosa. They 
are distinct from vascular ectasias, vas-
cular malformations, and s (also called 
lobular capillary haemangiomas).ICD-0 code 9120/0 
Epidemiology 
Haemangiomas are frequent childhood 
tumours with a female predominance. 
They occur commonly in the head and 
neck region in both children and adults, 
but only rarely in the oral cavity (including 
the tangue) {11,235,1290). However, 
haemangioma (infanti le haemangioma) 
is the most common benign tumour of 
the oral cavity and mobile tongue in the 
paediatric population {1502,2080) 
Localization 
In the oral cavity, haemangioma can 
arise in the tongue, lips, buccal mucosa, 
gingiva, and palate {1502,1669,2682}. 
Clinical features 
The tumours present as smooth reddish-
purple polypoid or pedunculated mass-
es, often with increasing size and occa-
sional bleeding. 
Histopathology 
Capil lary haemangiomas consist of 
multilobular arrangements of proliferat-
ing endothelial cells and capillaries of 
various shapes and sizes surrounded by 
pericytes. The lumina may be subtle or 
d ilated, especially in infantile haemangi-
omas {280,1 141). Cavernous haemangio-
mas show larger dilated vascular spaces 
lined by endothelial cells. The endothe-
lial cells are positive for CD34, CD31 , 
and ERG {280,1611). GLUT1 is positive 
in infantile haemangioma but negative 
in pyogenic granuloma, vascular ecta-
sias, and congenital haemangioma {280, 
1141,1746). Haemangiomas must be dis-
tinguished from pyogenic granulomas, 
which are ulcerated reactive lesions fre-
quently arising on the gingiva and char-
acterized by lobular accumulations of 
maturing vascular granulation t issue. 
Genetic susceptibility 
Haemangiomas have been described 
in carriers of various chromosomal ab-
normalities {39,2425,2484) and are fre-
quently associated with full or partial 
polysomy 13 {108,1443,2007] . 
Prognosis and predictiva factors 
lnfantile haemangiomas initially grow rap-
idly, but most subsequently involute and 
require no intervention. Successful treat-
ment options are beta blockers, steroid 
injection, endovascular sclerotherapy, 
and surgery {15,1669,2577). 
Schwannoma and neurofibroma 
Flucke U. 
Wenig B.M. 
Definition 
Schwannoma and neurofibroma are be-
nign peripheral nerve sheath tumours. 
Schwannoma consists of Schwann cells, 
and neurofibroma consists of an admix-
ture of Schwann cells, fibroblasts, peri-
neurial-like cells, and axons. 
ICD-0 codes 
Schwannoma 
Neurofibroma 
Synonyms 
Schwannoma: neurilemmoma; 
neurinoma 
Epidemiology 
9560/0 
9540/0 
Schwannomas usually occur in adults. 
Neurofibromas are the most common 
benign peripheral nerve sheath tumour 
affecting infants, children , adolescents, 
Soft tissue and neural tumours 123 
and adults {357,933,2005) . 
Etiology 
Most lesions occur sporadically (933, 
2005). 
Localization 
lntraorally, the tangue is the most corn-
mon site, followed by the palate, bucea! 
mucosa, floor of the mouth, lips, gingiva, 
and jaws {656,933,1311,1440,1499}. 
Clinical features 
Patients present with a slow-growing, 
sometimes painful, submucosal mass. 
Multiple neurofibromas are associated 
with neurofibromatosis type 1 {357,933, 
952). 
Macroscopy 
Both lesions are nodular with a tan-
white, glistening cut surface. An associ-
ated nerve can occasionally be identified 
{357,2005). 
Histopathology 
In mucosal sites, schwannomas are typi-
cally submucosal and circumscribed but 
unencapsulated. They are composed of 
a spindle-cell proliferation arranged in al-
ternating cellular Antoni A and hypocellu-
lar Antoni B areas. The spindle cells have 
oval, tapered, or buckled nuclei with poorly 
defined eosinophilic cytoplasm. Nuclear 
palisading is a frequent feature, occasion-
ally with Verocay body formation. Degen-
erative nuclear atypia and mitotic figures 
should not be interpreted as ominous 
signs. Associated hyalinized blood vessels 
and foamy histiocytes are common. Haem-
orrhage and lymphocytes may be present 
{952,2005). 
Neurofibromas are characterized by 
random rearrangement of spind le cells in a 
collagenous to myxoid stroma. The nuclei 
are wavy and the cytoplasm inconspicu-
ous. Mitotic figures are usually absent. The 
collagen bundles typically have a so-called 
shredded-carrots appearance {2005}. 
Schwannomas show strong and diffuse 
nuclear and cytoplasmic S100 protein 
expression, as well as nuclear S0X10 
reactivity. Scattered CD34-positive cells 
may be seen. In contras!, neurofibromas 
show heterogeneous expression of these 
markers (357,952,1183,1797,2005}. 
Genetic profile 
Schwannomas are characterized by loss 
of chromosome 22 and inactivating mu-
tations in NF2 {2267}. Neurofibromas 
are characterized by inactivation of NF1 
{357}. 
Genetic susceptibility 
Neurofibroma is associated with neurofi-
bromatosis type 1 (357,2005}. 
Prognosis and predictiva factors 
Both tumours follow a benign clinical 
course. Neurofibromas have the potential 
for malignan! transformation, especially 
in patients with neurofibromatosis type 1 
(357,933,952,2005,2069}. 
124 Tumours of the oral cavity and mobile tangue 
Kaposi sarcoma 
Thompson L.D.R. 
Ro J.Y. 
Wenig B.M. 
Definition 
Kaposi sarcoma is a locally aggressive 
vascular neoplasm of intermediate type, 
uniformly associated with HHV8. 
ICD-0 code 
Synonym 
Kaposi disease 
Epidemiology 
9140/3 
Kaposi sarcoma is separated into tour 
distinct epidemiological categories (Ta-
ble 4. 06); of these, only the AIDS-related 
(HIV-1-related) type is associated with 
oral manifestations {697,1812,1897). As 
many as 20% of individuals with HIV-1 
infection develop oral Kaposi sarcoma, 
usually in the fourth to fifth decades of 
lite. In industrialized countries, it is most 
common in horno- and bisexual HIV-1-
infected men, whereas there is no sex 
difference in developing countries {1811, 
2538). 
Etiology 
Kaposi sarcoma is always associated 
with the gamma-2 herpesvirus HHV8 
(also called Kaposi sarcoma- associ-
ated herpesvirus; KSHV). The neoplasm 
develops in a complex dynamic with 
HIV-induced immunosuppression and 
environmental and genetic factors alter 
exposure to HHV8 in saliva or blood (122, 
1347}. 
Table 4.06 Clinical and epidemiological forms of Kaposi sarcoma. Adapted from Barnes Letal. (146) and Fletcher CDM et al. {735} Myofibrob/astic sarcoma 
1 Type Risk group 
Classic 
> 70% elderly men; 
Slavic, Jewish, ltalian 
Endemic Children and middle-aged men 
(African) 
~ 
latrogenic/ 
Solid organ transplant recipients 
(0.5% of renal transplant patients}; 
transplant-
patients receiving immunosuppres-
associated 
sive therapy 
HIV-infected patients; more com-
AIDS-related 
mon in horno- and bisexual men 
at younger age than classic Kaposi 
1 
sarcoma 
Localization 
The hard palate, followed by the gingiva 
and tongue, is the most common oral site. 
Up to 70% of patients with cutaneous Ka-
posi sarcoma also have oral lesions. 
Clinical features 
Patients present with multiple red to viola-
ceous macules or papules that progress 
to plaques or nodules. Bleeding, ulcera-
tion, and pain may be seen in advanced 
disease. Lymphoedema is uncommon 
!697,1812,1837). 
Histopathology 
The histopathological appearance devel-
ops with disease progression. The patch 
stage shows irregularly shaped, slit-like 
vascular spaces dissecting collagen bun-
dles, often parallel to the epithelium, with 
extravasated erythrocytes and lympho-
cytes: the plaque stage shows further spin-
dle-cell proliferation associated with intra-
and extracellular hyaline globules; and 
the nodular stage shows widely infi ltrat-
ing atypical spindled cells with increased 
Siles of involvement Clinical course 
Skin of lower extremities lndolent 
Skin of extremities; visceral 
involvement common; lym- lndolent in adults; 
phadenopathic type common aggressive in children 
in children 
Variable; may resolve 
Skin of extremities; may have 
visceral involvement 
u pon cessation of im-
munosuppressanls 
Skin of head and neck, 
extremities, genitals, mucosa 
Aggressive of upper aerodigestive tract; 1 
lymph nodes 
mitoses {299,697,1811). Papillary tufting