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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 Thís book and ali other volumes of the series can be purchased: From al/ countries WHO Press World Healtlc Organ:zation CH-1211 Geneva 27 Switzer·ar¡d Tei. +41 22 791 3264 Fax +41 22 791 4857 booko·ders@who.:nc wvvw. v,;ho. i 1t/booko;ders/ From USA Sty,cs Publishing, ~LC 22883 Ouioksilver Orive PO Box 605 Herr,don, VA 20172-05 Tel. + 1 800 232 0223 or +17036611581 Fax ~17036611501 stylu-s•;.a!1@presswarehouse.com www.sty1uspub.com From Cana.da Renout PubEs:i:r_g Compary Umited 22-1010 Polytek Street Ottawa, 0:'J K1J 9Jt Tel +' 866 767 6766 Fax +·1 613 745 7660 orders@renoufbooks.com INWW .rnnoufbooks.corn 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), 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France © /nternational Agency far Research on Cancer, 2017 Distributed by WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Swítzerland Tel.: +4122791 3264; Fax: +4122791 4857; email: bookorders@who.int Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. AII rights reserved. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city, or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. The authors alone are responsible for the views expressed in this publication. The copyright of figures and tables remains with the authors. (See Sources offigures and tables, pages 294-297.) 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 usually
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