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 34 Adenosquamous 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 
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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 
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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 
347 
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CHAPTER 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 approach given 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 differential diagnosis·; 
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 nades less 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 into neighbour-
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!dlcdomainl 
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. 
11 ,...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 ring cell) . 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 
CD10, 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 histological features 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