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.~World Health Organization Classification of Tl.


Delellis HA. Lloyd R.V., Lakhani, Eilis 10., Schnitt S J. Mooh H., Hucnphrey PA,
Hetz P.U., Eng C. (Eds): World T2n P.H, var. de Vijver M.J, (Eds) e! bright T.M., Reuter V.E. (Eds):
Health Organization Classification of WHO Classmc2icn of Tumours of the WHO C1assificator: ot ot
Tumours. Pathology ard Genetics of Breast (4th editior). IARC: Lyon 2012. the Ur,nary Systerc 2nd Male Ger:ital
Tumours of Endocrine Orga.ns ISBN 978-92-832-2,]33-4 Organs (4th edition).
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LeBoit P.E., Burg G , Weedon D .. Hetcher C.O.M., Bridge J.A, Louis D.N , Ohgaki ..
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Organiz::1.ticn Class'ticalion o"' (Eas): \/JHO Ciassification of Twnours WHO Classiticaton of TJmcurs of the
Tumours. Patt1ology a:1d Genetics of of Soft T:ssue and Bone (4th edition). Centrai Nervous System (Rev:sed
Skin Tumours (3rd edltlor). iARC: Lyon 2013. 4t1 edltion). IARC: Lycn 2016.
IARC Press: Lyon 2006. iSBN 978-92832-2434-1 ISBN 97892 832-4492-9
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Swerdlow S.H., Campo S., Kurmar RJ . Carcangiu M L., Ei-Naggar AK, Chan J.K.C ..
Harris NL, Jaffe E.S., Pile<' S.A., Herr cgton C S, Young R.H. (Eds): Grandis J.R, Takata ,., Slo:,tweg .:>J.
Stein H., Thieie J., Vardiman r.W. WHO C:assifcat:or: of TuGours of (Eds): WHO Classlfication af Heaa
(Eds): WH:J Classification of Tumours Fema:e Rep:oductive Organs and Neck Tumours (.!t\ editio;1).
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Tissues (4th ed:ton). ISBN 978-92-832-2435-8 iSBN 978-92 832-2438-9
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WHO Class 1ficatimcf Tumours o: tne WHO Classiicaton of TJrrours
Oigest:ve System ( 4th edfon). ot tre Lung, ?leura, Thymus & Heact
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World Health Organization Classification of Tumours

\\ ,,

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-lsmer, 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

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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 2. Head and neck neoplasms - pathlogy
3. Odontogenic tumours - genetics 4. Odontogenic tumours - pathology

l. EI-Naggar, Adel K. 11. Series

ISBN 978-92-832-2438-9 (NLM Classification: WE 707)

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
Carcnomas 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 lntroducton 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 snonasal 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
Leomyoma 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 9 Tumours of the ear 261
Metastasizing ameloblastoma 218 WHO classification 262
Squamous odontogenic tumour 219 lntroduction 263
Calcifying epithelial odontogenic tumour 220 Tumours of the external auditory canal 263
Adenomatoid odontogenic tumour 221 Squamous cell carcinoma 263
Benign mixed epithelial & mesenchymal odontogenic tumours 222 Ceruminous adenocarcinoma 264_
Ameloblastic fibroma 222 Ceruminous adenoma 265
Primordial odontogenic tumour 223 Tumours of the middle and inner ear 266
Odontoma 224 Squamous cell carcinoma 266
Dentinogenic ghost cell tumour 226 Aggressive papillary tumour 266
Benign mesenchymal odontogenic tumours 228 Endolymphatic sac tumour 267
Odontogenic fibroma 228 Otosclerosis 268
Odontogenic myxoma/myxofibroma 229 Cholesteatoma 269
Cementoblastoma 230 Vestibular schwannoma 270
Cemento-ossifying fibroma 231 Meningioma 271
Odontogenic cysts of inflammatory origin 232 Middle ear adenoma 272
Radicular cyst 232
lnflammatory collateral cysts 233 10 Paraganglion tumours 275
Odontogenic and non-odontogenic developmental cysts 234 WHO classification 276
Dentigerous cyst 234 lntroduction 276
Odontogenic keratocyst 235 Carotid body paraganglioma 277
Lateral periodontal cyst and botryoid odontogenic cyst 236 Laryngeal paraganglioma 281
Gingival cysts 238 Middle ear paraganglioma 282
Glandular odontogenic cyst 238 Vagal paraganglioma 283
Calcifying odontogenic cyst 239
Orthokeratinized odontogenic cyst 241 Contributors 285
Nasopalatine duct cyst 241 Declaration of interests 292
Malignant maxillofacial bone and cartilage tumours 243
IARC/WHO Committee for ICD-0 293
Chondrosarcoma 243
Mesenchymal chondrosarcoma 244 Sources of figures 294
Osteosarcoma 244 Sources of tables 297
Benign maxillofacial bone and cartilage tumours 246 References 298
Chondroma 246 Subject index 340
Osteoma 246
List of abbreviations 347
Melanotic neuroectodermal tumour of infancy 247
Chondroblastoma 248
Chondromyxoid fibroma 249
Osteoid osteoma 249
Osteoblastoma 249
Desmoplastic fibroma 250
Fibro-osseous and osteochondromatous lesions 251
Ossifying fibroma 251
Familia! gigantiform cementoma 253
Fibrous dysplasia 253
Cemento-osseous dysplasia 254
Osteochondroma 255
Giant cell lesions and simple bone cyst 256
Central giant cell granuloma 256
Peripheral giant cell granuloma 257
Cherubism 257
Aneurysmal bone cyst 258
Simple bone cyst 259
Haematolymphoid tumours 260
Solitary plasmacytoma of bone 260

Tumours of the nasal cavity, paranasal

sinuses and skull base
Squamous cell carcinomas
Lymphoepithelial carcinoma
NUT carcinoma
Neuroendocrina carcinomas
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 Borderline/low-grade malignant soft tissue tumours

Keratinizing squamous cell carcinoma 8071/3 Desmoid-type fibromatosis 8821 /1
Non-keratinizing squamous cell carcinoma 8072/3 Sinonasal glomangiopericytoma 9 150/ 1
Spindle cell squamous cell carcinoma 8074/3 Solitary fibrous tumour 8815/1
Lymphoepithelial carcinoma 8082/3 Epithelioid haemangioendothelioma 9133/3
Sinonasal undifferentiated carcinoma 8020/3
NUT carcinoma 8023/3* Benign soft tissue tumours
Neuroendocrine carcinomas Leiomyoma 8890/0
Small cell neuroendocrine carcinoma 8041/3 Haemangioma 9120/0
Large cell neuroendocrine carcinoma 8013/3 Schwannoma 9560/0
Adenocarcinomas Neurofibroma 9540/0
lntestinal-type adenocarcinoma 814 4/3
Non-intestinal-type adenocarcinoma 8140/3 Other tumours
Meningioma 9530/0
Teratocarcinosarcoma 9081/3 Sinonasal ameloblastoma 9310/0
Chondromesenchymal hamartoma
Sinonasal papillomas
Sinonasal papilloma, inverted type 8121 /1 Haematolymphoid tumours
Sinonasal papilloma, oncocytic type 8121 /1 Extranodal NK/T-cell lymphoma 9719/3
Sinonasal papilloma, exophytic type 8121/0 Extraosseous plasmacytoma 9734/3

Respiratory epithelial lesions Neuroectodermal / melanocytic tumours

Respiratory epithelial adenomatoid hamartoma Ewing sarcoma/ primitive neuroectodermal
Seromucinous hamartoma tumour 9364/3
Olfactory neuroblastoma 9522/3
Salivary gland tumours Mucosa! melanoma 8720/3
Pleomorphic adenoma 8940/0

Malignant soft tissue tumours

Fibrosarcoma 8810/3
Undifferentiated pleomorphic sarcoma 8802/3
Leiomyosarcoma 8890/3
Rhabdomyosarcoma, NOS 8900/3
Embryonal rhabdomyosarcoma 8910/3
The morphology codes are from the lnternational Classification of Diseases
Alveolar rhabdomyosarcoma 8920/3 for Oncology (ICD-0) 1776AJ. Behaviour is coded /O for benign tumours;
Pleomorphic rhabdomyosarcoma, adult type 8901/3 /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in
Spindle cell rhabdomyosarcoma 8912/3 situ and grade 111 intraepithelial neoplasia; and /3 for malignan! tumours.
The classification is modified from the previous WHO classification , taking
Angiosarcoma 9120/3 into account changes in our understanding of these lesions.
Malignan! peripheral nerve sheath tumour 9540/3 'These new codes were approved by the IARC/WHO Committee for ICD-0.
Biphenotypic sinonasal sarcoma 9045/3*
Synovial sarcoma 9040/3

12 Tumours of the nasal cavity, paranasal sinuses and skull base

TNM classification of carcinomas of the nasal cavity and
paranasal sinuses

TNM classification" N - Regional lymph nodes (i.e. the cervical nodes)

T - Primary tumour NX Regional lymph nades cannot be assessed
TX Primary tumour cannot be assessed NO No regional lymph node metastasis
TO No evidence of primary tumour N1 Metastasis in a single ipsilateral lymph node, s; 3 cm in
Tis Carcinoma in situ g reatest dimension
N2 Metastasis as specified in N2a, N2b, or N2c below
Maxillary sinus N2a Metastasis in a single ipsilateral lymph nade, > 3 cm but
T1 Tumour limited to the antral mucosa. with no erosion or s; 6 cm in greatest dimension
destruction of bone N2b Metastasis in multiple ipsilateral lymph nodes, all s; 6 cm
T2 Tumour causing bone erosion or destruction, including in greatest dimension
extension into hard palate and/or middle nasal meatus, N2c Metastasis in bilateral or contralateral lymph nades, ali
except extension to posterior wall of maxillary sinus and s; 6 cm in greatest dimension
pterygoid plates N3 Metastasis in a lymph nade > 6 cm in greatest dimension
T3 Tumour invades any of the following: bone of posterior Note: Midline nodes are considered ipsilateral nodes.
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 M - Distant metastasis
contents, skin of cheek, pterygoid plates, infratemporal MO No distan! metastasis
fossa, cribriform plate, sphenoid or frontal sinuses M1 Distan! metastasis
T4b Tumour invades any of the following: orbital apex, dura,
brain, middle cranial fossa, cranial nerves other than max- Stage grouping
illary division of trigeminal nerve (V2), nasopharynx, clivus Stage O Tis NO MO
Stage 1 T1 NO MO
Nasal cavity and ethmoid sinus Stage 11 T2 NO MO
T1 Tumour limited to one subsite of nasal cavity or ethmoid Stage 111 T1 - 2 N1 MO
sinus, with or without bony invasion T3 N0-1 MO
T2 Tumour involves two subsites in a single site or extends to Stage IVA T1 - 3 N2 MO
involve an adjacent site within the nasoethmoidal T4a N0-2 MO
complex, with or without bony invasion Stage IVB T4b Any N MO
T3 Tumour extends to invade the medial wall or !loor of the AnyT N3 MO
orbit, maxillary sinus, palate, or cribriform plate Stage IVC AnyT Any N M1
T4a Tumour invades any of the following: anterior orbital
contents, skin of nose or cheek, minimal extension to
Adapted from Edge et al. [625AI - used with permission of the American
anterior cranial fossa, pterygoid plates, sphenoid or
Joint Committee on Cancer (AJCC), Chicago, lllinois; the original and prima-
frontal sinuses ry source for this information is the AJCC Cancer Staging Manual, Seventh
T4b Tumour invades any of the following: orbital apex, dura, Edition (2010) published by Springer Science+Business Media - and Sobin
brain, middle cranial fossa, cranial nerves other than V2, et al. [2228A) .
nasopharynx, clivus A help desk for specific questions about TNM classification is available at

TNM classification of carcinomas of th e nasal cavity and paranasal sinuses 13

Tumours of the nasal cavity, paranasal
sinuses and skull base

lntroduction carcinoma with adenoid cystic-like fea- carcinoma, and that there may be sorne
tures is provisionally listed as a subtype overlap between tumours, such as be-
Slootweg P.J . of non-keratinizing squamous cell carci- tween sorne sinonasal undifferentiated
Chan J.K.C. noma, with additional data needed to jus- carcinomas and high-grade neuroendo-
Stelow E.B. tify ful l recognition as a unique entity. Tu- crine carcinomas. More data are needed
Thompson L.D. R. mours of bone and cartilage, which were befare recommendations can be made
included in both the jaw and sinonasal on how best to classify tumours within
tract chapters in the previous edition, are these categories. In the meantime, we
The sinonasal tract (i.e. the nasal cav- in this edition discussed exclusively in have tried to remain consistent with pre-
ity and associated paranasal sinuses) Chapter 8 (Odontogenic and maxillofacial vious classification systems of tumours
is the site of origin for a wide variety of bone tumours, p. 203) - a more appropri- both at this site and at others (e.g. the
neoplasms. The entities included in th is ate approach given their morphological classification of high-grade neuroendo-
chapter meet one of three inclusion crite- overlap with sorne odontogenic tumours. crine carcinomas of the lung).
ria: (1) they occur exclusively in the sino- The role of immunohistochemical and Within the sinonasal trae!, CT is primarily
nasal tract , (2) they occur at other head genetic features in tumour characteriza- used to evaluate mass effect on adjacent
and neck sites but show a predilection tion is reported with a balance between osseous structures, whereas MRI is bet-
for the sinonasal tract, or (3) they are im- worldwide global application and the use ter for disti nguishing mucosa! thickening
portant in the sinonasal tract for differen- of more expensive diagnostic methods and fluid resulting from a pathological
tial diagnostic reaso ns. Th e first group is not everywhere available, in an effort to mass process. Thus, these imaging mo-
discussed extensively and the other two ensure a more universal applicability of dalities are complementary techniques.
more concisely, with the reader referred the classification . However, in general, cross-sectional im-
to other chapters for additional informa- lt is noted that sorne tumours may consti- aging findi ngs are not unique or tumour-
tion. This edition includes NUT carcino- tute a spectrum of entities, such as high- specific; therefore, information regarding
ma and biphenotypic sinonasal sarcoma grade non-intestinal-type adenocar- imaging findings is included only when it
as well-defi ned new entities. HPV-related cinoma and sinonasal undifferentiated is of specific diagnostic value.


Keratinizing squamous ce// Synonym

carcinoma Epidermoid carcinoma

Bishop J.A. Epidemiology

Bell D. Sinonasal KSCCs are rare, and the sino-
Westra W.H .. nasal tract is the least common head and
neck subsite involved by squamous cell
carcinoma (SCC) {82}. KSCC most often
Detinition affects patients in their sixth to seventh
Sinonasal keratinizing squamous cell decades of life, and men are affected
carcinoma (KSCC) is a malignant epi- twice as often as women (82,2065,.2438}.
thelial neoplasm arising from the surface
epithelium lining the nasal cavity and Etiology
paranasal sinuses and exhibiting squa- Cigarette smoking increases risk, al-
mous differentiation. though less dramatically than in other
head and neck sites {271,960,1458,
ICD-0 code 8071/3 2688}. Wood dust, leather dust, and other

14 Tumours of the nasal cavity, paranasal sinuses and skull base

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 cell carci-
noma (see Non-keratnizing 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 cell carcinoma
(1 750}.

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, diplopa, and proptosis
are indicative of more-advanced tumour
growth {1458}. lmaging determines ex-
tent of disease.

The tumour is exophytic or endophytic,
with various degrees of ulceration, ne-
crosis, and haemorrhage.

Aspirates of metastases are cellular, with
sheets and small clusters of malignant
squamous cells with intracellular and 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
extracellular keratinization. Mixed inflam-
a smooth stromal interface and no desmoplastic reaction. C Non-keratinizing squamoid cells with nuclear atypia,
mation and necrosis can be present. numerous mitotic figures, and peripheral palisading of tumour nuclei.

Histopathology similar to that of its counterpart in the oro- Non-keratinizing squamous

KSCC exhibits histological features iden- pharynx (447,1458,1474}. ce// carcinoma
tical to those of conventional squamous
cell carcinoma of other head and neck Prognosis and predictive factors Bishop J.A.
sites, with irregular nests and cords of The 5-year overall survival rate for sino- Brandwein-Gensler M.
eosinophilic cells demonstrating kerati- nasal squamous cell carcinoma is approx- Nicolai P.
nization . and inducing a desmoplastic imately 50-60%, and is stage-depend- Steens S.
stromal reaction. Grades include well, ent (2065,2397,2438) Carcinomas of Syrjanen S.
moderately, and poorly differentiated. the nasal cavity have a better prognosis Westra W.H.
See Chapter 3 ( Tumours of the hypophar- than carcinomas arising in the paranasal
ynx, /arynx, trachea and parapharyngeal sinuses {82,617,2397,2438]. This differ-
space, p. 77) for further detail. ence is likely in part because sinus carci- Definition
nomas present later and at higher stage; Non-keratinizing squamous cell carcino-
Genetic profile it is unclear whether there is a stage-for- ma (NKSCC) is a squamous cell carcino-
The genetic profile is similar to that of stage survival difference. Regional lymph ma (SCC) characterized by a distinctive
KSCC of other upper aerodigestive tract node metastasis is uncommon (1458). ribbon-like growth pattern with absent to
sites, whereas the genetic profile of non- limited maturation.
keratinizing squamous cell carcinoma is

Carcinomas 15
ICD-0 code 8072/3 Clinical features pattern is reminiscent of urothelial carci-
Presenting signs and symptoms include noma (hence the synonym "transitional
Synonyms nasal obstruction, discharge, epistaxis, cell carcinoma") and may be difficult
Schneiderian carcinoma; transitional cell facial pain or fullness, nasal mass or to recognize as invasive, particularly in
carcinoma; cylindrical cell carcinoma ulcer, and eye-related symptoms in ad- small biopsies. Papillary features can
vanced cases {1 458). Patients with para- be seen within the tumour or at the mu-
Epidemiology nasal sinus neoplasms present later and cosa! surface . NKSCC has an immature
NKSCC accounts for approximately 10- at a higher stage than do patients with appearance, with minimal or no kerati-
27% of sinonasal SCC. lt affects adults in nasal cavity carcinomas {82,2438). lm- nization; tumour nuclei are oval and the
their sixth to seventh decades of lite, and aging determines extent of disease. N:C ratio is high. Basal/superfic ial cel-
men more frequently than women {199, lular polarity is often apparent: basal-
636,1784,1999}. Macroscopy type cells often demonstrate peripheral
The tumours are variably exophytic and/ palisading, whereas superficial cells are
Etiology or inverted in growth, and often friable, more flattened. Scattered mucinous cells
In general, NKSCC has similar risk fac- with necrosis and/or haemorrhage. are occasionally present. The degree of
tors to keratinizing squamous cell car- nuclear atypia vares, but mitotic figures
cinoma, but 30-50% of cases harbour Cytology are typically numerous, and necrosis is
transcriptionally active high-risk HPV Aspirates of metastases are cellular, with common. There is no established role for
{199,636,1335). Sorne sinonasal papil- clusters of basaloid cells showing cyto- tumour grading in this variant.
lomas (2-10%) undergo malignan! trans- logical features typical of malignancy, There is a broad differential diagnosis;
formation. usually into keratinizing squa- with nuclear atypia and increased mitotic the growth pattern of NKSCC can mimic
mous cell carcinoma and less frequently figures . Mixed inflammation and necrosis that of a sinonasal papilloma with malig-
into NKSCC {1750). can be present. nant transformation. However, this would
require confirmation of metachronous
Localization Histopathology or synchronous sinonasal papilloma.
NKSCC arises most frequently from the NKSCC characteristi cally grows as ex- Sinonasal undifferentiated carcinoma,
maxillary sinus or nasal cavity {82,1402, panding nests or anastomosing ribbons neuroendocrine carcinoma, the salid
2065,24381. of cells in the submucosa, with a smooth variant of adenoid cystic carcinoma,
stromal interface and a pushing border and SMARCB1-deficient carcinomas
eliciting minimal or no desmoplasia. This should be considered in the differential

16 Tumours of the nasal cavity, paranasal sinuses and skull base

diagnosis. The presence of so-called cells align around cylindromatous micro-
abrupt keratinization should raise the cystic spaces and have hyperchromatic
possibility of NUT carcinoma. and slightly angu lated nuclei with a high
NKSCC is diffusely positive for cytokerat- N:e ratio. In contrast to typical NKSCe,
ins (including high-molecular-weight true ductal cells are also present (al-
forms such as CK5/6) and for p63 and though less conspicuous), often sur-
p40. lt retains nuclear expression of rounded by a peripheral layer of basaloid
SMARCB1 (INl1) and is negative for neu- to clear myoepithelial cells. When this
roendocrine markers, S100, and NUT1. bilayered pattern is well developed, it im-
HPV-related SCCs are diffuse ly p16- parts an appearance like th at of epithe-
positive by immunohistochemistry and lial-myoepithelial carcinoma. Although
positive for HPV by in situ hybridization overt squamous differentiation is not typi-
and PCR. cally present in the invasive component,
the surface epithelium may show various
Genetic profile degrees of dysplasia. Mitotic rates are
The distinctive mutational profiles of usually high, and necrosis may be seen. Etiology
HPV-positive and HPV-negative sinona- The basaloid cells show myoepithelial sesee is associated with smoking and
sal SCC are similar to those of their coun - differentiation (e.g. S100, calponin , p63, radiation exposure {1398 ,2396 }. HPV has
terparts in other head and neck sites, and actin), and the ductal cells are KIT- been negative in the few cases tested
such as the oropharynx [447,1458,1474). positive. Cytokeratins tend to be more {199).
strongly expressed in the ductal rather
Prognosis and predictive factors than myoepithelial cells . Both cell types Localization
The 5-year overall survival rate of sino- are p16-positive and harbour high-risk sesee arises in the nasal cavity and/
nasal SCCs as a group is approximately HPV as detected by in situ hybridization. or maxillary or frontal sinuses [787,912,
60%; it is unclear whether the survival rate No MYB translocations (typically seen in 1032,1035).
of NKSee differs from that of keratiniz- about 50% of adenoid cystic carcinomas)
ing squamous cell carcinoma {82,1999, have been identified [202} . To date, with Clinical features
2065,2397,2438). HPV positivity may be only a limited number of cases reported, Patients present with nasal obstruction,
associated with improved survival, al- local recurrence has been seen, but no epistaxis, and/or facial swelling, with
though the prognostic signif icance is not regional or distant metastases or tumour- masses apparent on e T or MR I {787,896,
as clearly defined as it is in the oropha- related deaths {202). 912,1032,1035}.
rynx {199,1335). Sorne studies have dem-
onstrated improved survival in sinonasal Macroscopy
sce harbouring high-risk HPV or overex- Spmdmcell(sarcomawid) Sorne SCSCCs grow as a polypoid mass
pressing EGFR [199,1335,2342}. squamous cell carcinoma with an ulcerated surface, similar to the
The newly recognized sinonasal tract more common laryngeal examples {896,
HPV-related carcinoma with adenoid Bishop J.A. 912).
cystic-like features is a distinctive HPV- Lewis J.S .
related carcinoma of the sinonasal tract, Cytology
with histological and immunophenotypic See Spindle ce!/ squamous ce!/ carcino-
features of both surface-derived and sali- Definition ma section (p. 87) in Chapter 3.
vary gland carcinoma - the latter show- Spindle cell squamous cell carcinoma
ing the appearance of a high -grade ad- (SCSCe) is a variant of squamous cell Histopathology
enoid cystic carcinoma. Among the few carcinoma characterized by predomi- For histology and diffe rential diagnosis,
cases of HPV-related carcinoma with ad- nan\ malignan! spind le and/or pleomor- see Spindle ce// squamous ce!! carcino-
enoid cystic- like features that have been phic cells. ma section (p. 87) in Chapter 3.
reported to date, the female-to-male ratio
is 7:2 and the patient age range is 40- ICD-0 code 8074/3 Prognosis and predictiva factors
75 years {199,202,1065). The presence No specific features are described for
of a high-risk HPV type suggests a viral Synonym the sinonasal tract regan.
etiology [202,1065). Most cases present Sarcomatoid carcinoma
with nasal obstruction and/or epistaxis,
with a tan-white, fleshy mass undermin- Epidemiology
ing normal-looking mucosa. The tumour sesee presents most commr;mly in el-
consists of highly cellular proliferations of derly men {156,1330,2396}. This variant
basaloid cells growing in various sizes, is rare in the sinonasal tract, accounting
separated by thin collagenized fibrous for < 5% of sinonasal squamous cell car-
bands. The growth pattern is predomi- cinomas {199,787,896,912,1032,1035}.
nantly salid, but cribriform structures are
frequently encountered . The basaloid

Carcinomas 17
Lymphoepithelial carcinoma Clinical features < 60 years, and of White ethnicity have
Patients present with nasal obstruction, significantly improved survival {38 1).
Bishop J.A. nasal discharge, and/or epistaxis. Pa- Sinonasal LEC metastasizes to regional
Gaulard P. tients may also have eye symptoms or lymph nades less frequently than does
Gillison M. cranial nerve palsies as a result of local nasopharyngeal carcinoma, and tends
tumour invasion {1125,2034,2584,2733}. to be radiosensitive even in the presence
of nada! disease {381,1125,2034,2584,
Definition Macroscopy 2733).
Lymphoepithelial carcinoma (LEC) is a The tumours are irregular or polypoid,
squamous cell carcinoma morphologi- tan-white, bulky masses that may be
cally similar to non-keratinizing naso- haemorrhagic {1155,2034,2347). Sinonasal undifferentiated
pharyngeal carcinoma, undifferentiated carcinoma
subtype. Cytology
The cytological findings are the same as Lewis J.S.
!CD-O code 8082/3 those far non-keratinizing nasopharyn- Bishop J.A
geal carcinoma, undifferentiated subtype Gill ison M.
Synonym (see Nasopharyngeal carcinoma, p. 65.) Westra W.H.
Lymphoepithelioma-like carcinoma Yarbrough W.G.
H istopathology
Epidemiology LEC is defined by its resemb lace to
Sinonasal LEC is rare, with only about 40 non-keratinizing nasopharyngeal carci- Definition
reported cases {1125,2034,2584,2733). noma, undifferentiated subtype (see Na- Sinonasal undifferentiated carcinoma
lt most frequently affects men in th eir sopharyngeal carcinoma, p. 65). (SNUC) is undifferentiated carcinoma of
fifth to seventh decades of life (median By immunohistochemistry, LEC is dif- the sinonasal tract without glandular or
patient age: 58 years) {381 ,11 25,2034, fusely positive far pancytokeratin, CK5/6, squamous features and not otherwise
2584,2733). Most reported cases have p63, and p40, and is negative for lym- classifiable .
been in patients from Asia, where EBV- phoid and melanocytic markers. Sino-
Table 1.01 Differential diagnosis of sinonasal
related malignancies are endemic. nasal LEC is usually positive far EBV-
undifferentiated carcinoma
encoded small RNA (EBER) by in situ
Etiology hybridization.
In the sinonasal tract, most cases Sinonasal LEC must be distinguished Non-keratinizing squamous cell carcinoma (including
(> 90%) of LEC harbour EBV {11 25,1392, from lymphoma and melanoma (potential HPV-related carcinoma with adenoid cystic- like
2034,2584,2733}. mimics), as well as from sinonasal undif-
ferentiated carcinoma, a neoplasm that Basaloid squamous ce!! carcinoma
Localization lacks th e syncytial growth pattern of LEC, High-grade neuroendocrina carcinoma
Sinonasal LEC arises in th e nasal cav- is consistently EBER-negative, and lacks Olfactory neuroblastoma
ity more frequently than in the paranasal CK5/6, with limited to absent p63 .
sinuses (2034,2584,2733}. For an LEC NUT carcinoma
to be considered truly primary to the Prognosis and predictive factors Alveolar rhabdomyosarcoma
sinonasal reg ion, spread from a nearby According to the SEER database, sinon- Ewing sarcoma / primitiva neuroectodermal tumour
nasopharyngeal carcinoma must be ex- asal LEC has a 5-year disease-specific Adenoid cystic carcinoma, solld-type (grade 111)
cluded on clinical, radiograph ical, and/or survival rate of approximately 50%;
pathological grounds. patients with localized disease, aged

18 Tumours of the nasal cavity, paranasal sinuses and skull base

other visual symptoms (2656). Proptosis
and periorbital swelling can be seen as
well, features reflecting frequent orbital

Tumours are usually large (> 4 cm) at
presentation, with a fungating endoscop-
ic appearance and poorly defined mar-
gins radiographically {1883).

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.

SNUC consists of sheets, lobules, and
trabeculae of overtly malignant cells with
moderately large round nuclei, varying
amounts of cytoplasm, and well-defined
cell borders. Nuclei vary from hyperchro-
matic to vesicular, but most tumours have
ICD-0 code 8020/3 be questioned {199,365,885,2518}. open chromatin with prominent nucleoli.
Apoptosis, mitoses, and necrosis are
Epidemiology Localization frequent. Despite their high-grade ap-
SNUC is rare, with about 0.02 cases Tumours arise most frequently in the na- pearance, SNUCs characteristically have
per 100 000 people, accounting for only sal cavity and ethmoid sin uses, and most tumour nuclei of relatively consisten! size
about 3-5% of ali sinonasal carcinomas present as very large masses involving and lack of pleomorphism. By definition,
(1458}. lt occurs in patients of a wide multiple sites. As many as 60% of cases there is no squamous or glandular differ-
range of ages, from teenagers to the el- have spread beyond the sinonasal trae! entiation, although adjacent carcinoma in
derly (average patient age: 50-60 years). to adjacent sites such as the orbital apex, situ has been described.
App roximately 60- 70% of patients are skull base, and brain {1974). Nodal me- By immunohistochemistry, the tumour
Caucasian males {371,1974}. tastases are relatively uncommon (occur- is positive for pancytokeratin (AE1/AE3)
ring in 10-15% of cases) despite large and simple cytokeratins such as CK7,
Etiology primary tumour size {416,885,1974}. CK8, and CK18, but is negative for
No consistent etiology of SNUC has been CK5/6. The tumour cells are variably pos-
identified. Sorne patients are smokers Clinical features itive for p63, but consistently negative for
but many are not {365). lf EBV or HPV is Patients present with nasal obstruction, its more squamous-specifi c isoform, p40
detected, the diagnosis of SNUC should epistaxis, headache, and diplopa or {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
The differential diagnosis is lengthy
(Table 1.1), but most importantly includes
lymphoma, non-ke ratinizing squamous
cell carcinoma, basaloid squamous cell

Carcinomas 19
carcinoma, and neuroendocrine carcino-
ma. Squamous cell carc inoma 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 ) p rotein by immu-
nohistochemistry has been reported. lt is
unclear whether these tumours constitute
a distinct entity {198).

Genetic profile
- -
Fig. 1.09 NUT carcinoma. A Sheets of moderate-sized monomorphic poorly differentiated epithelioid cells have pale
No specif ic genetic alterations have been 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
identified in SNUC {819). The S0X2gene is
NUT rearrangement when red and green probes flanking the NUT Jocus are split apart; the red and green signals
amplified in one third of tumours {2102}. KIT together are the normal NUT allele. D Diffuse, nuclear immunohistochemical staining with the NUT antibody is
(CD117) is frequently strongly expressed, diagnostic of NUT carcinoma; the speckled pattern is characteristic but not always this distinct.
but no activating mutations or gene amplifi-
cations have been identified {416). ICD-0 code 8023/3 Clinical features
NUT carcinoma presents with non-
Prognosis and predictive factors Synonyms specific symptoms caused by a rap idly
The prognosis of SNUC is poor, although NUT midline carcinoma; t(15;19) carci - growing mass. In the sinonasal tract,
it seems to have improved in recent noma; midline carcinoma of children and this manifests as nasal obstruction, pain,
years, likely dueto the use of aggressive young adults with NUT rearrangement epistaxis, nasal discharge, and frequent-
trimodality therapy {371}. Systemic che- ly eye-related symptoms such as prop-
motherapy is associated with particularly Epidemiology tosis {205,692). lmag ing studies reveal
high response rates (243}. A large analy- NUT carcinoma is a rare tumour in the extensive local invasion into neighbour-
sis of SEER data showed a median over- upper aerodigestive tract {t59,393, ing structures such as the orbit or brain
all survival of 22.1 months and 3-, 5-, and 2234}. Dueto its rarity, the true incidence (205 ,692}. In approximately 50% of cas-
10-year survival rates of 44.3%, 34.9%, is unknown. In the largest series report- es, NUT carcinoma presents with lymph
and 31.3%, respectively (371]. A recent ed (n = 40), the median patient age was nade involve ment or distant metastatic
meta-analysis had similarfindings {1974). 21 .9 years , but people of all ages were disease {159}.
Patient survival is significantly better with affected (range: 0.1- 82 years). A slight
primary surgical resection [1974,2685) . predominance of females was seen, with Macroscopy
55% of the cases occurring in females Few tumours are resected, due to early
{393). disease spread. No consistent macro-
NUT carcinoma scopic features have been described .
French C.A. The etiology is unknown . There is no as- Cytology
Bishop J.A. sociation with HPV, EBV, other viral in- Aspirates of metastases are cellular, with
Lewis J.S. fection; smoking; or other environmental variably sized clusters of malignant cells
Muller S. factors . and single malignant cells. Mitotic figu res
Westra W.H. and apoptotic bodies are seen. Squa-
Localization mous differentiation may be observed.
Most cases (65%) in the head and neck
Definition are in the nasal cavity and paranasal si- Histopathology
NUT carcinoma is a poorly differentiated nuses, but rare cases involve the orbital The diagnosis of NUT carcinoma is es-
carcinoma (often with evidence of squa- region, nasopharynx, oropharynx, lar- tab lished by demonstration of NUT re-
mous differentiation) defined by the pres- ynx, epiglottis, and majar salivary glands arrangement, rather than by histology.
ence of nuclear protein in testis (NUT) {159,508,763,2032}. The tumours are An unequivocal diagnosis can be made
gene (NUTM1) rearrangement. generally midline. by demonstration of diffuse (> 50%)

20 Tumours of the nasal cavity, paranasal sinuses and skull base

Chromosome 15q14 Neuroendocrine carcinomas
BRD4 N . ,_- -...............- -L.IJi._,,__
. i _ _ _ _ __ Chromosome 19pl3. l
Thompson L.D.R.
BRD3 N _,- -.....
=---'- -L.1Ji...._f _. Chromosome 9q34.2
Bell D.
Chromosome Bpll.23 Bishop J .A.

Sinonasal neuroendocrine carcinoma is
NSD3NUT N .__.-....--~:::a:::::::.J l.:;~=:;.....1u;;.:,.;;: a high-grade carcinoma with morpholog-
ical and immunohistochemical features
of neuroendoc rine differentiation.
PWWP Acidic doma in 2
1111 NES ICD-0 codes
- 1 SET
C/H rlch
- Ac!dlc domainl
- Bromo
Small cell neuroendocrine
carcinoma (SmCC) 8041/3
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 Large cell neuroendocrine
NUT transcript is preserved in every known translocation. PWWP, PWWP domain; PHD, plant homeodomain; SET, carcinoma (LCNEC) 8013/3
SET domain; C/H rich, Cys/His-rich domain; NLS, nuclear Jocalization signal sequence; NES, nuclear export signal
sequence; Bromo, bromodomain; ET, extraterminal domain. Synonyms
Poorly differentiated neuroendocrine
nuclear staining with the NUT monoclo- carcinoma. However, unlike NUT carci - carcinoma; high-grade neuroendocrine
nal antibody C52, which has a sensitiv- nomas, SMARCB1 -deficient sinonasal carcinoma
ity of 87% (916}. Other diagnostic tools carc inomas do not exhibit focal kerati-
include FISH, RT-PCR, conventional cy- nization. lnstead, the basaloid cells Epidemiology
togenetics, and targeted next-generation demonstrate various degrees of rhab- Sinonasal neuroendocrine carc inomas
sequencing approaches . doid or plasmacytoid features. Be- are rare, accounting for about 3% of
The histology is that of an undifferenti- cause SMARCB1-deficient sinonasal sinonasal tumours, but are more com-
ated carcinoma or poorly differentiated carcinomas have biallelic inactivation of mon in middle-aged to older men . The
squamous cell carcinoma. NUT carcino- SMARCB1 (IN/1), immunohistochemi- mean patient ages are 49-65 years for
ma consists of sheets of cells with mod- cal staining for SMARCB1 consistently LCNEC and 40-55 years for SmCC (370,
erately large, round to oval nuclei. The demonstrates loss of nuclear expres- 1831,1853,2222}.
chromatin is vesicu lar with distinct nucle- sion, an importan! fi nding for distinguish-
oli. Cytoplasm vares from scant to mod- ing SMARCB1 -deficient carcinoma from Etiology
erate, and can be clear. Mitotic activity is NUT carcinoma. There is rare association with transcrip -
brisk and necrosis is often present. Hall- tionally active high-risk HPV (199,1323}
mark features include monomorphism Genetic profile and previous irradiation (2535). but no
and the presence of so-called abru pt NUT carcinoma is genetically defi ned by strong smoki ng association {2296}.
foci of keratinization. Occasional tumours rearrangements of the nuclear protein
have more extensive squamous differen- in testis (NUTJ gene (NUTM1). In most Localization
tiation (764). lntratumoural acute inflam- NUT carcinomas, most of the codi ng The most common location is the ethmoid
mation can be brisk and is frequently sequence of NUTM1 on chromosome sinus, followed by the nasal cavity and
present. Glandular and mesenchymal 15q14 is fused with BRD4 (in 70% of the maxillary and sphenoid sinuses
differentiation, although described, is in- cases), BRD3 (in 6%), or WHSC1L1 (also (1631,2222,2296}.
frequent (566) . Markers other !han NUT called NS03), creating chimeric genes
that are commonly positive include p63, that encade NUT fusion proteins (159, Clinical features
p40, and cytokeratins (2265). NUT carci- 764,765,766,767,2318}. In the re maining Many patients present with non-spe-
noma occasionally (in 55% of cases) ex- cases, referred to as NUT-variant carci- cific symptoms (e.g. nasal obstruction,
presses CD34 {764). Occasional positiv- noma, NUTM1 is fused toan unknown part- discharge, and sinusitis) and have ad-
ity for neuroendocrine markers, p16, and ner gene. To date, no other oncogenic vanced local disease (pT3 or T4), with re-
TTF1 has also been described. mutations have been identified in NUT gional or distan! metastases (to lung, liv-
Due to the non-specific, poorly differenti- carcinoma. er, or bone) (11 4,1428,1631,1853}. Rarely,
ated nature of NUT carcinoma, it is often paraneoplastic syndromes are reported
confused with poorly differentiated squa- Prognosis and predictive fact9rs {114,1207,2018,2482}.
mous cel l carcinoma, Ewing sarcoma, Prognosis is poor, with a median overall
sinonasal undifferentiated carcinoma, survival of 9.8 months {393}. Sorne evi- Macroscopy
leukaemia, germ cell tumour, and even dence suggests that patients with NUT- The tumours are large and destructive,
olfactory neuroblastoma (763). A provi - variant carc inoma may have a longer with haemorrhage and necrosis.
sionally defined entity included in the dif- survival than do BRD-NUT carcinoma
ferential diagnosis is SMARCB1-deficient patients {159,763 }.

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 (perinuclear)
reaction with pancytokeratin in a small cell neuroendocrine carcinoma.

Cytology chromogranin, neuron-specific enolase, light-microscopic features of neuroendo-

Aspirates of metastases are identical to or CD56 (least specific) {486}. although crine differentiation.
those of SmCC and LCNEC sampled neuron-specific enolase is less common The differential diagnosis frequently in-
elsewhere. Malignant cells show less co- in LCNEC (114,2568}. In SmCC, S100 eludes olfactory neuroblastoma, sinona-
hesion than seen in other epithelial malig- protein staining (when positive) is diffuse sal undifferentiated carcinoma, and NUT
nancies and are more fragile, displaying rather than sustentacular {2222} . SmCC carcinoma. High-grade olfactory neu-
more crush artefact. Mitotic figures and and LCNEC are positive far p16 (which roblastoma may retain a focal lobular
apoptotic bodies are frequent. is negative in sinonasal undifferentiated architecture with a variable presence of
carcinoma); focally, they may be weakly peripheral sustentacular cells demon-
Histopathology positive for p63. The tumours are rarely strated by immunohistochemistry; cy-
Sinonasal neuroendocrine carcinoma is reactive with calretinin and are consist- tokeratins, if expressed, tend to be focal
histologically identical to its counterparts ently negative far CK5/6, EBV-encoded rather than diffuse. Sinonasal undifferen-
in lung and other head and neck sites; small RNA (EBER), and CK20 {378,390, tiated carcinomas occasionally express
for a detailed description, see Poorly dif- 2635). ASCL1 (also called hASH1), which neuroendocrine markers, but lack the
ferentiated neuroendocrine carcinoma is a master gene for neuroendocrine dif- morphological features of LCNEC [773,
(p. 97). The tumours are highly infiltrative, ferentiation, shows a higher degree of 1034,2568}. NUT carcinoma does not
with frequent perineural and lymphovas- expression in SmCC and LCNEC than show neuroendocrine differentiation, and
cular invasion (1853,2222). in olfactory neuroblastoma or rhabdo- typically shows diffuse expression of
LCNEC contains large cells that show myosarcoma (486,2331). Nuclear immu- CK5/6 and p63 (692).
light microscopic neuroendocrine fea- nohistochemistry for p53 correlates with
tures; for a detailed description of these TP53 mutations {758). Prognosis and predictiva factors
features , see Poorly differentiated neuro- Rare examples of sinonasal neuroendo- The 5-year disease-free survival rate is
endocrine carcinoma (p. 97). crine carcinoma combined with either about 50-65% overall, and is better for
SmCC and LCNEC are strongly immu- squamous cell carcinoma (in situ or in- sphenoid sinus tumours (-80%) than
nopositive for cytokeratins (e.g. CAM5.2 vasive) or adenocarcinoma ha'{e been for maxillary or ethmoid sinus tumours
and AE1/AE3) and EMA, frequently reported (1 14,758 ;1320}. However, squa- (-33%), in particular when managed by
showing a perinuclear or dot-like pattern mous cell carcinoma or adenocarcinoma combination surgery and/or neoadjuvant,
(1587). Neuroendocrine differentiation should not be regarded as sinonasal concurrent, or adjuvant chemoradiother-
can be confirmed by staining with at least neuroendocrine carcinoma based solely apy, with neoadjuvant therapy possibly
one neuroendocrine marker, such as syn- on the presence of focal neuroendo- yielding a better outcome (especially
aptophysin (most sensitive and specific), crine immunoreactivity in the absence of for LCNEC) (770,1428,1631,1831,2462).

22 Tumours of the nasal cavity, paranasal sinuses and skull base

Data are limited, but LCNECs tend to Epidemiology nasal wall, near the middle turbinate {139,
have a better prognosis than do SmCCs Sinonasal ITACs are uncommon, with 2063). lt is estimated that 40% of cases
{1587, 1631, 2016 ,2462}. Advanced-stage an overall incidence of < 1 case per develop in the ethmoid sinuses, 28% in the
disease is associated with poor progno- 1 million person-years. However, inci- nasal cavity, and 23% in the maxillary sinus.
sis {1831). dence vares drastically across popula-
tions, and the tumours are as much as Clinical features
500 times as prevalent among people Patients with ITACs typically present with
Jntestinal-type adenocarcinoma who work for prolonged periods in wood unilateral nasal obstruction, epistaxis,
or leather-working industries as they are and/or rhi norrhoea {139,2063}. Less
Stelow E.B. in the general population {9). Men are common symptoms include pain, facial
Franchi A. 3 - 4 times as likely to develop these tu- contour changes, and diplopa. The tu-
Wenig B.M. mours as women, which is thought to be mours present as soft tissue densities
due to differences in occupational ex- within the sinonasal tract {139}. Destruc-
posure rates (139,1238,2063}. Although tion of surrounding bone occurs in nearly
Definition the patient age range is reportedly wide, half of ali patients. Patients most often
Sinonasal intestinal-type adenocarci- most patients are older, with mean and present with multiple sites of involvement
noma (ITAC) is an adenocarcinoma of median reported patient ages at diagno- {139}. Osseous destruction with local
the sinonasal tract morphologically simi- sis in the sixth to seventh decades of lite. spread into surrounding tissues, includ-
lar to adenocarcinomas primary to the ing the orbit and brain, is frequently seen.
intestines. Etiology
Many ITACs are secondary to wood dust Macroscopy
ICD-0 code 8144/3 or leather dust exposure {9,10,9 18,1238). In vivo, ITACs are polypoid, papillary,
Formaldehyde and textile dust exposures nodular, and fungating {139,2063). Th ey
may also increase the risk of these tu- are usually friable, sometimes ulcerated
Synonyms mours {1490). or haemorrhagic, and uncommonly ge-
Colloid-type adenocarcinoma; colonic- latinous or mucoid.
type adenocarcinoma; enteric-type Localization
adenocarcinoma ITACs typically develop near the lateral

- ;,.... 1 ,...1
\ ,l 1 ' -
Fig. 1.12 Sinonasal intestinal-type adenocarcinoma. A This well-differentated 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 Stromal tissues are loase and fibrovas- patients being disease-free at 5 years.
Aspirates of rare metastatic lesions show cular, often containing abundant chronic Grade 2 and 3 papillary tumours have
findings identical to those seen with colo- inflammatory cells. Histological similarity 3-year survival rates of 54% and 36%,
rectal adenocarcinomas. to primary gastrointestinal trae! tumours respectively. Mucinous tumours with al-
necessitates exclusion of a metastatic veolar growth and mixed or transitional
Histopathology tumour. tumours have prognoses similar to that
ITACs show a morphological spectrum Proposed grading schemas are rather of grade 2 papillary tumours, whereas
similar to that of adenocarcinomas of complicated, given the rarity of these tu- tumours showing signet ring morphology
the intestines {139,1238,2063}. They mours {139,1238). Tumours that are pre- behave the most aggressively. Locally
are often exophytic with a papillary and dominately papillary can be graded as advanced tumours that invade into the
tubular growth (in approximately 75% well, moderately, or poorly differentiated orbit, skin, sphenoid or frontal sinuses, or
of cases) or may be mucinous or com- (papillary tubular cylinder cell 1, 11, and brain have a significantly worse progno-
posed predominantly of signe! ring cells. 111; or papillary, colonic, and salid). Mu- sis. Local disease is the most common
The degree of differentiation varies from cinous tumours are either moderately dif- cause of mortality. About 8% of patients
extremely well differentiated to poorly ferentiated (alveolar) or poorly differenti- have lymph nade metastases and 13%
differentiated. Papillae and tubules are ated (signet ring cell). Mixed tumours are have distan! metastases {139}.
lined by a single !ayer of columnar epi- typically well to moderately differentiat-
thelial cells that show differentiation and ed. Overall survival rates at 3 years have
cytological features similar to !hose seen been shown to vary depending on grade. Non-intestnal-type
in intestinal adenocarcinomas . Most cells Histochemical staining shows intracyto- adenocarcnoma
appear columnar with eosinophilic, mu- plasmic, intraluminal, and/or extracellu-
cinous cytoplasm. Paneth cells, goblet lar material that is mucicarmine-positive Stelow E.B.
cells, and endocri ne cells are typically and gives a diastase-resistant positive Brandwein-Gensler M.
also present in variable proportions. Al- periodic acid-Schiff (PAS) reaction Franchi A.
though atypia may be difficult to appreci- {139}. Neoplastic cells express pancy- Nicolai P.
ate, nuclear changes that appear at least tokeratins, are variably reactive with CK7 Wenig B.M.
adenomatous are the rule. Thus, nuctei and carcinoembryonic antigen, and are
are cigar-shaped, hyperchromatic, and mostly CK20-positive {1 213,1573}. Most
enlarged, and lose basement membrane tumours also express the markers CDX2, Definition
localization. Mitotic figures are frequent. MUC2, and vi llin (358,1213}. There may Sinonasal non-intestinal-type adeno-
Necrosis is usually present, typically be variable expression of neuroendo- carcinoma (non-lTAC) is an adenocar-
within the tubular and folded spaces, crine markers {1 573,1928}. cinoma of the sinonasal tract that does
similar to what is seen in intestinal adeno- not show the features of a salivary gland
carcinomas. As these tumours become Genetic profile neoplasia and does not have an intesti-
more poorly differentiated, tubular and KRAS mutations occur in 6-40% of cas- nal phenotype. Although these tumours
papillary structures are replaced by nest- es, whereas BRAF mutations occur in are morphologically heterogeneous, this
ed, cribriform , and salid growth patterns. < 10% {755 ,1926,2037,2327). 1 umours category may include sorne specific enti-
A minority of cases show abundan! mu- are microsatellite-stable and do not lose ties that are morphologically unique (e.g.
cus production (139,1238). These cases expression of mismatch repair proteins renal cell-like carcinoma).
are similar to sorne primary intestinal {1 546,1854). EGFR mutations are infre-
adenocarcinomas and consi st of small quent and amplifications are uncommon ICD-0 code 8140/3
to medium-sized cystic spaces (alveoli) {755,1926}. Expression of p53 is aber-
partially lined by (and containing strips of) rant in more than half of ali cases, and Synonyms
attenuated neoplastic epithelium rich in 41% have been shown to have TP53 Terminal tubulus adenocarcinoma; tubu-
goblet cells. The strips often float like rib- mutations {757). CDKN2A (also called lopapillary low-grade adenocarcinoma;
bons within mucus lakes and sometimes P16) is frequently altered , due either to low-grade adenocarcinoma; seromuci-
form small cribriform structures. The indi- promoter methylation or to loss of hete- nous adenocarcinoma; renal cell- like
vidual neoplastic cells have atypical and rozygosity at 9p21 {1857). Variable beta- carcinoma
hyperchromatic nuclei and abundant mu- catenin expression has been reported ,
cinous cytoplasm. Less commonly, the with sorne studies showing > 30% of Epidemiology
neoplastic cells are mostly single , with cases with aberrant nuclear expression Sinonasal low-grade non-intestinal-type
a large amount of intracytoplasmic mu- {757,1854}. adenocarcinomas (LG non-lTACs) are
cus that compresses the nucleus (signet very uncommon. There is no sex predi-
ring cells). Finally, sorne tumours have a Prognosis and predictive fact9rs lection {967,1139,1721). Patients have
mixed pattern of growth, appearing pap- The grading systems described above ranged in age from 9 to 89 years, with
illary and tubular in sorne areas and more predict survival and recurrence, althoug h a mean age at presentation in the sixth
mucinous in others. results have not been universal {1 39,754, decade of life. High-grade non-intestinal-
ITACs are invasive (often extensively in- 760,1238}. Low-grade papillary tumours type adenocarcinomas (HG non-lTACs)
filtrating the submucosa) and may show have the best outcomes, with > 80% of are rare, affect men more frequently,
perineural and osseous invasion {139}. patients surviving 3 years and > 60% of and occur over a wide age range, with a

24 Tumours of the nasal cavity, paranasal sinuses and skull base

mean patient age at presentation in the
sixth decade of lite {967,2266}.

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).

Most LG non-lTACs (64%) arise in the Fig. 1.13 Sinonasal low-grade non-intestinal-type adenocarcinoma. Endoscopic view of the right nasal fossa (A) and
nasal cavities (frequently the middle tur- coronal turbo spin echo T2-weighted MRI (B). The tumour (T) is centred on the superior meatus and laterally displaces
binate), and 20% arise in the ethmoid si- the ethmoidal complex (asterisks); the point of origin was on the upper part of the septum. LW, lateral wall; MT, middle
nuses (967,1139). The remaining tumours turbinate; NS, nasal septum.
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.

Clnica! 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 solid masses, filling 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).

Low-grade non-lTACs may appear red
and polypoid or raspberry-like and firm

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 occasional glandular structures and/ monomorphous cuboidal to columnar
structures. These cells have eosinophilic or individual mucocytes . Sorne have a glycogen-rich clear cells that lack mucin
cytoplasm and uniform, basally located nested growth and are infiltrative. Numer- production . The cellular cytoplasm may
nuclei. Mitotic figu res are rare and necro- ous mitotic figures are seen with necrosis be crystal clear or slight ly eosinophilic.
sis is not seen. lnvasive growth, includ- (individual-cel l and confluent), as well as Perineural invasion, lymphovascular in-
ing within the submucosa as well as into infiltrative growth with tissue destruction vasion, necrosis, and severe pleomor-
bone, may be present. Calcispherules and osseous invasion. phism are absent, and the overall histo-
are rarely seen (967). Occasional tu- Occasional cases are composed pre- logical impression is that of a low-grade
mours have more dilated glands (1237, dominately of clear cells, reminiscent of neoplasm.
1721). metastatic renal cell carcinoma {2287) . In most LG non-lTACs and HG non-
HG non-lTACs show much more diver- These tumours have been referred to lTACs, intraluminal mucin or material
sity in their histology {967,2266). Many as sinonasal renal cell-like carcino- that gives a diastase-resistant positive
have a predominately solid growth with mas. The tumours are composed of reaction with periodic acid-Schiff (PAS)

Carcinomas 25
B This tumour is

can be identified. In HG non-lTAC, cells neuroendocrine antigens (2266). Renal Prognosis and predictive factors
with intracytoplasmic mucin or diastase- cell- like carcinomas express CAIX and Approximately 25% of LG non- lTACs
resistant PAS positivity may be pres- CD1 0, but do not express PAX8 or renal recur, and only 6% of patients die from
ent. The tumours express cytokeratins cell carcinoma marker (2156}. Beta-cat- their tumours, usually as a result of loss
(typically CK7 and infrequently limited enin and mismatch repair protein expres- of local control {967,1139,1721). Patients
CK20) {2266}. Squamous antigens, such sion is wildtype {2679). Overexpression with HG non-lTAC tare much worse {967};
as p63, are typically not expressed orare of p53 may occur as well (2193}. most die from the disease within 5 years
expressed only focally (2193}. Markers of of diagnosis. Occasional HG non-lTACs
intestinal differentiation, such as CDX2 Genetic profile metastasize locally and distally. The re-
and MUC2, are also not expressed or Only rare LG non-lTACs have been stud- ported cases of renal cell- like carcinoma
are expressed only focally {358,2266}. ied fo r molecular abnormalities. RAS mu- have neither recu rred nor metastasized
Sorne authors have reported expres- tations are not seen (755). Rare BRAF (2156).
sion of D0G1, SOX10, and S100 (1933). mutations have been found (755).
HG non- lTACs can focally express

Teratocarcinosarcoma Franchi A.
Wenig B.M.

Definition nasal cavity, followed by the ethmoid si- Histopathology

Sinonasal teratocarcinosarcoma is a nus and the maxillary sinus {1628). lntrac- Teratocarcinosarcoma is composed of
malignant sinonasal neoplasm with com- ranial extension occurs in approximately an admixture of epithelial, mesenchy-
bined histological features of teratoma 20% of cases (1628). mal, and neuroep ithelial elements. The
and carcinosarcoma, lacking malignant epithelial components include kerati-
germ cell components. Clinical features nizing and non-keratinizing squamous
The most common presenting symptoms epithelium, pseudostratified columnar
ICD-0 code 9081/3 are nasal obstruction and epistaxis. lm- ciliated epithelium, and glandular/duct-
aging studies show a nasal cavity mass al structu res. An importan! diagnostic
Synonyms with opacification of paranasal sinuses feature is the presence of nests of
Malignant teratoma; blastoma; teratocar- and frequent bone destruction. immature squamous epithelium with clear
c inoma; teratoid carcinosarcoma so-called fetal-appearing cells {966}.
Macroscopy The most-represented mesenchymal ele-
Epidemiology Tumour tissue is firm to friable, with a ments are spindle cells with features of
Teratocarcinosarcoma is a rare tumour variegated reddish-purple to browri appear- f ibroblasts or myofibroblasts, but areas
affecting adults (median patient age: 60 ance. When present, the surface mucosa with rhabdomyoblastic, cartilaginous, os-
years), with a strong male predilection. is often ulcerated, and areas of necrosis teoblastic, smooth-muscle, or adipocytic
and haemorrhage are evident at the cut differentiation can be seen, with appear-
Localization surface. ances ranging from benign to frankly ma-
The tumour most commonly involves the lignant. The neuroepithelial component

26 Tumours of the nasal cavity, paranasal sinuses and skull base

consists of a proliferation of immature neuroepithelium related to the olfactory cell components, and the presence of tri-
round to oval cells either in solid nests membrane {1801,2054). somy 12 wit h a subclone of cells showing
or within a neurofibrillary background, loss of 1p in one case {2516). In another
sometimes with rosette formation. Genetic profile study, no amplification of 12p was found
The immunohistochemical profile matches There are limited reports in the literature in any of 3 cases {2054).
that of the tumour components, including on the cytogenetic abnormalities. These
epithelial, mesenchymal, and neuroepi- abnormalities include extra copies of Prognosis and predictive factors
thelial components. PLAP, alpha-fetopro- chromosome 12p in a subpopulation of Teratocarcinosarcoma is an aggressive
tein, hCG, and CD30 are negative. neoplastic cells in a hybrid case that also tumour, with frequent lymph node and
exhibited foci of yolk sac elements {2380) distan! metastasis. Reported survival
Cell of origin in addition to teratocarcinosarcoma fea- rates range from 50% to 70% in different
The favoured hypothesis is origin from tures, thus not completely meeting the series, with an average follow-up of 40
somatic pluripotent stem cells of the definition that excludes malignan! germ months {1628).

Teratocarcinosarcoma 27
Sinonasal papillomas

Sinonasal papilloma, has been reported in 1.9- 27% of cases Localization

inverted type in different series; most malignancies The nasal cavity and the maxillary sinus
were synchronous tumours (1750). are the most common locations of invert-
Hunt JL ed papilloma, with the medial wall being
Bell D. Etiology the most common site of origin in t he
Sarioglu S. Exposure to organic solvents seems to be maxillary sinus. Other locations as site
a risk factor for inverted papilloma devel- of primary origin are more rare, includ-
opment {505), whereas no such associa- ing the ethmoid sinus, frontal sinus, and
Definition tion far smoking or alcohol consumption nasal septum. About 30% of cases origi-
Sinonasal inverted papilloma is a surface has been shown . Varying rates of HPV nate from multiple sites. lnverted papil-
mucosa! lesion of the sinonasal tract that detection have been reported. In a meta- loma may rarely be bilateral and may
usually shows inverted growth and has analysis including 760 inverted papilloma originate from multiple extrasinonasal
multi layered epithelium with mucocytes cases, 38.5% of the cases were HPV- siles, including the nasopharynx, phar-
and transmigrating neutroph ils. positive by either in situ hybridization or ynx, lacrimal sac, middle ear, temporal
PCR {2323). Low-risk HPV (HPV 6 and bone, and neck (75,1224,2147).
ICD-0 code 8121/1 11) is 2.8 times as frequent as high-risk
HPV (HPV 16 and 18) in inverted papil- Clinical features
Synonyms loma. However, high-risk HPV is more Patients may present with non-specific
lnverting papilloma; inverted Schneide- frequent in cases with high-grade dys- symptoms such as nasal obstruction,
rian papil loma; Schneiderian papilloma, plasia and carcinoma (1352). E6 and E7 polyp s, epistaxis, rhinorrhoea, hyposmia,
inverted type mRNAs, associated with transcriptionally and headache of long duration . Rarely,
active high-risk HPV infection, were de- sensorineural and auditory symptoms
Epidemiology tected in ali cases in a series of 19 in- are described. Both CT and MRI are val-
lnverted papillomas are the most fre- verted papillomas; however, this expres- uable; CT may provide information about
quent papillomas of the sinonasal region, sion was seen in only 1% of the tumour the site of origin of the tumour, and MR I
arising from the sinonasal epithelial lin- cells in 58% of the cases, and HPV DNA shows the extent of the disease. On MRI,
ing. An estimated 0.74- 2.3 new cases was positive in only 2 cases. Expression the lesi on characteristically has a septate
may be expected per 100 000 population of p16, which is an accepted surrogate striated appearance (75). Several staging
annually (294,1750). The tumour is most biomarker for high-risk HPV infection in systems have been proposed for invert-
frequent in the fifth and sixth decades of oropharyngeal carcinoma, is controver- ed papilloma (75,1224). One commonly
lite (patient age range: 6- 84 years) and is sia! in inverted papilloma; in sorne series, used staging system {1283} depends
2.5-3 times as common in males as in fe- no correlation between p16 and HPV was on the extent of disease, considering
males {141,1224,251 1). Recurrences are seen {420,2283}. both rad iological and endoscopic find-
frequent and malignant transformation ings. The American Joint Committee on

28 Tumours of the nasal cavi ty, paranasal sinuses and skull base
Cancer (AJCC) staging system is also cell carcinoma, mucoepidermoid car- malignan! transformation {1352). However,
commonly used. cinoma, sinonasal undifferentiated car- no correlation was found between E6/E7
cinoma, and verrucous squamous cell transcriptional activity and progression,
Macroscopy carcinoma can ali be seen in malignan! recurrence, or malignan! transformation
lnverted papilloma is covered with a grey, transformation. Lymphovascular inva- (2283). In one series, malignant transfor-
undulating surface resembling a mulber- sion, atypical mitoses, desmoplasia, mation in inverted papilloma was identified
ry. Because of their cellular density, the bone invasion, decreased transmigrating more frequently in smokers (in 24.6% of
lesions do not transilluminate. neutrophils, paradoxical maturation, dys- cases) !han in non-smokers (in 2.8%), and
keratosis, increased Ki-67 expression, the odds ratio of malignancy for smoking
Histopathology and p53 expression in > 25% of cells are was 12.7 (1020). Type of surger.y is also an
Multiple inversions of the surface epi- among the most importan! features of importan! prognostic factor for recurrence
thelium into the underlying stroma, com- malignancy (1750}. {962).
posed of squamous and/or respiratory
cells and lined by a distinct and intact, Genetic profile
continuous basement membrane, is the lnverted papillomas are neoplastic and Sinonasal papilloma,
typical morphology of inverted papilloma. monoclonal proliferations, as shown by oncocytic type
Non-keratinizing squamous or transition- X chromosome analysis. However, the
al epithelium, 5-30 cells thick, frequently chromosomal LOHs at arms 3p, 9p21, Hunt J.L.
predominates, and is covered by a layer 11q13, 13q11, and 17p13 that occur fre- Chiosea S.
of ciliated columnar cells. lnfiltration of quently during neoplastic transformation Sarioglu S.
the epithelium by neutrophils (so-called of the upper respiratory tract have not
transmigrating neutrophils) is frequently been detected {315). In one small series
seen. Mitoses are sparse and confined of 7 cases, at least one epigenetic event Definition
to the basal layers {141,2002,2075). of aberrant DNA hypermethylation was Sinonasal oncocytic papilloma is a papil-
There is usually a loss of underlying se- observed, suggesting a role of epigenet- loma derived from the sinonasal epithe-
romucinous glands (2075}. The stroma ics in inverted papilloma development lium composed of both exophytic fronds
may be either loase or dense, and may (2276). Furthermore, from a small num- and endophytic invaginations lined by
be inflamed. Cells showing squamous ber of cases studied, it appears that acti- multiple layers of columnar cells with
and columnar differentiation are positive vating mutations in the EGFR gene have oncocytic features. lntraepithelial micro-
far cytokeratins (e.g. CK10, CK10/13, and a high prevalence in inverted papillomas cysts containing mucin and neutrophils
CK1/2/10/1 1) {2106}. and in concurrent squamous cell carci- are characteristic.
Premalignant and malignant features, nomas arising from inverted papilloma
dysplasia, carcinoma in situ, and inva- {2442A). ICD-0 code 8121/1
sive carcinoma can be seen arising in
inverted papilloma. Sampling should be Prognosis and predictive factors Synonyms
thorough, and evidence of malignan! In one large series, cases originating from Oncocytic Schneiderian papilloma; cylin-
transformation should be sought during the nasal cavity had a significantly lower drical cell papilloma; columnar cell papil-
histopathological evaluation. There is no recurrence rate {1224). The ratio of low- loma
consensus about the grading of dyspla- risk HPV (HPV 6 and 11) to high-risk HPV
sia in inverted papilloma, and the diag- (HPV 16 and 18) was 1.1:1 in inverted pap- Epidemiology
nosis of malignan! transformation may be illoma with high-grade dysplasia, versus Oncocytic papilloma is equally distribut-
challenging. Keratinizing squamous cell 4.8:1 in the rest of the cases, suggesting ed between the sexes, and most patients
carcinoma, non-keratinizing squamous an association between high-risk HPV and are aged > 50 years (2511 ).

Sinonasal papillomas 29
Etiology inverted papilloma. lf inadequately ex- Epidemiology
Unlike in exophytic and inverted papillo- c ised, especially using mucosa! strip- Exophytic papillomas are 2-1O times as
mas, HPV has not been identified in on- ping, at least 25- 35% of cases recur, common in men as in women, and typi-
cocytic papillomas (792}. usually within 5 years {962). Smaller tu- cally occur in individuals aged 20- 50
mours can be resected endoscopically. years (reported range: 2-87 years) (441}.
Localization About 4-17% of all oncocytic papillomas
Oncocytic papilloma almost always oc- harbour a carcinoma {1201,1441,2511 ). Etiology
curs unilaterally on the lateral nasal wall Most of these are squamous, but mu- Ther is increasing evidence to suggest
or in the paranasal sinuses (usually the coepidermoid, small cell, and sinonasal that exophytic papillomas may be etio-
maxillary or ethmoid). lt may remain lo- undifferentiated carcinomas have also logically related to HPV. In a large meta-
calized, involve both areas, or (if neglect- been described {2370,2511 }. Prognosis analysis, exophytic papil lomas were as-
ed) extend into contiguous areas. depends on the histological type, the sociated with HPV in 63.5% of cases,
degree of invasion, and the extent of tu- pre dominantly with the low-risk types 6
Clinical features mour. In sorne instances, the carcinoma and 11 , and rarely with types 16 and 57b
Patients present with nasal obstruction is in situ and of little consequence to the {2323).
and/or intermittent epistaxis. patient, whereas other cases are locally
aggressive and may metastasize. Localization
Macroscopy Exophytic papillomas usually arise on
Oncocytic papilloma is a fleshy, pink, the lower anterior nasal septum. As they
tan, or reddish-brown polypoid growth. Sinonasal papilloma, enlarge, they may secondarily involve the
exophytic type lateral nasal wall, but only intrequently
Histopathology originate from this location . lnvolvement
Oncocytic pap liorna exhibits both exo- Hunt J.L. of the paranasal sinuses is practically
phytic and endophytic growth. The epi- Lewis J.S. non-existent. Bilateral lesions are ex-
thelium is multilayered, 2-8 cells thick, Richardson M. ceptional. Benign keratinizing cutaneous
and composed of columnar cells with Sarioglu S. tumours of nasal vestibule origin do not
swollen, finely granular cytoplasm. The Syrjanen S. constitute sinonasal exophytic papilloma.
high content of cytochrome c oxidase
and ultrastructural presence of numerous Clinical features
mitochondria establish the papilloma's Definition The typical presenting symptoms are
oncocytic nature {145). The nuclei are Sinonasal exophytic papilloma is a papil- epistaxis, unilateral nasal obstruction,
either small, dark, and uniform or slightly loma derived from the sinonasal mucosa, and the presence of an asymptomatic
vesicular with barely discernible nucleoli . composed of papillary fronds with deli- mass.
Cilia in various stages of regression may cate fibrovascular cores covered by mul-
be observed in the outermost cells. The tilayered epithelium. Macroscopy
epithelium usually contains small cysts Th e lesions present as papillary or
tilled with mucin or neutrophils (microab- ICD-0 code 8121/0 warty; grey, pink, or tan; non-translucent
scesses). These cysts are not present in growths attached to the nasal septum by
the stroma, which helps distinguish this Synonyms a relatively broad base.
lesion from rhinosporidiosis. The stroma Schneiderian papilloma, exophytic type;
vares from oedematous to fibrous, and fungiform papilloma; everted papilloma; Histopathology
may contain modest numbers of lympho- transitional cell papilloma; septal papil- Exophytic papillomas are typically as
cytes, plasma cells, and neutrophils, but loma; Ringertz tumour large as about 2.0 cm. Microscopically,
few eosinophils. Seromucinous glands
are sparse to absent. Oncocytic pap-
illoma may rarely undergo malignant
transformation. lt is also occasionally
confused with low-grade papillary ade-
nocarcinoma {1403). The presence of in-
tact basement membranes and absence
of infiltrative growth are features that in-
dicate a benign lesion. In addition, the
presence of intraepithelial mucin-filled
cysts and microabscesses and the strati-
fied oncocytic epithelium of a papilloma
are rarely seen in low-grade adenocarci-

Prognosis and predictive factors

The clinical behaviour parallels that of Exophytic growth pattern with thickened epithelium and focal mucocytes.

30 Tumours of the nasal cavity, paranasal sinuses and skull base

they are composed ot papillary fronds Malignant change in exophytic papillo- Prognosis and predictive factors
with fibrovascular cores covered by ma is extremely rare {157,441}. Exophytic Complete surgical excision is the treat-
a multilayered epithelium that is 5-20 papillomas must be distinguished from ment of choice. lnadequate excision
cells thick. The epithelium vares trom keratinizing cutaneous squamous cell (rather than multiplicity of lesions) proba-
squamous to ciliated pseudostrati- papillomas, which are much more com- bly accounts for th e local recurrence rate
fied columnar (respiratory), or may be mon in the nasal vestibule. The absence of 22- 50% {441}. Exceptionally, carcino-
transitional between the two. Scat- ot extensive surface keratinization, pres- mas have been seen arising in exophytic
tered mucocytes are common. Surface ence of mucocytes, and presence ot cil i- papillomas, with reported cases including
keratinization is absent or scant, unless ated and/or transitional epithelium help squamous cell carcinoma; mucoepider-
the lesion has been irritated by trauma to contirm t he diagnosis ot exophytic moid carcinoma (1750}; and low-grade
or exposure to the drying effects ot air. papilloma. The presence ot seromuci- non-intestinal, non-salivary gland ad-
Mitoses are rare and are not usually nous glands and septal cartilage turther enocarcinoma {220). HPV status has not
atypical. Unless infected or irritated, the indicate that the lesion is ot mucosa! been clearly shown to correlate with re-
stroma contains few inflammatory cells. rather than cutaneous origin. currence risk or carcinoma development.

Respiratory epithelial lesions

Respiratory epithelial age from the third to ninth decades ot Macroscopy

adenomatoid hamartoma lite, with a median patient age in the sixth REAHs are polypoid or exophytic lesions
decade !1367,2588). with a rubbery consistency. They are tan-
Wenig B.M. white to reddish-brown and measure as
Franchi A. Localization much as 6 cm in greatest dimension .
Ro JY. The majority occur in the nasal cavity,
in particular the posterior nasal septum Histopathology
{2588} . lnvolvement of other intranasal Histopathology shows a glandular pro-
Definition sites occurs less often, and may be iden- liferation composed of widely spaced,
Sinonasal respiratory epithelial adenom- tified along the lateral nasal wall, middle small to medium-sized glands separated
atoid hamartoma (REAH) is a benign ac- meatus, and inferior turbinate. Uncom- by stromal tissue. The glands arise in
quired overgrowth ot indigenous glands monly, the lesions may occur in the na- direct contin uity with the surface epithe-
of the sinonasal tract arising trom the sur- sopharynx, ethmoid sinus, and frontal si- lium , which invaginates downwards into
tace epithelium. nus. Most lesions are unilateral but sorne the submucosa {1 852,2588}. The glands
are bilateral {2588) . are round to oval and composed of multi-
Synonym layered c iliated respiratory epithelium, of-
Glandular hamartoma Clinical features ten with admixed mucin-secreting (gob-
Patients present with nasal obstruction, let) cells; glandular dilatation distended
Epidemiology stuffiness, epistaxis, and chron ic (recur- with mucus can be seen. A characteristic
The lesions predominantly occur in adult rent) rhinosinusitis occurring over the finding is the presence of envelopment of
patients, with a distinct male predomi- course of months to years {2588}. the glands by a thickened, eosinophilic
nance {1367,2588}. Patients range in basement membrane {2588). Atrophic

Respiratory epithelial lesions 31

glandular alterations may be present, Seromucinous hamsrtoms a tan-white to reddish-brown appear-
lined by a single !ayer of flattened to ance. They measure 0.6-6 cm in grea-
cuboidal-appearing epithelium. Small re- Ro J.Y. WWtest dimension.
active-appearing seromucinous glands Franchi A.
are present among the glandular prolif- Histopathology
eration. Addtonal coexisting findings SH is a polypoid mass covered by respira-
may include sinonasal inflammatory pol- Definition tory epithelium, and contains small to large
yps, surface epithelial hyperplasia and/ Sinonasal seromucinous hamartoma glands and ducts lined by a single layer of
or squamous metaplasia, and osseous (SH) is a benign overgrowth of indige- cuboidal or flattened epithelal cells with
and/or chondroid metaplasia. Rarely, the nous seromucinous glands of the nasal bland, oval to round nuclei and ampho-
lesions may be associated with sinona- cavity and paranasal sinuses. philic to eosinophlc cytoplasm. Mitoses
sal inverted papilloma or solitary fibrous are absent. The surrounding fibrous stro-
tumour {2588}. The occasional pres- Synonyms ma often contains a lymphoplasmacytic
ence of both REAH and seromucinous Epithelial hamartoma; glandular hamarto- infiltrate (125,1044). Eosinophilic secretion
hamartoma suggests a spectrum from ma; microglandular adenosis of nose {445) can be seen in the lumen, and goblet or
pure REAH to seromucinous hamartoma clear cells may be observed. The tubular
{1218). Epidemiology glands may be encircled by thick base-
The glands are immunoreactive for cy- SHs are extremely rare (1218). They oc- ment membrane material. The proliferat-
tokeratins such as AE1/AE3, CAM5.2, cur predominantly in adults, with a male- ing tubules intermngle with the pre-ex-
and CK7 but negative for CK20 and to-female ratio 3:2. The patient age range isting seromucnous acini or invaginated
CDX2. Myoepithelial/basal cell markers is 14-85 years (mean: 56 years). respiratory epithelium forming glands or
(including p63) are typically present but cysts, similar to features of respiratory epi-
may be absent; the absence of markers Etiology thelial adenomatoid hamartoma, support-
for myoepithelial/basal cells does not SH has no association with any specific ing the possibility that SH and respiratory
confer a diagnosis of adenocarcinoma etiological agent, but it often arises in the epithelial adenomatoid hamartoma con-
{1 794). setting of inflammatory polyps. stitute a spectrum of lesons, often seen
together {2565,2567).
Genetic profile Localization lmmunohistochemistry shows positiv-
The reported increased fractional allelic SH usually occurs at the posterior nasal ity for CK17, CK19, EMA, lysozyme, and
loss of 31 % is unusually high for a non- septum or nasopharynx, and is rarely de- S100, with an absence of myoepthe-
neoplastic entity, raising the possibility scribed on the lateral nasal wall or in the lial (basal) cells around the seromuci-
that REAH may in fact be a benign neo- paranasal sinuses (2567). nous glands (731). The stroma around
plasm rather than a hamartoma {1796}. tubules is postive for calponn, SMA,
Clinical features and desmn, indicating myofibroblastc /
Prognosis and predictive factors The typical symptoms are nasal obstruc- smooth muscle differentiaton {1564}.
Complete surgical excision is curative. tion and epistaxis. The lesions are often
found incidentally, and are sometimes Prognosis and predictiva factors
associated with other medica! cond i- Conservative but complete surgical ex-
tions, such as rheumatoid arthritis, Par- c ison is curative. With follow-up avail-
kinson disease, and chronic sinl!sitis. able from 4 months to 10 years (mean: 6
Physical examination reveals a polypoid years), ali patients are alive and well after
mass without other aggressive features. surgical removal, with no documented
cases of metastasis and only one report
Macroscopy of recurrence (731}.
SHs are typically polypoid or exophytic,
typical ly with a rubbery consistency and

32 Tumours of the nasal cavity, paranasal snuses and skull base

Salivary gland tumours Bell D.
Bullerdiek J.
Gnepp D.R.
Hunt J.L.

P/eomorphic adenoma
Pleomorphic adenoma (PA) is a benign
tumour with variable cytomorphological
and architectural manifestations. The
identification of epithelial and myoepithe-
lial/stromal components is essential for
the diagnosis of PA.
See also the Pleomorphic adenoma
section (p. 185) in Chapter 7 (Tumours of
sa/ivary glands).

ICD-0 code 8940/0

Benign mixed tumour

Most intranasal PAs present in the third to
sixth decades of lite, with a slight female
. '...;
preponderance (8,477,2109,2257f. " . f' :,,
t, ..... \. ~-
.. ..
>. I

The tumour generally (in about 80% of ' .,. .- ..

cases) arises in the nasal septal mucosa,

despite the fact that the seromucinous .'.~
~ . "\.,1
~ '
glands are mainly located in the lateral
... -..
-. ..." ti
wall and turbinates (8,1286,2109}.
,. . . . ....
Clinical features ,
The most common presenting symptom
is unilateral nasal obstruction. Epistaxis
and sinusitis can occur secondary to
13 , . -.. j

extension into the maxillary sinus {2109}.

Affected patients present within 1 year of
the onset of symptoms {2109}.
Histopathology Prognosis and predictive factors
Macroscopy In the nasal cavity, these neoplasms Complete surgical excision is the treat-
The range of tumour size is 0.5- 7 cm, display a more dom inant epithelial com- ment of choice. The recurrence rate is
and the tumours are descri bed as exo- ponen! (vs stromal components) th an is lower than that of parotid PA. Malignan!
phytic or polyp oid (with a broad base), seen in PAs of the major salivary glands transformation of PA of the nasal cavity
oval, dome-shaped, firm, and grey {8,2109}. has been reported in 2.4-10% of cases
(8,2109}. No destruction of surrounding {8,451,2109).
tissue is seen .

Salivary gland tumours 33

Malignant soft tissue tumours

Franchi A.
Flucke U.
Thompson L. D.R.

Fibrosarcoma is a malignant spindle
cell tumour with fascicular architecture
and variable collagen matrix production,
showing fibroblastic/myofibroblastic dif-
ferentiation. lt is a diagnosis of exclusion.

ICD-Ocode 8810/3

Adult-type fibrosarcoma Histopathology occasionally with actins, but negative
Fibrosarcomas are moderately to highly for epithelial markers, S100 protein,
Epidemiology cellular proliferations of spindle cells, S0X10, HMB45, beta-catenin, desmin,
Sinonasal fibrosarcoma is a rare tumour arranged in intersecting fascicles, often myogenin, and CD34. Electron mi-
(accounting for < 3% of ali non-epithelial w ith a herringbone or chevron pattern, croscopy can confirm the fibroblastic
tumours), but is the second most com- and with a variable amount of co llagen differentiation of the tumour, demon-
mon head and neck sarcoma. lt affects production. There is moderate cel lular strating the presence of abundant cy-
adults (mean age: 55 years), with no sig- atypia, but profound pleomorphism is toplasmic rough endoplasmic reticulum
nifican! sex predilection {1829). usually lacking. Tumours with signifi- cisternae and excluding the presence
can! pleomorphi sm and storiform areas of epithelial, muscle, and melanocytic
Etiology are b etter categorized as undifferentiat- differe ntiation.
The etiology is uncertain, but sinonasal ed pleomorph ic sarcoma. Mitotic a.ctiv-
radiation-induced fibrosarcomas have ity is variable. Th e tumour borders are Genetic profile
been reported {314}. poorly defined and there is invasion of The genetic profile of sinonasal fi brosar-
the sinonasal mucosa and bone. Histo- coma has not been specifical ly investi-
Localization logical grading, w ith distinction of low- gated, but soft tissue fibrosarcomas in
The maxillary sinus is the most common grade and high-grade tumours, is per- general show a complex karyotype, with
site of involvement, followed by the nasal formed on the basis of cellularity, atypia, several numerical and structural chromo-
cavity {1829). mitotic activity, and tumour necrosis. somal abnormalities.
Because the histological appearance
Clinical features of th e tumour is non-specif ic, diagno- Prognosis and predictive factors
The most common presentations are na- sis requ ires the exclusion of other enti- The disease-specific survival rate is
sal obstruction, epistaxis, and a nasal ties, including sarcomatoid carcinoma, about 75%, with better survival among
mass, usually with short symptom dura- synovial sarcoma, leiomyosarcoma, patients treated with surgery (with or
tion {780}. spindle cell rhabdomyosarcoma, spin- without adjuvant radiotherapy) than
dle cell melanoma, malignan! periph- among those treated w ith radiotherapy
Macroscopy eral nerve sheath tumour, biphenotypic alone {1829). The rate of recurrence is
The tumour presents as a polypoid, poor- sinonasal sarcoma, glomangiopericy- high (-60%), and recurrence is usually
ly circumscribed, white, firm, and pedun- toma, desmoid f ibromatosis, and fibro- identified befare metastatic disease (to
culated or fungating mass projecting into blastic osteosarcoma. An appropriate lung or bone), which occurs in about
the lumen, with frequent infiltration of the immunohistochemical panel is neces- 15% of patients. The prognosis is worse
adjacent bone. Haemorrhage and necro- sary to rule out these other neoplasms, far male patients, and in cases of large
sis are present in high-grade examples. with the addition of selected molecular tumours, multisite involvement, high his-
studies as necessary. By convention, tological grade, and positive margins
the tumour is reactive with vimentin and {156,780,965,1263}.

34 Tumours of the nasal cavity, paranasal sinuses and skull base

Undifferentiated Clinical features and p leomorphic liposarcoma , and high-
pleomorphic sarcoma There are non-specific signs and symp- grade myxofibrosarcoma) {902l.
toms, including a painless mass, nasal
Flucke U. obstruction, proptosis, diplopa, and Genetic profile
Franchi A. epistaxis. Very rarely, undifferentiated There are com plex genetic aberrations
Thompson L.D.R. p leomorp hic sarcoma presents with re- {902).
gional or d istan! metastasis {2294).
Prognosis and predictive factors
Definition Macroscopy The 5-year survival rate is 60-70%
Undifferentiated pleomorphic sarcoma is The tumours consist of a multilob ulated {2326,2529). Surgery seems to be es-
a high-grade soft tissue sarcoma with no greyish-white fl eshy mass. Cut surface sential regardless of the margin status,
line of differentiation. lt is a d iagnosis of often shows haemorrhagic, myxoid, and/ and radiation therapy seems to be nec-
exclusion . or necrotic changes. Most neoplasms essary for local control {2326). Previous
appear circumscribed. but extension into radiation has been reported as an ad-
ICD-0 code 8802/3 adjacent structures may be seen {2578). verse prognostic factor for d isease-free
survival {2534l.
Synonym Histopathology
Malignant fibrous histiocytoma The tumour is composed of an admixture
of spindle and pl eomorphic cells set in a Leiomyosarcoma
Epidemiology variably collagenized extracellular matrix.
This sarcoma occurs in adults, and Cellularity vares. Pleomorphism, numer- Flucke U.
sinonasal examples are rare. However, ous mitoses, atyp ical mitoses. areas of Franchi A.
undifferentiated pleomorphic sarcoma is tumour necrosis, histiocyte-like cells, and
the third most frequently reported histo- foamy cells, as well as giant tumour cells
type in !he sinonasal tract, after rhabdo- with enlarged, polylobulated nuclei are Definition
myosarcomas and fibrosarcomas (2326, commonly observed. Leiomyosarcoma is defined as sarcoma
2534). lmmunohistochemically, there are sorn e with smooth muscle d ifferentiation.
limited foci of SMA reactivity, whereas
Etiology h-caldesmon, desmin, S100 protein, and ICD-Ocode 8890/3
Radiation therapy contributes to the risk epithelial markers are usually not ex-
of developing an undifferentiated pleo- pressed. Histiocytic antigens are of no Epidemiology
morphic sarcoma {2294,2534). utility. Smooth muscle tumours of the sinona-
Ultrastructurally, many tumour cells show sal tract are very rare. Most cases arise
Localization features of f ibroblasts, myofi broblasts, or in adults. Children are rarely affected
Lesions are generally evenly distributed histiocytes. (538,606,902,1047).
among the sinonasal tract (i.e. maxillary Undiffe rentiated pleomorphic sarcoma is
sinus, nasop harynx, and nasal cavity), a diagnosis of exclusion. Other potential Etiology
upper aerodigestive system, and parotid mimics must be ru led out, including car- Radiation therapy contrib utes to the risk
reg ion (2294,2326,2534}. The mass is cinomas, melanoma, lymp homa, and sar- of developing a leiomyosarcoma {778).
usually subcutaneous or submucosal in comas (including rhabdomyosarcoma,
location, regardless of the affected site, leiomyosarcoma, malignan! peripheral Localization
but may also arise in bone (2294). nerve sheath tumo ur, dedifferentiated The nasal cavities, nasopharynx, and
paranasal sinuses may be involved
{778,1312,2326). Tumours can also
arise in the oral cavity or perioral reg ion

Clinical features
The tumou rs present as a polypoid soft
tissue mass. Symptoms depend on the
site of involvement and include pain,
nasal obstruction, and epistaxis. The
lesions can also affect the c raniofa-
cial bone, either p rimarily or secondar-
ily. Leiomyosarcomas metastasize to the
lung, liver, brain, other soft tissue sites, or
bone. Lymph nade metastases are rarely
reported {606,778,1312,2326,2664}. Me-
tastasis from other siles (e.g . the uterus)
should be excluded {606,2104l .

Malignant soft tissue tumours 35

Pleomorphic rhabdomyosarcoma ,
adult type 8901/3
Spindle cel l rhabdomyosarcoma 8912/3

Rhabdosarcoma; myosarcoma;
malignant rhabdomyoma

Sinonasal rhabdomyosarcoma is a ra re
tumour, with an overall annual incidence
of 0.034 cases per 100 000 population
{2066}. lt is the most common sinona-
sal sarcoma in both children and adults
(317,983,2326}. The peak incidence is in
patients in the first decade of life, with no
significan! sex predilection (2066) .

Macroscopy pathobiology of leiomyosarcomas, inclu- Etiology

The tumours are polypoid , fi rm , and ei- ding TP53, FANCA, ATM, RB1, CDK2NA. Rare examples of rad iation-induced
ther poorly defined or well circumscribed PTEN, MYOCO, ROR2, and MED12 sinonasal rhabdomyosarcoma have
b ut unencapsulated. On sectioning, they {9 02,1607,1961}. been reported {1191}.
are whorled and whitish or tan-grey, with
areas of haemorrhage, cystic degenera- Prognosis and predictive factors Localization
tion, and necrosis {538,778,1590). Clinical behaviour depends mainly on The most com monly involved siles are
tumour location, with sinonasal tumours the paranasal sinuses, followed by the
Histopathology being more aggressive d ueto th eir clase nasal cavity (2066}.
The tumours show infiltrative growth or proximity to both orbital and cerebral cav-
sharply demarcated borders. They are ities. Surgery is the treatment of choice, Clinical features
composed of spindle cells arran ged in in- but wide resection is often impossible. Symptoms include nasal obstruction,
terlacing fascicles. Storiform architecture Radiotherapy can be given. One third of pain, facial swelling, proptosis, and
can be focally present. The tumour cel l ali patients d ie of their tumour, as a re- epistaxis (317,779}.
nuclei are oval to elongate and frequently sult of either distant metastases or un-
blunt-ended. There is variable atypia, contro lled local recurrence involving vital Macroscopy
with enlarged nuclei and hyperchro ma- head and neck structures. Complete sur- Most lesions present as polypo id, poorly
sia. Nucleoli are sometimes obvious. The gical excision seems to be an important c ircumscribed masses with smooth sur-
eosinophilic cytoplasm often shows small predictor of disease-free survival. 'Mor- faces, often extending into the adjacent
perinuclear vacuoles. Epithelioid cyto- phologically high-grade sarcomas seem structures . They are fle shy, gelatinous le-
morphology is rarely seen . Osteoclastic to be more aggressive {467,606 ,778,902, sions with a tan to g rey cut surface. Bot-
and pleomorphic giant cells may occur. 1607,2294,2326}. ryoid rhabdomyosarcoma presents with
Tumours with a myxoid background must multiple g rape-like polypo id masses. The
not be confused with spind le cell myoepi- spindle-cell variant is tan-white with a
thelioma. Scattered inflammatory cells Rhabdomyosarcoma f irm cons istency.
are seen in sorne cases. Rarely, dys-
trophic or psammomatous calcification Franchi A. Histopathology
has been reported . The French Fdra- Flucke U. In th e sinonasal tract. embryonal rhab-
tion Nationale des Centres de Lutte Con- Thompson L.D.R . domyosarcoma (including the botryoid
tre le Cancer (FNCLCC) grading criteria variant) is the most frequent histological
depend on mitotic activity, necrosis, and subtype in young patients. lt consists
resemblance to normal tissue {467,538, Definition of primitive round to spin dle cells, with
606,902,1312,1590,1607}. Rhabdomyosarcoma is a malignant mes- scant cytoplasm and hyperchromatic
lmmunohistochemically, smooth muscle enchymal tum our with skeletal muscle nuclei. Scattered rhabdomyob lasts with
differentiation is demonstrated by diffuse differentiation. Embryonal, alveolar, pleo- brig htly eosinophilic eccentric cytoplasm
staining for desmin, h-caldesmon, SMA, morphic, and spindle-cell subtypes are are observed. Their number increases
and MSA, with positivity for at least two of recognized . in tumours treated with chemotherapy.
these markers {467,1312,1607). Botryoid rhabdomyosarcoma typically
ICD-0 codes has a polypoid arch itecture, and pre-
Genetic profile Rhabdomyosarcoma, NOS 8900/3 sents linear aggregates of tumour ce lls
There is a complex genomic profile, Embryonal rhabdomyosarcoma 8910/3 clase to the surface epithelium (cambium
with a variety of genes involved in the Alveolar rhabdomyosarcoma 8920/3 layer), yielding a gradient of cellularity.

36 Tumours of the nasal cavity, paranasal sinuses and skull base

Sinonasal alveolar rhabdomyosarcoma fashion, which provides a clue as to their clinical settings (e.g. in older adults) and/
is more frequent in the adult population subclassification (1819). MYOD1, tasi or with atypical morphology and immu-
(2326}, and typically presents f ibrovas- myosin, myoglobin, and MSA are also nohistochemical profiles {2671). To date,
cular septa separating nests of round, positive, but less specific. SMA is posi- no specific recurren! genetic abnorma lity
small to medium-sized neoplastic cells, tive in about 10% of cases {983). Rh ab- has been identified in embryonal rhab-
which tend to coalesce in the centre domyosarcoma, in particular the alveolar domyosarcoma. Most of these tumours
with dyscohesion at the periphery. Giant subtype, may coexpress non-myogenic have allelic losses in various chromo-
cells with multiple peripheral nuclei may markers, including cytokeratins (in 5- 8% some 11 loci. Paediatric spindle cell
be present. The salid variant of alveolar of cases), EMA , CD56, chromogranin, rhabdomyosarcoma shows a consisten!
rhabdomyosarcoma lacks the fib rovas - synaptophysin, CD20, and CD99, and NCOA 2 rearrangement (1661 ).
cular septa, and the tumour cells grow in this may be a source of diagnostic con-
sheets. The spindle-cell subtype is very fus ion with carcinomas, neuroendocrine Genetic susceptibility
rarely observed in the sinonasal region tumours, and haematolymphoid tumours Rhabdomyosarcoma can arise in chil-
{1707); it consists of a fasciculated pro- {1707,2671). dren affected by genetic syndromes,
liferation of spindle cells with elongated Ultrastructurally, rud imentary sarcom- including Li- Fraumeni syndrome (asso-
nuclei and pale indistinct cytoplasm, with eric structures, consisting of alternating ciated with an inactivating mutation of
interspersed spindled or polygonal rhab- thin and thick filaments with Z band- TP53), Costello syndrome (also called
domyoblasts with abundan!, brightly eo- like structures, are recognized in the fac iocutaneoskeletal syndrome; HRAS
sinophilic cytoplasm. cytoplasm. mutation), neurofibromatosis type 1 (in-
lmmunohistochemically, the most use- activating mutation of one allele of the
fu l myogenic markers are desmin and Genetic profile NF1 gene), and Beckwith-Wiedemann
MYF4 (myogenin), which are expressed Most alveolar rhabdomyosarcomas (70- syndrome (mutation or deletion of the
in all tumours. Compared with alveolar 80%) harbour a PAX3-FOX01 fusion, 11 p15.5 chromosomal region) {506).
rhabdomyosarcomas, in which there and the PAX7-FOX01 fusion is less fre-
is MYF4 staining in almos! 100% of the quently detected. ldentification of these Prognosis and predictiva factors
nuclei, embryonal rhabdomyosarcomas gene fusions is particularly useful for the Overall , rhabdomyosarcoma carries a rel-
stain for MYF4 in a more heterogeneous diagnosis of tumours arising in unusual atively poor prognosis among sinonasal

Malignan! soft tissue tumours 37

sarcomas, with a 5-year survival rate of and neck, but sinonasal angiosarcoma
40-45% (2326,2645,2648}. Patient age accounts for < 0.1 % of ali head and neck
< 18 years and female sex are associ- malignancies and < 1% of all sinona-
ated with better survival (2066,2381). sal malignancies (107,1540,1706,1718}.
Patients with alveolar rhabdomyosarco- Sinonasal angiosarcomas can develop
mas present more often with regional and in patients of any age (reported range:
distant metastases and have a higher re- 8-82 years), with peak incidence in
currence rate and poorer survival {2381) the fifth decade of life (mean patient
th an do patients with the embryonal or age: 47 years), younger than the co r- 1 .
botryoid subtype. lnfiltration of the skull
base and the presence of a residual tu-
responding age for skin and soft tissue
angiosarcomas of the head and neck
6.. ' ~ --.- ......._............_ '
Fig. 1.29 Sinonasal angiosarcoma. Neolumen formation
mour after primary therapy have also {107,1508,1540). There is a male predi- is seen within this angiosarcoma, where there is only mild
been associated with an unfavourable lection, with a male-to-female ratio of 3:2 nuclear pleomorphism; vascular channels are apparent
clinical course (2648). (777,1718,2419,2613,2626}. throughout.

Etiology facilitating pre-surgical embolization

Angiosarcoma Environmental exposure to rad iation (1718,241 9}. Staging is not applied to
(1472,1508,1706}, vinyl chloride (2613), sinonasal angiosarcoma, but lymph node
Bullerdiek J. and coal dust are rarely reported risk and distant metastasis are not common
Flucke U. factors. at initial presentation.
Franchi A.
Thompson L.D.R. Localization Macroscopy
A single site of involvement within the The tumours can be as large as 8 cm
sinonasal tract is more common than (mean: 3.9 cm); paranasal sinus tumours
Definition multiple sites ; the nasal cavity and max- are typically larger than sinonasal cav-
Angiosarcoma is a malignant neoplasm illary sinus are most frequently affected ity tumours (6.8 vs 2.2 cm). The tumours
of vascular origin. (777,1718,241 9,2613,2626}. are nodular to polypoid , soft, friable,
purple to red, and often ulcerated, with
ICD-0 code 9120/3 Clinical features associated haemorrhage and necrosis
The presenting signs and symptoms, (777,1718,2419,2613,2626}.
Synonyms which are non-specific and usually of
Epithelioid haemangioendothelioma; ma- short duration (mean: 9.8 months), are Histopathology
lignant haemangioendothelioma; malig- most commonly recurrent epistaxi s and The tumours develop below an intact,
nant angioendothelioma; haemangiosar- obstruction (1718} along with nasal dis- uninvolved epithelium, with vasoforma-
coma; haemangioblastoma charge, enlarging mass, sinusitis, epi- tive neoplastic cells expanding into soft
The use of these synonyms is discour- phora, pain, diplopa, and headaches. tissue and bone, frequently accompa-
aged, particularly given that epithelioid Sinonasal angiosarcomas are infi ltrative nied by necrosis and haemorrhage. The
haemangioendothelioma is a unique entity. tumours, often associated with bone tortuous, irregu lar, freely anastomosing
erosion. The tumours show contrast vascular channels create cleft-like spac-
Epidemiology enhancement or a bright signal on T2- es, rudimentary vessels, capillary-sized
Nearly 50% of cases develop in the skin weighted MRI. Angiography reveals vessels, and/or large cavernous spaces
and superficial soft tissues of the head tumour extent and feeder vessel(s), filled with erythrocytes and lined by
plump, enlarged, atypical, spindled or
epithelioid endothelial ce lls protruding
into the vascular spaces in multiple layers
or papillae. lntracytoplasmic lumina (of-
ten containing erythrocytes) are patho-
gnomonic. Enlarged pleomorphic nuclei
show coarse, heavy nuclear chromatin
distribution, irregular nuclear contours,
and prominent nucleoli. Mitotic figu res,
including atypical forms , are easily iden-
tifi ed throughout (1718,2419,2613,2626).
The tumours are diffusely immunoreac-
tive with vimentin, CD34, CD31, claudin 5,
ERG, FLl 1, 02-40, and factor Vlll-related
antigen, and focally reactive with keratin
(in particular the epithelioid variant) and
actin {1609,1718,2626}. Grading is not
applied to sinonasal angiosarcoma.

38 Tumours of the nasal cavity, paranasal sinuses and skull base

Genetic profile Histopathology
There are no specific cytogenetic find- MPNSTs are usually unencapsulated,
ings {2626}. highly infiltrative tumours with a range
of cell morphologies (including spin-
Prognosis and predictive factors dle, epithelioid, pleomorphic, and small
Although recu rrences are com- round cel l). Common growth patterns
mon (occurring in -40% of cases), include a marbled effect with alternating
the overall survival rate far angio- cellular and myxoid areas, perivascular
sarcoma is still approximately 60% cuffs, poorly defined nuclear palisad-
{7?7,1706,1718,2419,2613,2626}. Meta- ing, and neuroid whorls. A rosette-like
static disease occurs most commonly appearance with hyaline bands is less
to the lung, liver, spleen, and bone common . Tumours often show multiple
(marrow) {171 8} . Specific etiological fac- patterns with in the same lesion , including
tors are associated with shorter survival pleomorphic or small-cel l areas. Spindle
{2613,2675}. cell MPNSTs are often arranged in long
Fig. 1.30 Sinonasal malignan! peripheral nerve sheath fascicles or a herringbone pattern. The
tumour. Coronal T2-weighted MRI demonstrates a large,
cells have elongated , tapered, buckled,
heterogeneously enhancing mass filling the maxillary
Malignant peripheral sinus.
or wavy nuclei and scant amphophilic cy-
nerve sheath tumour toplasm. The nuclei may be hyp erchro-
Localization matic or may be vesicular with coarse
Flucke U. Cranial nerves are involved, with the chromatin. Mitoses, haemorrhage, and
Franchi A. vestibular and vagal nerves being most necrosis are frequent. Heterologous (e.g.
Thompson L.D. R. com monly atfected (613,1626). osteoid, cartilage, striated muscle, oran-
giosarcoma) elements are seen in about
Clinical features 15% of cases {613,965,2005,2398}. Ma-
Definition The tumours arise de novo, commonly in lignan! triton tumour shows MPNST with
Malignant peripheral nerve sheath tu- a majar nerve trunk or from a pre-existing rhabdomyosarcoma {965}. Glandular
mours (MPNSTs) are malignant soft tis- neurofibroma, and rarely from schwan- MPNST may have goblet cells, with be-
sue neoplasms that arise fro m peripheral noma. Patients may present with a painful nign or malignant glands present. The
nerves or benign nerve sheath tumours and/or rapidly enlarging mass, with asso - tumours are c lassified as low-grade or
with variable differentiation towards one ciated neurological deficits {2398}. high-grade on the basis of mitotic index,
of the cellular components of the nerve atypical mitoses, pleomorphism, and ne-
sheath (i.e. Schwann cells, fibroblasts, or Macroscopy crosis {2005,2398}.
perineurial cells). The tumours may be within or attached to There is no diagnostic immunoprofile,
a nerve trunk or neurofibroma with a fusi- but neoplasti c cells show nuclear and
ICD-0 code 9540/3 form appearance. They tend to be white, cytoplasmic S100 protein and nuclear
salid, and fleshy, sometimes with myxoid S0X10 immunoreactivity {1608}. Epithe-
Synonyms change and frequent necrosis and haem- lioid MPNSTs show strong S100 protein
Malignant schwannoma; neurofibrosar- orrhage {965,2398}. expression and loss of SMARCB1 (INl1)
coma; malignant neurilemmoma (in 70% of c ases), whereas only scat-
tered cells are reactive with S100 protein
About 20% of all MPNSTs develop in the
head and neck, with 25~30% of cases
associated with neurofibromatosis type
1 (NF1). MPNSTs occur mainly in adults,
with a wide patient age range and a
mean patient age in the fifth decade of
life {965,972}. Cases associated with NF1
tend to occur in younger patients, with a
mean patient age in the third to fourth
decade {613}. More rarely, MPNSTs de-
velop during childhood (2398).

MPNST develops in the setting of NF1
and infrequently in patients who have
been irradiated (2005}.

Malignant soft tissue tumours 39

in spindle cell MPNSTs in which INl1 is most frequently characterized by a recur- superior aspect of the nasal cavity and
retained. Nestin shows strong cytoplas- rent PAX3-MAML3 gene fusion. ethmoid sinus. Tumour may also extend
mic staining and is useful in combination to the orbit or cribrifo rm plate.
with other markers. Cytokeratins, EMA, ICD-0 code 9045/3
and C034 may be positive, but their ex- Clinical features
pression has not b een described in the Synonym The symptoms, whic h are relatively non-
epithelio id variant (1138,2398}. Low-grade sinonasal sarcoma with neu- specific and reflect the presence of a
ral and myogenic features sinonasal mass, include difficulty breath-
Genetic profile ing through the nose, facial pressure,
The most frequent gene alterations in- Epidemiology and co ngestion.
elude loss of NF1 on 17q1 1 and of TP53on BSNS predominantly affects females,
17q13. lnactivation of the N F1 tumour sup- with a female-to -male ratio of 2:1. The re- Macroscopy
pressor gene can occur both in sporadic ported patient age range is 24-85 years The gross specimen usually presents as
cases and in patients with NF1 {2398}. (mean: 52 years) {1051,1409,1913}. multiple polypoid fragments of somewhat
firm, reddish-pink to tan or grey tissue, as
Genetic susceptibility Localization large as approximately 4 cm in greatest
The tumours are associated with NF1. BSNS typically involves multiple siles aggregate dimension.
in the sinonasal tract, in particu lar the
Prognosis and predictive factors
MPNSTs are aggressive tumours. Worse
prognosis is associated with large tu-
mours (> 5 cm), NF1 association, high tu-
mour grade, trunca! location, high mitotic
index (> 6 mitoses per 1O high-power
fields), and incomplete resection. The
recurrence rate is as high as 40%, and
ap proximately two thi rd of cases metas-
tasize, usually haematogenously to the
lungs and bone {965,972,2398}.

Biphenotypic sinonasal
Lewis J.E.
Oliveira A. M.

Biphenotypic sinonasal sarcoma (BSNS)
is a low-grade spindle cell sarcoma with
distinctive histological, immunohisto-
c hemical, and molecular features . lt is

40 Tumours of the nasal cavity, paranasal sinuses and skull base

Histopathology A B
The tumour is characterized by a cel-
lular submucosal spindle-ce ll prolifera-
tion, composed of elongated spindle PAX3
cells arranged in medium-length to long
intersecting fascicles. A herringbone
pattern, which resembles the histology PAX3-MAML3 -1._._I-.l_.1
of synovial sarcoma, is frequently seen.
1 1l l1 1 1 1 1i 1 1
Tumours are unencapsulated and infil- PAX3
1 1 j 1
1 N

trative, including into bone. There is a ''-111\111-H

,1 .
MA~L3 j
scant. delicate collagen matrix. Nuclei 60

are slender and relatively uniform in ap- !!!!

' "PAXJ-MAML:J !! f"g
pearance, without significant pleomor-
phism or hyperchromasia. Mitotic activity e D

-' 40

is sparse (1051 ,1409,1913}. Most tumours ~e

show a striking concomitant proliferation
~ 20
of the covering epithelium, the invagi- 1u
nations of which are intimately admixed
with neoplastic spindle cells. Squamous
or oncocytic metaplasia of the epithe- Control PAX3 PAX3 PAX3-
lial proliferation can resemble that seen
Fig. 1.34 Biphenotypic sinonasal sarcoma. Structure and transactivation potential of the PAX3-MAML3 fusion protein.
in sinonasal papillomas. Other frequent A,B The t(2;4) translocation /uses exons 1-7 of PAX3 to exons 2-5 of MAML3 to create a novel PAX3-MAML3 fusion
findings include haemangiopericytoma- protein that retains the DNA-binding domains of PAX3 but lacks the Notch-binding site of MAML3; the arrows along the
tous vascular pattern and the presence chromosomes indicate the transcription orientation of PAX3, MAML3, and PAX3-MAML3. C Fusion-signal FISH shows
of scattered small lymphocytes. A minor- the juxtaposition of the 5' PAX3 (red) locus to the 3' MAML3 (green) locus; the location of these probes is shown in
ity of cases (11%) show focal rhabdo- panel A. D Transient transcription assays demonstrate the poten! transactivation potential of PAX3-MAML3. PD, paired
myoblastic differentiation, a histological domain; HD, homeodomain; TAO, transactivation domain. Reprinted from Wang X et al. {2545}.
feature that may be associated with an
invasion of local structures. Nearly 50% sarcomas in children, adolescents, and
alternate fusion partner {1051).
of patients with follow-up in the original young adults, with a mean patient age at
lmmunohistochemical features are also series experienced local recurrence, as first diagnosis in the third to fo urth dec-
distinctive. Ali tumours show at least fo- long as 9 years after initial treatment. ade of life {121 5).
cal positivity for S100 and most (96%) Neither metastatic disease nor death
also stain with either SMA or MSA. S100 from disease has been reported {1409}. Etiology
zand actin staining patterns may be fo- Specific predictive factors have not been Synovial sarcomas are exception-
cal, patchy, or diffuse. Focal and/or weak defined. ally associated with prior radiotherapy
reactivity for CD34, desmin, MYOD1 , my- {568 ,629,2459).
ogenin, EMA , and cytokeratin has been
noted in severa! cases (1051,1409}. Synovial sarcoma Localization
The sinonasal tract and skull are rare
Genetic profile Bullerdiek J. localizations.
At the cytogenetic and molecular levels, Bell D.
BSNS is characterized by the chromo- Clinical features
somal translocation t(2;4)(q35;q31.1), There are palpable, deep-seated swell-
which results in an in-trame fusion of Definition ings, with or without associated pain or
exon 7 of the transcription factor PAX3 Synovial sarcoma is a mesenchymal tu- tenderness.
to exon 2 of MAML3, a coactivator of mour that displays a variable degree of
the Notch signalling pathway. The fu- epithelial differentiation, including gland Macroscopy
sion transcript is highly expressed and formation, and has a specific chromo- Lesions are yellow or grey to white, and
may contribute to the unusual phenotype somal translocation t(X;1 B)(p11 ;q11) that well circumscribed when slow-growing.
of this tumour {2545}. PAX3-MAML3 is leads to formation of an SS18-SSX fusion
found in most examples, but a subset of gene (735). Histopathology
cases harbour alternate PAX3 or MAML3 Severa! monophasic subtypes (i.e. spin-
fusion genes, including PAX3-FOX01 ICD-0 code 9040/3 dle-cell, calcifying/ossifying, myxoid,
and PAX3-NCOA 1, the same fusion tran- and poorly differentiated) and biphasic
scripts found in alveolar rhabdomyosar- Synonyms subtypes with glandular or solid epithe-
coma (1051,2305,2628}. Synovial cell sarcoma; synovioma lial cells can be distinguished. Poorly
differentiated tumours may contain ar-
Prognosis and predictive factors Epidemiology eas with frequent mitoses and necrosis
The natural history of BSNS is character- Synovial sarcomas are the most com- {726,2399}. There is TLE1 nuclear immu-
ized by slowly progressive growth with mon non-rhabdomyosarcoma soft tissue noreactivity in as many as 95% of cases;

Malignant soft tissue tumours 41

variable positivity for CD99, BCL2, and
CD56; and patchy to focal reactivity with
epithelial markers (EMA), cytokeratins
(CK7), and BerEP4. The tumours are usu-
ally negative for S100 and WT1.

Genetic profile
The chromosomal translocation t(X;18)
(p11 ;q11), likely acting as driver mutation,
is a specific genetic alteration in synovial
sarcomas (2436), and is also described
among skull base and sinonasal tract tu-
mours {181,450,835,2299}. lt results in a
gene fusion between SS18 (also called
SYT) and one of three SSX genes (454).
The fusion can be detected by classic
cytogenetics, quantitative RT-PCR {903},
or FISH {827) . Variant translocations ex-
ist, and a considerable percentage of
synovial sarcomas do not show these

Prognosis and predictive factors

The prognosis vares depending on stag-
ing, grading, resectab ility, use of radia-
tion therapy, site of primary tumour, and
presence of metastases {2507). Clinically
aggressive behaviour, apparently deter-
mined early during tumorigenesis, is as-
sociated with more-complex genomes Fig. 1.36 Biphasic synovial sarcoma. A lmmunoreactivity with a pancytokeratin cocktail. B Nuclear immunoreactivity
and upregulation of AURKA and KIF18A with TLE1 .

42 Tumours of the nasal cavity, paranasal sinuses and skull base

Borderline / low-grade malignant
soft tissue tumours

Desmoid-type fibromatosis Localization focally be myxoid or mucoid-appearing,

Soft tissues of the neck are most com- and may be characterized by keloid-like
Wenig B. M. monly affected {155,551}. whereas collagen. Vascularity varies, consisting
Flucke U. the maxillary sinus, nasopharynx, and of compressed vessels that tend to be
Thompson L.D. R. oral cavity are infrequently involved evenly spaced. Lesiona! cells are reac-
{753,780,856}. Multifocality may be seen tive for vimentn, nuclear beta-caten in (in
in syndromic cases. 70-75% of cases), actins, and occasion-
Definition ally desmin {184,335,1818,2400).
Oesmoid-type fibromatosis is a locally in- Clinical features
filtrative, non-metastasizing, cytologically Symptoms include an enlarging painless Genetic profile
bland (myo)fibroblastic neoplasm. neck mass, as well as nasal obstruction Cytogenetic abnormalities on chromo-
and epistaxis in the sinonasal tract. Fa- somes 8 and 20 support a monoclonal
ICD-0 code 8821/1 cial deformity, proptoss, and dysphagia neoplastic nature (269). Germline mu-
may occur with disease progression. tations of the APC gene are primarily
Synonyms identified in the setting of Gardner-type
Desmoid tumour; aggressive fibroma- Macroscopy familia! adenomatous polyposis, where-
tosis; infantile fibromatosis (desmoid Desmoid-type fbromatosis presents as as mutations in the beta-catenin gene
variant) a f rm , tan-white, poorly delineated or (CTNNB1) are identified in as many as
infiltratng leson of variable size, wth a 85% of sporadic cases (738,1059, 1355).
Epidemiology trabecu lar or whorled appearance on cut with T41A, S45F, and S45P mutations be-
About 10-15% of cases occur in the section. ing the most frequent {1 059,1355).
head and neck {528,1556,2532). As
many as 30% of cases occur in children Histopathology Genetic susceptibility
(551,738,1018,1847). There is no sex Histopathology shows a poorly circu m- Patients with Gardner syndrome {463} or
predilection. scribed, infiltrative (to muscle and/or Gardner-type familia! adenomatous poly-
bone), fascicular growth of moderate posis are at increased rsk {472,2094).
Etiology cellularity composed of spindle-shaped
There is an association with Gardner cells with tapering to plump _vesicular Prognosis and predictiva factors
syndrome (familia! colorectal polyposis) nuclei, small nucleoli, and indistinct cyto- In general, the prognosis is good (1 193},
{463), including familia! adenomatous plasm, separated by abundant collagen. with positve surgical margins associated
polyposis (472,2094). Surgery-rel ated Mild nuclear pleomorphism and rare mi- with recurrence, usually < 2 years after
trauma may be a contributory factor. totic figures may be identified; atypical surgery (1050}. Young patient age and
mtoses and necrosis are absent. The CTNNB1 S45F mutaton may be indepen-
stroma is variably collagenized, may dent risk factors for recurrence (473,2457).

Borderline/low-grade malignan! soft tssue tumours 43

Sinonasal Macroscopy
glomangiopericytoma The tumours are generally polypoid, non-
translucent, beefy red to pink, soft, and
Thompson L.O.R. fleshy to friable, with an average size of
Flucke U. 3.0cm.
Wenig B.M.
Th e unencapsulated tumour is identified
Definition below an intact epithelium , although fric-
Sinonasal glomangioperi cytoma is a tion surface erosion may be seen in large
sinonasal tumour demonstrating a perivas- tumours. There is a so-called patternless
cu lar myoid phenotype. diffuse architecture, frequently effacing or
enveloping normal tissue. The cells may
ICD-Ocode 9150/1 be arranged in short fascicles; in stori- glomangiopericytomas show pro-
form, whorled, meningothelial, or reticu- found pleomorphism, necrosis, and
Synonym lar arrangements; or in short palisades increased mitoses {2389). By immuno-
Sinonasal haemangiopericytoma- like of closely packed cells. The cells are histochemical analysis, glomangiopericy-
tumour separated by a vascular plexus ranging tomas usually show diffuse reactivity with
from capillaries to large patulous spaces. actins (SMA > MSA), nuclear beta-
Epidemiology Prominent, thick, acellular, perithelioma- catenin, cycl in 01 , factor Xllla, 1 and vi-
Glomangiopericytomas account for tous hyalinization is a characteristic fea- mentin, and lack significan! expression
< 0.5% of all sinonasal tract neoplasms ture. There is a syncytial architecture to of CD34, CD31, CD11 7, STAT6, BCL2,
{356,476,2389). with a slight female pre- the c losely packed, uniform, oval to elon- cytokeratin, EMA, desmin, or S100 pro-
dilection and a peak incidence in the sev- gate cells, with indistinct cell borders. The tein {17,356,630,1274,1339,2389}.
enth decade of lite, although individuals nuclei are oval to spindle-shaped, vesic-
of any age may be affected. ular to hyperchromatic, and surrounded Genetic profile
by nondescript cytoplasm. Mitoses are Somatic, single-nucleotide-substitution,
Localization limited (< 3 per 10 high-power fields), heterozygous mutations in the beta-
The tumour is nearly always unilateral and nuclear pleomorphism is absent to catenin gene (CTNNB1), specifically in
(only 5% are bilateral), affecting the na- mild. Mast cells, eosinophils, and extrav- the GSK3beta region (codons 32, 33,
sal cavity alone and frequently extending asated erythrocytes are variably present. 37, 41 , and 45 encoded by exon 3) have
into paranasal sinuses. lsolated parana- Tumour giant cells are rarely identified, been identified in glomangiopericytoma
sal sinus involvement has also been re- but an aggregation of degenerating tu- {923,1339]. Accumu lation of beta-catenin
ported {189,356,476,640,2389]. mour cells, similar to those of symplas- results in nuclear translocation, which
tic glomus tumour, may be seen {657). has been shown to upregulate cyclin 01
Clinical features lnfrequently, fibrosis or myxoid change and lead to its oncogenic activation. Ac-
Most patients present with nasal obstruc- may be identified . Rarely, glomangio- tivation of beta-catenin and the resulting
tion and epistaxis, with other non-specific pericytoma may contain mature adipose cyclin 01 overexpression are important
fi ndings present for an average duration tissue (lipomatous) or extramedullary pathogenetic events {1339}. In the dif-
of < 1 year {2389}. Associated severe on- haematopoiesis {742,904,1732,2389}. ferential diagnosis it is importan! to note
cogenic osteomalacia has been reported Concurrent collision tumours, most that NAB2-STAT6 gene fusion in solitary
{257,356). often solitary fibrous tumours, have fibrous tumours {603}. MIR143-NOTCH
been reported {17,822,2389). Malignant fusion in glomus tumours {1 660} and

t..._. , I a ..a,Ullll- .:.lll.- _ _.L_ _ __ ,._

Fig. 1.38 Nasal glomangiopericytoma. A The surface respiratory epithelium is uninvolved by !he patternless proliferation of spindled neoplastic cells; there is well-developed
peritheliomatous hyalinzation. B Spindled cells with ovoid nuclei in a syncytial arrangement; numerous eosnophils and mast cells are apparent.

44 Tumours of the nasal cavity, paranasal sinuses and skull base

ACTB-GL/1 fusion in pericytoma (514}
are not seen in glomangiopericytoma.

Prognosis and predictiva factors

Glomangiopericytoma is an indolent tu-
mour with an excellent survival rate. Re-
currence (which occurs in as many as 40%
of cases) is usually a resu lt of inadequate
surgery {356,640,2389}. Aggressive (ma-
lignan!) behaviour is suggested by tumour
size > 5 cm, bone invasion, profound
nuclear pleomorphism, high mitotic rate
(> 4 mitoses per 10 high-power fields),
and necrosis {356,476,1274,2389}.

Solitsry fibrous tumour

Flucke U.
Thompson L.D.R.
Wenig B.M.

Solitary fibrous tumour is a fusion gene-
associated tumour of fibroblastic pheno-
type, with a branching vasculature.

ICD-0 code 8815/1

Haemangiopericytoma; giant cell

Epidemiology Fig. 1.40 Solitary fibrous tumour. A Note the pattemless architecture of the fibroblastic cells; there is a collagenous
background, and sinonasal mucosa is seen in the upper part of the field. B Nuclear STAT6 expression is !he most
Solitary fi brous tumours are rare , account-
specific immunohistochemical marker.
ing for < 0.1% of ali sinonasal neoplasms
(1 51). Adults are mainly affected, with no
sex predilection (17,564,861,2620,2735}. Histopathology Genetic profile
Tumours are submucosal, pseudoen- NAB2-STAT6 gene fusion seems to be
Localization capsulated, and variably cellular, con- specific {33,511,565,1634].
Tumours affect the nasal cavity (2620, sisting of bland spindle-shaped cells
2735}. arranged in a haphazard architecture. Prognosis and predictive factors
Multinucleated giant cells may be pre- Complete surgical resection is usu-
Clinical features sent. The vessels are stellate to stag- ally curative. Patient age > 55 years,
Patients experience nasal obstruction horn-like in shape. There is a variable tumour size > 15 cm, necrosis, and > 4
and epistaxis, among other non-specific collagenous background that includes mitoses per 10 high-power fields prob-
findings (1 51,2620,2735}. ropey, keloidal, or amianthoid collagen ably suggest more aggressive behaviour
bundles. lmmunohistochemically, the {564,1297,2659).
Macroscopy cells show a specific reaction with STAT6
Tumours are polypoid, firm, and (nuclear) and CD34, but are non-reactive
white, and are usually small due to the with desmin, S100 protein, actins, and
confined space of the sinonasal tract nuclear beta-catenin (489,563,603,923,
(151,2620,2735}. 2620,2683,2735}.

Borderline/low-grade malignan! soft tissue tumours 45

Flucke U.
Franchi A.

A malignant neoplasm of low- to inter-
mediate-grade, composed of neoplastic
cells that have an endothelial phenotype,
epithelioid morphology, and a hyalinized,
chondroid, or basophilic stroma.

ICD-0 code 9133/3

There is a wide patient age distribu-
tion, with children rarely being affected

Occurrence in the head and neck is rare.
Epithelioid haemangioendothelioma may
arise in soft tissue, skin, and bone. The
neck, oral cavity, salivary glands, and
jawbones may be affected . Very rarely,
a lymph node may be the primary site

Clinical features
Epithelioid haemangioendotheliomas
are classically slow-growing, infiltrative,
and (rarely) metastasizing lesions (280).
Symptoms are mostly non-specific.
Pain and tend erness may be present
{1589,2579). There is a propensity for
lymph node metastasis (739). Endothelial markers are expressed, with Prognosis and predictive factors
CD31, ERG, and FLl1 being the most Most cases behave in an indolent man-
Macroscopy sensitive. Cytokeratin expression is seen ner. A progressive clinical course with tu-
The (multi)nodular mass typically shows in about 30% of cases, which may as a mour-related fatality has been document-
a pale, solid cut surface, sometimes with result b e confused with carcinomas or ed in sorne instances {574,1589,2579).
sorne haemorrhage {280}. myoepithelial tumours (739,1589}. There A proposal for ri sk stratification showed
is nuclear positivity for CAMTA1 in cases that > 3 mitoses per 50 high-power fields
Histopathology with WWTR1-CAMTA1 fusion . There is and tumour size > 3 cm are associated
The epithelioid- and histiocytoid-ap- nuclear expression of TFE3 in cases with with higher mortality, irrespective of local-
pearing endothelial cells are arranged in YAP1-TFE3 fusion, but this marker should ization , atypia, cell spindling, or necrosis
short cords and strands in a myxohyaline be used with caution due to the possibil- (574).
stroma. They show subtle intracytoplas- ity of unspecific staining (662,739,2161).
mic lumina and an abundant hyaline cy-
toplasm. Striking nuclear atypia is seen in Genetic profile
approximately 30% of cases. Mitotic ac- WWTR1-CAMTA1 fusion is present in
tivity is usually low. Multicellular vascular most of the cases. A small subset of
channels are present in individual cases tumours harbour a YAP1-TFE:J fusion
{574,739,1589,2579}. (85,662,739,2351}.

46 Tumours of the nasal cavity, paranasal sinuses and skull base

Benign soft tissue tumours Thompson L.D.R .
Bullerdiek J.
Flucke U.
Franchi A.

Leiomyoma Macroscopy Haemangioma

Lesions are polypoid, nodular, and usual-
Definition ly sharply demarcated, with a white to tan Definition
Leiomyomas are benign tumours with trabecular cut surface {20,1047,2488). Haemangioma is a benign neoplasm of
smooth muscle differentiation (and vascular phenotype.
vascular differentiation in the case of Histopathology
angioleiomyoma). Tumours are subepithelial with infre- ICD-0 code 9120/0
quent mucosa! ulceration. Spindled tu-
ICD-0 code 8890/0 mour cells are arranged in intersecting Synonyms
fascicles. The nuclei are oval to elongate Lobular capillary haemangioma; pyogen-
Epidemiology and cigar-shaped, without atypia. There ic granuloma; capillary haemangioma;
Leiomyomas are extremely rare in the is eosinophilic fibrillary cytoplasm. Un- cavernous haemangioma
head and neck reg ion, accounting for like in leiomyosarcoma, mitotic figures
< 1% of all leiomyomas (2488}. Adults are are absent. Angioleiomyoma, the most Epidemiology
rnost commonly affected, with an equal common smooth muscle tumour in this Mucosa! haemangiomas account for
sex distribution {1047,2488). lt seems that reg ion, shows a prominent vasculature about 10% of head and neck haeman-
most sinonasal tract examples are angio- surrounded by smooth muscle cells with giomas and about 25% of non-epithelial
leiomyomas {20,1047,1607}. which the vessels are intimately associat- sinonasal tract neoplasms {777,1620,
ed. Calcification, ossification, fatty meta- 1936,2221). Haemangiomas occur in
Localization plasia, or myxohyaline degeneration may patients of all ages (median: 40 years).
The most common site of leiomyoma be seen and may suggest regression in There are incidence peaks among boys
in the head and neck region is the lips, longstanding lesions {20,606,778,1047, and adolescent males and among preg-
followed by the tangue, cheeks, pal- 1606). A fatty componen! is more com- nant women, with an equal sex distribu-
ate, gingiva, and mandible (2488}. The mon in males and older patients {20). tion in patients aged > 40 years {644,
tumours are extraordinarily rare in the lmmunohistochemically, lesions express 777,963,1174, 1620,2221J.
sinonasal tract, with involvement of the smooth muscle markers (alpha-SMA,
nasal cavity in most of the cases and MSA, desmin, and caldesmon) but are Etiology
more rarely of the paranasal sinuses (20, negative far HMB45, S0X10, and S100 Lobular capillary haernangioma is associ-
778,1047). (20,1047,1606}. ated with injury, hormonal factors (pregnan-
cy and oral contraceptive use) (559,1292,
Clinical features Genetic profile 1936). and drugs (vemurafenib) {2061).
The tumours are clinically indistinct Angioleiomyomas show loss of 22q1 1.2
and present as longstanding polypoid and low-level amplification of Xq {1741). Localization
rnasses with nasal obstruction, epistaxis, The anterior septum is most frequently
and pain (20,778,1047,2488). Prognosis and predictive factors affected, followed by turbinates and
The prognosis is excellent {20,1047}. sinuses (644,1620,1936,2221}.

Benign soft tissue tumours 47

Fig. 1.43 Lobular capillary haemangioma.
surrounding a central penetraling vessel.

Clinical features expression of estrogen and progesterone Localization

Presenting symptoms include epistaxis receptors. Sinonasal schwannomas arise from the
and obstruction, usually of short duration branches of the cranial nerves (V and IX-
(559,1620,1936,2221). lmaging studies Genetic profile XII) and autonomic nervous system, af-
show an intensely enhancing tumour sur- A single case had a clonal del(21) fecting (in descending arder of frequen -
rounded by a hypoattenuated peripheral (q21. 2q22.12) {2425. cy) the ethmoid and maxillary sinuses,
rim, often with bony remodelling (1 174, nasal cavity, and sphenoid and frontal
1360,2669}. Genetic susceptibility sinuses {952,994,1866,2170,2314).
Associations with Sturge- Weber syn-
Macroscopy drome (encephalotrigeminal angiomato- Clinical features
The mean size is < 1.0 cm, but examples sis) and von Hippel-Lindau disease have The most common presenting symp -
as large as 8 cm have been reported been reported. toms are headache, nasal obstruction,
{1936,2221). The gross appearance facial pain, and Horner syndrome (ocu -
ranges from that of a diffuse, flat mass Prognosis and predictive factors losympathetic palsy), followed by other
to that of a bulging, polypoid nodule. The Recurrences, which occur in as many non-specific findings {929,1866,2 170,
lesions are soft and usually have surface as 42% of cases, are usually identifi ed 2314). lmaging shows an inhomogene-
epithelial ulceration {644,777,963,11 74, in older patients. Pregnancy-relate d re- ous, low-density soft tissue mass, with
1620). gression occurs after parturiti<5n {134, bone erosion occasionall y noted {1230,
559,1936,2221). Angiosarcomas arise de 1866,2170,2314). Tumours may expand
Histopathology novo {1718). into the orbit, nasopharynx, and cranial
Haemangiomas in the sinonasal tract cavity (1866,2170).
are divided primarily into capillary and
cavernous types {1174,1620,1936,1956, Schwannoma Macroscopy
2221}. Other variants are repo rted rarely. Sinonasal schwannomas can reach 7 cm
Lobular capillary haemangioma is a cir- Definition in size (mean: 2.5 cm). They are well-
cumscribed proliferation of capillaries Schwannoma is a benign tumour of circumscribed , globular, firm to rubbery,
with plump endothelial cells surrounded Schwann-cell phenotype. yellowish-tan tumours with a solid to myx-
by pericytes in a fibromyxoid stroma, ar- oid and cystic cut su rface, frequently with
ranged in one or more lobules (which may ICD-0 code 9560/0 haemorrhage.
show high cellularity). Each lobule has a
large central vein surrounded by small Synonyms Histopathology
capillaries, with an overlying collarette of Neurilemmoma; benign peripheral nerve Schwannomas are unencapsulated tu-
epithelium (often ulcerated or atrophic). sheath tumour mours composed of Antoni A cellular
Mitoses are often identified, without atyp- areas with nuclear palisad ing alternating
ical forms. Cavernous haemangiomas Epide miology with hypocellular, myxoid Antoni B areas.
are composed of multiple, large, cystic, Less than 4% of schwannomas involve the The tumour cells are fusiform with elon-
thin-walled, blood -filled spaces lined by nasal cavity and paranasal sinuses (929, gated cytoplasmic extensions imparting a
endothelial cells and separated by scant 952,994,2170). developing in middle- wavy to spindled appearance. The nuclei
connective tissue stroma. The neoplastic aged adults (mean patient age: 50 years; are wavy and tapered , with heterochro-
cells react with FLl1, CD34, CD31, and range: 17-81 years) with an equal sex dis- matin. In Antoni B areas, a perivascular
factor Vl ll-related antigen, with variable tribution {747,1594,2170,2314). hyali nization is characteristic. Mitoses are

48 Tumours of the nasal cavity, paranasal sinuses and skull base

scant and necrosis is absent. Extensive Neurofibroma the maxillary sinus {1 09,281); the majority
degeneration may result in a narrow rim are unilateral {211 ,1308}.
of recogn izable tumour at the periphery Definition
(300,952}. Epithelioid variants and hybrid Neurofibroma is a benign peripheral Clinical features
tumours (i.e . neurofibroma and perineuri- nerve sheath tumour composed of mixed Non-specific symptoms include a mass,
oma) are rare in the sinonasal tract {109). Schwann cells, perineu ral-like cells, and obstruction, epistaxis, and pain {81,109,
intraneural fibroblasts. 1866).
The neoplastic cells are strongly and ICD-0 code 9540/0 Macroscopy
diffusely reactive with S100 protein and Tumours are firm, glistening, fusiform ,
SOX10, with CD34-positive fibroblasts Synonym and sometimes polypoid, with a mean
in the Antoni B areas. Focal GFAP and Fibroneuroma size of 3.1 cm (81,109,998).
AE1/AE3 immunoreactivity has been de-
scribed, but neurofilament protein (NFP) Epidemiology Histopathology
and actin are negative {1608}. Neurofibromas are exceptional in the Neurofibromas are unencapsulated
sinonasal tract. They show no sex pre- tumours intimately associated with nerve
Prognosis and predictive factors dilection. The mean patient age is in the twigs. Lesiona! cells (modified Schwann
Schwannomas exceptionally undergo fifth decade of life overall, and 35 years cells, intraneural fibroblasts, and perineu-
malignan! transformation {972,1575,1626, among patients with neurofibromatosis rial hybrid ce lls) intermix with coarse col-
2422). but otherwise have a very low re- type 1 {109}. lagen bundles and mast cel ls within a mu-
currence potential. copolysaccharide-rich stroma. There are
Localization ovoid to spindled cells with undulating,
Sinonasal neurofibromas arise most com- pointy nuclei with thin cytoplasmic pro-
monly at the nasal vestibu le, followed by cesses extending into the stroma, often

e: ~ ,':::r;~\;. , :, ,, .t ~~ ;::.:' ;;_:Jf}1{j

.. , . " , IP' ', ' ' ' ... lit~~ , .., .,-.. ,-.,"1g;:J/\f:{f:;;;;{( .v, ,,-, ' . ' ,. ,. . " ' .

1' ... ..,..--: ~ -'- ~~...: ., '- ~\ ~ .. \. ~ ._ ~'V~ _. .,d,-!1 , .,; " ,,.,- t.:,, .
~ .. .:. .:.-:.,. :.:.!-. ,. , , 't~ , ,\ ,_..... .. --:.- ~, .. , '.. . n.1 ,, ~.''., ; .. ~
. ;/': .... ~ ~:;: i~ : ..~i._)l~.::~~<-:. ~\"!'::.:' :._;~- -:..._~~~~~;'~_.; /~/~ .;_ .'f:-i~~ .~.. ~ ~

Fig. 1.45 Nasal neurofibroma. A An intact squamous mucosa overlies a proliferation of Schwann cells, perineurial cells, and fibroblasts blended with collagen libres. B Nerve fibre
twigs are interspersed among Schwann cells, perineurial cells, and collagen fibres; mast cells are also present.

Benign soft tissue tumours 49

with a centripetal gradient of cellularity. are highlighted with S100 protein, GFAP, Genetic susceptibility
lncreased cellularity, a storiform growth CD34, and BCL2, with S0X10, NFP, and About 10% of sinonasal neurofibromas
pattern, and pleomorphism may be seen, calretinin highlighting the axons specifi- arise within neurofibromatosis type 1
but fascicular growth or increased mi- cally (109,719}. {109,2001,2453).
toses (in particular atypical mitoses) sug -
gest malignan! change {109,994,1866). Geneti c profile Prognosis and predictive factors
Plexiform neurofibroma and composite Neurofibromatosis type 1- related neu- Neurofibromas are benign, with a 5% re-
tumours (i.e. schwannoma and perineu- rofi bromas have associated biallelic inac- currence rate due to incomplete excision
rioma) are exceptional {109,1026,1308), tivation by germline mutations of the NF1 {1866,2001 }. Malignan! transformation is
and the diffuse type has not been report- gene (17q11 .2) {6,1836). exceptional {1866).
ed. The subpopulations of neurofibroma

Other tumours

Meningioma is much more common, with 20% of men- Clinical features

ingiomas showing extracranial extension Symptoms are non-specific, present for a
Ro J.Y. {772,1867,2029,2388). By consensus, a long duration (mean: 4 years), and most
Bell D. diagnosis of primary sinonasal menin- commonly include a mass or p olyp and
Nicolai P. gioma should not be rendered when a nasal obstruction {772,823,1006,1867,
Thompson L.D.R. detectable intracranial mass is present 2388). The imag ing fi ndings are non-
{1666,2029). Sinonasal mening iomas af- specific, revealing opacification, sorne-
fect women and men equally (with a ra- times with bone erosion or hyperosto-
Definition tio of 1:1), and have a mean patient age sis . In most cases, direct extension by
Meningioma is a neoplasm composed of of 48 years (range: 13- 88 years) {2160, permeative growth from an intracranial
meningothelial cells. 2388). primary can be documented; the intrac-
ranial primary may be a small en plaque
ICD-0 code 9530/0 Etiology meningioma \1666,2388).
Radiation exposure and sex hormones
Synonym are unproven etiological factors {772, Macroscopy
Sinonasal trae! meningioma 1006,1039). The tumours are often polypoid , covered
by an intact epithelium, and expanding
Epidemiology Localization into bone. They can reach 8.0 cm in size
Primary extracranial (i.e. ectopic or ext- Sinonasal meningiomas involve the nasal (mean: 3 cm).
racalvarial) meningiomas of the sinona- cavity most commonly, followed by the
sal tract are rare, accounting for 0 .1 % of paranasal sinuses (most commonly the Histopathology
primary sinonasal neoplasms, 2% of all frontal sinus), with multiple siles frequent- Sinonasal meningiomas, often blended
meningiomas, and 24% of all primary ex- ly affected . Most tumours are left-sided with surface squamous or respiratory
tracranial meningiomas. Direct extension {772,1006,1867,2029,2388}. epithelium, are arranged in lobules of

50 Tumours of the nasal cavity, paranasal sinuses and skull base

whorled syncytial meningothelial cells.
Nuclei are bland and round to oval, with
small nucleoli and occasional intranu-
clear cytoplasmic inclusions {2388}.
Psammoma bodies are occasionally
ot the i 5 histological types of menin-
gioma, the most common in the sinona-
sal trae! are meningothelial , transitional,
metaplastic, and psammomatous, and
most are grade i tumours {i858,i859}.
Grade 2 and 3 meningiomas are rare
Meningiomas typically react with EMA,
CK18, and vi mentin. Rare tumours may
react with pancytokeratin and CK? (in a
pre-psammomatous pattern), CD34 (fi-
brous and atyp ical types), and SiOO pro-
tein (fibrous type), whereas GFAP, STAT6,
and SMA are non-reactive {2160). Pro- ameloblastoma occurring in the jaws) procedure but may occur years after the
gesterone and estrogen receptor reactiv- {2090}. surgery {2090}. No tumour deaths, me-
ity is present {2388l. tastases, or instances of malignan! trans-
Localization tormation have been reported.
Genetic susceptibility The tumours may involve the nasal cav-
Neurofibromatosis type 2 association is ity only, the paranasal sinuses only, or
not significan! in sinonasal meningiomas. both the nasal cavity and the paranasal Chondromesenchymal
sinuses {2090}. hamartoma
Prognosis and predictive factors
The prognosis of sinonasal meningiomas Clinical features Toner M.
is good . Although recurrences develop Patients usually present with a mass le- Hunt J.L.
in about 30% of cases (due to incom- sion and nasal obstruction; symptom
pletely excised tumours), metastasis and duration ranges from 1 month to severa!
malignan! transformation have not been years {2090}. Unlike gnathic ameloblas- Definition
reported [i006,i858,1867,2388). tomas, which have a characteri stic mul- Chondromesenchymal hamartoma is a be-
tilocular and radiolucent presentation, nign, locally destructive, tumour-like growth
sinonasal ameloblastomas are described containing mixed mesenchymal elements.
Sinonasal ame/oblastoma radiograph ically as salid ma:sses or
opacifications {2090l. Bone destruction, Synonyms
Wenig B.M. erosion , and remodelling (with remnant Nasal chon dromesenchymal hamarto-
of bony shell delimiting the lesion as it ma; mesenchymoma
grows) may be present {2090).
Definition Epidemiology
Sinonasal ameloblastoma is a locally ag- Histopathology This rare lesion occurs predominantly in
gressive, primarily gnathic (jaw) tumour Histologically, sinonasal ameloblastomas infants, but occasionally in older ch ildren
with a high propensity for recurrence. are similar in appearance to their gnath- and adults, with amale predominance.
lt originales wholly within the sinonasal ic counterparts. In the sinonasal trae!,
trae!, without connection to gnathic siles, ameloblastomatous proliferation can be Localization
arising from sinonasal epithelium and seen arising in direct continuity with the The most common sites are the parana-
showing histological features identical to intact sinonasal surface mucosa! epithe- sal sinuses, nasal cavity, and orbit. lntra-
!hose of its counterpart originating in the lium, a finding th at in conjunction with the cranial and skull base extension may oc-
jaw. absence of continuity with gnathic sites cur [1568}.
confirm s primary sinonasal origin.
ICD-0 code 93i0/0 Clinical features
Prognosis and predictive factors This is a slow-growing expansile lesion
Epidemiology Overall treatment success correiates with that can be locally destructive. Patients
Sinonasal ameloblastomas are un- complete surgical eradication performed may present with nasal congestion or
common tumours. There is a decided in conjunction with thoroughly detailed symptoms related to a polypoid mass.
male predilection and the mean palien! rad iographical imaging. Radiological tindings may appear de-
age at presentation is 59.7 years (ap- The tumour may recur, which generally ceptively aggressive, with bone erosion
proximately 15-25 years older than far happens within 1-2 years of the initial and intracranial extension.

Other tumours 5i
The tissue is typically firm and white, re-
sembling cartilage.

Histopathology shows a fabular prolifera-
tion of mature and immature hyaline car-
tilage in a variably ce llular fibrous back-
ground {1568). The stromal component
may be highly cellular, and mitoses may
be present. The stromal and carti laginous
elements may be admixed with bony tra-
beculae or may surround bony islands
{1795). The cartilaginous areas are S100-
positive; the stromal cells are SMA-posi -
tive and cytokeratin-negative {1795). ..
Fig. 1.48 Chondromesenchymal hamartoma. Fibrovascular stroma with cellular lobules of cartilage that surround bony
Genetic susceptibility
There is an association with the pleuro- in which chondromesenchymal hamar- Prognosis and predictive factors
pulmonary blastoma-associated O!CER1 toma may be the presenting lesion After surgical removal, the recurrence
familia! tumour susceptibility syndrome, (2281). rate is generally low (1554).

Haematolymphoid tumours

Overview 9% between 2000 and 2011 (607}. myeloid sarcoma, and histiocytic neo-
plasm (484,500,1012).
Chuang S.-S. Localization
Ferry J.A. ENKTL has a predilection for the nasal Prognosis and predictive factors
cavity and may also arise from paranasal Modern therapies have significantly
sinuses (86,446,607,1349}. Diffuse large improved the prog nosis of sinonasal
Definition B-cell lymphoma (DLBCL) most com - DLBCL. lnvolvement of multiple sinuses
Nearly ali haematolymphoid tumours monly arises from the paranasal sinuses is a negative prognostic indicator (11 69).
arising from the nasal cavity or paranasal but may arise from the nasal cavity (1169).
sinuses are non-H odgkin lymphomas,
although extramedullary plasmacytomas Clinical features Extranoda/NK/T-celllymphoma
and rare myeloid and histiocytic neo- Patients with nasal tumours present with
p lasms also occur {116,1027,1830,1888}. nasal obstruction, epistaxis, and/or a de- Chuang S.-S.
structive mass involving nose, nasal sep- Gaulard P.
Epidemiology tum, palate, orbit, or facial skin. Patients Jaffe E.S.
Sinonasal lymphoma accounts for 12- with paranasal tumours present with Ko Y. -H.
15% of ali head and neck cancers. lt is symptoms of chronic paranasal sinusitis
the third most common sinonasal malig- and soft tissue or bony destruction. B
nancy, after squamous cell carcinoma symptoms (e.g. fever, night sweats, and Definition
and adenocarcinoma {484,1012}. In the weight loss) occur in about 20% and 10% Extranodal NK/T-cell lym phoma, nasal-
USA, the frequency decreased in the of patients, respectively, with sinonasal type (EN KTL) is an extranodal lymphoma
early 21st century, probably reflecting ENKTL and DLBCL. with a cytotoxic phenotype and a univer-
a reduction in HIV-associated lympho- sal association with EBV.
mas due to antiretroviral therapy {484). Histopathology
However, extranodal NK/T-cell lym- In addition to DLBCL and ENKTL" there ICD-0 code 9719/3
phoma, nasal-type (ENKTL), which has have been rare cases of other sinona-
a predilection for East Asians and Latn sal haematolymphoid tumours , such as Synonyms
Americans {86,446,607,1349), is increas- sinonasal Burkitt lymphoma, peripheral Angiocentric lymphoma; lethal midline
ing in the USA, with an average annual T-cell lymphoma, MALT lymphoma, extra- granuloma; malignan! midline reticu losis;
increase in incidence of approximately osseous plasmacytoma, extramedullary polymorphic reticulosis

52 Tumours of the nasal cavity, paranasal sinuses and skull base

mimic a benign infiltrate but exh ibit cel-
lular atypia such as irregular nuclear con-
tours and mitoses.
lmmunohistochemically, the tumour cells
express CD3, cytotoxic markers (i.e. TIA1,
granzyme B, or perforin), and frequently
CD56 (1132,19091. They rarely express
CD4,CD5, or CDS. Examples with large-
cell morphology often express CD30.
CD57 is nearly always negative (11 32}.
The tumours are mainly derived from
NK cells, with a minority (10-40%) hav-
ing T-cell lineage (gamma delta or more
rarely alpha beta) {102,1132,1418,19091.
CD56 is more frequently expressed in
tumours of NK-cell origin, whereas CD5
fig. 1.49 Extranodal NK/T-cell lymphoma, nasal-type. A Right nasal tumour with obstruction, ecchymosis of the nasal
side wall and facial skin, and invasion to the right nasal ala with tumour formation. B Postcontrast CT of the same case
expression usually indicates a T-cell lin-
shows a homogeneously enhancing soft tissue mass in !he right nasal cavity involving the right nostril, nasal ala, and eage {1132,19091. EN KTL is positive for
perinasal facial skin, and destruction of !he anterior lower aspee! of the nasal septum. EBV-encoded small RNA (EBER) in the
majority of cells by in situ hybridization
Epidemiology Clinical features {443,444,2322) . LMP1 is usually weak or
Extranodal NK/T-cell lymphoma is more Patients with nasal tumours present with negative. Cases showing a similar phe-
prevalent among East Asians and the nasal obstruction and/or epistaxis. Nasal notype but EBV negativity are consid-
indigenous populations of Mexico and tumours may cause perforation of the ered peripheral T-cell lymphoma, NOS
Central and South America than in other nasal septum or palate and may spread {1108,2322).
populations {86,446,1349,19401. to the skin or orbit with ecchymosis or
ulcerative tumours. Paranasal tumours Genetic profile
Etiology may mimic chronic paranasal sinusitis. ENKTL shows complex genetic alter-
The precise etiology is unknown, al- Most cases present with stage I or 11 dis- ations, with numerous chromosomal
though EBV is crucial in pathogenesis. ease, with as many as 10- 20% of cases gains and losses {1695). The commonly
Lifestyle and environmental factors such spreading to skin, gastrointestinal tract, deleted chromosomal region at 6q21-23
as being a farmer, pesticide use, and liv- testis, or distan! nodal regions. contains severa! candidate tumour sup-
ing near incinerators might be risk factors pressor genes, including PRDM1, ATG5,
(2657). Histopathology AIM1, HACE1, and FOX03 {1091,1189,
ENKTL infiltrates nasal tissue in a diffuse 1289}. ENKTL has a distinctive genetic
Localization pattern, frequently with an angiocentric/ signature shared by cases with NK-cell
ENKTL occurs most commonly in the angioinvasive growth pattern, leading to and T-cell origin (1053). The JAK/STAT
upper aerodigestive tract (in 70- 85% of geographical tumour necrosis. In rare pathway is activated in most cases, by
cases), mainly in the nasal cavity, para- instances, multiple biopsies might be genetic alterations of JAK3, STAT3, or
nasal sinuses, and Waldeyer ring (pha- needed to identify tumours showing ex- PTPRK {406,485,1053,1272,1370}. Re-
ryngeal lymphoid ring), with sorne cases tensive necrosis with few viable cells. The current mutations are frequent in tumour
occurring in the skin, gastrointestinal neoplastic cells vary in size and have ir- suppressor genes, including TP53 (in
tract, soft tissue, and other extranodal regularly folded nuclei, granular chroma- 20- 60% of cases) {1941) and DDX3X
siles {1132,1229,1909,2317}. tin, and small nucleoli. Small cells might (in 20% of cases) (1134). EBV infection

Haematolymphoid tumours 53
severely deregulates host microRNA pro- significance (1221,1319,2431). EBV DNA and other soft tissues in th e head and
fi les; downregulation of miR-146a and and PET findings have been integrated neck must be distinguished from 8-cell
miR-15a promotes cell proliferation and into prognostic algorithms {1226). With lymphomas with plasmacytic/plasmab-
predicts poor prognosis in ENKTL {1266, curren! regimens, durable re mission can lastic differentiation, in particular MALT
1802]. be achieved in 70-80% of stage 1/11 cas- lymphoma and plasmablastic lymphoma.
es, and as many as 50% of stage 111/IV
Genetic susceptibility cases (1318,2431 }. ICD-0 code 9734/3
The strong EBV association and ethnic
predisposition suggest a genetic defect Synonyms
in the host immune response to EBV in- Extraosseous plasmacytoma Extramedullary plasmacytoma;
fection [534,535}. The lymphotoxin alpha plasmacytoma
gene (LTA) +252 (AG) polymorphism is Feldman A.L.
associated with increased risk of ENKTL Ott G. Epidemiology
(409}. The median patient age is 60 years and
there is a male predominance, with a
Prognosis and predictiva factors Definition male-to-female ratio of 3- 4: 1 [46,1 617).
Prognostication of ENKTL traditionally Extraosseous plasmacytoma is a mass-
depends on clinicopathological param- forming proliferation of monoclonal plas- Localization
eters, including stage (1364,2431). How- ma cells with extraosseous (extramed- About 80% of extraosseous plasmacyto-
ever, the amount of EBV DNA in plasma ullary) presentation, in the absence of mas involve the upper respiratory tract,
is a surrogate biomarker of lymphoma underlying multiple myeloma. Extraosse- most commonly the nasal cavity and
load, with diagnostic and prognostic ous plasmacytomas in the nasopharynx paranasal sinuses, followed by the na-
sopharynx, oropharynx, and larynx (46,
1617). Less common primary sites in the
head and neck include the hypophar-
ynx, salivary and thyroid glands, cervical
lymph nodes, !rachea, and oesophagus.
Cervical lymph nades are involved sec-
ondarily in about 15% of cases [1586).

Clinical features
Extraosseous plasmacytomas are typi-
cally solitary, and examples occurring in
the head and neck most commonly (in
80% of cases) presentas a mass {1617).
Add itional fin dings at presentation in-
elude airway obstruction, epistaxis, lo-
cal pain, proptosis, rhinorrhoea, cervical
lymphadenopathy, and cranial nerve pal-
sies. A minority of patients (< 25%) have
a monoclonal serum paraprotein (M pro-
tein), typically of lgA type {2245). By defi-
nition, diagnostic features of plasma cell
myeloma are absent {1476).

H istopathology
Microscopic evaluation typically shows

54 Tumours of the nasal cavity, paranasal sinuses and skull base

Fig. 1.54 Plasmacytoma. Monotonous infiltrate of
plasma cells.

(1278). Monotypic immunoglobulin light

chains can typically be demonstrated by
immunohistochemistry or in situ hybri di-
zation. Staining fo r heavy chains may
reveal expression of lgA or lgG, whereas
staining for lgM should raise suspicion
for B-cell lymphoma. EBV has been re-
ported to be positive in 15% of cases
{26), but the presence of EBV should also
prompt consideration of plasmablastic

Genetic profile
diffuse infiltration by sheets of plasma poorly differentiated non-haematological Sorne genetic features are similar to
cells, which may be well, moderately, or neoplasms {1172). !hose of plasma cell myeloma (232},
poorly differentiated {1617,2316}. Amy- but diffe rences have been reported, in
loid deposits may be present {2316, lmmunophenotype particular different IGH translocation
2616). Moderately and well-differentiated The neoplastic cells often express mark- partners {1 93}.
extraosseous plasmacytomas mus! be ers of plasmacytic differentiation, such
distinguished from B-cell Jymphoma, in as C0138, C038, VS38, and MUM1/IRF4 Prognosis and predictive factors
particular from MALT lymphoma with ex- {232} . They variably express C079a, The prognosis of extraosseous plasma-
tensive plasmacytic differentiation (584, only rarely express C020, and are typi- cytoma is much better than that of plas-
1062). Poorly differentiated extraosseous cally negative for PAX5. Extraosseous ma cell myeloma, and most patients are
plasmacytomas must be distinguished plasmacytomas may express EMA. Cyc- treated with local radiation therapy {504,
from plasmablastic lymphoma (2316}; lin 0 1 has been reported to be negative. 583). Regional recurrence or spread to
sorne cases may be anaplastic to the C056 is expressed less frequently than other extraosseous siles may occur, and
point that plasma-cell differentiation is in plasma cell myeloma, and the Ki-67 in- about 15% of patients develop multiple
not apparent, prompting consideration of dex is lower !han in plasma cell myeloma myeloma {46}.

Haematolymphoid tumours 55
Neuroectodermal / melanocytic tumours

Ewing sarcoma/primitive 2617l; older patients may occasionally variable, with 5-10 mitoses per 10 high-
neuroectodermaltumour be affected {921,2617}. power f ields. Prominent intratumoural
thin-walled vessels are present, which
Wenig B.M. Localization may be compressed and obscured by
Flucke U. The most common head and neck sites the cellular proliferation . A minimal stro-
Thompson L.D.R . include the skull and jaws (49,2601}; less mal componen! is present, which may
common siles include the sinonasal trae\ include thin fibrous strands separating
(most commonly the maxillary sinus or tumour lobules. Pseudorosettes (Hom-
Definition nasal fossa) {921,1036,1331,2617}, orbit, er Wright rosettes) are present in most
Ewing sarcoma / primitive (peripheral) and various mucosa! sites . Extension to cases; less often, true neural rosettes
neuroectodermal tumours are high-grade dura, orbit, or brain may be present (921). (Flexner-Wintersteiner rosettes) may be
pri mitive small round cell sarcomas with identifi ed . Histological variants include
variable neuroectodermal differentiation, Clinical features atypical or large-cell, clear-cell, haeman-
characterized by the presence of trans- Symptoms include pain, mass lesion, gioendothelioma-like, adamantinoma-
locations between the EWSR1 gene on and nasal obstruction, which often de- like, spindled , and sclerosing forms (197,
chromosome 22 and a member of the velop rapidly (within months) (261 7). 743}.
ETS family of transcription factors. lntracytoplasmic material that gives a
Macroscopy diastase-sensitive positi ve reaction with
ICD-0 code 9364/3 Sinonasal tract tumours may appear periodic acid-Schiff (PAS) is present.
polypoid or multilobular, greyish-white, Neoplastic cells strongly and diffusely
Synonyms and glistening, with associated haemor- express membranous C099 in nearly ali
Peri pheral neuroectodermal tumour; pe- rhage; ulceration is often present. cases. Nuclear FLl1 is seen in a large
ripheral neuroepithelioma; peripheral percentage of cases; those with EWSR1-
neuroblastoma; adult neuroblastoma Histopathology FL/1 fusion show strong nuclear reactions
The tumour is markedly cellular with dif- with the C-terminus of FL/1 (1506,2411,
Epidemiology fuse (sheet-like) or lobular growth; the ap- 2544). Vimentin is positive. Cytokeratins
Ewing sarcoma and primitive neuroec- pearance may occasionally be trabecu- show stro ng, focal to diffuse staining with
todermal tumour primarily occur in non- lar or cord-like. The tumour is composed a dot-like pattern in as many as one third
head and neck sites, with only 2-10% of uniform small cells with round to oval of cases, and in particular in adamanti-
developing in th e head and neck {49). nuclei, fine-appearing (powdery) nuclear noma-like tumours {197,894,921 }. There
The tumours are slightly more common in chromatin , a distinct nuclear membrane, is reactivity for at least one neural marker
males {49,921}, and occur predominant- inconspicuous to small nucleoli, sean\ (e.g. neuron-specific enolase, S100 pro-
ly (but not exclusively) in children and pale to vacuolated (clear) cytoplasm, and tein, synaptophysin, c hromogranin, NFP,
young adults {921,1017,1036,1331,2601, indistinct cell borders. Mitotic activity is or GFAP). KIT (CD 11 7) expression is

A.. ....t::~ :Mlllla:-.J.:a:'l.i:.

- ~ ,. ... ....,,-.;~ '.!:l. . . . ._.;..:...; ~ .lii--J.::!ll~-Eo,,;,;~olCL-:=...,.,;=1--
Fig. 1.56 Sinonasal Ewing sarcoma / primitive neuroectodermal tumour. A Hypercellular neoplasm with diffuse growth composed of uniform small cells with round to oval nuclei,
fine-appearing nuclear chromatin, and pale to vacuolated cytoplasm. B Neoplastic cells show diffuse and strong membranous CD99 staining in nearly all cases; CD99 is sensitive bul
not specific for the diagnosis of Ewing sarcoma I primitive neuroectodermal tumour.

56 Tumours of the nasal cavity, paranasal sinuses and skull base

0/fsctory neuroblastoma
Bell D.
Franchi A.
Gillison M.
Thompson L.D.R.
Wenig B.M.

Olfactory neuroblastoma (ONB) is a ma-
lignan! neuroectodermal neoplasm with
neuroblastic differentiation, most often
localized in the superior nasal cavity.

ICD-0 code 9522/3

Fig. 1.57 Ewing sarcoma/ primitive neuroectodermal tumour. On EWSR1 dual-colour break-apart FISH, Ewing
sarcoma cells that have the chromosomal rearrangement show a red signa! distanced from a green signa!, indicating
a translocation involving one EWSR1 allele, whereas the second allele is intact, as shown by red and green signals Synonyms
that overlap. Aesthesioneuroblastoma; aesthesioneu-
rocytoma; aesthesioneuroepithelioma;
present in approximately 25% of cases Prognosis and predictive factors olfactory placode tumour
(743). Rarely, desmin staining is present, The 5-year survival rate for sinonasal Ew-
but myogenic and haematolym phoid ing sarcoma/ primitive neuroectodermal Epidemiology
markers are typical ly absent. tumour is 50-75%, reflecting a better ONB has an estimated annual incidence
overall prognosis at this site compared of 4 cases per 10 million population, and
Genetic profile with cases at other siles (49,921}. The accounts for approximately 3% of all
There is consisten! rec iproca! translo- 5-year survival rate for patients with ad- sinonasal tumours (273). Patients range
cation between chromosome 11 and vanced disease is < 25% (2617}. Local in age from 2 to 90 years. Althoug h a
chromosome 22 (present in 90- 95% of recurrence and distan! metastases may bimodal age distribution was initially re-
cases). The most common translocation occur within 2 years, even in patients with ported, recen! data support an even dis-
involves the EWSR1 gene (on chromo- localized disease. When metastases oc- tri bution across ali ages, with a peak in
some 22) and the FL/1 gene (on chromo- cur, the most common sites include the the fifth and sixth decades of life (273 ,
some 11), resulting in an EWSR1-FLl1 fu- lungs and bone; lymph nade metastasis 1130,1903}. Males are affected slightly
sion transcript. C/C-DUX4 fusion, a result is less common, occurring in approxi- more often than females (male-to-female
of a t(4;19) or t(10;19) translocation, may mately 20% of cases. ratio: 1.2:1 ). There is no reported ethnic or
be identified in EWSR1 fusion- negative Prognosis has been found to be linked fami lia! predilection.
cases (1101}. CIC-DUX4 fusion-positive to tumour stage as determinea by the
tumours occur mainly in young adult lntergroup Rhabdomyosarcoma Study Localization
men, most frequently in the soft tissues of Group (IRSG) staging system (126}. tu- The anatomical distribution of ONB is
extremities. They show a higher degree mour size (with size > 8 cm associated confined to the cribriform p late, the su-
of heterogeneity in nuclear morphol- with adverse behaviour) (127,2601}, TP53 perior turbinate (nasal concha), and the
ogy and have vari able CD99 expres- alteration (which appears to define a cli n- superior half of the nasal septum. The
sion (membranous, not diffuse) than do ical subset with a markedly poorer out- vomeronasal organ (also called Jacob-
EWSR1 fusion-positive cases, raising the come) {1592}, the presence of the type 1 son's organ), sphenopalatine ganglion,
possibility that CIC-DUX4 fusion tumour EWSR1 -FLl1 fusion transcript (thought olfactory placode, and the term inal nerve
may be outside the scope of Ewing sar- to suggest a better prognosis !han other (also called the ganglion of Loci) are in-
coma (2246). fusion transcripts) (542}, and poor his- cluded in the areas of proposed origin.
tological or radiological response at the Ectopic tumours within the paranasal si-
Genetic susceptibility site of primary tumour and incomplete nuses (other than the ethmoid sinuses)
Heritable retinoblastoma may predispose radiological remission of lung metasta- are vanishingly rare (except in recurrent
patients to Ewing sarcoma and perhaps ses alter primary chemotherapy (associ- cases), and the diagnosis of ONB with no
to a subset of poorly differentiated neu- ated with adverse behaviour) (31,49,127}. invo lvement of the cribriform p late is a di-
roectodermal tumours in the sinonasal There is an increased incidence of radia- agnosis of exclusion (1619,2383}.
region that may be re lated to olfactory tion-induced sarcomas later in life among
neuroblastoma (1236). surviving patients (1838} .

Neuroectodermal / melanocytic tumours 57

speckled calcifications are characteristic Table 1.02 Olfactory neuroblastoma staging systems
proposed by Kadish and Merita; reprinted from Ow TJ
of ONB.
et al. {1789)
Severa! staging systems have been
proposed, with no single system univer- Kadish stage
sally accepted. The first staging system A Tumour confined to the nasal cavity
proposed, and the one most commonly Tumour involvement of the nasal
applied, is that of Kadish (1162), which B cavity and paranasal sinuses
stages local disease only; it distinguish- Tumour extends beyond the nasal
es tumours that involve the nasal cav- e cavity and paranasal sinuses
ity only (Kadish stage A), from those
Morlta modiflcatlon
that extend into the paranasal sinuses
(Kadish stage B), and those that extend A Tumour confined to the nasal cavity
beyond the paranasal sinuses (Kadish Tumour involvement of the nasal
stage C) {11 62}. Morita (1650} modified cavity and paranasal sinuses
the Kadish system by adding a stage D, Tumour extends beyond the nasal
Fig. 1.58 Olfactory neuroblastoma. lmaging studies defined by the presence of metastases
e cavity and paranasal sinuses
show a dumbbell-shaped tumour. (either regional nodal disease or distan! Presence of metastases (regional
metastasis). The TNM staging system for D
or distan!)
paranasal sinus tumours can potentially
be applied (626}; however, the Kadish
system and Morita modification are more in small cell neuroendocrine carcinoma
applicable, due to the biologically unique aspira tes.
behaviour of ONB compared with other
sinonasal tumours. Histopathology
Low-grade ONBs form submucosal,
Fig. 1.59 Olfactory neuroblastoma. The gross Macroscopy sharply demarcated nests, lobules, or
appearance is that of a polypoid reddish-grey mass, with The tumours are usua\ly unilateral, poly- sheets ot cells, often separated by richly
hypervascular cut surface. poid, glistening, soft, reddish-grey mass- vascular or hyalinized fi brous stroma.
es with an intact mucosa; the cut surface Pseudorosettes (Homer Wright rosettes),
Clinical features appears greyish-tan to pinkish-red and with neoplastic cells palisading or cuffed
Clinically, ONBs often have a subtle pre- hypervascularized. The tumours range around the central delicate fibri llar neu-
sentation mimicking that of benign inflam- from < 1 cm in size to large masses in- ral matrix, may be seen. The cells are
matory/infectious diseases, and delay in volving the nasal cavity and intracrar1ial often uniform, with sparse cytoplasm
diagnosis is frequent. Nasal obstruction region. They frequently expand into the and round or ovoid nuclei with punctate
and epistaxis are typical early manifes- adjacent paranasal sinuses, orbit, and salt-and-pepper chromatin and nucleoli
tations; headaches, pain, excessive lac- cranial vault (2383). that are either small or absent. ONB is
rimation, rhinorrhoea, and visual distur- characterized by fibrillary cytoplasm and
bances are uncommon. Anosm ia occurs Cytology interdigitating neuronal processes (neu-
in < 5% of patients. Paraneoplastic syn- Aspirates of metastatic lesions show cy- ropil), created by a syncytium ot cells.
dromes (i.e. ectopic adrenocorticotropic tological fi ndings most similar to those Higher-grade tumours show tumour
hormone syndrome or syndrome of in- seen in low-grade neuroendocrine car- necrosis, pleomorphism, increased mi-
appropriate antidiuretic hormone secre- cinoma aspirates, with nests of some- toses, decreased to absent neuropil, and
tion) are detected in about 2% of patients what monomorphic, fragile epithelioid a less overt lobular growth pattern. The
(789}. Physical examination and flexible cells with delicate chromatin and cyto- cells can be arranged in gland-like rings
fi bre-optic endoscopic evaluation, com- plasm. Aspirates of high-grade tumours or ti ght annular formations with a true
plemented with CT and MRI, are useful in may show features similar to !hose seen lumen (Flexner-Wintersteiner rosettes).
the diagnostic work-up.
The classic imaging findings include
a dumbbell-shaped mass extending
across the cribriform plate, with the waist
at the cribritorm plate. MRI better deline-
ates sinonasal and intraorbital or intracer-
ebral extension . ONB is T1-hypointense
and T2-isointense or T2-hyperintense to
grey matter, with avid homogeneous en-
hancement with contrast. Bone erosion
is better demonstrated by CT, with care-
ful evaluation for erosion of the lamina
papyracea, cribritorm plate, and fovea
ethmoidalis. Peripheral tumour cysts and

58 Tumours of t11e nasal cavity, paranasal sinuses and skull base

Table 1.03 Olfactory neuroblastoma staging systems. Key features and criteria for Hyams grades 1-IV and corresponding hstopathological H&E slides
Hyams grade
Key feature/crlterlon
11 111 IV
Architecture Lobular Lobular Variable Variable
Mitotic activity Absent Present Prominent Marked
- - --
Nuclear polymorphism Absent Moderate Prominent Marked
- - - - t - - - - ------+-- -- - - - - --t--
Fibrillary matrix _._____ Prominent Present Minimal Absent
Rosettes Homer Wright rosettes Homer Wright reselles Flexner-Wintersteiner rosettes Flexner-Wintersteiner rosettes
Necrosis Absent Absent +/- present Common
- - - - -- - 1 - -- - - - - - -- + - - - - - - - - - - - 1 - -- - - -- - -- -1- -- - - - - - ----j


Rosettes alone are not diagnostic of beta-tubulin, as well as variable S100 these regions may harbour genes with
ONB, although the Homer Wright rosettes protein reactivity, which is typically in a functional relevance in ONB. The detec-
are nearly pathognomonic in the nasal sustentacular cell pattern highlighting tion of PTCH1, GL/1, and GL/2 in 70%,
cavity when containing true neuropil. only cells at the periphery of the nests, 70%, and 65% , res pectively, of human
Perivascular pseudorosettes (like those often limited in higher-grade tumours. ONB specimens suggests that the SHH
seen in ependymomas) are non-specific. Sustentacular cells may also be posi- signalling pathway may be involved in the
The mitotic rate is variable, but is usually tive for GFAP. Calretinin staining (nuclear pathogenesis of this neoplasm {1534}.
low, especially in lower-grade tumours. and cytoplasmic) has been reported The OMP and RICBB genes have been
Calcifications (concretion-like or psam- in ONB {2635) but can also be seen in found to be expressed in ONBs {875}.
momatous) may be seen, less frequently other sinonasal tumours. As many as one
as the grade increases. Melanin pig- third of ONBs may also stain focally far Prognosis and predictive factors
ment, ganglion cells, rhabdomyoblasts, cytokeratin (CAM5.2, CK18) {1014,1619). In addition to staging, histological grade
divergen! differentiation as islands of true Negative markers include C045RB, is usefu l in prognostication and manage-
epithelium (squamous pearls or gland CD99, p63, and FLl 1. Proliferation mark- ment of ONB {174,1203,1519,2468}. High-
formation), and clear-cell change may er studies reveal a variable Ki: 67 prolif- grade tumours tend to have a poorer
occasionally be encountered in ONB eration index (2- 50%) {1619,2383}, and outcome {174,616,1130,1 519}. A single in-
[149,694,1457,1632}. BCL2 expression increases with tumour stitutional retrospective review found that
The most widely used gradi ng system grade. Rare desmin or myogenin reactiv- high tumour grade was significantly asso-
for ONB was developed by Hyams et ity is seen in ONB with rhabdomyoblastic ciated with poor outcome, but advanced
al. {950). This system divides the spec- differentiation (203). stage was not {174). Metastatic ONB is
trum of ONB maturation into tour grades, associated with significantly worse over-
ranging from most differentiated (grade 1) Genetic protile all survival, and high-grade ONB with
to least differentiated (grade IV), on the ONB demonstrates numerous chromo- significantly worse disease-free survival.
basis of tumour architecture, mitotic ac- somal aberrations, deletions, and gains, High Hyams grade (111/IV) is associated
tivity, nuclear pleomorphism, fibrillary but with no consistent pattern {221,907, with more aggressive locoregional dis-
matrix and rosettes, necrosis, gland pro- 1015,1983}. In one study, a specific dele- ease {1519} and is a predictor of worse
liferation, and calcifications. This grading tion on chromosome 11 and gain on chro- disease-free survival (174). lt is yet to be
scheme has been independently vali- mosome 1p were associated with metas- determined whether histopathological
dated in relation to prognosis {802,1203, tasis anda worse prognosis {221 }. Gains grading alone is a sufficient stratifica-
2036, 2336}. have been shown to be more freq uent tion tool and an independent predictor
The typical immunohistochemical pro- than losses, and high-stage ONBs show of overall survival {616,802,1203,2036,
file includes diffuse staining for neuron- more alterations than low-stage_tumours. 2336,2468).
specific enolase [2424}, synaptophysin, Gains in 20q and 13q may be impor-
chromogranin A, CD56 (NCAM) and tan! in the progression of this neoplasm;

Neuroectodermal / melanocytic tumours 59

Mucosa/ melanoma
Williams M.O.
Speight P.
Wenig B.M.

Mucosal melanoma is a malignant neo-
plasm arising from melanocytes in the
mucosa. Fig. 1.61 Sinonasal mucosa! melanoma. T2-weighted Fig. 1.62 Sinonasal mucosa! melanoma. A polypoid
axial MRI of sinonasal mucosa! melanoma of the nasal slightly pigmentad mass distends the submucosa.
ICD-0 code 8720/3 septum (arrow).
pigmented (black) and friable to tan or
Epidemiology Localization grey and firm.
Sinonasal mucosal melanomas con- Sinonasal mucosa! melanomas most fre-
stitute 1% of all melanomas and about quently arise in the nasal cavity or sep- Cytology
4% of ali sinonasal tumours (796,1645). tum, and rarely in the nasopharynx or Asp irates of metastatic lesions show the
There is a wide patient age range, with maxillary sinuses (1645,2395). diversity of featu res discussed within the
an incidence peak in the seventh decade histopathology section below, similar to
of lite (2395). There is no sex predilection Clinical features the features seen in aspirates of meta-
(2395}. Patients may present with non-specif- static dermal melanoma. The diagnosis
ic symptoms of epistaxis or sinonasal must be considered within the differential
Etiology congestion. for any aspirate showing a malignancy
Mucosal melanomas are biologically dis- that is not obviously epithelial.
tinct from cutaneous melanomas. Etio- Macroscopy
logical factors, including melanocytosis, Sinonasal mucosal melanomas are Histopathology
remain speculative. often polypoid, and range from deeply Solid sheets or nests of epithelioid cel ls

. :J. '' .
Fig. 1.63 Sinonasal mucosa! melanoma. The histological features vary from (A) clear, non-pigmented, slightly spindled cells to (B) pigmented epithelioid cells with prominent nucleoli.
The histological spectrum of melanoma includes (C) spindled, fasciculated growth pattern and (D) rhabdoid proliferation.

60 Tumours of the nasal cavity, paranasal sinuses and skull base

with variable N:C ratios infiltrate the sub- cell carcinoma, NUT carcinoma, and NRAS mutations and rare BRAF muta-
mucosa. Surface ulceration is often pre- SMARCB1 -deficient carcinoma), neu- tions (Table 1.04) (1,2467,2708}.
sent, but with intact surface epithelium , roendocrine carcinomas, diffuse large
pagetoid and/or surface spread may 8-cell lymphoma, and Ewing sarcoma/ Genetic susceptibility
be present. Variable cellular morphol- primitive neuroectodermal tumour. Sinonasal mucosal melanomas have a
ogy is present from case to case and lmmunohistochemical evaluation is possible association with melanocytosis,
within individual cases, ranging from necessary, particularly in amelanotic which is strongly associated with uveal
epithelioid/undifferentiated cells to spin- tumours. S100 protein and melanocytic melanomas.
dled, plasmacytoid, and rhabdoid cells, markers (HMB45, tyrosinase, melan-A,
with or without prominent nucleoli. In MITF, and S0X10) show variable sensi- Prognosis and predictive factors
neoplasms with a prominent spindle- tivity depending on morphological type. Distinguishing mucosa! from cutaneous
cell componen!, fascicu lar to storiform S100 protein highlights > 95% of epithe- origin and excluding metastasis to the
growth can be seen. Mitoses are read- lioid/undifferentiated melanomas, versus sinonasal region are importan! for stag-
ily identified and atypical forms are often 85% of spindled mucosal melanomas ing and prognosis. The seventh edition of
present. Discohesion leads to cuffing of (1917,2395). Similar variability has been the American Joint Committee on Cancer
endothelial cells (resulting in a pseudo- noted far melanocytic markers, which (AJCC) cancer staging manual added
papillary or peritheliomatous pattern). As highlight 75- 80% of melanomas with epi- head and neck mucosa! melanoma stag -
many as 50% of lesions are amelanotic, thelioid morphology versus 65-70% of ing: ali tumours are T3- 4, associated
resulting in a broader differential diagno- spindle cell melanomas (2395). with poor overall survival (< 30%) at 5
sis at this site, including small blue cell years {1 17,530,1495}. Metastatic disease
tumours (olfactory neuroblastoma and Genetic profile (stage IV) and advanced patient age
rhabdomyosarcoma), high-grade carci- The molecular profile is distinct from those are the most importan! prognostic fac-
nomas (sinonasal undifferentiated car- of cutaneous and uveal melanomas, with tors. K/T-mutant tumours have shown re-
cinoma, poorly differentiated squamous higher rates of K/Tmutations, followed by sponse to KIT inhibitor therapy; however,
the response is not durable (1009,2439}.
Table 1.04 Molecular alterations in melanomas vary by site of origin Future therapeutic development requires
Frequency by site of orlgln trials specifically evaluating mucosa!
melanomas; findings in cutaneous mela-
Molecular alteration Mucosa! {2708} Cutaneous {1} Ocular (uveal) {2467}
nomas may not be applicable, due to the
BRAF mutations <6% 50% 0% different genetic profile {1354). Cutane-
NRAS 15-20% 30% <5% ous melanoma prognostic factors (e.g.
K/Tmutationl Clark level of invasion and Breslow tu-
25% (10-37%) 6- 8% < 1% mour thickness) do not apply.
BAP1 mutation Unknown 3% 50% (metastases)
GNAQ 0% 2% 50%
GNA11 Rare 4% 36/.o
Monosomy of chromosome
Treatment and clinical trials are on-golng for:
BRAF inhibitors (cutaneous) and
blmatinib (mucosa!; most patients develop resistance).
lmmunotherapy trials are also underway; evaluation in all subsites will be critica! for determining efficacy.

Neuroectodermal/melanocytic tumours 61

Tumours of the nasopharynx

Nasopharyngeal carcinoma
Nasopharyngeal papillary adenocarcinoma
Salivary gland tumours
Benign and borderline lesions
Soft tissue tumours
Haematolymphoid turnours
Notochordal tumours
WHO classification of tumours of the nasopharynx

Carcinomas Soft tissue tumours

Nasopharyngeal carcinoma Nasopharyngeal angiofibroma 9160/0
Non-keratinizing squamous cell carcinoma 8072/3
Keratinizing squamous cell carcinoma 8071/3 Haematolymphoid tumours
Basaloid squamous cell carcinoma 8083/3 Diffuse large B-cell lymphoma 9680/3
Nasopharyngeal papillary adenocarcinoma 8260/3 Extraosseous plasmacytoma 9734/3
Extramedullary myeloid sarcoma 9930/3
Salivary gland tumours
Adenoid cystic carcinoma 8200/3 Notochordal tumours
Salivary gland anlage tumour Chordoma 9370/3

Benign and borderline lesions

Hairy polyp The morphology codes are from the lnternational Classification of Diseases
for Oncology (ICD-0) 1776A}. Behaviour is coded /0 for benign tumours:
Ectopic pituitary adenoma 8272/0 /1 for unspecified, borderline, or uncertain behaviour; /2 far carcinoma in
Craniopharyngioma 9350/1 situ and grade 111 intraepithelial neoplasia; and /3 for malignant tumours.
The classification is modilied from the previous WHO classification, taking
into account changes in our understanding of these lesions.

TNM classification of carcinomas of the nasopharynx

TNM classification,b M - Distant metastasis

MO No distan! metastasis
T - Primary tumour M1 Distan! metastasis
TX Primary tumour cannot be assessed
TO No evidence of primary tumour Stage grouping
Tis Carcinoma in situ Stage O Tis NO MD
T1 Tumour confined to nasopharynx, or extends to Stage 1 T1 NO MD
oropharynx and/or nasal cavity Stage 11 T1 N1 MO
T2 Tumour with parapharyngeal extension (which denotes 12 N0-1 MD
posterolateral infiltration of tumour) Stage 111 T1-2 N2 MO
T3 Tumour invades bony structures of skull base and/or T3 N0-2 MO
paranasal sinuses Stage IVA T4 N0-2 MO
T4 Tumour with intracranial extension and/or involvement of Stage IVB AnyT N3 MO
cranial nerves, infratemporal fossa, hypopharynx, orbit, or Stage IVC AnyT Any N M1
masticator space

N - Regional lymph nodes (i.e. the cervical nodes) 'Adapted from Edge et al. {625A} - used with permission of the American
Joint Committee on Cancer (AJCC), Chicago, lllinois; the original and prima
NX Regional lymph nades cannot be assessed ry source for this information is the AJCC Cancer Staging Manual, Seventh
NO No regional lymph nade metastasis Edition {2010) published by Springer Science+Business Media - and Sobin
N1 Unilateral metastasis in cervical lymph node(s), and/ et al. {2228A).
or unilateral or bilateral metastasis in retropharyngeal "A help desk for specific questions about TNM classification is available at
lymph nades, s: 6 cm in greatest dimension, above the
The supraclavicular fossa is !he triangular region defined by three points:
supraclavicular fossa (1) !he superior margin of the sternal end of the clavicle, (2) the superior mar
N2 Bilateral metastasis in cervical lymph node(s), s: 6 cm in gin of the lateral end of the clavicle, and (3) !he point where the neck meets
greatest dimension, above the supraclavicular fossa the shoulder; this includes caudal portions of levels IV and V.
N3 Metastasis in cervical lymph node(s), > 6 cm and/or in the
supraclavicular fossa
N3a > 6 cm in greatest dimension
N3b In the supraclavicular fossa

Note: Midline nades are considered ipsilateral nades.

64 WHO and TNM classification of tumours of the nasopharynx

lntroduction Chan J.K.C.
Slootweg P.J.

A broad range of neoplasms can arise common tumour types and site-specific of the hypopharynx, /arynx, trachea and
in tl1e nasopharynx, from epithelial to tumour types are described in detail. parapharyngea/ space, p. 77), Chapter 4
mesenchymal, lymphoid, and neuro- Other tumour types that can occur in the (Tumours of the oral cavity and mobile
ectodermal. The most common is na- nasopharynx are covered in other chap - tangue, p. 105), and Chapter 5 (Tumours
sopharyngeal carcinoma, which shows ters, including Chapter 1 (Tumours of of the oropharynx, p. 133).
remarkable geographical differences in the nasal cavity, paranasal sinuses and
incidence. In this chapter, only the more sku/1 base, p. 11 ), Chapter 3 (Tumours

Nasopharyngeal carcinoma Pete rsson B.F. Lewis J .S.

Bel! D. Nadal A.
EI-Mofty S.K. Nicolai P.
Gillison M. Wenig B.M.

Definition including the lnuit, Northern Africans, Table 2.01 Structures involved by local infiltration of
nasopharyngeal carcinoma; MRI data of 308 patients ,
Nasopharyngeal carcinoma (NPC) is a and Chinese from south-eastern Asia. Pamela Youde Nethersole Eastern Hospital, Hong Kong.
carcinoma arising in the nasopharyngeal Sorne of the highest incidences of NPC
Structures involved Frequency
mucosa that shows light microscopic or have been observed in Hong Kong SAR,
ultrastructural evidence of squamous d if- China, with 2012 age-standardized inci- Adjacent soft tissues
ferentiation . The term encompasses non- dences of 12.5 cases and 4.1 cases per Nasal cavity 87%
keratinizing, keratinizing, and basalo id 100 000 males and females, respective - Oropharyngeal wall, soft palate 21 %
squamous cell carcinoma. ly {363}. The annual incidence of NPC
Parapharyngeal space, carotid space 68%
in southern China is 15-50 cases per
ICD-0 codes 100 000 population {1004}. The rates in Pterygoid muscle (medial, lateral) 48%
Non-keratinizing squamous cell menare commonly double or trip le those Prevertebral muscle 19%
carcinoma 8072/3 in women. NPC affects predominantly Bony erosion / paranasal sinus
Keratinizing squamous cell adults, but rare cases are seen in the
Nasal septum 3%
carcinoma 8071/3 paediatric population . In high-ri sk popu-
Basaloid squamous cell lations, NPC incidence rises alter the age Pterygoid plate(s), pterygomaxillary
fissure, pterygopalatine fossa
carcinoma 8083/3 of 30 years, peaks at 40- 60 years, and
then declines {1822} In Chinese who mi- Maxillary antrum 4%
Synonyms grate to North America, the incidence of Ethmoid sinus 6%
Lymphoepithelial carcinoma; undiffer- NPC declines, but remains significantly
Sphenoid sinus; sphenoid bone;
entiated carcinoma with lymphoid stro - higher than in th e general North Ameri- 38%
foramina lacerum, ovale, and rotundum
ma; squamous cell carcinoma (WHO can population {296}.
Clivus 41%
grade 1); non-keratinizing carcinoma The age-standardized incidences of
(WHO grade 2); undifferentiated carci- NPC have decreased over the past dec- Petrous bone, petro-occipital fissure 19%
noma (WHO grade 3) ades, particularly among Ch inese in Jugular foramen, hypoglossal canal 4%
Hong Kong SAR {826,2693). Pituitary fossa/gland 3%
Extensive/intracraniat extension
NPC is an uncommon tumour among Etiology
Caucasians, with an age-adjusted an- Causative carcinogens have not yet Cavernous sinus 16%
nual incidence of less than 1 case per been definitively identified , but tobacco Cerebrum, meninges, cisterns 4%
100 000 population. The annual inci- smoking and alcohol consumption are lnfratemporal fossa 9%
dence in North America is 0.3-0.7 cases likely contributing factors for keratiniz-
Orbit, orbital fissure(s) 4%
per 100 000 population {1 124). NPC is ing NPC (K-NPC); and a high consump-
common among sorne ethnic groups, tion of salted and fermented foods with Hypopharynx 2%

Nasopharyngeal carcinoma 65
generally absent in K-NPC, especially in
non-endemic regions (1542,1731). EBV
infection is necessary but not sufficient
for tumorigenesis.
Oncogenic (h igh-risk) HPV types may
play a role in a subset of NPCs, espe-
cially in non-endemic regions. Like in the
oropharynx, HPV-related NPCs most fre-
quently show non-keratinizing histology

The pharyngeal recess (fossa of Rosen-
mller) is the most common site of ori-
gin {1010,1011). The next most common
site is the superior posterior wall of the

Clinical features
Most patients present with locoregionally
advanced disease, commonly with cervi-
1984 l9S6 l98S 1990 1992 199~ 1996 199S 2000 cal lymph node metastases (1040,2508)
The presenting symptoms are related
to the presence of a mass in the naso-
Fig. 2.01 Age-standardized incidence rates (per 100 000 population} of malignan! neoplasm of nasopharynx by sex in
Hong Kong SAR, China, 1983-2000; compiled based on the World Standard Population specified by Ahmad 08 et al. pharynx (e.g. epistaxis, obstruction, and
{29). Note: Data from 1996 onwards are based on population estimates using the resident population approach rather blood-stained postnasal drip), Eustachi-
than the extended de facto approach. The Hong Kong Population Census conducted in June to August 2011 provides an tube dysfunction (e.g. hearing impair-
a benchmark for revising population figures compiled since the 2006 Hong Kong Population By-census. Classification ment, tinnitus, and serous otitis media),
of diseases and causes of death is based on the lnternational Statistical Classification of Diseases and Related Health skull base involvement with impairment
Problems, 10th Revision (ICD-1O) from 2001 onwards; figures from 2001 onwards may not be comparable with figures
of the fifth and sixth cranial nerves (e.g.
for previous years, which were compilad based on ICD-9. Reprinted from Hong Kong Cancer Registry {363).
headache, diplopa, facial pain, numb-
ness, and paraesthesia), and painless
Table 2.02 Common presenting symptoms and signs of high nitrosamine content has been im- neck mass dueto lymph node metastasis
nasopharyngeal carcinoma; data from 722 consecutiva plicated in non-keratinizing NPC (NK- (1358). Distant metastasis at presentation
patients treated at Pamela Youde Nethersole Eastern NPC) in populations where that histologi- has been reported in approximately 5% of
Hospital, Hong Kong SAR, China, in 1994-2001.
cal subtype is endemic. NK-NPC has a patients {2368}, and 10% of patients with
Presenting features Frequency multifactorial etiology, including genetic NPC are asymptomatic . In endemic are-
Symptoms susceptibility, EBV infection, and pos- as, 12% of patients with dermatomyositis
Neck mass 42% sibly consumption of salted fish {96,97,
1003, 1005,1740,2693,2694,2695,2696).
Nasal (postnasal drip, discharge, 46%
Salted fish contains volatile carcinogenic
bleeding, obstruction)
nitrosamines or their precursors, as well
Aura! (tinnitus, discharge, earache, 42% as EBV-activating substances [1045,
1046,2144,2734}. The importance of ex-
Headache 16% posure in early life is indicated by studies
Double vision, squint, blindness 6% showing that low-risk ethnic groups born
Facial numbness 5%
in high-risk areas have higher risk of NPC
{1120,1121). In low-incidence regions
Speech/swallowing problem 2%
like northern China, the consumption of
Weight loss 4% salted fish still carries an adjusted rela-
Fig. 2.02 MRI of nasopharyngeal carcinoma (NPC}. A
Physical signs tive risk as high as 5.6 {295}. Other envi - 40-year-old woman presented wilh a 2-month history
Enlarged neck node(s}
ronmental factors, such as occupational of tinnitus, followed by neck masses, nasal symptoms,
exposure to wood dust, formaldehyde, headache, and diplopia. Physical examination revealed
Bilateral neck nades 35% heat, smoke, dust, and chemica[ fumes left sixth nerve palsy and bilateral upper-middle cervical
Neck nodes extending to supraclavicular 12% have also been proposed as possible lymph nades. Endoscopy revealed tumour in the
fossa contributing or causative factors {98, nasopharynx extending to the posterior nasal cavity.
Biopsy confirmad undifferentiated carcinoma. MRI
Cranial nerve palsy 10% 1740,2693).
showed NPC with extensiva local infiltration of adjacent
Deafness 3% Most studies show that NK-NPC has a soft tissues, erosion of skull base/ paranasal sinuses,
strong association with EBV, especially and intracranial extension, together with bilateral
Dermatomyositis 1%
in endemic reg ions; conversely, EBV is retropharyngeal and cervical nodes.

66 Tumours of the nasopharynx

have NPC as an underlying malignancy TNMstaging Macroscopy
[1848). whereas only 1% of patients with The main differences between the sixth The tumour can present as a smooth
NPC have dermatomyositis (2367). and seventh editions of the AJCC can- bulge in the mucosa, a discrete raised
cer staging manual are that (1) tumours nodule with or without surface ulceration,
Tumour spread classified in the sixth edition as T2a (i.e. or a frankly infiltrative fungating mass. In
NPC is notorious for its highly malignan! tumour extending to oropharynx and/or sorne cases, there is no grossly visible le-
behaviour, with extensive locoregional in- nasal cavity without parapharyngeal ex- sion (1468}.
filtration and early lymphatic spread, ero- tension) are classified in the seventh edi-
sion of skull base and paranasal sinuses, tion as T1 and (2) retropharyngeal lymph Cytology
intracranial spread, infiltration of cranial node(s). regardless of unilateral or bilat- Aspirates of metastatic K-NPCs and NK-
nerves, and extension to adjacent struc- eral location, are conside red N1 in the NPCs show findings similar to those at
tures (e.g. infratemporal fossa, orbit, and seventh edition. other sites. Aspirates often show a back-
hypopharynx). Given the rich lymphatic ground of lymphocytes and plasma cells,
plexus in the nasopharynx, lymphatic Serology with irregu lar clusters of large cells with
spread occurs early in the course of dis- EBV serology is positive in most patients overlapping vesicular nuclei and large
ease. In cases staged by imaging, about with NK-NPC (917). lgA antibody against nucleoli (384,1265). The cytoplasm of
20% of patients have no enlarged nodes, EBV viral capsid antigen and lgG/ lgA these cells is often frag ile and barely
and about half have retropharyngeal against EBV early antigens are the most visib le. There are commonly many na-
node involvement {21 40}. The jugulodi- extensively used diagnostic tools, with ked nuclei (1636} The diagnosis can be
gastric node is the most commonly pal - detection rates of 69-93% {383,525). read ily confirmed by immunostaining for
pable node at presentation, and involve- Another approach is to test for elevated cytokeratin and in situ hybridization for
ment of the posterior cervica l chain is levels of circulating EBV DNA or RNA, EBER.
more frequent than with other head and using techniques for detecting the
neck cancers. The most common sites of BamHI-W region of the EBV genome, Histopathology
distan! metastasis (in descending arder EBV-encoded small RNAs (EBERs), or Non-keratinizing squamous ce//
of frequency) are bone, lung, liver, and EBNA1 in the plasma or serum, with re- carcinoma
distan! nades {2369). ported sensitivity in NPC as high as 96% NK-NPC exhibits a variety of architec-
{382,1433,1463,2 168). tural patterns, frequently mixed within the

Nasopharyngeal carcinoma 67
same tumour mass, ranging from solid highly variable. When abundant, the in- oedema fluid or mucosubstances, and
sheets to irregular islands, trabeculae, flammatory cells break up the tumour into presence of intracytoplasmic mucin in
and discohesive sheets of malignant tiny clusters or single cells, making it dif- very rare cells {11 09,1302).
cells intimately intermi ngled with variable ficult to recognize the epithelial nature of In cervical lymph node metastases,
numbers of lymphocytes and plasma the neoplasm. Sorne cases may demon- malignant cells within the lymph nodes
cells. strate abundant eosinophils, neutrophils, may be arranged in various patterns. In
The undifferentiated subtype, which is or epithelioid granulomas {399,781,1379, particular, neoplastic cells may display
more common, is characterized by large 1471). A desmoplastic stromal reaction is Reed- Sternberg cell-like features in a
tumour cells with a syncytial appearance, uncommon. mixed inflammatory background, mim-
round to oval vesicular nuclei, and large lsolated or scattered groups of tu- icking Hodgkin lymphoma (329,1384).
central nucleoli. The nuclei can be chro- mour cells may appear shrunken, with Epithelioid granulomas (sometimes ne-
matin-rich rather than vesicular and the smudged nuclei and dense amphophilic crotizing) are present in approximately
neoplastic cells generally have scant am- or eosinophilic cytoplasm. In as many as 20% of cases (1384). A cystic appear-
phophilic or eosinophilic cytoplasm. The 10% of cases, there are interspersed in- ance of NK-NPC metastases to lymph
malignant cells can assume spindle-cell tra- or extracellular small spherical amy- nodes may simulate a metastasis from
features in fascicular arrangements. loid globules {1919]. Uncommon features the oropharynx.
The differentiated subtype exhibits cel- include papillary frond formation, clear-
lular stratification and pavementing, o/- cell change, accumulation of extracellular Keratinizing squamous ce// carcinoma
ten with plexiform growth; occasional K-NPCs are a group of invasive carci-
keratinized cells may be present. Com- nomas showing obvious squamous dif-
pared with those in the undifferentiated ferentiation at the light microscopic leve!,
subtype, the neoplastic cells are often in the form of intercellular bridges and/or
slightly smaller, the N:C ratio is lower, various degrees of keratinization, accom-
the nuclei are o/ten more chromatin -rich, panied by a desmoplastic stroma, akin to
and the nucleoli are usually less promi- that seen in squamous cell carcinoma at
nent. Focally, intercellular bridges may other head and neck sites. K-NPC can
be present. arise de novo or (more rarely) secondary
However, subclassification into undiffer- to radiotherapy {398).
entiated and differentiated subtypes has
no clinical or prognostic value. Basaloid squamous ce// carcinoma
The density of lymphocytes and plasma This tumour is morph0logically identical
cells within the tumour cell aggregates is to analogous tumours more commonlY

68 Tumours of the nasopharynx

occurring in other head and neck sites, (1056). Genomic sequencing reveals a with an estimated 1% increase in risk of
and has infrequently been reported to distinctive mutational signature, with nine local failure per 1 cm 3 increase in vol-
occur as a p ri mary tumour of the naso- significantly mutated genes (1431}. The ume (386,2330). Circulating plasma/se-
pharynx (132,133,1672,1839,2528}. EBV significance of these genes in p athogen- rum levels of EBV DNA are substantially
may be positive, especially in high-inci- esis, prognosis, and response to therapy elevated in patients with active disease
dence ethnic groups (1672,2528}. has yet to be determined. (in particular distan! metastasis); drop to
very low l itres upan rem ission (374,1462,
/mmunohistochemistry Genetic susceptibility 1728,2168}; and correlate with advanced
NPC stains strongly far p63, pancy- The risk of developing NPC is linked to stage {1463} and survival {374,1462}.
tokeratin, and high-molecular-weight cy- genes coding far certain tissue antigens Other unfavourable prognostic factors
tokeratins, with often patchy expression (i.e. HLA genes). In Chinese populat ions, are fixation of involved neck nades, male
of low-molecular-weight cytokeratins and HLA-A*02 alleles and HLA-8*46 alleles sex, patient age > 40 years, cranial nerve
EMA. CK7 and CK20 are negative (756}. are associated with a high risk of NPC palsy, and ear symptoms at presentation
(864,1042). High-resolution genotyping (1851,2139,2368).
EBV detection has shown a consisten! association be - The issue of histopathological type
NK-N PC is associated with EBV in almost tween NPC and the HLA-A*0207 allele, (keratin izing vs non-keratinizing) in rela-
ali cases. The most reliable way to dem- which is common in Chinese popu lations tion to prognosis is complex. Compared
onstrate EBV is in situ hybridization far {990]. Genetic polymorph isms in genes with NK-NPC, K-NPC shows a greater
EBER {1037,1066,1085,1904,2428}. This coding for metabolic enzymes (CYP2E1 propensity far locally advanced tumour
test is helpful in the evaluation of cervi- and GSTM1) and DN A repai r enzymes growth (which occurs in 76% vs 55% of
cal lymph nades harbouri ng undifferen - (OGG1 and XRCC1) have also been as- cases, respectively) (1966} and a lower
tiated ar poorly differentiated squamous sociated with increased risk of NPC {989, propens ity for lymph nade metastasis
cell carcinoma of unknown arigin, with 991). Linkage studies have suggested (which occurs in 29% vs 70% of cases,
a positive result strongly suggesting the that susceptibility loci for NPC are pres- respectively) (1715). Sorne studies have
possibility of NPC. ent on chromosomes 3, 4, and 14 {700, suggested that K-NPC is less respon-
lmmunostaining for LMP 1 is not a sensi- 2654). Familia! clustering of NPC is well sive to radiation therapy and has a worse
tive ar reliable method far demonstrating reported (1003,1 133,1157,2609}. The prognosis than NK-NPC {1023,1715,
lhe presence of EBV {908,1833,1904). relative risk in fi rst-degree relatives of 1966,2142}, but other studies have not
PCR far EBV is not rel iable either, be- patients with NPC vares from 6.3 to 21.3 found any differences in biological be-
cause even a few bystander EBV-positive {397,1362,2692,2722} . There are no clini- haviour (375,737}.
lymphocytes can give rise to a positive cal characteristics that sep arate sporadic The significance of the presence of high-
result {2428). from fami lia! cases. risk HPV is not wel l established. Severa!
studies have suggested that HPV-related
Genetic profile Prognosis and predictive factors tumours have a worse prognosis than do
Deletions on 3p and 9p are early events The most powerful prognostic factor of EBV-related cases, but perhaps a bet-
in NPC (442), and the chromosomal re- NPC is stage at presentation. A study us- ter outcome than do cases negative far
gions that most frequent show gain and ing the 2002 TNM staging system found both viruses {592,1435,1460,1561,2000,
loss are on chromosome 12 and 3p. Ar- that the 5-year disease-specific survival 2273}.
ray comparative genomic hybridization rate for stage I disease was 98%; for With improved treatment protocols, the
studies have identified frequent copy- stage IIA- B, 95%; far stage 111, 86% ; and development of a second malignan! tu-
number gains of MYCL (1p34.3), TERC for stage IVA-B, 73%. lncreasing tumour mour becomes significan!. Squamous
(3q26.3), ESR1 (6q25.1), and PIK3CA volume is a negative prognostic factor, cell carcinoma and various sarcomas

Nasopharyngeal carcinoma 69
are most common. The annual incidence 6.4- 15.8 years) {380). Postradiation Many prognostic molecular and immuno-
of postradiation squamous cell carci- squamous cell carcinoma may occur at histochemical markers have been stud-
noma has been reported to be 0.55-1 % uncommon siles, such as the externa! ied, but only that of plasma/serum levels
{1270,2531}; in one study, the mean la- auditory canal, middle ear, and temporal of EBV DNA {2717} has been incorporat-
tency period was 10.5 years (range: bone {1430,1461,1752,2364}. ed into clinical practice.

Nasopharyngeal papillary Stelow E.B.

Bell O.
adenocarcinoma Wenig B.M.

Definition Macroscopy
Nasopharyngeal papillary adenocarci- Nasopharyngeal papillary adenocarcino-
noma is a low-grade adenocarcinoma mas are exophytic and appear papillary,
with predominately papillary architecture, polypoid, or nodular. They may be soft or
found in the nasopharynx. gritty (2590}.

ICD-0 code 8260/3 Histopathology

Nasopharyngeal papillary adenocarcino-
Synonym mas are composed of complex, arboriz-
Thyroid -like low-grade nasopharyngeal ing papillae with hyalinized fibrovascular
papillary adenocarcinoma cores and glands {1894,2590] . The le-
sions are invasive and typically involve
Epidemiology the surface epithelium, tocally merging
Nasopharyngeal papillary adenocarcino- with non-neoplastic epithelium. Papillae
mas account tor < 1% of nasopharyngeal are lined by a single layer of cuboidal low-grade nasopharyngeal papillary ad-
malignancies. They can occur in patients to co lumnar cells that have a moder- enocarcinoma, but thyroglobulin is nega-
of any age (reported range: 9- 64 years) ate amount of eosinophilic cytoplasm. tive. S100 protein expression is seen fo -
{1894,2590). No sex predilection has Similar to those seen in papillary thyroid cally in many cases.
been shown. carcinomas, the nuclei vary trom round
to oval and have moderate membrane Genetic profile
Localization irregularity with vesicular to clear c hro- BRAF mutations have not been identified
Nasopharyngeal papillary adenocarci- matin. Psammomatoid calcifications are (1768,1870).
nomas can involve any part of the naso- seen in about one third of cases. Mitotic
pharynx {2590). figu res are uncommon and necrosis is Prognosis and predictiva factors
rare. Perineural and angiolymphatic inva- Most patients with nasopharyngeal papil-
Clinical features sion are not seen. lary adenocarcinoma have been treated
Patients typically present with nasal ob- The tumours express EMA, CK5/6, and with surgery alone, although sorne have
struction (1894,2590}. Subsets of pa- often CK7 {1894,2590}. The subset of also received radiation therapy {1894,
tients present with rhinorrhoea, epistaxis, cases positive for CK19 and TTF1 {342} 2590}. No patients have developed re-
otitis media, or hearing problems. has been referred to as thyroid-like c urrences or metastases.

70 Tumours of the nasopharynx

Salivary gland tumours

Adenoid cystic carcinoma findings 'are similar to those fo r adenoid 2406,2516). The affected patients are
cystic carcinomas found elsewhere infants (diagnosed by 3 months of age),
Stelow E.B. (2391). They are described in detail in and there is a male predilection. A case
Bell D. the Adenoid cystic carcinoma section suspected to have developed in utero
Seethala R. in Chapter 7, p. 164. The tumours are has been reported {1945).
Stenman G. mostly submucosal, but sorne may show
mucosa! extension. Localization
Salivary gland anlage tumours occur in
Definition Genetic profile the posterior nasal septum or the poste-
Adenoid cystic carcinoma is a slow- The adenoid cystic carcinoma- specific rio r nasopharyngeal wall.
growing and relentless salivary gland 1(6;9) chromosomal translocation, result-
malignancy composed of epithelial and ing in a MYB-NF/8 gene fusion, has been Clinical features
myoepithelial neoplastic cells that form detected in tumours at this site (987,1862, Patients present with respiratory distress
various patterns, including tubular, c ribri- 2391). due to nasal airway obstruction {979). Be-
form , and solid forms. fore birth, salivary gland anlage tumour may
Prognosis and predictiva factors be associated with polyhydramnios {1945).
ICD-0 code 8200/3 The reported 5-year disease-free and
overall survival rates are 30-65% and Macroscopy
Epidemiology 5 4-70%, respectively {325,1447). The typical appearance is that of a poly-
Approximately 2-8% of adenoid cystic poid to peduncu lated smooth tan -brown
carcinomas involve the nasopharynx mass with solid to microcystic cut sur-
(1709,1864). The tumours are the most Salivary g/and anlage tumour tace (979).
common salivary gland malignancy af-
fecting the area and account for almos! Chiosea S. Histopathology
one quarter of ali adenocarcinomas found Seethala R. Salivary gland anlage tumours display
at the site {1894). The mean patient age Sklov A. a complex polypoid configuration, with
at presentation is 45 years, and men and a submucosal network of tu bules and
women are equally affected {1894,2391). ducts with variable keratinization that are
Definition continuous with the surface squamous
Localization Salivary gland anlage tumour is a mid- epithelium. The spindle ce ll componen!
Adenoid cystic carcinoma can involve line nasopharyngeal lesion with biphasic vares from hypocell ular to more cellu lar
the nasopharynx either in isolation or epithelial and myoepithelial components myoepithelial nodules in the centre of the
through spread from !he sinonasal trae!. (979). polyp. Cellular atypia and mitoses are
absent {979). The epithelial components
Clinical features Synonym are positive for cytokeratins and EMA,
Patients most often present with epistax- Congenital pleomorphic adenoma {554, and the myoepithelial nodules express
is, nasal obstruction, and tinnitus {1447). 937) SMA and cytokeratins .
Most patients present with advanced -
stage disease {325,2391). Epidemiology Prognosis and predictive factors
Approximately 35 examples of salivary No recurrences alter excision have been
Histopathology gland anlage tumour have been reported reported.
The histological and immunohistochemical {554,8 16,978,979, 1537,1633, 1945,2282,

Fig. 2.1 O Salivary gland anlage tumour.


Salivary gland tumours 71

Benign and borderline lesions Katabi N.
Hunt J.L.
Thompson L.D.R.
Wenig B.M.

Hairypolyp Ectopic pituitary adenoma Histopathology

Ectopic pituitary adenoma is a submu-
Definition Definition cosal epithe lioid neoplasm with solid, or-
Hairy polyp is a benign polypoid lesion Ectopic pituitary adenoma is a benign ganoid, and trabecular growth patterns.
with a suspected developmental orgin, anterior pituitary gland neoplasm that The epithelioid cells have round nuclei,
composed of ectoderm and mesoderm. does not involve the sella turcica. with a dispersed chromatin pattern and
granular eosinophilic cytoplasm. Plas-
Synonyms ICD-0 code 8272/0 macytoid-appearing cells may be pres-
Teratoid polyp; dermoid polyp ent. Gland-like spaces may be seen,
Synonyms but there is no squamous differentiation.
Epidemiology Extrasellar pituitary adenoma; extracra- There is mild to moderate nuclear varia-
Hary polyp occurs primarly in neonates nial pituitary adenoma tion (so-called endocrine atypia). Scat-
and older nfants, and extremely rarely in tered mitotic figures may be present, but
adults {364,888}. There is a femare pre- Epidemiology not atypical mitoses or necrosis. Cai-
dominance, wth a female-to-male ratio of Pituitary adenomas account for < 3% ot cifications and psammoma-like bodies
6:1 (89,622,1210). tumours ot the sphenoid sinus or naso- may be identified [1459,1493,2166). The
pharynx (683,1782,2392} . Palien! age stroma is usually richly vascularized and
Localization at presentation vares widely (range: often heavly collagenized.
The most common locaton is the lateral wall 2-84 years; mean: 54 years). The tumour cel ls express cytokeratins
of the nasopharynx (accounting for 60% ot Females are affected slightly more than (often in a perinuclear dot-li ke pattern)
cases), but hairy polyp may also occur in males, with a female-to-male ratio of 1.3:1 and neuroendocrine markers (e.g . syn-
the oropharynx, palate, tonsil, tangue, lip, (2392} . aptophysin, CD56, and chromogran in).
and middle ear (622,1210,1223]. S100 protein may be positive, but the
Localization sustentacular pattern of oltactory neuro-
Clinical features Ectopic ptuitary adenomas occur most blastoma s absent. Reactivity with two
The presentaton includes a peduncu- trequently in the sphenoid sinus/bone or more pi tuitary hormones is seen in as
lated mass that may be assocated wth {301,1459,1959,2392,2417). followed by many as 50% of cases. About one third
cough , dyspnoea, vomiting, and difficulty the nasopharynx, with rare cases re- of ali cases express a single hormone,
in swallowing . Rarely, it is associated with ported in the nasal cavity, ethmoid sinus, most commonly prolactin. Approximately
other congenital malformations, such as temporal bone, and nasal bridge (87, 20% of ectopic pituitary adenomas are
cleft palate or Dandy- Walker syndrome 1959). null cell adenomas - lacking expression
{106,2359}. of any hormone marker. The diagnosis
Clinical features of null cell adenoma is preferably sup-
Macroscopy Symptoms include obstruction, sinusi- ported by the demonstration of pituitary
The polyp has a skin-like surface and tis, rhinorrhoea, discharge, headache, transcription factors (e.g. PIT1 , TPIT, SF1,
can be as large as 6 cm in greatest di- and pain. Visual disturbances and ER-alpha, GATA2, and alpha subunits)
mension, with an attachment to the lateral nerve changes are uncommon (2392) .
wall of the nasopharynx {1623}. Sorne patients present with endocrino-
pathic manifestations, such as Cush-
Histopathology ing syndrome (hypercortisolism), acro-
The polyp is covered by keratinized megaly, amenorrhoea, or galactorrhoea
squamous epithelium containing pi- (468,483,1030,1932,2175).
losebaceous units. The core consists Asymptomatic presentation occurs in
of fibroadipose tissue. Skeletal muscle, about 10% of cases. lmaging studies are
carti lage, and bone may be present. required to exclude direct extension from
Meningothelial remnants have been iden- the sella. Bone destruction is often pres-
tified {1770). Hairy polyp is differentiated ent (873,958,2207,2668).
from teratoma by a lack of endodermal
components. Macroscopy
Fig. 2.11 Ectopic pituitary adenoma. Strong and diffuse
Macroscopically, ectopic pituitary ade- granular cytoplasmic immunoreactivity for prolaclin, one
Prognosis and predictive factors nomas are polypoid tumours measuring of the peptides mas! commonly identified in ectopic
Surgical excision is curative {23591. 0.8-8 cm (mean: 3.4 cm) (1459,21661. pituitary adenoma.

72 Tumours of the nasopharynx

.,._,, \
Fig. 2.1 2 Ectopic pituitary adenoma. A Organoid growth pattern with rich vascularity. B Marked sclerosing fibrosis associated with compressed neoplastic cells. e Rosettes and
pseudorosettes. D Profound nuclear pleomorphism can frequently be seen in pituitary adenoma; there is a spicule of bone noted, as bone destruction may be seen.

[87,1459). Ectopic pituitary adenoma Localization type cells. In addition, so-called wet kera-
must be distinguished from other neu- Craniopharyngioma can occur extra- tin (composed of eosinophilic keratinized
roendocrine neoplasms. c ranially in the nasopharynx 11622). and ce lls with ghost nuclei) and associated
exceptionally in the sinonasal tract 11064, calcifi cation is present. The papillary
Prognosis and predictive factors 1748,2716). type includes sheets of dyscohesive
Surgical resection can be curative, but squamous epithelium that form pseudo-
recurrences are not uncommon. Clinical features papillae with anastomosing fibrovascu lar
Nasopharyngeal involvement is associ- stroma {1 905,2333}.
ated with headache, impaired vision, and
Craniopharyngioma nasal obstruction. Genetic profile
The adamantinomatous type harbours
Definition Macroscopy CTNNB1 (b eta-catenin) mutations and
Craniopharyngioma is a benign epithelial Most craniopharyngiomas have a cystic the papillary type harbours BRAFV600E
tumour thought to derive from the Rathke component containing brown (so called mutations {263,1547).
cleft. machine-oil) fluid {2697).
Prognosis and predictive factors
ICD-0 code 9350/1 H istopathology Treatment includes surgery with or with-
The adamantinomatous type shows out radiation 12697}. Craniopharyngioma
Synonym cords of basaloid cells with peripheral may be associated with long-term mor-
Pituitary adamantinoma palisading surrounding loose stellate- bidity and recurrence {1948).

Benign and borderline lesions 73

Soft tissue tumours Prasad M.L.
Franchi A.
Thompson L.D.R.

Nasopharyngeal angiofibroma
Nasopharyngeal angiofibroma is a locally
aggressive, variably cellular fibrovascular
neoplasm arising in the nasopharynx of
young males.

ICD-0 code 9160/0

\: . -:cr
Angiofibroma; juvenile angiofibroma;
juvenile nasopharyngeal angiofibroma
- '.. , I "
..,..:. \
Nasopharyngeal angiofibroma is rare,
constituting < 0.5% of ali head and neck
tumours {230,2700). lts incidence is
0.4 cases per million in the general popu
, _..,.,,.
. .. .'
,, .I ' . r..
lation and 3.7 per million in the at-risk ,- ~ ..,,, '-' '
population (i.e. 1O- to 24-year-old males) , .D, .:' ' ' .- - .J..: . . ..

{845). The tumour develops almost exclu Fig. 2.14 Nasopharyngeal angiofibroma. A A richly vascular tumour underlying the nasopharyngeal respiratory-type
mucosa, showing variously sized blood vessels in a cellular fibroblastic stroma. The vascular componen! ranges
sively in adolescent and young males (av from capillaries to large dilated vessels. B The vascular componen! is variable, ranging from thin, slit-like branching
erage patient age: 17 years) (230,1716, capillaries supported only by endothelial cells to dilated vessels; the stroma shows dense collagen with spindled to
2621). Female patients should be evalu stellate fibroblasts. C In this area, the stroma is loose and myxoid, and contains stellate fibroblasts. The blood vessel
ated for underlying testicular feminization. walls range from !hin (supported only by endothelium) to unevenly thick, due to !he variable mural smooth muscle
content. D Nuclear localization of beta-catenin is seen in stromal cells only; in endothelial cells, the expression remains
Etiology membranous and cytoplasmic.
There is evidence of hormonal depend
ency of nasopharyngeal angiofibroma. Localization cranial fossa) is seen in 10-30% of cases
Tumour growth is associated with pu Nasopharyngeal angiofibroma arises in {230,1388,1559,1716}. Angiography is
berty in boys, and tumour cells frequently the nasopharynx or posterolateral nasal diagnostic, identifies the feeding vessel
express androgen receptor (1063,1716, cavity wall (230,1716,2700}. (usually the interna! maxillary artery), and
2621). is essential for pre-surgical embolization
Clnica! features {219). Due to the characteristic imaging
Patients present with the classic triad appearance, diagnostic biopsy (which
of nasal obstruction, epistaxis, and na carries a risk of life-threatening haemor

.,,,-.-;-: - .. "',..i:; ./
sopharyngeal mass (230,1222). Other rhage) is often unnecessary.
. - ........ symptoms include nasal discharge, si

'1' ' 1- r.:
nusitis, facial deformity, deafness, otitis, Macroscopy
\ }':-.-, - . - ' . - -1-;
diplopa, proptosis, headache, and pain The average tumour size is 4 cm, but tu
\ ...
' {1716,2700}. Radiological imaging fre mours as large as 22 cm have been re
quently shows a tumour in the nasophar ported. The neoplasm is polypoid and

.. ynx and nasal cavity with sinus opacity lobulated and often takes the shape of
and bone destruction. Anterior bowing of surrounding structures.
-. , the posterior wall of the maxillary antrum
Fig. 2.13 Nasopharyngeal angiofibroma. 30 reconstruction (called the Holman-Miller sign or the an Histopathology
of CT angiography of a 15-year-old boy with a hypervascular tral sign) is typical {1716,2700}. Large tu The tumour has two components: vascu
left nasal mass centred in the sphenopalatine foramen lar and stromal. The blood vessels are of
mours can extend into maxillary, ethmoid,
and extending into the pterygopalatine fossa, with
supply from an enlarged left interna! maxillary artery and sphenoid sinuses; pterygopalatine various sizes, shapes, and thicknesses,
(arrow), which is a branch of the externa! carotid artery and infratemporal fossa; and orbit. lntrac ranging from slit-like capillaries to ir
(arrowhead). ranial extension (usually into the middle regularly dilated and branching vessels.

74 Tumours of the nasopharynx

The vessel walls may be thin (support- highlights the endothelium of blood ves- Genetic susceptibility
ed only by endothelial cells) or may be seis, and SMA highlights the smooth There have been isolated reports of na-
ensheathed focally or continuously by muscle in the vessels. The stromal cells sopharyngeal angiof1broma arising in
smooth muscle of varying thickness. No show nuclear expression of androgen association with familial adenomatous
elastic tissue is identified except in feed- receptor and beta-catenin - the latter in polyposis 1712,832,2454).
ing arteries. > 90% of tumours 15,1063}. The stromal No germline mutations of APC, C TNN81,
The stroma consists of bipolar or stellate cells occasionally express SMA, espe- or any other gene have been reported in
fibroblastic cells with plump, vesicular, cially at the periphery of the tumour, but sporadic nasopharyngeal angiofibroma.
spindled nuclei, and the cells may ap- are negative for desmin and S100 pro-
pear to be arranged around the blood tein. Expression of estrogen receptor, Prognosis and predictiva factors
vessels. Nucleoli are indistinct and mi- progesterone receptor, and KIT (CD117) One or more recurrences occur in 5- 25%
toses are usually absent. Scattered multi- has been reported 11452,1641 ,1978}. of patients {230,1222,1388}. Prognosis
nucleated stellate stromal giant cells may depends on the size and extent of the
be seen. The stroma varies from loose, Genetic profile tumour, the presence of multiple feeding
oedematous, and cellular to densely col- Nasopharyngeal angiofibroma is charac- vessels (including bilateral vascularity),
lagenous and paucicellular; mast cells terized by chromosomal gains 1282}. Loss and the completeness of surgical resec-
are frequently present. Tumours treated of the Y chromosome with gain of the tion {1559,2227}.
with embolization show areas of necrosis X chromosome is frequently document- Sarcomatous transformation has been
and intravascular foreign material. Tu- ed 12092}. Somatic mutation in exon 3 of reported in association with radiotherapy,
mours treated with the androgen recep- the beta-catenin gene (CTNNB1) is seen as has metastasis {2621 }. Spontaneous
tor blocker flutamide are hypocellular, in 75% of the tumours, although nuclear regression after puberty can rarely occur
with increased stromal collagen {815}. localization of beta-catenin is seen in {2621}.
CD31 and CD34 immunohistochemistry > 90% of cases {5}.

Haematolymphoid tumours Ferry J.A.

Ko Y.-H.

Definltion slightly younger patients, with a higher cervical lymph nodes at presentation,
Haematolymphoid tumours of the na- male-to-female ratio, than does diffuse and more-distant spread is not uncom-
sopharynx are neoplasms of lymphoid, large 8-cell lymphoma (see Diffuse large mon {37,50,432,1054,1635}.
plasma cell, or myeloid origin arising in 8-cell lymphoma) {2652}. Burkitt lym-
the nasopharynx. phoma is a common type among children Clinical features
12642}. Patients present with nasal obstruction,
ICD-0 codas Nasopharyngeal extraosseous plasma- epistaxis, hearing loss, headache, dysp-
Extraosseous plasmacytoma 9734/3 cytoma accounts for 10-16% of ali head noea, and/or cervical lymphadenopathy.
Extramedullary myeloid sarcoma 9930/3 and neck extraosseous plasmacyto- A minority have constitutional symptoms
Diffuse large B-cell lymphoma 9680/3 mas {116,494,2078}. Nasopharyngeal {50,1054,2228,2652}.
myeloid sarcoma is rare {433,1957).
Epidemiology Histopathology
Nasopharyngeal lymphomas account Etiology Diffuse large B-cell lymphoma is most
for about 15% {37,666,934} of all head Most lymphomas, plasmacytomas, and common, followed by NK/T-cell lym-
and neck lymphomas and for 9% {1372} myeloid sarcomas arise sporadically. phoma and peripheral T-cell lymphoma,
to 35% {682} of Waldeyer ring (pharyn- EBV contributes to the pathogenesis of NOS {50,432,1054,1372,2652}. Other
geal lymphoid ring) lymphomas. Oiffuse NK/T-cell lymphoma. Sorne patients with lymphomas include MALT lymphoma
large 8-cell lymphoma is the most com- high-grade 8-cell lymphoma or classical {50,1372,2652). follicular lymphoma
mon type {37,50,682,2652}. NK-cell and Hodgkin lymphoma are immunocompro- {50,432,1372). Burkitt lymphoma {2228,
T-cell lymphomas occur more trequently mised {1939,2228}. 2652}, and mantle cell lymphoma
in Asia than in western countries {1054}. {2652}, as well as the rare anaplastic
Adults and (rarely) children are affected Localization large cell lymphoma {1054,2652), 8-
{50,432,1635}. The average patient age Lymphoma forms an often bulky, usually and T-lymphoblastic lymphomas {1054,
symmetrical lesion, commonly with inva- 1473), and classical Hodgkin lymphoma
and male-to-female ratio vary by type of
lymphoma. For example, extranodal NK/ sion of adjacent structures {432,2652). {1143,1939).
T-cell lymphoma (see Extranodal NK!T- Stage at presentation vares by type of
ce/1 /ymphoma, p.52) {1108,23221 affects
lymphoma, but most lymphomas involve

Haematolymphoid tumours 75

Scanned by CamScanner
Notochordal tumours Baumhoer D.
Bullerdiek J .
Nicolai P.

'.' .. ...,, ' ,....- .-. .. ~-r~

....,, ' .: ...-- . -


.. ' .......... .:., ...

... ;, .
. . '

'.f. I . / l ''
.. ., l,
_.>:.~.r ....
.. ..'

, ... .
_,.,. .
,. - . .: ..:. ... ..O ' -141,~ .
Fig. 2.15 Chordoma. A Nests of epilhelioid cells with eosinophilic and vacuolated cytoplasm showing osteodestructive growth. B lmmunohistochemical double-stain with CK19 (red,
staining of cytoplasm) and brachyury (brown, staining of nuclei).

Chordoma primary occurrence at these sites is ex- variable pleomorphism . Necrosis is fre-
ceedingly rare {2665). quently present. Chordoma typically
Definition shows expression of cytokeratins, EMA,
Chordoma is a malignant tumour with no- Clinical features S100, and brachyury {1610,2517). Vari-
tochordal differentiation. Chordomas p resent with headache, era- ants include chondroid chordoma, which
nial nerve palsy, or brain stem compres- shows matrix rem iniscent of hyaline car-
ICD-0 code 9370/3 sion, depending on the anatomical struc- tilage, and dedifferentiated chordoma,
tures comprom ised. which is a biphasic tumour with classic
Epidemiology chordoma juxtaposed to high-grade un-
The annual incidence of chordoma is Macroscopy d iffe rentiated sarcoma.
0.8 cases per 100 000 population, with The tumours generally show bone-de-
32- 42% arising in cranial sites, mainly in structive growth; the cut surface is gelati- Genetic susceptibility
the base of the skull. nous or cartilage-like. In rare familia! cases, a duplication of
There is a male predominance, with a the T (brachyury) gene can be found
male-to-female ratio of 1.6:1. lndividu- Histopathology (2670}.
als of any age can be affected , although Chordomas consist of cords and lobules
chordoma is rare in chi ldhood (372, of cells in a myxoid stroma, separated Prognosis and predictive factors
2224). by thin fibrous sepia. The characteristic The most importan! prognostic factor is
ce lls are physaliphorous, with abundant comp lete surgical resection, which can
Localization and highly vacuolated (bubbly) cyto- be achieved only rarely in cranial sites
The clivus is most commonly involved. plasm, but many tumour cells are non- {2259 }. The 3-, 5 -, an d 10-year overall
The nasopharynx and nasal cavity can descriptly epithelioid in appearance. survival rates are 80.9%, 73 .5%, and
be involved by local extension, but The nuclei are uniform and round, with 58.7%, respectively {372}.

76 Tumours of the nasopharynx


Tumours of the hypopharynx, larynx,

trachea and parapharyngeal space
Malignant surface epithelial tumours
Precursor lesions
Neuroendocrine tumours
Salivary gland tumours
Soft tissue tumours
Cartilage tumours
Haematolymphoid tumours
WHO classification of tumours of the hypopharynx, larynx,
trachea and parapharyngeal space

Malignant surface epithelial tumours Salivary gland tumours

Conventional squamous cell carcinoma 8070/3 Adenoid cystic carcinoma 8200/3
Verrucous squamous cell carcinoma 8051/3 Pleomorphic adenoma 8940/0
Basaloid squamous cell carcinoma 8083/3 Oncocytic papillary cystadenoma 8290/0
Papillary squamous cell carcinoma 8052/3
Spindle cell squamous cell carcinoma 8074/3 Soft tissue tumours
Adenosquamous carcinoma 8560/3 Granular cell tumour 9580/0
Lymphoepithelial carcinoma 8082/3 Liposarcoma 8850/3
lnfl ammatory myofibroblastic tumour 8825/1
Precursor lesions
Dysplasia, low grade 8077/0 Cartilage tumours
Dysplasia, high grade 8077/2 Chondroma 9220/0
Squamous cell papilloma 8052/0 Chondrosarcoma 9220/3
Squamous cell papillomatosis 8060/0 Chondrosarcoma, grade 1 9222/1
Chondrosarcoma, grade 2/3 9220/3
Neuroendocrine tumours
Well-differentiated neuroendocrine carcinoma 8240/3 Haematolymphoid tumours
Moderately differentiated neuroendocrine
carcinoma 8249/3
The morphology codes are from the lnternational Classification of Diseases
Poorly differentiated neuroendocrine carcinoma for Oncology (ICD-0) {776A}. Behaviour is coded /Ofor benign tumours:
Small cell neuroendocrine carcinoma 8041/3 /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in
Large cell neuroendocrine carcinoma 8013/3 situ and grade 111 intraepithelial neoplasia; and /3 for malignant tumours.
The classification is modified from the previous WHO classification, taking
into account changes in our understanding of these lesions.

78 WHO classification of tumours of the hypopharynx, larynx, trachea and parapharyngeal space
TNM classification of carcinomas of the larynx

TNM classification,b T3 Tumour limited to larynx, with vocal cord fixation

T4a Tumour invades cricoid or thyroid cartilage and/or
T - Primary tumour invades tissues beyond the larynx; for example, trachea,
TX Primary tumour cannot be assessed soft tissues of neck including deep/extrinsic muscle of
TO No evidence of primary tumour tongue (genioglossus, hyoglossus, palatoglossus, and
Tis Carcinoma in situ styloglossus), strap muscles, thyroid, oesophagus
T4b Tumour invades prevertebral space or mediastinal
Supraglottis structures, or encases carotid artery
T1 Tumour limited to one subsite of supraglottis, with normal
vocal cord mobility N - Regional lymph nodes (i.e. the cervical nades)
T2 Tumour invades mucosa of more than one adjacent NX Regional lymph nades cannot be assessed
subsite of supraglottis or glottis or region outside the NO No regional lymph node metastasis
supraglottis (e.g. mucosa of base of tongue , vallecula, or N1 Metastasis in a single ipsilateral lymph node,;::; 3 cm in
medial wall of pyriform sinus), without fixation of the larynx greatest dimension
T3 Tumour limited to larynx with vocal cord fixation and/or in- N2 Metastasis as specified in N2a, N2b, or N2c below
vades any of the following: postcricoid area, pre-epiglottic N2a Metastasis in a single ipsilateral lymph node, > 3 cm
space, paraglottic space, inner cortex of thyroid cartilage but ;::; 6 cm in greatest dimension
T4a Tumour invades through the thyroid cartilage and/or N2b Metastasis in multiple ipsilateral lymph nodes,
invades tissues beyond the larynx; for example, !rachea, all ;::; 6 cm in greatest dimension
soft tissues of neck including deep/extrinsic muscle of N2c Metastasis in bilateral or contralateral lymph nodes,
tongue (genioglossus, hyoglossus, palatoglossus, and all;::; 6 cm in greatest dimension
styloglossus), strap muscles, thyroid , oesophagus N3 Metastasis in a lymph node > 6 cm in greatest dimension
T4b Tumour invades prevertebral space or mediastinal struc-
tures, or encases carotid artery Note: Midline nodes are considered ipsilateral nodes.

Glottis M - Distant metastasis

T1 Tumour limited to vocal cord(s) (may involve anterior or MO No distan! metastasis
posterior commissure), with normal vocal cord mobility M1 Distan! metastasis
T1a Tumour limited to one vocal cord
T1 b Tumour involves both vocal cords Stage grouping
T2 Tumour extends to supraglottis and/or subglottis, and/or StageO Tis NO MO
with impaired vocal cord mobility Stage 1 T1 NO MO
T3 Tumour limited to larynx with vocal cord fixation and/or in- Stage 11 T2 NO MO
vades paraglottic space and/or inner cortex of the thyroid Stage 11 1 T1-2 N1 MO
cartilage T3 N0-1 MO
T4a Tumour invades through the outer cortex of the thyroid Stage IVA T1-3 N2 MO
cartilage and/or invades tissues beyond the larynx; for T4a N0-2 MO
example, trachea, soft tissues of neck including deep/ Stage IVB T4b AnyN MO
extrinsic muscle of tongue (genioglossus, hyoglossus, AnyT N3 MO
palatoglossus, and styloglossus), strap muscles, thyroid, Stage IVC AnyT AnyN M1
T4b Tumour invades prevertebral space or mediastinal struc-
'Adapted from Edge et al. (625A} - used with permission of the American
tures, or encases carotid artery
Joint Committee on Cancer (AJCC), Chicago, lllinois; the original and prima-
ry source for this information is the AJCC Cancer Staging Manual, Seventh
Subglottis Edition (2010) published by Springer Science+Business Med ia - and Sobin
T1 Tumour limited to subglottis et al. (2228A}.
T2 Tumour extends to vocal cord(s), with normal or impaired "A help desk for specific questions about TNM classification is available at

TNM c lassification of carcinomas of the larynx 79

TNM classification of carcinomas of the hypopharynx

TNM classification,b
M - Distant metastasis
T - Primary tumour MO No distan! metastasis
TX Primary tumour cannot be assessed M1 Distan! metastasis
TO No evidence of primary tumour
Tis Carcinoma in situ Stage grouping
T1 Tumour limited to one subsite of hypopharynx and/or Stage O Tis NO MO
s 2 cm in greatest dimension Stage 1 T1 NO MO
T2 Tumour invades more than one subsite of hypopharynx or Stage 11 T2 NO MO
an adjacent site, or measures > 2 cm but s 4 cm in Stage 111 T1 -2 N1 MO
greatest dimension, without fixation of hemilarynx T3 N0--1 MO
T3 Tumour > 4 cm in greatest dimension, or with tixation of Stage IVA T1-3 N2 MO
hemilarynx or extension to oesophagus T4a N0--2 MO
T4a Tumour invades any of the foliowing: thyroid/cricoid Stage IVB T4b Any N MO
cartilage, hyoid bone, thyroid gland, oesophagus, central AnyT N3 MO
compartment soft tissue (which includes prelaryngeal Stage IVC AnyT Any N M1
strap muscles and subcutaneous fat)
T4b Tumour invades prevertebral fascia, encases carotid
artery, or invades mediastinal structures

N - Regional lymph nodes (i.e. the cervical nodes)

NX Regional lymph nades cannot be assessed
NO No regional lymph node metastasis
N1 Metastasis in a single ipsilateral lymph nade, s 3 cm in
greatest dimension
N2 Metastasis as specitied in N2a, N2b, or N2c below
N2a Metastasis in a single ipsilateral lymph node, > 3 cm
but s 6 cm in greatest dimension
N2b Metastasis in multiple ipsilateral lymph nodes,
ali s 6 cm in greatest dimension
Adapted from Edge et al. {625AJ - used with permission of the American
N2c Metastasis in bilateral or contralateral lymph nodes,
Joint Committee on Cancer (AJCC), Chicago, lllinois; the original and prima-
ali s 6 cm in greatest dimension ry source for this information is the AJCC Cancer Staging Manual , Sevent11
N3 Metastasis in a lymph nade > 6 cm in greatest dimension Edition (201 O) published by Springer Science+Business Media - and Sobin
et al. {2228AJ.
bA help desk for specific questions about TNM classification is available at
Note: Midline nades are considered ipsilateral nades.

80 Tumours of the hypopharynx, larynx, trachea and parapharyngeal space

Tumours of the hypopharynx, larynx, Slootweg P.J.
Grandis J.R.
trachea and parapharyngeal space

/ntroduction was to achieve a universally accepted accepted distinction between low-, inter-
consensus in arder to put an end to the mediate-, and high-grade carcinoma has
Laryngeal and hypopharyngeal pathol- confusion that can arise from the use of been used, in line with the nomenclature
ogy mainly encompasses lesions of the severa! difieren! classification systems. for histologically similar lesions at other
covering mucous membrane, with un- Currently, a two-tiered classification body siles. Discussion of soft tissue and
derlying soft tissues, salivary gland tis- (consisting of low-grade and high-grade salivary gland lesions, as well as haema-
sue, and cartilage playing a minar role. dysplasia) is recommended, to which tolymphoid tumours, has been limited to
Therefore, this chapter emphasizes le- guidelines have been added on how to the specific entities that are often faund
sions that arise from the mucosa! lining. recognize carcinoma in situ within the in the laryngohypopharynx or that have
The main difference from the previous high-grade dysplasia group in case a an importan! differential diagnostic role
edition is in the discussion of mucosa! three-tiered system is preferred. For al this site.
premalignancies, about which the aim neuroendocrine carcinomas, the widely

Malignant surface epithelial tumours

ce// carcinoma
Zidar N.
Brandwein-Gensler M.
Cardesa A.
Helliwell T.
Hille J.
Nadal A.

Conventional squamous cell carcinoma
(SCC) is a malignant epithelial tumour with
Fig. 3.01 Macroscopic appearance of conventional squamous cell carcinoma. A Supraglottic carcinoma of the larynx:
evidence of squamous differentiation.
an ulcerated tumour with raised edges at the base of the epiglottis. B Subglottic carcinoma of the larynx: a partially
flat and partially exophytic nodular tumour of the subglottis, extending to the anterior commissure. C Hypopharyngeal
ICD-0 code 8070/3 carcinoma of the piriform sinus: a large, ulcerated tumour with raised edges in the piriform sinus, extending to the
aryepiglottic fold.
Epidermoid carcinoma been described in children (137,1766}. Etiology
The tumours are more common in men Cigarette smoking and (to a lesser ex-
Epidemiology (359,1947). although the male-to-female tent) alcohol consumption are the most
SCC of the larynx and hypopharynx is ratio is decreasing in sorne countries, important risk factors far laryngeal and
the second most common respiratory possibly due to increased incidence of hypopharyngeal SCC (953). Eliminat-
tract cancer, after lung cancer (359]. lt smoking among women over the past ing smoking and alcohol consumption
accounts for 1.6-2% of ali malignant tu- two decades (569). could prevent as many as 90% of laryn-
mours in men and 0.2- 0.4% in women Tracheal carcinoma is rare, with ap- geal cancers {695). Other factors, such
(238}. There is marked geographical proximately 1 tracheal carcin.oma far as gastro-oesophageal reflux, diet, nu-
variation in the frequency of SCC, both every 75 laryngeal cases; it accounts far tritional factors, and socioeconomic sta-
between countries and in different parts < 0.1% of cancer deaths. SCC accounts tus, have been linked to increased risk of
of the same country. far 55-73% of all tracheal carcinomas laryngeal cancer, particularly in patients
lt occurs most frequently in the sixth and (143,820) . who lack the majar risk factors (480,665,
seventh decades of lite. Rare cases have 762,1333}.

Malignan! surface epithelial tumours 81

HPVs play a limited role in the pathogen- lung, liver, and bones (2248); intracra- more mitoses, including abnormal mi-
esis of SCC of the larynx. In recent stud- nial metastases have also been reported toses; there is usually less keratinization.
ies, transcriptionally active HPVs were {544,2418). In poorly differentiated SCC, basal-type
detected in 4-15% of cases {417,922, The TNM staging system is widely used cells predominate, with frequent mitoses
1408,2095). Unlike in the oropharynx, the for SCC. lt is presented in the text on (includ ing abnormal mitoses), b arely
morphology of laryngeal SCC does not pages 79 and 80. discernible intercellular bridges, and
predict viral etiology {1408). minimal or no keratinization. Although
Macroscopy keratinization is more likely to be present
Localization Laryngeal and hypopharyngeal SCC in well - or moderately differentiated SCC,
There are geographical differences in the may present as an exophytic, flat, or it should not be cons idered an important
topographical distri bution of laryngeal nodular tumour with raised edges; as a histological criterion in grading SCC . Of-
SCC. The most common location for la- polypoid lesion; or as a depressed, en- ten, in the presence of an intact surface
ryngeal SCC is the supraglottis in sorne dophytic lesion. Central ulceration is fre- epithe lium, intraepithelial dysplasia may
countries (e.g. France, Spain , ltaly, Fin- quently present. be seen in direct continu ity with the SCC.
land, and the Netherlands) and the glot- Tracheal SCC usually presents as a Tumour growth at the invasive front can
tis in others (e.g. the USA, Canada, the polypoid mass projecting into the lu- show an expansive or cohesive pattern
United Kingdom, and Sweden) [143). The men. Rarely, it grows as a circumferential (characterized by large tumour islands
rarest localization of laryngeal cancer is mass. with well-defined pushing margins) and
the subglottis {2067). an infiltrative pattern (characterized by
Hypopharyngeal SCC occurs most fre- Cytology scattered small irregular cords or single
quently in the piriform sinus (60-85% of Aspirates of metastases are cellular, with tumour cells, with poorly defined infiltrat-
cases) and rarely in other localizations, sheets and small cl usters of malig nan! ing marg ins).
such as the posterior pharyngeal wall squamous cells with intracellular and
(10- 20%) and postcricoid area (5-15%) extracellular keratinization. Mixed inflam- lmmunophenotype
{971 ,2449). mation and necrosis can b e present. SCC expresses various epithelial mark-
Tracheal SCC is usually located in the ers (e.g. cytokeratins, p63, and EMA).
lower third of the trachea (> 50% of cas- Histopathology Well-differentiated SCC expresses me-
es) and less frequently in the upper or The main histological features of SCC dium/high-molecular-weight cytokerat-
middle third {820). are sq uamous differentiation and inva- ins (e.g. CK5/6) but not low-molecular-
sion. Squamous differentiation is charac- weight cytokeratins (e.g. CK8 and CK18),
Clinical features terized by keratinization (with or without similar to normal squamous epithelium.
The most common early symptoms of la- keratin pearl fo rmation) and/or intercel- Poorly differentiated SCC tends to lose
ryngeal SCC are hoarseness (with glot- lular bridges. lnvasion manifests as in- expression of medium/high -molecular-
tic and supraglottic SCC) and dyspnoea terruption of the basement membrane weight cytokeratins , and expresses low-
and stridor (with subglottic SCC). Other of the surface epithelium and the down- molecular-weight cytokeratins {1518} and
symptoms include dysphagia, change wards growth of tumour islands, cords, vimentin {2474).
in the quality of voice, sensation of a for- or isolated tumour cells in the underly-
eign body in the throat, haemoptysis, and ing tissue. lnvasion is almost always ac- Differentia/ diagnosis
odynophagia {707,1949). companied by a desmoplastic stromal We ll-differentiated SCC must be distin-
The most frequent symptoms of hy- reaction, which consists of proliferation guished from verrucous and papillary
popharyngeal SCC are odynophagia, of myofibroblasts, excessive deposition carcinomas, as well as fro m benign con-
dysphagia, and neck mass. Other symp- of an extracellular matrix, and neovascu- ditions such as p seudoepitheliomatous
toms include voice changes, otalgia, and larization [2728,2729}. Tumour cells may hyperplasia. Verrucous carcinoma lacks
constitutional symptoms {2449). invade the lymphatic and blood vessels atypia, which is always present in SCC.
Tracheal SCC usually presents with or spread in the perineural plane or along Papillae formation and the absence of
dyspnoea, wheezing or stridor, acute res- nerves. keratinization characterize papillary SCC,
piratory failure, cough, haemoptysis, and SCCs are traditionally graded as well , distinguishing it from SCC . Pseudoepi-
hoarseness {1970). moderately, or poorly differentiated, ac- theliomatous hyperplasia is a benign
Laryngeal, hypopharyngeal, and tra- cording to th e deg ree of differentiation, condition that consists of deep, irregular
cheal SCCs can spread directly to con - cellular pleomorphism, and mitotic ac- tangues of epithelium that lack the atypia
tiguous structures or via lymphatic and tivity. Well-differentiated SCC c losely and abnormal mitoses seen in SCC.
blood vessels, giving rise to lymph node resembles normal squamous epithe- Poorly diffe rentiated SCC must be dif-
and distant metastases. These tumours lium and contains large, differentiated, ferentiated from melanoma, lymphoma,
have a strong tendency to metastasize to keratinocyte-like squamous ce lls and and neuroendocrine carcinoma. The cor-
the regional lymph nades. The localiza- small basal-type cells, which are usually ree! diagnosis is best determined by the
tion and frequency of lymph node metas- located at the periphery of the tumour is- use of appropriate immunohistochem-
tases depend on the site of the primary lands. There are intercellular bridges and istry and special stains fo r demonstra-
tumou r. Haematog enous metastases are typically full keratinization; mitoses are tion of mucin production. Melanoma is
infrequent, but may occur in late stages scarce. Moderately differentiated SCC distinguished from SCC by its expres-
of the disease, most frequently to the exhibits more nuclear pleomorphism and sion of S100, HMB45, melan A and other

82 Tumours of the hypopharynx, larynx, !rachea and parapharyngeal space

melanocytic markers. metalloproteinases {360,1515). Specific Other factors that may have a significan!
Neuroendocrine carcinoma expresses tumour suppressor microRNAs (the let-7 impact on the outcome of SCC include
neuroendocri ne markers (e.g. synapto- family, miR-7, and miR-206) are down- patient age at presentation {425,2184),
physin and chromogranin) but typically regulated {2627). comorbidity (concurrent diseases) {395},
lacks p63 expression and does not show and performance status (425).
significant squamous differentiation. Prognosis and predictive factors
whereas SCC does not express neu- The overall 5-year survival rate is 80- Histopatho/ogical prognostic factors
roendocri ne markers. Lymphoma is dis- 85% for glottic SCC, 65- 75% for supra-
tinguished from SCC by the presence of glottic SCC, about 40% for subglottic Differentiation. The reports on the prog-
CD45 (leukocyte common antigen) and SCC {1431, 62.5% for hypopharyngeal nostic significance of traditional grading
markers of 8 -cell or T-cell differentiation. SCC {2247). and 25- 47% for tracheal into well-, moderately, and poorly dif-
scc {820,1970}. ferentiated SCC are conflicting. Sorne
Genetic profile investigators have suggested that the
Laryngeal and hypopharyngeal SCCs Clinical prognostic factors grading system has a significan! asso-
develop as a result of multiple genetic ciation with survival {1896,2134,2607}.
abnormalities and the development of Stage remains the most significan! pre- whereas others have not confirmed this
aneuploidy {478,846). LOH and com- dictor of survival, and is discussed in observation {425,1113). The main criti-
parative genomic hyb ridization studies detail elsewhere. Depth of invasion and cism of this widely used system of grad-
have shown gains of 3q, 5p, 8q, 11q13, the presence of reg ional and distant me- ing is related to its subjective nature and
and 18p with losses at 3p, 5q, 8p, 9p, tastases are independent predictors of lack of objective criteria.
11 q23-24, 13q, and 18q {1117,2100, survival.
2310). Loss of multiple tumour suppres- Invasiva front. lt has been shown that
sors is common. with the most commonly Localization is an important prognos- the histological features at the invasive
affected genes including CDKN2A and tic factor {143}. The best prognosis has front are prognostically much more im-
TP53. Amplified and mutated oncogenes been reported for glottic SCC, and the portant than those in the central and su-
include EGFR, VEGFA (previously called worst prognosis for subglottic and tra- perficial parts of the tumour {284,285,
VEGF), PTGS2, PIK3CA, and matrix cheal SCC. 2677). A simple grading system has

Malignan! surface epithelial tumours 83

been proposed for evaluation of the in- Verrucous squamous
vasive front, which correlates closely with ce// carcinoma
prognosis. Four histological features are
evaluated: degree of keratinization, nu- Zidar N.
clear polymorphism, pattern of growth, Cardesa A.
and inflammatory response. The score Gillison M.
for each parameter is summarized as a Helliwell T.
total malignancy score, with a high score Hille J.
indicating poor prognosis {284,285}. Pat- Nadal A.
tern of invasion also features prominently
in a multiparameter risk model for see
{258}. Definition
Verrucous squamous cell carcinoma
Vascular and perineural invasion. The (VC) is a variant of wel l-differentiated
penetration of tumour cells in the lym- squamous cell carcinoma (SeC) that
phatic and/or blood vessels is associat- lacks the cytological features of malig- Fig. 3.03 Laryngeal verrucous carcinoma. A broad-
ed with a high probability of lymph node nancy, grows slowly, and is locally inva- based exophytic tumour with a warty surface.
and/or distant metastases. Vascular inva- sive but does not metastasize.
sion tends to occur in aggressive see Etiology
and is associated with recurrence and ICD-0 code 8051/3 ve has been etiologically linked to to-
poor survival (2678}. Similarly, perineural bacco smoking (1255,1565,1783,2252}.
invasion is associated with an increased Synonym Recent studies using highly sensitive and
risk of local recurrence, regional lymph Ackerman tumour (453} specific molecular methods suggest that
node metastases, and poorer survival ve is not associated with HPV infection
{258,684,2134,2241,2678}. Epidemiology (557,1760,1825).
ve is a rare tumour; in the USA, the in-
Extracapsular spread in lymph node cidence between 2000 and 201 1 was Localization
metastases. Metastases in the lymph 0.024 cases per 100 000 population . The larynx is the second most common
nodes are the single most adverse prog- Most cases present in older males, in site of occurrence of ve in the head and
nostic factor in head and neck see (710, their sixth or seventh decades of life (610, neck, after the oral cavity (1255}. Most
1353}. The presence of extracapsu lar 1565}. cases arise from the true vocal cords, but
spread in lymph nodes is also prognos- ve may also occur in the supraglottis and
tically important and is strongly associ- subglottis (610,1 255,1565}, hypopharynx
ated with both regional recurrence and {1255}, and !rachea {2278).
the development of distant metastases,
resulting in poorer survival (262,710,996,
2315). However, sorne studies have failed
to confirm the independent prognostic
significance of extracapsular spread

Resection margins. Resection margins

clear of tumour are associated with a
lower recurrence rate and better surviv-
al (1148,2211}. Margins are considered
clear if there is no invasive see, see
in situ, or dysplasia. An adequate mar-
gin of resection has not been precisely
defined, but a margin of 5 mm is gener-
ally believed to be adequate (995}. Sorne
studies have shown that even margins
of 1-2 mm are adequate, particularly in
glottic cancer (1698).

Molecular factors. A systematic review

failed to show any prognostic value of
p53 expression in laryngeal carcinomas
Fig. 3.04 Verrucous carcinoma. Fu\1-thickness view showing hyperkeratotic surface and projections and invaginations
of well-differentiated squamous epithelium, invading the stroma with well-defined pushing margins.

84 Tumours of the hypopharynx, larynx, trachea and parapharyngeal space

Clinical features see are considered hybrid (mixed) Prognosis and predictive factors
The symptoms and signs of ve are simi- tumours {158}. ve is locally invasive and can cause
lar to those of conventional sce, with The diagnosis of ve requires careful clini- extensive destruction if left untreated. lt
hoarseness as the most common pre- cal and pathological correlation because does not metastasize to regional lymph
senting symptom. Other symptoms in- the histological features have a wide dif- nades or distant organs. lt has a better
elude airway obstruction, weight loss, ferential diagnosis, including epithelial prognosis than does conventional see;
dysphagia, and throat pain {1565,1783}. hyperplasia, squamous cell papilloma, the repo rted 5-year survival rate far la-
well-differentiated conventional see, ryngeal ve is 85-95% [610,1255}. The
Macroscopy papillary see, and hybrid carcinoma (in - most important prognostic factor is stage
ve presents as a large, tan to white, vasive see and VC). lnvasion below the at diagnosis; treatment is by surgery or
broad-based exophytic tumour with a basal cell layer of the neighbouring nor- radiotherapy (1052). Hybrid carcinoma
warty surface. On cut surface, it is usu- mal epithelium differentiates VG from ver- has the potential for metastasis and
ally firm, with sharply defined margins. rucous hyperplasia, but these diseases should be treated as conventional see
may occur concurrently, with a confluent (1783}.
Histopathology interface. Squamous cell papilloma has
VC consists of thickened, club-shaped thin, well-formed papillary fronds and is
projections and invaginations of well-dif- less keratinized. The lack of cytological Basa/od squamous
terentiated squamous epithelium, com- atypia in ve distinguishes it from con- ce// carcinoma
posed of one to several layers of basal ventional see, papillary see, and hybrid
cells and an expanded layer of spinous carcinoma {330}. An apparent discrep- Lewis J.S.
cells that lack cytological atypia . There is ancy between the clinical impression of Gillison M.
marked surface keratinization (so-called malignancy and benign-looking mor- Westra W.H .
church-spire ke ratosis). Mitoses are rare phology should raise the suspicion of ve. Zidar N.
and contined to the basal ce ll layer, and There is no specific immunohistochemi-
there are no abnormal mitoses. VC in- cal marker for ve {1759,1761}.
vades the stroma with a well-defined Definition
pushing border, and invasion below the Genetic profile Basaloid squamous cell carcinoma
level of adjacent epithelium may be dif- Molecular studies on ve are limited, and (BSee) is a clinically unfavourable vari-
ficult to demonstrate in small biopsies the genetic profile of laryngeal ve is ant of squamous cell carcinoma (SeC)
unless the edge of the carcinoma is in- largely unknown. The pattern of expres- composed of a prominent basaloid com-
cluded . Lymphoplasmacytic inflamma- sion of microRNAs in ve differs from that ponent and with evidence of squamous
tion is common. lntraepithelial microab- in conventional see; the importance of ce ll differentiation.
scesses may be present in association this finding in the pathogenesis and di-
with Gandida species superinfection. agnosis of ve remains to be determ ined ICD-0 code 8083/3
Ves that contain foci of conventional (1 758,1759}.

Malignant surface epithelial tumours 85

Epidemiology discern. Necrosis and mixed inflamma- overt histological evidence of squamous
Approximately 80% of patients with tion are often present. differentiation. However, there must be
BSCC are White men in their mid-60s. definitive immunohistochemical evidence
Histopathology of squamous differenti ation, and adenoid
Etiology BSCC consists of basaloid and conven- cystic carcinoma and neuroendocrine
Laryngeal and hypopharyngeal BSCC is tional squamous components {2521). The carcinoma must be ruled out.
strongly linked to tobacco use (reported tumours are submucosal, with rounded
in 80-90% of patients) and alcohol con - nests with smooth borders and peripheral Prognosis and predictive factors
sumption {658]. Transcriptionally active palisading. Th ey tend to be closely ap- lt has been debated whether BSCC has
high-risk HPV, an established etiological posed, with thin lines of hyalinized stroma a worse prognosis than conventional
factor at other sites, is consistently ab- between them, as if they are moulding to- SCC. Most investigators have found la-
sent in BSCC arising at these anatomical gether in a jigsaw-puzzle pattern. There ryngeal/hypopharyngeal BSCC to be
subsites {171,415}. is frequent comedonecrosis, and the tu- more aggressive than conventional SCC
mour cells are round to oval and hyper- {776) . Patients with laryngeal BSCC have
Localization chromatic. Nucleoli are usually lacking higher rates of nodal metastasis (-50-
The larynx is a common site for BSCC, but occasionally prominent. Gland-like 70%) (658), significantly higher rates of
with a predilection far the supraglottis . foci with basophilic myxoid or mucoid ma- distant metastasis, and poorer progno-
The tumours also occur in the hypophar- terial are common and mimic true gland sis than do patients with conventional
ynx (pirifo rm sinus) {658,775) and rarely formation. A variable degree of nuclear SCC {133,776,1439,2618). Active smok-
in the trachea (11 52). pleomorphism is present, and high mitotic ers and patients with nodal metastases
activity, apoptosis, and necrosis are com- at presentation have worse prognosis.
Clinical features mon. Stromal hyalinization is characteris- Given the relative rarity of laryngeal and
The symptoms and signs vary according tic; it can be linear between and around hypopharyngeal BSCC, no predictive
to the site of origin, but usually include nests and nodular within nests. The con- markers of proven clinical significance
dysphagia, hoarseness, weight loss, ventional componen! may include abrupt have been developed. Because HPV-
sore throat, cough, haemoptysis, and keratinization adjacent to basaloid cells , related oropharyngeal basaloid carcino-
neck mass. BSCC usually presents at an dysplastic changes in the squamous epi- mas can be otherwise indistinguishable
advanced stage at the time of initial diag- thelium, and conventional SCC. from laryngeal/hypopharyngeal BSCC,
nosis, with lymph node metastases and lmmunohistochemistry is strongly posi- any tumour that appears to arise in the
occasionally distant metastases {658). tive for high-molecular-weight cytokerat- larynx/hypopharynx but involves the oro-
ins, p63, and p40 (in a diffuse pattern). pharynx should be tested for p16 and/
Macroscopy BSCC is negative for synaptophysin and or high-risk HPV. This allows far the dis-
There is no characteristic gross appear- chromogranin {1649,2129}. The differ- t inction of aggressive BSCC from more
ance. The tumour usually appears as a ential diagnosis includes adenoid cystic prognostically favourable HPV-related
flat or slightly elevated lesion with central carcinoma - which lacks squamous oropharyngeal carcinomas that are histo-
ulceration and poorly defined borders. differentiation and shows partial p63 logically similar.
Rarely, it presents as a polypoid tumour reactivity {655) - and small cell
{658). neuroendocrine carcinoma - which has
angulated nuclei with speckled chromatin,
Cytology is positive for neuroendocrine markers,
Aspirates of metastatic BSCC are cellu- shows punctate perinuclear reactivity for
lar, with variably sized basaloid clusters cytokeratin (CAM5.2), and usually lacks
of malignant cells exhibiting numerous reactivity for high-molecular-weight cy-
mitotic figures and apoptotic bodies. tokeratins {2129}. The diagnosis of BSCC
Keratinization and definitive squamous can still be made for tumours with all of
differentiation may be rare and difficult to the basaloid features even if they lack any

86 Tumours of the hypopharynx, larynx, !rachea and parapharyngeal space

Papil/ary squamous ce// site in the upper aerodigestive tract {587, Prognosis and predictive factors
carcinoma 1140,1 580,2030,2298,2394). PSCC has a better prognosis than con-
ventional squamous cel l carcinoma,
EI-Mofty S.K. Clinical features primarily due to low-stage presentation,
Cardesa A . The lesions are described as exophytic with a low metastatic potential {587,623,
Helliwell T. growths that may be painless or painful. 1580,2030,2394). HPV-related PSCCs
HilleJ . They can be pink, white, or both pink and of the oropharynx show a trend towards
Nada! A. white. Laryngeal tumours are associated better patient survival than is associated
with hoarseness and airway obstruction. with HPV-negative PSCC {1580).
Nodal metastasis is uncommon, and dis-
Definition tan! metastasis is rare (587,623,2030,
Papillary squamous cell carcinoma 2298,2394). Spindle ce// squamous
(PSCC) is characterized by a papillary ce// carcinoma
growth pattern, with thin fibrovascu lar Macroscopy
cores covered by severely dysplastic Grossly, the lesion is papillary, friable, Bishop J.A.
epithelial cells or immature basaloid cells and soft, with a pinkish -grey colour. Cardesa A.
with minimal or no maturation. Tumour size ranges from 0.2 to 4.0 cm Helliwell T.
{2298,2394). Hille J.
ICD-0 code 8052/3 Nada! A.
Epidemiology Aspirates of metastatic lesions show fea-
PSCC is uncommon; its exact prevalence tures of keratin izing or non-keratinizing Definition
in the head and neck is unknown . lt is squamous cell carcinoma. Spindle cell squamous cell carcinoma (SC-
more common in male patients, with a SCC) is a variant of squamous cell carci-
male-to-female ratio of 2-3:1 (623,1140, Histopathology noma (SCC) characterized by predominan!
2030,2298, 2394). In one study, PSCC A significan! componen! of PSCC is malignan! spindle and/or pleomorphic cells.
constituted 0.5% of all laryngeal cancers composed of papillary projections with
(623). The average patient age is report- central fibrovascular cores. lnvasion ICD-0 code 8074/3
ed as mid-60s, with a slightly older aver- may be difficult to establish morpho-
age age among patients with oral PSCC logically, but is implied by metastatic
{587,728,2030,2298). potential. The papillae are cove red with
malignant epithelial cells with little ar
Etiology no keratinization. Two types of surface
Etiological factors inc lude tobacco use epithelium are described: one resem-
and alcohol consumption {728,2030, bles high-grade keratinizing epithelial
2394), and HPV has recently been dysplasia, and in the other, the epithelial
shown to be an etiological agent in a cells are immature and basaloid, with no
subset of PSCCs, particularly in the oro- evidence of maturation or keratinization.
pharynx and sinonasal tract {1140 ,1580, Laryngeal tumours are not frequently
2298). HPV-associated, whereas oropharyn-
geal tumours are typically strongly posi-
Localization tive for p16 and are HPV-related [1580, Fig. 3.08 Laryngeal spindle cell squamous cell carcinoma.
PSCC has been reported in almost every 2298). A polypoid mass involving the larynx.

Malignan! surface epithelial tumours 87

logous mesenchymal differentiation in
the form of malignan! bone, cartilage,
or skeletal muscle {1398,2396,2702).
sesee is usually overtly malignant,
with hypercellularity, necrosis, atypi-
cal mitotic figures, and hyperchromatic
nuclei demonstrating marked nuclear
pleomorphism. However, a subset of
sesees are deceptively bland in areas,
with or without prominent areas of hya-
linization, mimicking reactive myofibro-
blastic proliferation or granulation tissue.
The d iagnosis of sesee rests Ol dem-
onstrating epithelial differentiation, either
on routine morphology (i.e. squamous
dysplasia of residual surface epithelium
or foci of conventional see mixed with
sarcomatoid tumour) or by immunohisto-
Synonyms Macroscopy chemistry for cytokeratins (e.g. AE1 /AE3),
Sarcomatoid carcinoma; carcinosarcoma sesee is usually a polypoid mass pro- EMA, p63, or p40 {1406,1749). Howev-
truding into the airway, often with an ul- er, as many as one third of sesees are
Epidemiology cerated surface mucosa {1 398,2396, purely spindled , and a significant subset
sesee is rare, accounting for < 1% of 2506). is negative for epithelial markers {1398,
all laryngeal malignancies {608,2396). 1749,2396,2506). True sarcomas of the
lt generally affects elderly patients, and Cytology larynx/hypopharynx are rare, and a ma-
has a male predilection {608,2396,2506). Aspirates of metastatic sesee often lignant spindle cell neoplasm arising at
show at leas! focal keratinizing see, but these sites is best cons idered an sesee
Etiology a malignan! spindle cel l componen! 'Tlay until proven otherwise.
sesee is linked to cigarette smok- be all that is observed in sorne cases.
ing and alcohol consumption. A subset Genetic profile
of sesees may be radiation-induced. Histopathology sesee harbours complex genetic al-
sesees of the larynx and hypopharynx sesee is derived from the squamous terations, similar to poorly differentiated
are almost always negative for HPV {201, epithelium and demonstrates divergen! sees {436,437).
2396,2555). differentiation by epithelial- mesenchy-
mal transition {437,1259,1749,27271. lt Prognosis and predictive factors
Localization c haracteristically grows as an exophytic Despite its poorly differentiated appear-
The larynx, especially the glottis, is the mass with a predominantly ulcerated sur- ance, sesee of the larynx/hypopharynx
most frequently involved site. The hy- face, sometimes containing remnants of (in particular the true vocal co rd) tends
popharynx is infrequently affected {608, dysplastic squamous epithelium and fre- to present at a low stage and, stage-for-
1398,1749,2396). quently showing areas of transition toma- stage, has a prognosis similar to that of
lignant spindled or pleomorphic tumour conventi onal see {187,608,1398,2396,
Clinical features cells. Most sesees demonstrate a hap- 2506}. Exophytic sesees are more eas-
Patients present with airway obstru ction hazard growth pattern of the spindled ily resected and have the best prognosis
and/or hoarseness (1398,2396) . ce lls, and 7- 15% of cases exhibit hetera- (2396).

88 Tumours of the hypopharynx, larynx, trachea and parapharyngeal space

Adenosquamous carcinoma
Prasad M.L.
Cardesa A.
Helliwell T.
Nadal A.

Adenosquamous carcinoma (ASC) is
a malignan! tumour that arises from the
surface epithelium and shows both squa-
mous and glandular differentiation.

ICD-0 code 8560/3

. .. ,.:

Fig. 3.11 Laryngeal adenosquamous carcinoma. A blending of the squamous and glandular components.

Epidemiology in close proximity, an important diagnostic 3.01). Demonstration of mucin and carci-
ASC is rare. lt has a male predisposition feature. The adenocarcinoma consists of noembryon ic antigen helps to distinguish
and usually develops in the sixth or sev- cribriform and tubuloglandular structures ASC from adenoid SCC. Conventional
enth decade of life (patient age range: and tends to occur in the deeper parts of SCC invading or entrapping seromuci-
34- 81 years) /1209). the tumour /1209). lntraluminal (or rarely, nous glands is d ifferentiated by its lobular
intracytoplasmic) mucin may be demon- architecture and the benign cytomorphol-
Etiology strated by special stains, such as peri- ogy of its g landular cells /1209). Necrotiz-
As with squamous cell carcinoma (SCC), odie acid-Schiff (PAS), Alcian blue, and ing sialometaplasia, wh ich is rare in the
smoking and alcohol consumption are like- mucicarmine. The tumour shows necrosis, larynx, is characterized by the retention
ly predisposing factors {1209). No associa- mitoses, and vascular and perineural in- of the lobular architecture of the seromu-
tion with HPV has been reported in ASC vasion consisten! with its high-grade na- cous glands (despite being replaced by
from the larynx and hypopharynx /1553). ture. Metastatic ASC may display only one squamous metaplasia), ischaemic necro-
componen!. sis of the acini, chronic inflammation, and
Localization lmmunohistochemistry shows the expres- pseudoepitheliomatous hyperplasia of the
The larynx is a frequently affected site in sion of p63 in the squamous componen!; overlying squamous epithelium (1962}.
the head and neck /60,1194,1209). A few carc inoembryonic antigen, low-molecu-
cases in the hypopharynx have been re- lar-weight cytokeratin (CAM5.2), and CK7 Prognosis and predictiva factors
ported /1314,1548,1553,2093}. in the adenocarcinomatous componen!; ASC is more aggressive than convention-
and high-molecular-weight cytokeratin in al SCC, with a propensity far recurrence
Clinical features both components /1314,1548}. CK20 is and dissemination {60,703}. Reg ional
Patients may present with hoarseness, usually negative {1509}. lymph node metastases occur in about
sore throat, dysphagia, haemoptysis, or The differential d iagnosis includes mu- 75% of patients, and nearly 25% of pa-
neck mass (1209). coepidermoid carcinoma, adenoid SCC, tients develop distant metastases, most
and conventional SCC invading the se- co mmonly to lung /1 209}. C linical stage
Macroscopy romucinous glands. Distinction from mu- al presentation seems to co rrelate with
ASC may present as an exophytic or coepidermoid carcinoma is importan! be- prognosis. The 5-year survival rate is ap-
polypoid mass (median size: 4 cm) or as cause ASC has a worse prognosis (Table proximately 13- 50% {1194,1209,2093}.
mucosal induration or ulceration, similar
Table 3.01 Differences between adenosquamous and mucoepidermoid carcinoma
to SCC /825,1209}.
Adenosquamous carcinoma Mucoepidermoid carcinoma
Cytology Evidence of origin from overlying squamous epithelium No evidence of origin from overlying squamous
Aspirates of metastases show features (e.g. dysplasia) epithelium
of keratinizing SCC. Malignan! glandular Keratinization in squamous cells, keratin pearls No keratinization or keratin pearls
components, including cells with intracy-
lnfiltrative glands al deeper parts Glands widespread with lobular arrangement
toplasmic mucin, can be seen.
Epidermoid and glandular cells closely intermingled
Squamous and adenocarcinoma adjacent to each other
within lobules of tumour
ASC has a biphasic morphology, with Secondary invasion of submucosal glands Arising from submucosal glands
squamous and glandular differentiation. No intermediate cells lntermediate cells present
Origin from surface epithelium is support-
No MAML2 translocation Usually associated with MAML2 translocation
ed by the presence of squamous dyspla-
sia. The squamous and adenocarcinoma- 8The presence of MAML2 lranslocalon rules out adenosquamous carcinoma, bul MAML2 lranslocalon is sorne-
tous components are distinct but located limes absenl in mucoepidermod carcinoma {1194}.

Malignan! surface epithelial tumou rs 89

Lymphoepithelial carcinoma
Bishop J.A.
Gaulard P.
Gillison M.

Lymphoepithelial carcinoma (LEC) is a
squamous cell carci noma morphological-
ly similar to non-keratinizing nasopharyn-
geal carcinoma, undifferentiated subtype.

ICD-0 code 8082/3

Lymphoepithelioma-like carcinoma

Epidemiology Localization Histopathology

LEC of the larynx, hypopharynx, and !ra- LEC occurs more frequently in the lar- LEC is defined by its resemblance to
chea is rare, with only about 40 reported ynx than in the hypopharynx. Rare cases non-keratinizing und ifferentiated naso-
cases. lt affects older patients (mean pa- have arisen in the !rachea (1363,1777, pharyngeal carcinoma (see Nasop haryn-
l ien! age: 62 years), and there is a male 2340). geal carcinoma, p. 65, Chapter 2). Unlike
predominance. Unlike nasopharyngeal in the nasopharynx, LEC uncommonly
carcinoma, which most frequently affects Clinical features harbours EBV in the larynx.
Asan patients, LEC in the larynx usually Patients present with hoarseness, neck
occurs in White patients {381,1507,2584, mass, dysphonia, dysphagia, neck pain, Prognosis and predictiva factors
2706}. and/or haemoptysis (604,1507,2584}. Accord ing to SEER data, laryngeal LEC
has a 5 -year disease-specific survival
Etiology Cytology rate of approximately 60% (381 }. Re-
There is an association with smoking and As pirates of metastases show findings gional lymph node metastasis occurs in
alcohol consumption {604,1507,25841. similar to those seen in aspirates of non- approximately 75% of cases, with dis-
There is also an association with EBV, keratinizing undifferentiated nasopharyn- tan! metastasis in approximately 25%
although not as strong an association as in geal carcinoma. (1507).
nasopharyngeal cases (1214,2584,2706).

90 Tumours of the hypopharynx, larynx. !rachea and parapharyngeal space

Precursor lesions

Table 3.02 Morphological critaria far tha classification of laryngeal precursor lesions {797)
Low-grade dysplasia (including previous category of mild dysplasia):
Low malignan! potantial; a spactrum of morphological changas ranging from squamous hyperplasia toan
Gale N.
augmentation of basal and parabasal calls occupying as much as the lower half of the epithelium, while the upper
Hille J. portian ratains maturation
Jordan R.C.
Stratification is preserved: transition of basal cells ar augmented basal/parabasal
Nadal A .
cell layer with perpendicular orientation to tha basement membrane to prickle cells
Williams M.O. horizontally oriented in the upper part
Spinous layer: spectrum of changes ranging from increased spinous layer in the
Architectural criteria
whola thickness up to changas in which prickle cells are seen only in the upper
Definition epithalial hall
Dysplasia at this body site constitutes a Basal/parabasal layer: spectrum of changes, from 2-3 unchanged layers to
spectrum of architectural and cytological augmentation of basal and parabasal cells in the lower half of the epithelium
epithelial changes of the upper aerodi-
At most minimal cellular atypia
gestive tract, caused by an accumulation
Parabasal cells: slightly incraased cytoplasm comparad to basal cells, enlarged
of genetic changes that can be associ-
Cytological criteria nuclai, uniformly distributed chromatin, no intercellular bridges
ated with an increased likelihood of pro-
gression to squamous cell carcinoma. Rare regular mitoses in or near basal layer
Few dyskeratotic cells present
ICD-0 codes High-grade dysplasia (including previous categories of moderate dysplasia, severe dysplasia, and
Dysplasia, low grade 8077/0 carcinoma in situ):
Dysplasia, high grade 8077/2 A premalignant lesion; a spectrum of changes including immature epithelial cells occupying al leas! the lower half of
the epithelium and as much as the whole epithelial thickness
Synonyms Abnormal maturation
Squamous intraepithelial lesions; squa- Variable degrees of disordered stratification and polarity in as much as the whole
mous intraepithelial neoplasia epithelium
Altered epithelial cells usually occupying from half to the entire epithelial thickness
Epidemiology Architectural criteria
Two subtypes: keratinizing (spinous-cell type) and non-keratinizing (basal-cell type)
Dysplasia is seen mostly in adults and af- Variable degree of irregularly shaped rete (bulbous, downwardly extending), with an
fects men more often than women, with a intact basement membrane
male-to-female ratio as high as 4.6:1 {799}. No stromal alterations
This disparity is especially evident alter
Easily identified to conspicuous cellular and nuclear atypia, including marked
the sixth decade of life. Epidemiological
variation in size and shape, marked variation in staining intensity with fraquent
studies of laryngeal dysplasia are scarce. hyperchromasia, nucleoli increased in number and size
The annual incidence of laryngeal pre- Cytological criteria lncreased N:C ratio
cancerous mucosal changes in the USA
lncreased mitoses at or above the suprabasal level, with or without atypical forms
is 10.2 and 2 .1 lesions per 100 000 males
and females, respectively (245}. Dyskeratotic and apoptotic cells are frequent throughout the entire epithelium
Complete loss of stratification and polarity and/or severe cytological atypia and atypical mitoses qualifies as
Etiology carcinoma in situ if a three-liered system is used.
Cigarette smoking has been established
as the princ ipal risk facto r in laryng eal studies published since 2005 is 12% Voice change, hoarseness, sore throat,
carcinogenesis, especially in combina- (range: 0- 38%) (621,803,1644,1799}. and chronic cough are most common.
tion with alcohol abuse. The increased
risk is linked to age at the start of smok- Localization Macroscopy
ing, duration of smoking, and quality of Dysplasia can occur anywhere in the lar- Dysplasias are clinically identified as leu-
tobacco (2039,2451 }. Gastro-oesoph- ynx, but it occurs most frequently along koplakias (white patches), erythroplakias
ageal reflux disease is also considered one vocal cord and less frequently along (red patches), erythroleukoplakias (red
to be a possible risk factor {1395,2128}. both vocal cords. The commissures as and white patches), or chronic laryngitis.
High-risk HPV infection plays a minor role well as hypopharyngeal and. tracheal They present as small or large patches
in dysplasia development {62 1,803,1644, regions are rarely involved {801,1158, that are localized or diffuse , or as flat or
1799 }. Only integrated and transcription- 2349). exophytic and papillary lesions. Macro-
ally active HPV can play a significan! role scopic appearance does not have any
in carcinogenesis, and HPV 16 is the Clinical features specific connotations fo r microscopy,
most freq uent genotype (922,1408}. Th e The symptoms and signs vary accord- which must always be determined histo-
overall prevalence of HPV in dysplasia ing to the location and size of the lesion. logically (247,80 1}.

Precursor lesions 91
Table 3.03 Terminology and grading systems used for dysplasia I squamous intraepithelial lesion (SIL) epithelial changes in arder to determine
Level of 1 1 the appropriate treatment {733,1574,
SIN Ljubljana 2076). A review of the currently used
abnormal WH02005 Amended Ljubljana WH02017
classification classification histological grading systems and their
maturation {146} classificalion {797}
{850} {799}
(WH02005) approximate relationship is presented in

Lower 113



l Squam~os
Low-grade SIL
Table 3.03 {2592).
In an effort to harmonize the various
concepts of the listed classifications,
with their various morphological crite-
dysplasia hyperplasia
ria and different terminology, a unified,
113 to 112 Moderate
ISIN 1 or SIN 2 two-grade system is proposed, with
clear morphological criteria far defining
Moderate Atypical
Upper 112 to 314 High-grade SIL the prognostic groups: low-grade (mild
dysplasia hyperplasia High-grade

Full thickness

l SIN 2
dysplasia) and high-grade (moderate
and severe dysplasia / carcinoma in situ)
- ,___ {797). lf a three-tiered system is preferred
Carcinoma Carcinoma far treatment purposes, the high-grade
Carcinoma in situ
in situ in situ category can be further separated into
*lf a three-tiered system is used, carcinoma in situ is separated from high-grade dysplasia. high-grade dysplasia and carc inoma in
SIN, squamous intraepithelial neoplasia. situ {797}. Far a morphological descrip-
tion of each grade of dysplasia, see Ta-
ble 3.02.
Ancil lary studies (e.g. p53, p16, Ki-67,
and EGFR) are currently not recommend-
ed for dysplasia classification.

Genetic profile
Accumulation of genetic alterations
produces aneuploidy in preneoplastic
cells (2072,2680). Laryngeal dysplas-
tic lesions show freq uent chromosomal
changes/LOH al 9p21, 17p13, 3p26,
Fig. 3.13 Leukoplakia of the left vocal cord. The anterior Fig. 3.14 Low-grade dysplasia. Hyperplastic squamous and 3p14, with alterations al 9p21 be-
part of the left vocal cord is irregularly thickened and epithelium shows augmented parabasal cells extending ing the earliest and most frequent, sug-
covered by whitish plaques. up to one third of the epithelium thickness; the upper half
gesting the implication of the CDKN2A
of the epithelium is unchanged.
gene in the early phases of neoplastic
Histopathology Although the grading of upper aerodi- transfarmation. The most likely target of
Several classification systems have been gestive tract dysplasia is to a certain 17p13 LOH is TP53 {1679). Other mo-
devised to represent the spectrum of his- degree a subjective process, grade is lecular alterations consistently detected
tological changes and their relation to bi- the most important prognostic factor far in premalignant laryngeal lesions include
ological behaviour, especially malignant the biological behaviour of disease, be- cyclin D1 overexpression (1814) and tel-
progression {732,797,1291,2582). cause clinicians need a descriptor of the omerase activity reactivation (1451 ,1496,

92 Tumours of the hypopharynx, larynx, !rachea and parapharyngeal space

occurs in both children and adults. The
true incidence and prevalence of RRP
are uncertain. The best projected esti-
mates of annual incidence are 4.3 cases
per 100 000 c hildren and approximately
1.8 cases per 100 000 adults {331 ,570}.
The bimodal age distribution demon-
strates the first peak in children aged
< 5 years (juvenile cases) and the sec-
ond peak in patients aged 20-40 years
(adult cases) {331,1257). RRP is more
common in children and is the most ag-
gressive form of the disease, with 25% of
cases presenting during infancy {1969,
2604). There is no sex predominance
in children, but in adult patients there is
a male-to-female ratio of 3:2 {570,602,
1774). Although the disease is rare, mor-
bidity is notoriously high, compromising
functions such as vocalization, swallow-
ing, and breathing {821, 2605).
Fig. 3.16 High-grade dysplasia / carcinoma in situ. Prominent architectural disorder; epithelial cells show severe
cellular and nuclear atypia, mitoses are present, the basement membrana is intact, and a thick parakeratotic !ayer is
evident on the surface (see Table 3.02, p. 91 ). Etiology
HPV 6 and 11 are the most frequent
1497). None of these find ings are cur- Squamous ce// paplloma and genotypes (seen in 90% of cases) asso-
rently of diagnostic or prognostic utility. squamous ce// papllomatoss ciated with RRP as well as solitary pap-
illomas {800,2605). A minority of cases
Prognosis and predictive factors Richardson M. (4- 5%) have coinfection with genotypes
A retrospective follow-up study found a Gale N. HPV 6 and 11, and fewer cases (3- 4%)
highly significan! difference in the risk HilleJ. with other HPV genotypes (e.g. 16, 31,
of malignan! progression between low- Zidar N. 33, 35, and 39) (260 5).
and high-grade lesions, at 1.6% and The modes of HPV transmission include
12.5%, respectively (797,1184). Certain sexual contact, non-sexual contact,
high-grade dysplasias (i.e. carcinomas Definition and maternal contact (direct or indirect)
in situ) are associated with higher risk of Squamous cell papilloma and squamous (1324). Most neonatal HPV infection oc-
progression to invasive growth (occurring cell papillomatosis are benign exophytic curs by vertical transmission at birth
in 40% of cases) and may require more squamous epithelial tumours cbmposed {2325). A triad of factors (first-born
extensive surgery or rad iation th erapy, of branching fibrovascular cores, usu- child, vaginal delivery, and maternal age
depending on the specific site (e.g. an- ally associated with HPV infection (geno- < 20 years) has been noted to correlate
terior commissure) and contributing risk types 6 and 11). with RRP in children {1192). Caesarean
factors (e.g. alcohol consumption and to- section provides a lower risk of trans-
bacco use) {2710). ICD-0 codes mission but is not completely protective
Squamous cell papilloma 8052/0 against infection. In contras!, active ma-
Squamous cell papillomatosis 8060/0 ternal genital HPV infection at the time of
delivery increases exposure to a signifi-
Synonyms can! viral load, with a high risk for trans-
Recurrent resp iratory papillomatosis; la- mitting infection {1324,2325). In adults,
ryngeal papillomatosis; juvenile papillo- the mode of viral transmission remains
matosis; adult papillomatosis unclear; transmission during sexual con-
tact and reactivation of a slow-progress-
Epidemiology ing latent infection from childhood have
Squamous cell papilloma is the most been suggested (1 199,1775,2028}. The
common benign epithelial tumour of the unpredictable c linical course of RRP
larynx. Recurren! respiratory papilloma- suggests possible host-specific genetic
tosi s (RRP) is characterized by multiple and immunological factors. Differences
contiguous, locally recurren! squamous in HPV-specific immune response have
cell papillomas, although solitary lesions been demonstrated between patients
present infrequently. RRP is a rare dis- with RRP and controls {234,331,1742,
ease involving the respi ratory tract that 2003}.

Precursor lesions 93
Localization features are seen in the upper layers of
The p apillomas usually involve th e vo- the epithelium. Mitotic features are seen
cal cords and ventricles, followed by along the basal to medial aspee! of the
transm ission to the false cords, epig lot- epith elium. Premature keratinization of
tis, subglottic area, hypopharynx, and individual epithelial cells contributes to
nasopharynx. Rarely (in 1-3% of cases), a disorganized appearance. Surface
the papillomas may extend to the lower keratinization is mnima!. Premalignant
respiratory trae!, which is associated with features are infrequent but should be re-
high mortality {821 ,1742,2325}. The d istri- ported if present.
bution of RRP follows a predictable pat- HPV genotype and variants can be de-
tern, with the tumours occurring at siles te rmined using sensitive conve ntional or
where c iliated and squamous epithe lium real-time PCR (1774}. A lthough far less
is juxtaposed. sensitive, and unable to detect H PV vari-
ants, in situ hybridization has also been
Clinical features used. Failu re to detect HPV by in situ hy-
The presentation includes progressive b ridization is considered cons istent with
hoarseness and stridor associated with a low copy numb er of HPV, below the de-
growths of exophytic lesions within the tection sensitivity threshold of the in situ
larynx. hybridization technique. However, spe-
cific patterns of in situ hybridization sig-
Macroscopy nals indicate that the viral status is either
The proliferative luminal growths are exo- episomal (a diffuse signa! pattern) or in-
phytic, sessile, or pedunculated masses tegrate d (a punctate signa! pattern). The
with bosselated surfaces. The papil la- mechanism of squamous cel l papi lloma
mas often g row as a friable cluster and recurrence in juveniles may be more al-
bleed easily w ith minar trauma. tributable to HPV integration (274} .

Histopathology Prognosis and predictiva factors

Squamous cell papillomas have a core The c li nical course of RRP is unpredicta-
composed of an arborizing fibrovascular ble and ranges from complete remission,
Fig. 3.17 Laryngeal papillomatosis. A Recurren! res-
network covered by squamous epithe- to relatively stable lesions, to an aggres-
piratory papillomatosis fills the endolaryngeal space.
lium. Parabasal cell hyperplasia is often sive c linical course of rapid progressive
B Endoscopic view of multicoated clusters of papillomas
seen involving the lower half of the epi- within a larynx. recurrences requiring surg ical interven -
thelium. Pronounced to subtle koi locyti c tion, and potentially life-threatening res-
p iratory obstruction {570,1522,2325}.
The clinical significance of variants of the
H PV 6 and 11 genotypes in patients with
RRP is unknown {1522}.
Sorne studies have found the HPV 11
genotype to be the most importan! risk
factor for aggressive c linical course, but
this finding has not been consistently rep-
licated (1774, 2605}. Other studies sug-
gest that pati ent age at onset is im portan!
(286}. Children diagnosed at < 3 years of
age are 3.6 times as likely to have more
than tour surgeries per year as are chil-
d ren diagnosed at an older age (1 774,
1969}. HPV 11 is more closely associated
with a younger age at diagnosis, and in
sorne studies it is associated with an ag-
gressive clinical course (2605}. In adults,
both HPV 11 and an observation time
> 1O years have been found to be as-
sociated with aggressive clinical course
(1774). These data suggest that there are
factors other !han HPV typ e and patient
age that determine disease course (286).
Fig. 3.18 Laryngeal papillomatosis. Florid papillomas line the endolarynx in this case of recurren! respiratory A retrospective sequence analysis of
papillomatosis. HPV in RRP showed no evidence of

94 Tumours of the hypopharynx, larynx , !rachea and parapharyngeal space

Scanned by CamScanner
Moderately differentiated
neuroendocrine carcinoma
Perez-Ordonez B.
Bishop J.A.
Gnepp D.R.
Hunt J. L.
Thompson L.D. R.

Moderately differentiated neuroendocrine
carcinoma is an epithelial neoplasm
demonstrating neuroendocrine differen-
tiation with a histological grade between
well-differentiated and poorly differenti-
ated neuroendocrine carcinoma.

Clinical features 10 high-power fields), and necrosis is ab- ICD-0 code 8249/3
Patients present with hoarseness, dys- sent. The tumour stroma is often fibrotic
phagia, and airway obstruction {639, and highly vascular. Synonyms
2463). Rarely, a paraneoplastic syn- The neoplastic cells are positive for cy- Atypical carcinoid; neuroendocrine car-
drome (due to aberran! hormone pro- tokeratins, EMA, and al least one neu- cinoma, grade 11
duction by the tumour) may be identified roendocrine marker (e.g. synaptophysin,
(218 ,709,2463,2586]. chromogranin, or CD56). Peptides (e.g. Epidemiology
serotonin, calcitonin, and somatostatin) These are the most common neuroen-
Macroscopy may be positive, and TTF1 is variably docrine carcinomas of the larynx (2463,
The tumours present as submucosal positive. Ki-67 immunohistochem istry is 2586,2631). They occur more frequently
fleshy polypoid or sessile masses, not used in the grading of neuroendo- in men, with a male-to-female ratio of
0.5~3 cm in size (2586). crine tumours. 2.4:1, and have a peak incidence in the
sixth and seventh decades of life (mean
Histopathology Prognosis and predictiva factors patient age: 63 years) {2463,2586,2589).
The tum:Jur cells grow in nests, cords, The prognosis is difficult to determine
sheets, rnd trabeculae of round to slight- due to the rarity of this tumour, but seems Etiology
ly spindled cells with ample amphophilic to be good alter surgery or laser resec- Most patients are heavy tobacco users
to eosinophilic granular (sometimes on- tion. Recurrence and metastasis rates as (2463,2589}.
cocytic) cytoplasm . Gland-like structures high as 30% have been reported : with
or rosettes may be seen, exceptionally a 5-year survival rate of approximately Local ization
containing mucin vacuoles. The tumour 80% {639,2463). Older studies reported More than 90% of cases occur in the su-
nuclei exhibit stippled, evenly dispersed a more aggressive behaviour, due to the p raglottic reg ion {2463,2589).
chromatin in a salt-and -pepper pattern . inclusion of moderately differentiated
Minimal nuclear atypia is seen, mitotic neuroendocrine carcinomas {2229,2230,
rates are low (< 2 mitoses per 2 mm? or 2463).

96 Tumours of the hypopharynx. larynx. !rachea and parapharyngeal space

Poorly differentiated Localization
neuroendocrine carcinoma Within the larynx, the re is a predilection
for the supraglottic larynx, followed by
Perez-Ordonez B. the subglottis {848,855,2463).
Bishop J.A.
Gnepp D'. R. Clinical features
Hunt J.L. Patients present with non-specific symp-
Thompson L.D.R. toms, including hoarseness and/or dys-
phagia {848,855,1407,2463}. Many pa-
tients have regional or distan! metastases
Definition al presentation ["1612). Rarely, paraneo-
Poorly differentiated neuroendoc rine car- plastic syndromes are reported {709).
cinoma is a high-grade malignan! epithe-
Clinical features lial neoplasm with evidence of neuroen- Macroscopy
Patients present with hoarseness, docrine differentiation. Two subtypes are The tumour is a fleshy, ulcerated submu-
dysphagia, sore throat, and occasion - recogn ized: small cell neuroendocrine cosal mass {848,1404f.
ally haemoptysis {2586,2589}. Rarely, a carcinoma (SmCC) and large cell neu-
paraneoplastic syndrome (due to aber- roendocrine carcinoma (LCNEC). Histopathology
ran! hormone production by the tumour) SmCC grows in nests, sheets, and tra-
may be identified {709,2463). !CD-O codes beculae of cells, with occasional nuclear
Small cell neuroendocrine carcinoma palisading or rosette -like structures. lt is
Macroscopy 8041/3 highly infiltrative, with frequent perineural
The tumours are tan-pink polypoid sub- Large cell neuroendocrine carcinoma and lymphovascular invasion. The tu-
mucosal masses, 0.2- 4 cm in size, and 8013/3 mour is composed of small to medium-
often cove red by an ulcerated surface Synonyms sized cells with hyperchromatic nuclei,
mucosa (2586,2589}. Small cell carcinoma, neuroendocrine finely granular chromatin, and indistinct
type; oat cell carcinoma; neuroendo- nucleoli with scant cytoplasm. Nuclear
Histopathology crine carcinoma, grade 111 moulding, prominent crush artefact, ne-
The tumour cells grow in nests, cords, crosis, apoptosis, and DNA coating of
sheets, and trabeculae of round to Epidemiology vessel walls (the Azzopardi phenome -
slightly spindled cells with ample ampho- lt is th e second most common neuroen- non) are classic features , accompanied
philic to eosinophilic granular cytoplasm. docrine carcinoma of the larynx, tends to by a high mitotic rate (> 1O mitoses per
Gland-like structures or rosettes may be arise in older men (median patient age: 2 mm 2 or 10 high-power fields)
seen. The tumour nuclei may exhibit stip- 60 years), and has a male-to-female ra- LCNEC shows organoid nesting, pali-
pled, evenly dispersed chromatin or may tio of 2.3-4.3:1 {848 ,855,"1407,2463). sading, rosettes , and/or trabeculae. lt is
show more nuclear atypia with promi- composed of medium-sized to large cells
nent nucleoli. The defining featu res are Etiology with abundan! cytoplasm. The nuclei
necrosis and/or 2-1O mitoses per 2 mm 2 More than 90% of patients are cigarette have coarse chromatin (sometimes with
or iO high-power fields. Sorne tumours smokers {"1407,2463). An association a speckled, salt-and-pepper quality) and
demonstrate oncocytic cytoplasm or with HPV has been identified, but may usually have a single prominent nucleo-
stromal amyloid deposition . not be as significan! as the association lus. The tumour exhibits comedonecrosis
The neoplastic cells are positive for cy- of HPV with oropharynx or sinonasal tract and a high mitotic rate (> 10 mitoses per
tokeratins and at leas! one neuroendo- tumours {2382). 2 mm 2 or 1O high-power fields).
crine marker (e .g. synaptophysin, chro-
mogranin, or CD56). TTF1 is variably
expressed. These tumours are frequently
positive for calcitonin, which creates a
potential diagnostic pitfal l, particularly in
a lymph nade metastasis, where the tu-
mour can be mistaken for medullary thy-
roid carcinoma.

Prognosis and predictive factors

Approximately 30% of patients present
with advanced disease, with a recurrence
rate of about 60% and a 5-year survival
rate of 50% {2463,2589,2632). There are
no specific histological features that p re-
dict outcome.

Neuroendocrine tu mours 97
Rare examples of SmCC and LCNEC marker (e.g. synaptophysin, chromogra-
harbour a component of squamous cell nin , or C056). TTF1 immunoexpression is
carcinoma, either within the invasive tu- variable. SmCC and LCNEC are negative
mour or within the overlying mucosa (i.e. or only weakly positive for p63 and are
squamous cell carcinoma in situ). Com- consistently negative for CK5/6.
bined SmCC- LCNEC cases are rarely
seen (2631). Prognosis and predictive factors
Both SmCC and LCNEC are positive for These highly aggressive malignancies
cytokeratins (in particular low-molecu- have high rates of regional and distan!
lar-weight cytokeratins) by immunohis- metastasis, with about 70% of patients
tochemistry, and SmCC may exhibit a presenting with advanced disease, and
perinuclear or dot-like pattern. Neuroen- 5-year survival rates of 5- 20% (708,848,
docrine differentiation is confirmed by 1170,2463}.
staining with at least one neuroendocrine

98 Tumours of the hypopharynx, larynx, !rachea and parapharyngeal space

Salivary gland tumours

Adenoid cystic carcinoma Prognosis and predictiva factors Prognosis and pred ictiva factors
Tracheal ACC o/ten presents at an ad- Complete resection is curative. Recurren!
Stenman G . vanced stage (2300). More than 50% of lesions are associated with an unfavour-
Gnepp D.R. patients have metastases, frequently to able clinical course.
Wenig B.M. the lungs {631 ). The 10-year survival rate
is influenced by margin status {2319).
In one study, most patients with larynge- Oncocytic papillary
Definition al ACC had T4 lesions at initial diagnosis, cystadenoma
Adenoid cystic carcinoma (ACC) is a although 87.9% had NO disease and only
slow-growing and relentless salivary 6.1% had distant metastasis. The 5-year Bloemena E.
gland malignancy composed of epithelial disease specif ic survival rate was higher Bel! D.
and myoepithelial neoplastic cel ls that among patients with laryngeal ACC who Hunt JL
form various patterns , including tubular, underwent surgery versus !hose who did
cribriform, and solid forms. not {609).
See also the Adenoid cystic carcinoma Defin ition
section (p. 164) in Chapter 7. Oncocytic papillary cystadenoma is a
Pleomorphic adenoma cystic lesion lined by oncocytic epithe-
ICD-0 code 8200/3 lium, with occasional luminal papillary
Bel! O. projections.
Epidemiology Bullerdiek J.
ACC is uncommon at these siles, but is Hunt J.L. ICD-0 code 8290/0
the most common salivary gland malig-
nancy in this location {318,426,609,704, Synonyms
795,1058,1734,2371,2557]. There is no Definition Oncocytic cyst; oncocytic papillary cys-
sex predilection and the tumours occur Pleomorphic adenoma (PA) is a benign tadenomatosis; oncocytic adenomatous
over a wide patient age range , but are tumour with variable cytomorphological hyperplasia; oxyphilic adenoma; onco-
most common in the sixth to eighth dec- and architectural manifestations. The cytoma; adenoma in laryngocoele
ades of life. identification of epithelial and myoepithe-
lial/stromal components is essential far Epidemiology
Localization the diagnosis of PA. The tumour affects elderly patients, in the
Most laryngeal tumours are subglottic, See also the P!eomorphic adenoma sec- sixth and seventh decades of life {253}.
with the supraglottis being the next most tion (p . 185) in Chapter 7 (Tumours of sa!i-
common location {609,1665,1734,2371, vary glands) . Localization
2699). The tumour occurs in the larynx, typically
ICD-0 code 8940/0 in the supraglottis {1382,2274).
Clinical features
Symptoms include airway obstruction, Synonym Clinical features
dysphagia, dyspnoea, cough, hoarse- Benign mixed tumour The symptoms are hoarseness, dyspho-
ness, sore throat, haemoptysis, and pain nia, and rarely, airway obstruction {175,
{1058,2557,2673) . Tracheal tumours may Localization 2274).
present with specific and asthma-mim- Only a few examples of PA in the larynx and
icking symptoms {1022) . hypopharynx have been reported in the
literature (612,2085). They are typically lo-
Macroscopy cated in the epiglottis or aryepiglottic folds.
The tumour is a submucosal mass with or
without surface ulceration . Clinical features
The common clinical presentatin of PA
Histopathology is that of a slow-growing, p ainless mass.
The histology is similar to that seen in
ACCs found in the majar and other minar Histopathology
salivary gland siles; see the Adenoid cys- See the Pleomorphic adenoma section
tic carcinoma section (p . 164). (p. 185) in Chapter 7.

Salivary gland tumours 99

The tumour consists of unilocular or mul-
tilocular cysts lined by oncocytic epitheli-
um, with occasional intraluminal papillary
projections. The lesion can be multifocal.
Hyperplastic cellu lar formation may re-
sult in more-solid nests of oncocytic cells

Cell of origin
The cell of origin is the minor salivary
gland duct cell {1382,2274).

Prognosis and predictive factors

These lesions show benign behaviour
but may recur. An association with squa-
mous cell carcino ma has been describ ed
in a case report (2274).

Soft tissue tumours

Granular ce// tumour Localization a substantial proportion of these lesions,

Laryngeal granular cell tumours most and care should be taken when evaluat-
Allen C.M. com monly involve the posterior third of ing a superficial biopsy sample to pre-
Gnepp D.R . the true vocal fold; tracheal granular cell vent an overdiagnosis of squamou s cell
Wen ig B.M. tumours usually affect the cervical por- carcinoma, because occasional tumours
tian {2602]. may be associated with mild to moderate
cytological atypia in the pseudoepithe-
Definition Clinical features liomatous hyperplasic component. The
Granular cell tumour is an uncommon Laryngeal granular cel l tumours usu- granular cells are often intimately associ-
benign tumour of Schwann-cell differen- ally present with hoarseness. Tracheal ated with nerves . The cytop lasmic gran-
tiation characterized by poorly demar- granular cell tumours may cause stridor, ules give a diastase-resistant positive
cated accumulations of plump granular cough, or haemoptysis {11 53). Other periodic acid-Schiff (PAS) reaction. The
ce lls {2458). symptoms include sensation of a mass tu mour cells express 8 100 protein, CD57,
See also the Granular ce!! tumoursection and dysphagia. As many as 10% of cas- an d S0X10 {72}, as well as CD68.
(p. 121) in Chapter 4. es involve two or more tumours {2602).
Prognosis and predictive factors
ICD-0 code 9580/0 Macroscopy Surgical excision is curative. The risk of
Granular ce ll tumours present as sessile recurrence is low (< 10%).
Synonyms nodules measuring < 2 cm in diameter
Granular cell myoblastoma; granular cell (92). On cut surface, the tumours are
schwannoma; granular cell neurofibro- pale tan to yellowish-white. Lposarcoma
ma; Abrikossoff tumour
Histopathology Flucke U.
Epidemiology The tumour shows submucosal unen- Franchi A.
Granular cell tumou rs most trequently capsulated or poorly circumscrib ed cel- Thompson L.D.R.
occur in the third to fifth decades of lite lular p roliferation with syncytial, trabec u-
{1057). No sex predilection has been lar, or nested growth, composed of cells
noted far laryngeal granular cell tumour, with round to oval nuclei and abundant Definition
but tracheal granular cell tumour has a coarsely granular eosinophilic cyto- Li posarcoma is a malignant neoplasrn
female predilection. Black populations plasm. There is usually minimal nuclear recapitulating fat. Three b iologically dis-
appear to be disproportionately affected pleomorphism and mitotic activity. Pseu- tinct categories are recognized: well-
compared with other ethnic groups. doepitheliomatous hyperplasia of the differentiated/dedifferentiated (the most
overlying epithelium may also be seen in common), myxoid, and pleomorphic.

100 Tumours of the hypopharynx, larynx, trachea and parapharyngeal space

infiltrate of plasma cells, lymphocytes,
and/or eosinophils.

ICD-0 code 8825/1

lnflammatory pseudotumour; plasma cell

lnflammatory myofibroblastic tumours of
the head and neck tend to occur in men
and are most common in adults, although
they can occur in children {462,2004).

Laryngeal inflammatory myofibroblas-
tic tumours primarily arise in the glottic
ICD-0 code 8850/3 sarcoma shows 12q13-15 amplification, regan {194,2509,2585). Non-Jaryngeal
including MDM2 and COK4 {192). sites include the oral cavity, sinonasal
Synonym tract, pharynx, tonsils, parapharyngeal
Well-differentiated liposarcoma: atypical Prognosis and predictiva factors space, salivary glands, and trachea
lipomatous tumour Multiple recurrences of lipoma-like/well- {404,405,573,961,1776).
differentiated lesions may occur alter
Epidemiology surgical treatment, with late dedifferen- Clinical features
These rare t1..1mours predominantly affect tiation. Tumour site and grade seem to Laryngeal inflammatory myofibroblastic
older males (mean patient age: 60 years) influence prognosis, with laryngeal lipo- tumours present with hoarseness, stridor,
(691,867}. sarcoma having a better outcome than dysphonia, ora foreign body sensation in
oral tumours, possibly due to earlier rec- the throat (194,2509,2585). In other sites,
Localization ognition {867). symptoms include obstruction, epistaxis,
The tumours occur in the pharynx, headaches, and dysphagia.
mouth, larynx, and neck. The tangue is a
common intraoral location {55,691,867}. lnflammatory Macroscopy
myofibroblastic tumour The tumour is a polypoid, pedunculated
Clinical features or nodular firm lesion with a smooth ap-
The tumour is a slow-growing, painless Wenig B.M. pearance and a fleshy to fi rm consist-
mass causing dysphagia and airway ob- Flucke U. ency, measuring 0.4- 3 cm in greatest
struction {867,1708). Franchi A. dimension.

Macroscopy Histopathology
The tumou rs present as submucosal, well- Definition The tumour is a submucosal storiform
circumscribed, fatty- fibrous nodules (1708). lnflammatory myofibroblastic tumour to fascicular loosely cellular proliferation
is a distinctive neoplasm composed of composed of spindle-shaped, stellate,
Histopathology myofibroblastic and fibroblastic spindle epithelioid, and/or axonal (spider- like)
The most common lipoma-like subtype cells accompanied by an inflammatory cells with enlarged round to oval nuclei,
shows variation in ad ipocyte size, with
hyperchromatic, enlarged nuclei. The ir-
regu lar fibrous septa have atypical stro-
mal cells {1708). Dedifferentiated non-
lipogenic areas can exhibit a wide variety
of growth patterns and cytomorphology
(e.g. spindle-cell, pleomorphic, giant-
cell, round-cel l, and meningothelial-like).
Heterologous elements (e.g. cartilage
and bone) are rare {1538). MDM2 and
CDK4 are positive in > 90% of the tu-
mours {192,1538}.

Genetic profile
Well -differentiated/ded ifferentiated lipo-

Soft tissue tumours 101

inapparent to prominent nucleoli, and
abundant fibrillar-looking cytoplasm . ln-
tranuclear inclusions may be present in
epithelioid cells. Mitotic figures may be
numerous but atypical mitoses are not
seen. There is a variable admixture of
lymphocytes, plasma cells, and/or eo-
sinophils. lnflammatory myofibroblastic
tumours are immunoreactive for actins
(focally to diffusely). Staining for desmin
and cytokeratin is reported in 33% {464)
to 77% {1581) of cases . ALK expression
is seen in 36-60% of cases {366,376,
481). Distinction from spindle cell squa-
mous cell carcinoma is critica!; areas of
squamous dysplasia or differentiation are
helpful in this differential diagnosis (see
Spind!e ce// squamous ce!/ carcinoma,
p. 87) .

Genetic profile
About 50-70% of cases (mainly in chil-
dren) have clona! rearrangements involv-
ing chromosome band 2p23 that fuse the
...~-' . ~
Fig. 3.30 lnfiammatory myofibroblastic tumour. A The myofibroblasts may also appear epithelioid or histiocytoid,
3' kinase region of the ALK gene {890). characterized by round to oval nuclei, enlarged nucleoli, and ample basophillc to eosinophilic granular cytoplasm;
Fusion partners include TPM3, TPM4, an inflammatory cell infiltrate is present. B The myofibroblasts include spindle-shaped to stellate cells with enlarged
CLTC, RANBP2, and ATIC/268,481,1351, round to oblong nuclei and abundan! basophilic-appearing fibrillar cytoplasm; cells with long cytoplasmic extensions are
1416,1808}. seen. C lmmunohistochemical expression of ALK, including cytoplasmic staining as well as staining of the intranuclear
Prognosis and predictive factors
For laryngeal inflammatory myofibro- (non-head and neck) inflammatory myo- a favou rable prognostic indicator {462).
blastic tumour, surgical resection is usu- fib roblastic tumour metastasize and ALK-negative cases may carry higher
ally curative {573,901 ,2004,2585), but may be associated with the presence ris k of metastasis and death from dis-
recurrence can rarely occur {901 ,2004, of RANBP2 and round cel l morphol- ease {462).
2585). Rare examples of extrapulmonary ogy {402,1539}. ALK reactivity may be

Cartilage tumours

Chondroma and Chondrosarcoma, grade 1 9222/1

chondrosarcoma Chondrosarcoma, grade 2/3 9220/3

Gale N. Epidemiology
Hunt J.L. Cartilaginous tumours account for
Lewis J.S. < 0.2% of ali laryngeal tumours, but
Thompson L.D.R. are the most common non-epithelial
tumours, with chondrosarcomas being
much more common than chondromas
Definition {347,460,711,1397}. Chondromas oc-
Chondroma is a benign mesenchymal cur across a wide patient age range,
tumour of larynx hyaline carti lage. Chon- of 24-7 9 years (mean: 56 years), with a
drosarcoma is a malignan! mesenchymal male-to-female ratio of 2:1 {1397).
tumour of larynx hyaline cartilage. Chondrosarcomas tend to occur in
slightly older patients, with a patient age Fig. 3.31 Laryngeal chondrosarcoma. Cut section of a
ICD-0 codes range of 25- 91 years (mean: 63 years), chondrosarcoma arising from the cricoid cartilage and
Chondroma 9220/0 and have a male-to-female rati o of 3.2:1 showing a solid, focally lobular and glistening greyish-
Chondrosarcoma 9220/3 {611,1397,2387). Chondrosarcomas are blue surface.

102 Tumours of the hypopharynx, larynx, !rachea and parapharyngeal space

significantly more common in Whites single nuclei surrounded by eosinophilic
than in Blacks, al a ratio of 7:1 (112). cytoplasm and there is usually only one
cell per !acuna. Cellular pleomorphism,
Etiology mitoses, and binucleated chondrocytes
The etiology remains unclear, although are absent. Scattered foci of calcification
severa! hypotheses have been proposed. and ossification may be seen.
Disordered ossification, which is found Chondrosarcomas show variably in-
only in hyaline cartilage (cricoid and rare- \ . creas.ed cellularity, pleomorp hism, multi-
ly thyroid cartilage) in older patients and
whlch occurs in areas of muscle inser-

,1,- ,:-.

nucleation, and mitoses, features useful
in tumour grading. Most laryngeal chon -
~ - -" . . . ., .., ' f
tion, may serve as a nidus for tumour de- Fig. 3.32 Chondroma. Well-circumscribed tumour drosarcomas are low-grade (grade 1),
velopment (112). lschaemic changes in composed of hyaline cartilage, with low cellularity, lack showing a pattern of lobular disarray
chondroma may be a predisposing fac- of nuclear atypia of chondrocytes, and a single nucleus and destructive invasion o/ native carti -
tor (2387}. Other possible predisposing within a lacuna. lage and bone. Chondrosarcomas have
factors are radiotherapy, polytetrafluoro- higher cellularity !han chondromas, bi-
ethylene (Te/Ion) injection, and repeated tumour extent (112) CT reveals a hy- nucleation in !he !acunar spaces , slight
laryngeal trauma (1773). podense, well-defined tumour with inter- nuclear pleomorphism, and nuclear hy-
na! calcifications, cartilage destruction, perchromasia. Moderately differentiated
Localization and structural distortion {166,25 41 ,2619). (grade 2) tumours show a higher degree
The most common site for laryngeal FDG -PET may help with tumour grading, of cellularity and nuclear pleomorphism
chondromas is the cricoid cartilage (ac- metastasis detection, and local recur- than do grade 1 tumours, and may have
counting for -70% of cases), followed by rence assessment (1773). scattered mitoses. High-grade (grade 3)
the thyroid, arytenoid, and tracheal carti- tumours have high cellularity; significan!
lages, in decreasing order of frequency Macroscopy multinucleation, nuclear pleomorphism,
{112,1361,1397}. Chondrosarcomas de- Both tumours present as smooth, lobulat- and hyperchromasia; necrosis; and in-
velop in the same locations, specifically ed, submucosal masses covered by nor- creased mitoses. Ossification and calci -
along the anterior surface of !he posterior mal mucosa. On cut surface, the lesions fication can be seen in ali grades (112,
lamina of the cricoid cartilage {112,1773, are glassy, firm , white, or grey. Chon- 1397,2387).
2387}. Rare tumours arise in the epiglot- dromas are usually < 2 cm in diameter, Rare cases of laryngeal clear cell chon-
tis (2387}. whereas chondrosarcomas can be as drosarcoma have also been described,
large as 12 cm (mean diameter: 3.5 cm. characterized by a sharp transition of
Clinical features Dedifferentiated chondrosarcomas have conventional chondrosarcoma to a pop-
Both tumours grow slowly, commonly as foci with a fleshy appearance {347,809, ulation of large clear cells with distinct
endolaryngeal masses. The symptoms 1397,2387}. cellular membranes but lacking typical,
of chondroma and chondrosarcoma are dense chondroid matrix (45). High-grade
similar and depend on tumour size and H istopathology chondrosarcomas are rare, accounting
location. Slowly progressive hoarseness, Chondromas are composed of mature for only about 5% o/ ali laryngeal chon-
dyspnoea, dysphagia, and stridor are hyaline cartilage histologically resembling drosarcomas {2387). Dedifferenti ated
usually present. lf the tumour is located normal cartilage. Hypocellular areas con- laryngeal chondrosarcomas are exceed-
in the thyroid cartilage, the palien! may tain evenly distributed, bland-looking ingly rare; they show a biphasic appear-
present with a palpable neck mass {112, chondrocytes in an abundan! basophilic ance with well-differentiated chondro-
1773,2387). MRI may help in delineating matrix. Chondrocytes have small, uniform , sarcoma juxtaposed with a high-grade

, . B ,'P. tr
~ 'f ... ' ,., - - - . . - .-
Fig. 3.33 Chondrosarcoma. A Neoplastic proliferation with increased cellularity, chondrocytes showing mild nuclear and cellular pleomorphism and hyperchromasia, and invasion
of the ossified region of the cricoid cartilage. B Moderately differentiated chondrosarcoma, grade 2. Remarkable cellularity, frequent binucleation in the !acunar spaces, and more
pronounced nuclear and cellular pleomorphism.

Cartilage tumours 103

Wmacytomas constitute 5- 6% of extra-
osseous plasmacytomas of the head
and neck (1 16,2078); nearly ali patients
are adults. Extramedullary myeloid sar-
coma and mast cell neoplasms are very
rare (1028}. Among patients with wide-
spread lymphoma or leukaemia , subtle
laryngeal involvement is common {1028).

Lymphoma and plasmacytoma involve
the larynx more often than the trachea.
Lymphoma involves the supraglottic lar-
ynx more often than the subglottic larynx.
Primary parapharyngeal or hypopharyn-
geal origin of haematolymphoid neo-
plasms is very rare. Lymphomas (545,
1028,1300,1444) and plasmacytomas
{1 483,2143,2304) are usually localized;
sorne MALT lymphomas involve multi-
ple mucosa-associated lymphoid tissue
siles (997).

Clinical features
Patients present with coug h, dyspnoea,
and hoarseness (1300,1 444,2304 ,2718].

Lymphomas and extraosseous plasma-
cytomas are usually smooth-su rfaced,
raised or polypoid lesions {1028,1300,
2718). Lymphomas may be multinodular
and/or circumferential (586,2701 }.
1 -
Fig. 3.35 MALT lymphoma arising in the larynx. There is a dense, diffuse infiltrate of marginal zone cells; neoplastic Histopathology
cells invade a submucosal gland to form a lymphoepithelial lesion. The most common primary lymphoma at
this body site is MALT lymphoma (586,
non-cartilaginous sarcoma {809,2387). Haematolymphoid tumours 1300,1 444,2343,2718], but rare cases
lmmunohistochemistry is rarely neces- of diffuse large B-cell lymphoma (1028),
sary, but the chondroid cells are immu- Ferry J. A. extranodal NK/T-cell lymphoma (1 637},
noreactive with S100 protein and D2-40. Chuang S.-S. anaplastic large cell lymphoma (1220),
and other lymphomas have also been
Prognosis and predictive factors repo rted. Laryngeal extraosseous plas-
The 1-year, 5-year, and 10-year disease- Definition macytoma is sometimes associated with
specific survival rates for chondrosar- Haematolymphoid tumours are primary laryngeal amyloidosis (1483).
coma are 96.5%, 88.6%, and 84.8%, re- malignan! neoplasms of lymphoid, plas-
spectively, although the local recurrence ma cell, or myeloid origin . Prognosis and predictive factors
rate is relatively high (18-50%), usually The prognoses of lymphomas at this
dueto incomplete resection (611,2387). Epidemiology body site are similar to those of their
Tumour grade and tumour subtype do not Lymphomas arising in the larynx and counterparts in other sites. Extraosseous
seem to influence outcome (other than trachea are rare, accounting fo r < 1% plasmacytoma has a favourable progno-
possibly for dedifferentiated tumours) of neoplasms at these sites {717,1028, sis (1 028). al though patients may devel-
(1992), which encourages conservative, 1541]. Approximately 4% of head and op recurrences and a mi nority of cases
function-preserving surgery (including neck lymphomas arise in the larynx; progress to plasma cell myeloma (116,
laser therapy) as primary treatment (347, tracheal lymphomas are even less com- 2078).
2387]. Distant metastases are exceed- mon (934). Lymphomas affect women
ingly rare {460) . more often th an men. Laryngeal plas

104 Tumours of the hypopharynx, larynx, trachea and parapharyngeal space



Tumours of the oral cavity and

mobile tongue
Malignant surface epithelial tumours
Oral potentially malignant disorders and
oral epithelial dysplasia
Tumours of uncertain histogenesis
Soft tissue and neural tumours

Oral mucosal melanma
Salivary type tumours
Haematolymphoid tumours

WHO classification of tumours of the oral cavity and
mobile tongue

Epithelial tumours and lesions Neurofibroma 9540/0

Squamous cell carcinoma 8070/3 Kaposi sarcoma 9 140/3
Oral epithelial dysplasia Myofibroblastic sarcoma 8825/3
Low grade 8077/0
High grade 8077/2 Oral mucosa! melanoma 8720/3
Proliferative verrucous leukoplakia
Salivary type tumours
Papillomas Mucoepidermoid carcinoma 8430/3
Squamous cell papilloma 8052/0 Pleomorphic adenoma 8940/0
Condyloma acuminatum
Verruca vulgaris Haematolymphoid tumours
Multifocal epithelial hyperplasia CD30-positive T-cell lymphoproliferative
disorder 9718/3
Tumours of uncertain histogenesis Plasmablastic lymphoma 9735/3
Congenital granular cell epulis Langerhans cell histiocytosis 9751/3
Ectomesenchymal chondromyxoid tumour 8982/0 Extramedullary myeloid sarcoma 9930/3

Soft tissue and neural tumours

Granular ce ll tumour 9580/0 The morphology codes are lrom the lnternational Classilication ol Diseases lar
Oncology (!CD-O) (776A}. Behaviour is coded /0 far benign tumours;
Rhabdomyoma 8900/0 /1 far unspecified, borderline, or uncertain behaviour; /2 far carcinoma in
Lymphangioma 9170/0 situ and grade 111 intraepithelial neoplasia; and /3 lar malignan! tumours. The
Haemangioma 9120/0 classification is modified from the previous WHO classilication, taking into
account changes in our understanding of these lesions.
Schwannoma 9560/0

106 Tumours of the oral cavity and mobile tongue

TNM classification of carcinomas of the lip and oral cavity

TNM classification of carcinomas of the lip and oral cavity,b N2b Metastasis in multple ipsilateral lymph nodes,
ali s 6 cm in greatest dimension
T - Primary tumour N2c Metastasis in bilateral or contralateral lymph nodes,
TX Primary tumour cannot be assessed ali s 6 cm in greatest dimension
TO No evidence of primary tumour N3 Metastasis in a lymph node > 6 cm in greatest dimension
Tis Carcinoma in situ
T1 Tumour s 2 cm in greatest dimension Note: Midline nades are considered ipsilateral nodes.
T2 Tumour > 2 cm but s 4 cm in greatest dimension
T3 Tumour > 4 cm in greatest dimension M - Distant metastasis
T4a (lip) MO No distan! metastasis
Tumour invades through cortical bone, inferior alveolar M1 Distan! metastasis
nerve, !loor of mouth, or skin (of chin or nose)
T4a (oral cavity) Stage grouping
Tumour invades through cortical bone, into deep/extrinsic StageO Tis NO MO
muscle of tangue (genioglossus, hyoglossus, palatoglos- Stage 1 T1 NO MO
sus, and styloglossus), maxillary sinus, or skin of tace Stage 11 T2 NO MO
T4b (lip and oral cavity) Stage 111 T1-2 N1 MO
Tumour invades masticator space, pterygoid platas, or T3 N0-1 MO
skull base; or encases interna! carotid artery Stage IVA T1-3 N2 MO
T4a N0-2 MO
Note: Superficial erosion alone of bone / tooth socket by Stage IVB AnyT N3 MO
gingival primary is no! sufficient to classify a tumour as T4. T4b Any N MO
Stage IVC AnyT Any N M1
N - Regional lymph nodes (i.e. the cervical nodes)
NX Regional lymph nodes cannot be assessed
Adapted from Edge et al. (625A} - used with permission of the American
NO No regional lymph node metastasis
Joint Committee on Cancer (AJCC), Chicago, lllinois; the original and prima-
N1 Metastasis in a single ipsilateral lymph node, s 3 cm in ry source for this information is the AJCC Cancer Staging Manual, Seventh
greatest dimension Edition {201 O) published by Springer Science+Business Media - and Sobin
N2 Metastasis as specified in N2a, N2b, or N2c below et al. (2228AI.
hA help desk for specific questions about TNM classification is available at
N2a Metastasis in a single ipsilateral lymph node, > 3 cm
but s 6 cm in greatest dimension

TNM classification of carcinomas of the lip and oral cavity 107

Tumours of the oral cavity and Takata T.
Slootweg P.J.
mobile tongue

lntroducton cavity and mobile tongue is squamous grading system and a binary system are
cell carcinoma (SCC) arising from the described . For other grading systems and
In the previous edition, tumours of the oral mucosa! epithelium . More than 90% of related terminology used for dysplasia/
cavity and oropharynx were discussed oral cancers are SCC. Most cases of oral squamous intraep ithelial lesion, refer to
together in one chapter. Now, diseases SCC are moderately to well differenti- the corresponding sections in Chapter 3
of these two anatomical reg ions are the ated. For more detailed information on (Tumours of the hypopharynx, larynx, tra-
subjects of two separate chapters; this subtypes of SCC, see the correspond- chea and parapharyngeal space, p . 77).
chapter being devoted to the oral cavity ing sections in Chapter 3 (Tumours of the Although the cause of oral SCC is mul-
and Chapter 5 (p. 133) to the oropharynx. hypopharynx, /arynx, trachea and para- tifactorial, accumulated information on
Furthermore, as in other chapters, in an pharyngeal space, p . 77). etiological and genetic factors in oral
effort to minimize overlap, only selected Oral potentially malignant disorders, SCC and related precursor lesions sup-
non-epithelial and soft tissue tumours, cl inical presentations carrying a risk of ports targeted diagnosis and therapy
salivary neoplasms and haematolym- cancer development. and oral epithelial of oral SCC. The content of th is chapter
phoid tumours are highlighted . The out- dysplasia, a spectrum of histological and reflects the increase in knowledge on
come of this approach is that the content cytological changes with an increased oral diseases and its practica! applica-
of this chapter is much reduced in com- risk of progression to SCC, are also im- tion in diagnosis and treatment. Hitherto
parison with the previous edition. portan! lesions for secondary prevention unrecognized new entities deserving to
Lesions that deserve prime attention in of oral SCCs. There are difieren! kinds of be listed as such in this chapter have not
this chapter are the mucosa! diseases. grading systems for epithelial dysplasia. been identified.
The most pivotal malignancy of the oral In this chapter, a traditional three-tiered

108 Tumours of the oral cavity and mobile tongue

Malignant surface epithelial tumours Sloan P.
Gale N.
Nylander K
Reibel J.
Hunter K. Salo T.
Lingen M. Zain R.B .

Squamous ce// carcinoma
oral squamous cell carcinoma (OSCC) is
a carcinoma with squamous differentia-
tion arising from the mucosal epithelium.
The proportion of cases that arise in clini -
cally evident oral potentially malignan!
disorders is unknown. lt is most frequent Cnoe1 ofthf' 1/p and 011111ity
in the fifth and sixth decades of lite and
- 5.1
is typically associated with risk factors - 3.8-5.1

such as smoking, alcohol consumption, 1:1 2.5-3.S

and betel-quid chewing. D u -2_5

D <1_9

ICD-0 code 8070/3

More than 90% of cancers in the oral BOl~ H XU

cavity are OSCCs. With respect to the

epidemiology of oral cancer, specific ge-
ographical regions must be considered
separately, because there is marked vari-
ation in incidence. Overall, oral cancer
(when oropharyngeal siles are included)
is the sixth most common cancer in the
world [2548). The GLOBOCAN project Csnc:e-r ol the lip 111'\d 0<a! cevity

estimated 300 373 new cases in 2012,

- 2 .2
with a global age-standardized incidence - l.&-2.2
rate of 4.0 cases per 100 000 population
per year and a global mortality rate of

1,1.1 .c

0 .07-1 .1
1.9 deaths per 100 000 population per D <Q.e1

No Data
year [702). High incidence of oral can-
cer is found in southern Asia (e.g . India; B
Pakistan; Sri Lanka; and Taiwan, China),
Fig. 4.01 Worldwide age-standardized rate (ASR) of (A) incidence and (B) mortality per 100 000 population per year,
with age-standardized incidence rates of
both sexes, of lip and oral cavity cancer. Reprinted from GLOBOCAN 2012, Ferlay J et al. {702}.
> 10 cases per 100 000 population per
year in parts ot India and Pakistan (702). incidence of intraoral cancer is decreas- tobacco) or dipping (snuff). Smokeless
lncidence is also high in eastern and ing in sorne countries, whereas slight tobacco in chewing or dipping torms
western Europe (e.g. Hungary, Slovakia, increases among younger patients have causes oral cancer; however, sorne
Slovenia, and France), Latin America been reported in other countries (1456, studies (in particular studies ot Swedish
and the Caribbean (e.g. Brazil , Uruguay, 2159). snuft) show negligible risk {229,1072).
and Puerto Rico), and Melanesia (e.g. Areca nut and/or tobacco can be mixed
Papua New Guinea) (702). Worldwide, Etiology with other substances (e.g. slaked lime,
oral cancer incidence is higher among Smoking is by far the most importan! betel inflorescence, condiments, sweet-
males (5.5 cases per 100 000 popula- cause ot oral cancer. There is a dose- ening agents, and spices) to create b e-
tion per year) than temales (2.5 cases dependent increase in risk, and. risk de- tel quid. Betel- quid chewing increases
per 100 000). However, the rat io is the creases after smoking cessation {1071, the risk of oral cancer whether or not to-
reverse in India and Thailand, where the 2550). Alcohol consumption interacts bacco is added (900). HPV, in particu lar
reported male-to -temale ratios are 1:2 synergistica lly with smoking, resulting in type 16, is a recogn ized etiological factor
and U .56, respectively (1 280). Most a more than additive risk [121, 865,1073). in oropharyngeal cancer but is only seen
oral cance rs occur in patients aged 50- Smokeless tobacco is used orally in most in a small minority (3%) of osees (515,
70 years . As smoking rates decline, the parts ot the world, by chewing (chewing 840,1438,2135). Exposure to sunlight is

Malignan! surtace epithelial tumours 109

an established risk factor fo r lip cancer. Table 4.01 Subtypes of squamous cell carcinoma (SCC) of the oral cavity and mobile tongue
In Western Australia, lip cancer accounts Oral SCC subtype Features References
for as many cases as ali intraoral sites to-
Basaloid SCC High-grade carcinoma, more-frequent metastasis but overall
gether {7) . Poor oral health is associated prognosis comparable to that of conventional SCC {774,2653)
with oral cancer {591,899) but has not
been proven an independent risk factor Worse prognosis than conventional SCC in oral cavity and mobile
Spindle cell SCC tongue; typically occurs as postradiation recurrence or second {187,824}
{2547}. A diet rich in fruits and vegetables primary
seems to have sorne protective effect - ---
against oral cancer {264,1503}. Adenosquamous Highly infiltrative and aggressive, frequent metastasis, worse
carcinoma prognosis than conventional SCC (1194,1553,2113)
Oral cancer can affect any area of the Carcinoma Well differentiated, usually on mucoperiosteum, locally destructive --
oral mucosa. The most common siles for cuniculatum deep burrowing pattern, metastasis rare, recurs locally but rarely if (2312)
ever metastasizes
intraoral cance r in many populations are
the tongue, floor of the mouth, and gin- Well-differentiated non-metastatic variant with pushingsuperficial
Verrucous SCC invasion, exophytic, lacks atypia, good prognosis; may progress to {1517,1759,2060)
giva, accounting for more than half of all
invasiva conventional SCC
oral cancers (1337,1544,2423}. However,
site distribution varies depending on Lymphoepithelial Rare, present at high stage, 70% associated with regional lymph
carcinoma nade metastasis; not ali are EBV-positive (2034)
the prevailing risk factors. Among many
Asian populations, osee most common - Papillary SCC Keratinizing and non-keratinizing types, often arises on gingivae;
better prognosis than conventional SCC {1517,2060}
ly affects the buccal mucosa, due to to-
bacco chewing and betel-quid chewing. High-risk cutaneous variant that may occur on the lip; acantholysis
Acantholytic SCC can result in an adenoid appearance inpoorly differentiated intraoral {605,807,2730}
Clinical features scc
Oral cancers can be detected by visual
inspection and palpation followed by bi- Cytology differentiated; poorly differentiated squa-
opsy and histopathological examination. lntraoral tumours are usually evaluated mous cell carc inoma is less freq uent.
Evaluation of the neck is also importan!. by surgical biopsy. Meta-analys is shows Well-differentiated osee is characterized
Small cancers may be asymptomatic, that adjunctive tests cannot replace scal- by nests, cords, and islands of large cells
whereas advanced tumours give rise to pel biopsy and histological assessment with pink cytoplasm, prominent intercellu-
various symptoms and signs such as for oral cancer diagnosis {1985}. Fine- lar brid ges, and round nuc lei, which may
discomfort, pain, reduced mobility of the needle aspiration is useful for the detec- not be obviously hyperchromatic. Dys-
tongue, and irritation from wearing den- tion of lymph node metastasis. Aspirates keratotic cells and squamous pearls are
tures. The clinical presentation is that are cellu lar, with sheets and small clus- prominent. Cellular and nuclear pleomor-
of variably white, erythematous, mixed, ters of malignan! squamous ce lls with phism , nuclear hyperchromasia, and mi-
nodular, and ulcerated changes; when intracellular and extracellu lar keratiniza- totic figures (including atypical forms) in-
present, ulcerated changes often have tion. Mixed inflammation and necrosis crease with tumour grade. Grading alone
raised margins {120}. Non-healing ulcer- can be present. does not correlate well with p rognosis. In
ation is a feature suggestive of malignan- poorly differentiated osee, features of
cy; however, in a recent study, ulceration Histopathology squamous differentiation are minimal or
in osee (including its variants) was seen Most cancers of the oral cavity and absent, requiring immunohistochemical
in slightly less than hall of the cases (56). mobile tang ue are moderately or well confirmation; AE1 /AE3, e K5/6, p 63, and
eancer of the lower lip typically presents
as a crusting lesion, often preceded by
actinic cheilitis. An essential part of the
diagnostic procedure for oral cancer is
palpation of the lesion, typical ly revealing
induration. Untortunately, small cancers
are often unapparent to both patients
and health professionals, resu lting in di-
agnostic delay (872). One reason is that
small cancers can mimic other lesions
commonly seen in the oral cavity.

Squamous cell carcinomas are firm in-
fi ltrative tumours, with a tan or wh ite cut
surface .
,. ,.
Fig. 4.02 Conventional, moderately differentiated oral squamous cell carcinoma showing keratin pearl formation.

110 Tumours of the oral cavity and mobile tongue

Genetic susceptibility
The evidence of inherited genetic sus-
ceptibility for the development of osee
is limited. osee may arise as part of a
more general cancer syndrome, such as
in patients with Li-Frau meni syndrome
(1924] or Fanconi anaemia (223} .

Prognosis and predictiva factors

eonventional osee is aggressive, with
a propensity for local invasion and early
lymph node metastasis. The most signifi-

can! prognostic factors are tumour size,
nodal status, and distan! metastasis.
;__... eonventional histological grading corre-
lates poorly with clinical outcomes (259).
Fig. 4.03 Oral squamous cell carcinoma of mobile tongue showing an adverse pattern of infiltration.
Histological risk factors associated with a
p40 are useful markers. Well-differentiat- Genetic profile worse prognosis include a non-cohesive
ed tumours tend to invade in large islands, Most osees are genetically unstable pattern of invasion {1424). perineural and
whereas less-differentiated tumours tend (183,1885,2070). with chromosomal loss lymphovascular invasion {2636,2640).
to have jagged or finger-like projections at 3p, 8p, 9p, 17p and gains at 3q and bone invasion {625], and thickness
or small islands and dispersed ind ividual 11q {396,2375}. These changes may ex- > 4 mm {57}. Margins from the resec-
cells at the invasive front. Significan! des- tend for sorne distance from the clinical tion specimen predict local control better
moplastic stroma with inflammatory host lesion, underpinning the clinical phe- than margins from the tumour bed {1562}.
response can be found around nests nomenon of f ield cancerization (249). High-grade dysplasia at a mucosa! mar-
of invading tumour cells. Adjacent mu- Genes reported to have a role in osee gin correlates with local recurrence and
cosa frequently shows various grades (e.g. TP53, CDKN2A , PTEN, HRAS, and second primary tumours (1424,2561). Ex-
of epithelial dysplasia. Perineural and PIK3CA) are mutated with sufficient fre- tracapsular spread f rom metastasis in the
lymphovascular invasion are seen, more quency to support their potential role neck, two or more positive nodes, and
frequently in poorly differentiated tumours as drivers in cancer development {818, involvement of levels IV and V correlate
{258,297,1424,2494). 1492,1712,1885,2288,2375}. with adverse outcome.

Malignan! surface epithelial tumours 11 1

Oral potentially malignant disorders Reibel J .
Gale N.
Tilakaratne W.M.
Westra W.H .
and oral epithelial dysplasia HilleJ.
Hunt J .L.
Williams M.O.
Vigneswaran N.
U ngen M . Fatani H A
Muller S. Odell E.W.
Sloan P Zain R.B.

Oral potentially malignant {1567,2629), and whether it plays a role in Oral epithelial dysplasia
disorders transformation has yet to be determ ined.
Definition Localization Oral epithelial dysplasia (OED) is a spec-
Oral potentially m alignant d isorders OPMDs can involve any intraoral site. trum of architectural and cytolog ical epi-
(OPMDs) are c linical presentations that Their distri bution vares by specific d is- thelial changes caused by accumulation
carry a risk of cancer development in the order, with etiological factors, and to a of genetic changes , associated w ith an
oral c avity, whethe r in a clinically defin- certain extent patient age and sex {1704}. increased risk of progression to squa-
able precursor lesion or in clinically nor- Erythrop lakia is most frequently seen on mous cel l carcinoma.
mal oral mucosa. the soft palate, floor of the mouth, and
bucea! mucosa {1972). ICD-0 codes
Epidemiology Low grade 8077/0
In western countries, the reported preva- Clinical features High grade 8077/2
lence of leukoplakia generally ranges Most high-risk OPMDs form red, wh ite,
from 1% to 4%. Higher prevalence rates or sp eckled oral lesions. "Leukoplakia" Synonyms
are reported in parts of south-eastern is a clinical term used to describe white Epithelial precursor lesions; intraepithe-
Asia {1704}. The g lobal prevalence of leu- plaques of q uestionable risk, once other lial neoplasia; squamous intraepithelial
koplakia is 2- 3% {1871}. In contras\, oral specific con ditions and other OPMDs lesions
erythroplakia is a rare lesio n, w ith preva- have b een ruled out {2551}, which nor-
lence between 0.02% and 0.83% {1972} . mally requ ires biopsy. Leukopl akias can Histopathology
Men are affected m uch more commonly be homogeneously white or predomi- OED includes abnormal proliferation, matu-
than women. Other O PMDs can be com- nantly white with nodular, verrucous , or ration , and differentiation of epithelial cells.
mon, but have much lower transformation red areas . Predominantly wh ite examples The epithelium may be atrophic, acanthot-
rates. with red areas are called erythroleuko- ic, keratinized, or non-keratinized. Dyspla-
plakias (speckled leukoplakias). Oral sia is present in a minority of leukoplakias
Etiology erythroplakia is defi ned equivalently, but is a consisten! finding in erythroplakia
OPMDs have different causes. Tobacco but as a red patch. Specifically defined and erythroleukoplakia.
use (smoking and/or chewing) and al- OPMDs have characteristic presenta- Tab le 4.03 lists the architectural and cyto-
coho l consumption are associated with tions, and epithelial dysplasia may or logical disturbances that are used to diag-
sorne leukoplakias {1704). The use of may not be present. Other OPMDs have nose OED. The number and combination
areca nut, w ith o r without tobacco, caus- been reviewed elsewhere {2475). of featu res vary between lesions. There is
es oral submucous fibrosis {2404). For no good evidence to indicate how the pres-
many cases of OPMDs, no etiological Genetic susceptibility ence of individual features cou ld be trans-
factors are known . High-risk HPV infec- OPMDs are seen in the rare disorders lated into a grade of dysplasia . No specific
tion is only very rarely present in OPMDs Fanconi anaemia {889) and dyskeratosis combination of features reliably distinguish-
congenita {932), but no genetic predis- es hyperplasia from mild dysplasia. OED
Table 4.02 Oral potentially malignan! disorders position is present in most cases. may be diagnosed on the basis of architec-
Erythroplakia tural or cytological features alone.
Erythroleukoplakia Prognosis and predictive factors Traditio nally, OED is divided into th ree
Leukoplakia The transformation risk in many OPMDs grades of severity. Judging the number
is low, and many regress (1307}. For leu- of thirds of the epithelium affected is one
Oral submucous fibrosis
koplakia, a mean global transformation factor in defining a grade. Mild dysplasia
Dyskeratosis congenita rate of 1- 2% has been estimated {1871}. can be defined by cytological atypia lim-
Smokeless tobacco keratosis A meta-analysis of cases with oral epithe- ited to the basal third, moderate dysplasia
Palatal lesions associated with reverse smoking lial dysplasia found a transformation rate by extension into the middle third , and se-
of 12% (1579). Presence of oral epitrielial vere dysplasia by extension into the upper
Chronic candidiasis
dysplasia is the most important prognos- third. However, arch itectural and cytologi-
Lichen planus tic factor for malignant transformation, cal atypia and the architecture of the con-
Discoid lupus erythematosus but clinical characteristics such as ap- nective tissue interface should increase the
pearance (homogeneous vs. non-homo- grade. Marked atypia in the basal third of
Syphilitic glossitis
geneous), size, and site also have impli- the epithelium may be sufficient for a di-
Actinic keratosis (lip only)
cations for clinical management {1704}. agnosis of severe dysplasi a. Carcinoma in

112 Tumours of the oral cavity and mobile tangue

Table 4.03 Diagnostic criteria for epithelial dysplasia; adapted from Barnes Letal. {146) {316,2017) in combination with two addi-
Architectural changas _____ Cytological changes tional markers at 4q and 17p {2712}.
Irregular epithelal stratification Abnormal variation in nuclear size
Prognosis and predictive factors
Loss of polarity of basal cells Abnormal variation in nuclear shape Although the presence of dysplasia
Drop-shaped rete ridges Abnormal variation in cell size corre lates with the development of
lncreased number of mitotic figures Abnormal variation in cell shape squamous cell carcinoma, most OEDs
never progress to carc inoma. A meta-
Abnormally superficial mitotic figures lncreased N:C ratio
analysis of lesions with OED showed a
Premature keratinization in single cells Atypical mitotic figures transformation rate of 12% [1579). Gen-
Keratin pearls within rete ridges lncreased number and size of nucleol erally, the more advanced the degree
Loss of epit11elal cell cohesion Hyperchromasia of dysplasia, the higher the likelihood of
developing squamous cell carc inoma
Table 4.04 Grading systems for epithelal dysplasia
{1366,1579,2176,2552}. The 15-year
mal ignan! transformation rates of mild,
WHO dysplasia grade Binary system
moderate, and severe dysplasia (as
Mild dysplasia Low-grade dysplasia defined by the traditional three-grade
- - system) are approximately 6%, 18% ,
Moderate dysplasia
and 39%, respectively, and the pres-
e -- High-grade dysplasia
Severe dysplasia ence of dysplasia indicates long-term

risk {2250) . The general problem of low

The cut-off point betweenlow-grade and high-grade dysplasia, as suggested by Kujan O et al. {1291), is tour
architectural and five cytological changes (see Table 4.03}, irrespective of the level within the epithelium. reproducibility of curren! diagnostic c ri-
According to Nankivell P et al. {1702), a cut-off point of tour architectural and four cytological changes may improve teria underlies the poor correlation with
prognostication. transformation found in sorne studies
situ in the oral cavity is considered synony- HPV has been described, histologically
mous with severe dysplasia. characterized by epithelial hyperplasia
Dysplasia grading is poorly reproducible and marked karyorrhexis and apoptosis Prolferative verrucous
between observers. Sorne studies show throughout the epithelium {2629). Accord- leukoplakia
good prognostic value (2250). but others ing to conventional criteria, these qualify
find a poor association with outcome {721, as severe dysplasia, but the risk of trans- Definition
1505) . Consensus grading after review by formation has yet to be determined . lmmu- Proliferative verrucous leukoplakia (PVL)
more than one pathologist may enhance nostaining far p16 alone cannot be used is a distinct and aggressive form of oral
diagnostic reliabil ity (733,2249,2250). To as a surrogate marker for HPV infection in potenti ally malignan\ disorder {2551). lt is
improve reproducibility, sorne authors ad- OED. multifocal, has a progressive course, and
vocate a binary system (1291 ,1702,2553}, is associated with high recurrence and ma-
in line with proposals for laryngeal lesions Genetic profile lignan! transformation rates {2,839,936).
(798), but binary scoring requires validation Prognostic genetic and molecular mark-
befare it can be routinely applied in the oral ers for malignan! transformation have Epidemiology
cavity. been reported {1902,1971). most notably PVL is rare in comparison with conven-
An unusual subset of OEDs positive for LOH at chromosomal arms 3p and 9p tional oral leukoplakia. lt occurs in older
Table 4.05 Selected recen! reports on malignan! transformation of oral leukoplakia; in part adapted from Warnakulasuriya S and Ariyawardana A {2549)
Observation period of malignan!
Authors/year Country Cases Notes
(years) transforma-

Saito T et al. 2001 {2046) Japan 142 a, b 4 (0.6-16) 6.3%

~ lmstrup P et al. 2006 {1016) Denmark 254 a, b 6 (1.1-20.2) 6.7%
Warnakulasuriya Set al. 2011 {2552); 9 6.9%
United Kingdom 335 a,b
Sperandio M etal. 2013 {2250)

Ho MW et al. 2012 {1007) United Kingdom 83 a,c

- 5 24.1%
Liu W et al. 2012 {1450) China 320 a, c 5.1 (1-20) 17.8%
Brouns E et al. 2014 {276)
Dos! F et al. 2013 {600)
- a,b
4.7 (1-14.9)
Not available
Mehanna HM et al. 2009 {1579) Meta-analysis 992 c, d Not applicable 12.1%
>- -
"rreated and untreated cases. bWith and without dysplasia. coysplasias only. dlncludes clinical diagnoses other !han leukoplakia. "Annual transformation rate: 1%.

Oral potentially malignan! disorders and oral epithelial dysplasia 113

exophytic growth resulting in a warty (ver-
rucoid) surface with focal erythematous
areas, and (4) development of verrucous
or squamous cell carcinoma {839}. How-
ever, not every PVL goes through these
clinical stages, and development of car-
cinoma has been noted in PVL clinically
presenting as multifocal flat patches.

Fig. 4.04 Proliferative verrucous leukoplakia. A61-year-old woman presented with an advanced proliferative verrucous
Histopathology corresponds to the varied
leukoplakia involving the dorsal (A) and ventral surfaces of the tongue and palate (B). The patient had undergone clinical features of PVL: localized flat or
multiple biopsies and surgeries during the previous 4 years, which had resulted in diagnoses of invasive and in situ verrucous hyperorthokeratosis with mini-
squamous cell carcinomas. mal or no dysplasia, resulting in the un-
derestimation of risk of malignan! trans-
patients (aged > 60 years), with a female- Localization formation of these lesions during their
to-male ratio of 4:1 {2,311}. PVL frequently involves gingiva, alveolar early stages. Dysplasia develops only
mucosa, and palate {839). The lateral during th e late stages of PVL, before pro-
Etiology and ventral surfaces of the tangue and gressing into either verrucous or squa-
The etiology is unknown. In Europe and floor of the mouth are rarely involved dur- mous cell carcinoma (839). Definitive
North America, PVL is not associated ing the early stages of PVL. diagnosis of PVL requires clinical and his-
with known risk factors of oral cancers topathological correlation. PVL frequently
(i.e. tobacco use and alcohol consump - Clinical features shows interface mucositis characterized
tion). Neither HPV nor any other virus is PVL exhibits varied clinical features in four by a band-like, lymphohistiocytic infiltrate
associated with the development of PVL clinical stages: (1) focal flat white kerato- subjacent to the basal cells; therefore, it
(81 1). sis, (2) diffuse and multifocal white patch- may be misdiagnosed as lichen planus
es, (3) slowly progressive horizontal and in early stages {311,839}. However, the

f'l'\,~ f l::.~
Fig. 4.05 Oral epithelial dysplasia. A Hyperkeratosis with normal architecture and cytology. B Mild dysplasia: lack of polarization of basal cells, abnormal variation in nuclear size,
shape, and stainability (hyperchromasia), and increased number of mitotic figures. Changes are confined to the basal third of the epithelium. C Moderate dysplasia: drop-shaped
rete ridges, mild abnormal variation in nuclear size and stainability (hyperchromatism), increased nuclear/cytoplasmic ratio, and atypical mitotic figures in the basal/parabasal area.
Changes extend to the mid-third of the epithelium.

114 Tumours of the oral cavity and mobile tangue

presence of any dysplasia precludes the suppressor proteins p16 (p161NK4a) and rate of 30-40% (2,311 ). Carcinomas aris-
diagnosis of lichen planus. Diagnosis p14ARF, is more frequent in PVL {1279} ing from PVL have better prognosis and
also requires the distinction of PVL from than in other oral potentially malignan! long -term survival !han do conventional
other white oral lesions by correlating the disorders. Like other oral potentially ma- oral cancers. The development of multi-
clin ical and microscopic presentations lignan! disorders, PVLs also develop ple primaries at different locations is not
both retrospectively and prospectively chromosomal instability, and DNA an- uncommon in patients with PVL {36).
through clase surveillance. euploidy can predict their risk of devel-
oping into carcinoma {1234).
Genetic profile
lnactivation (by homozygous deletion) Prognosis and predictiva factors
of COKN2A (also called P16/NK4a and As many as 70% of PVLs develop into
P14ARF), which codes for the tumour invasive cancer, resulting in a mortality


Squamous ce// papilloma Etiology dome-shaped and have a more nodular,

HPV infection has been reported, with papillary, ar verrucous surface (1925,
Muller S. the most common types being 6 and 11 2284). Most squamous cell papillomas
Gale N. (886,1168,1668,2324}. Reported preva- are solitary and grow rapidly to about
Odell E.W. lence rates of HPV DNA in oral squa- 0.5 cm. Clinically distinguishing oral
Richardson M. mous cell papillomas range from 0% to squamous cel l papilloma from verruca
Syrjanen S. 100% (average: 34%) {1168,1668). This vulgaris, condyloma acuminatum, and
considerable variation may be due to dif- multifocal epithelial hyperplasia is diffi-
ferences in the HPV detection techniques cult [2325). Multiple papillomas can be
Definition used . seen in the setting of solid organ trans-
Squamous cell papilloma is a benign hy- plant and HIV infection .
perplastic exophytic localized prolifera- Localization
tion with a verrucous or cau liflower-like Any oral site can be involved, but the Histopathology
morphology [2284l. most common sites are the soft palate, The lesions are exophytic, composed
tangue, lips, and gingiva (1914,1925, of papillary proliferations of hyperplas-
ICD-0 code 8052/0 2284). tic stratified epithelium that are either
covered by a layer of parakeratin or or-
Epidemiology Clinical features thokeratin of variab le thickness or are
Squamous cell papillomas are common Squamous cell papillomas may" be pe- non-keratinized (2284} . The finger-like
and can occur in patients of any age, dunculated or sessile. The pedunculated epithel ial projections extend from a nar-
although they occur more frequently lesions are composed of a cluster of fin- row base, supported by fibrovascular
in the third to fifth decades of lite ger-like fronds and may be white or mu- cores containing dilated capillaries. The
{1914,1925,2284) . There is an equal sex cosa! in colour, depending on the degree stroma may be oedematous or hya-
distribution. of keratinization. The sessile lesions are linized. Koilocytes are infrequent and

Papillomas 115
mitotic activity unusual, except in the set- Etiology Histopathology
ting of trauma or inflammation [2284). HPV type 6 or 11 is identified in most Histopathology shows a hyperplastic
cases. Neither histological appearance squamous proliferation associated with
Prognosis and predictiva factors nor HPV type is an accurate indicator of fibrovascular cores, exophytic growth,
Treatment is simple excision, and recur- genital origin, and non-sexual transmis- and a broad base. Basilar nuclear en-
rence is unusual {1914). There have been sion is possible {2325}. largement may be present, but keratino-
no reports of malignan! transformation or cyte maturation is maintairied, typically
dissemination. Localization without the keratinizati on seen in verruca
CAs most o/ten occur on the labial mu- vulgaris. Compared with squamous cell
cosa, soft palate, and frenulum {2284}. papillomas, CAs have broader papillae,
Condyloma acuminatum wh ich are o/ten blunted. The rete pro-
Clinical features cesses are bulbous, short, and straighter
Vigneswaran N. Clinically, CA presents as a single or than those seen in papillomas, and
Lippman S. cluster of asymptomatic, painless ses- koilocytes are more readily identified
Muller S. sile masses with an exophytic growth [77). In situ DNA hybridization or PCR
Williams M.O. pattern. The surface is finely nodular, amplification studies may be required
pink to slightly red , and tlatter than that far detection and typing of HPV to distin-
of verruca vulgaris. The lesions are larger guish these lesions from other exophytic
Definition than squamous cell papillomas; reaching growths, including verrucous squamous
Oral condyloma acuminatum (CA) is the 15 mm in diameter {976,2284). ce ll carcinoma.
oral equivalent to anogenital CA.
Prognosis and pred ictiva factors
Synonym Recurrence after excision is common and
Venereal condyloma more frequent than in squamous cell pap-
illomas. Malignant transformation has not
Epidemiology been reported in oral CA. HPV vaccines
Oral CAs are frequently transmitted that protect against types 6 and 11 could
sexually, with a peak incidence in young also help to prevent associated CA {993}.
adults and a male predominance {1258,
2284). Autoinocu lation in patients with
genital CA has been reported. Occur-
rence in children may be associated with Fig. 4.09 Condyloma acuminatum. Clinically, a sessile,
sexual abuse {2284). Multiple CAs may flnely nodular, pink mass is identifled on the frenulum of
indicate immunodeficiency. the tangue.

116 Tumours of the oral cavity and mobile tang ue

Verruca vulgaris The elongated rete ridges converge to- Epidemiology
wards the centre. A prominent granular M ultifocal epithelia l hyperplasia (MFEH)
Muller S. cell layer with keratohyalin granules often is more prevalen! in ch ildren and ado-
Lippman S. shows koilocytic changes. lescents with a female predominance as
Wil liams M.O. high as 5:1 {1965,2042). First reported in
Prognosis and predictive factors Native Americans and Eskimo peoples,
Spontaneous regression is seen, par- it is panracial, documented in a lmost
Definition ticu larly in ch ildren. Treatment is simple every ethnic group and geographical
Verruca vu lgaris (VV) is a benign virus- excision, and recurrence can occur (886, reg ion {2042).
induced hyperplastic localizad pro lifera- 1455,1925).
tion w ith a verrucous or caulif lower-like Etiology
morphology {2284). HPV types 13 and 32 are implicated.
Mulfocalepfthellalhyperplasia However, other genotypes such as 1, 6,
Epidemiology 11 , 16, 18 and 55 have also been detect-
VV is the most common HPV-related le- Vigneswaran N. ed {974,2042}. MFEH in o lder patients is
sion of the skin, but can also occur in the Carlos R. mainly caused by HPV 32 (2042). Low
oral mucosa, perhaps as a result of au- Lippman S. socioeconomic status, malnutrition and
toinoculation {886,1925). Oral VV is most Mosqueda-Taylor A. c rowded living conditions are thought
common in the third to fourth decade of Muller S. to be contributing factors. These prob-
life, w ith a slight male pred ilection. Williams M.O. ably explain the striking epidemio logi-
cal d ifferences between developed and
Etiology developing countries . HIV patients have
Commonly reported HPV types include Definition increased risk for MFEH (2042,1 233}.
2, 4, 40, and 57 {541,1455,2284). Multifocal benign squamous epithe-
lial proliferation exclusively affecting oral Localization
Localization mucosa, caused by human papilloma The most common locations for MFEH
The most common ly reported oral sites virus (HPV) {1965,2042). are the lips, buccal mucosa, and bor-
are the lips, hard palate, anterior tongue, ders of the tongue. Hard palate and g in-
and gingiva. Synonyms giva are rare ly affected {2042}. The low-
Heck disease; focal epithelial hyperplasia e r lip is characteristically more affected
Clinical features than the upper lip, and most lesions in
VV is asymptomatic. lt may be peduncu- the buccal mucosa are located along the
lated or sessile with a rough pebbly or occlusal plane.
papillary white surface {1455,1925,2284).
VVs grow rapidly (to a maximum size Clinical features
of < 5 mm), and multiple or cluste red MFEH presents as multiple papules sim-
lesions can occur. ilar in colour to the adjacent mucosa,
measuring up to 5-10 mm. They may
Histopathology coalesce, forming plaques that may be-
VVs are exophytic, composed of papil- come secondarily ke ratinized. The most
lary proliferations of hyperplastic strati- common appearance is a papulonodula r
fied epithelium that are covered by a Fig. 4.11 Multiple papules in the lower lip mucosa of a form w ith a smooth surface that occurs in
thick layer of orthokerati n 1925,2284). 15-year-old boy. the non-keratinized mucosa.

Papillomas 117
functional inactivation of the RB gene
and hence p16 immunohistochemistry
has no diagnosti c role.

Genetic susceptibility
Familia! transmission of MFEH is linked to
the presence of HLA-DRB1*0404 (810).

Prognosis and predictive factors

Most lesions in children spontaneously
disappear al puberty or with improved
living conditions.

Fig. 4.12 Focal epithelial hyperplasia, viral change and mitosoid body (inset).

Histopathology representing a cytopathic nuclear viral

MFEH shows mild hyperkeratosis and damage, are noted within ali epithelial
prominent acanthosis, with preserva- layers {2042). The mitosoid figures are
tion of normal cell maturation {2042). the most importan! feature of this entity;
Occasional koilocytes and "mitosoid" they are not present or are extremely rare
figures composed of cells with karyor- in other HPV-related lesions. HPV sub-
rhectic nuclei that may mimic mitoses, types implicated in MFEH do not cause

118 Tumours of the oral cavity and mobile tangue

Tumours of uncertain histogenesis

congenital granular ce// epulis overlying surface epithelium is usually at-

tenuated, and pseudoepitheliomatous
Allen C.M . hyperplasia is not a feature. The tumour
Bullerdiek J. nuclei are typically small, uniform, and
RoJY pale-staining, with no evidence of mitotic
activity {428). In most cases , numerous
small, thin-walled blood vessels are uni-
Definition formly distributed throughout the lesion .
Congenital granular cell epulis is a rare Unlike the lesiona! cells of granular cell
benign tumour that affects the alveo- tumour of the tangue, those of congenital
lar processes of newborns and is com- Fig. 4.14 Congenital granular cell epulis of the maxilla. granular cell epulis show no reactivity for
posed of sheets and nests of cells with S100 protein.
abundan! granular cytoplasm {479).
Prognosis and predictiva factors
Synonyms Conservative excision is the treatment
Congenital epulis; congenital epulis of of choice, particularly if the lesion in-
the newborn; congenital gingival granu- terferes with eating or breathing !1304).
lar cell tumour; Neumann tumour Excisional biopsy may also be indicated
if the clinical diagnosis is uncertain. For
Epidemiology smaller lesions, observation may be ap-
Congenital granular cell epulis affects propriate, because spontaneous regres-
newborns. Most series identify a striking sion has been noted occasionally. Recur-
female predilection {2698). Fig. 4.15 Congenital granular cell epulis. Lesiona! rence is not seen.
cells with small, uniform nuclei and abundan! granular
Localization cytoplasm.
Most cases develop on the maxillary Ectomesenchymal
anterior alveolar process, although the from < 1 cm to severa! centimetres in di- chondromyxoid tumour
mandibular anterior alveolar process can ameter {1293).
also be affected {428}. Bishop J. A.
Histopathology Gnepp D.R.
Clinical features Congenital granular cell epulis is char- Ro J.Y.
Congenital granular cell epulis typically acterized by sheets and nests of larg e
presents as a pedunculated soft tissue polygonal cells with demarc ated cell
mass of normal mucosa! colour, ranging membranes and granular cytoplasm . The Definition
Ectomesenchymal chondromyxoid tu-
... mour (EMCMT) is a benign mesenchy-

- ,
..~ 1:. -
,.- J
; ". . . "'.

,{.,~ -...
~ ,
'_,; - _,;.t~.. .;' ~,.,,, ...-... ~~ ..~ . ~ . ~., ~ - ~";. ...:. ..
/ 41':,,~.,' . . ~ .... ,., .:~.

:..;,.1,,.- ;.. ~ ...-...... ' --:k ~. .._ ,

" ... -... ... ,.
--9:. . - ~ - - : ;
>-#:. . ,,
- , .
i~'-li'i''j mal neoplasm composed of cells pheno-
typically resembling myoepith elial cells.

: >;
., _-,. -:. ti ~-.. ~!J: .... a_ ,. .. -.. ...>_~... ..

1, .,,


... ...~ -- . .


l.-.. .. t .

:...: :. ~
# ,


-- ~.. .....


...... . . . . .

. ,.... -
,. 'IJ


~~w,: ; . - ,-~,. : ."'~--- -:

"' - ~

, ~
. ...


~ ! ...,..,~

, ..... ~~ !...,,

ICD-0 code 8982/0

'le ~-,
,'.. . '.ti
,111~ ..:--,,..,. ,,._."/

,./ /
\ , ,.: . ...
._"t... -


.. ., -.__..

...,_~ ... - -

.:~ , .,

, ... '\ "'"'
~ -.

.... /. -
_,., ' :, ' ,~~
. , ~ .
, , ,..-. ,. -..!' "' )-.,,.,. \""'.,.,. , }- 7 ": ; ., ..... ,, -"'
. : ...,.-'~.. . . Myoepithelioma {1736,2630}
,.~ " , ,. .... f # _,
', ' ' -; ; ... 'L , J * ~ "' ..,, . ...., ~ 1~
, l -, ,~"
\ ~ """,. . , , . .,. .. , ,- ',; . ,, .. . , ... 61. Epidemiology

I ' ..
... ..._
..., ,,
.. "".

.J. ,
:" ,.

r ' / '' - . -

A. ,
' 7
About 60 cases of EMCMT have been
~ .... __, "' " .... , ' ,, ,. ' ,.,, , ' ..... . .. tlll!" reported, affecting a wide patient age
1'4 , .,. ~" 1111! .. ~

~" L ' .....

!:' ~~
.M ' ',, . ; _ , . , " ' , ' , ' ... - .. .
. ~ ., ~ . .. ..l. t ., . ,,, .. ..... t ~- 1 ... t range (7- 78 years), with a mean patient
J, ~ 4 1'
..,. ' I .,,,
1 ,. '
~ ~ ~~ ~, ..-, . ' .
., -
' ~"i
;. ~ ~
, -
~- .. - ....
'1 ' . . . 4(1' ., " _..
, ..... . . .,.
. ~ .... ., . " . '

.. .


Fig. 4.13 Congenltal granular cell epulis. Bland, attenuated surface oral epithelium and underlying sheets of uniformly
- . ' . "} '
age of 37 years. No sex predilection is
apparent (44,2218}.

distributed lesiona! cells with scattered delicate blood vessels.

Tumours of uncertain histogenesis 119

Localization Histopathology EMCMT is consistently immunoreactive
In the oral cavity, EMCMT arises almos! ex- EMCMT is an unencapsulated but fa r GFAP and usually immunoreactive far
clusively in the dorsum of the anterior tangue. generally well-circumscribed neoplasm S100 protein and CD57. lmmu nostaining
Rare cases have been reported in the poste- within the tangue submucosa. Entrap- far cytoke ratins, EMA, actin, and p63 is
rior tangue and hard palate {44,1735). ment of skeletal muscle fi bres may be variable [44,2218).
seen. At low power, EMCMT grows as
Clinical features lobules of cells separated by fibrous Cell of origin
EMCMT presents as a longstanding bands, with freq uent slit-like clefts within The cell of orig in is unknown . EMCMT
(present fo r months or even years), pain- the tumour. The tumour cells are round, may arise from undifferentiated ectomes-
less, submucosal tangue mass without fusiform, or spindled cells arranged in enchymal cells from the embryonic neu-
ulceration. cords, sheets , or a reticulated pattern ral crest mesenchyme of the first b ranchi-
within a myxoid or chondromyxoid al arch [2218). Minar salivary gland origin
Macroscopy stroma. Tumour cells have moderate is less likely, given th e inconsistent cy-
EMCMTs are generally small (< 2 cm), amounts of eosinophilic to amphophilic tokeratin immunostaining and absence of
circumscribed, tan-g rey nodules with a cytoplasm, indistinct cel l borders, and minor salivary glands in the dorsal ante-
gelatinous gross appearance. nuclei with irregular membranes (e.g. rior tangue {880}.
with indentations or pseudoinclusions).
Cytology Hyperchromatic nuclei and nuclear Prognosis and predictive factors
Cytology shows cellu lar smears with enlargement or multinucleation may be The prognosis is excellent, with a low risk
myxoid to thick fibrillary tissue fragments, encountered . Mitotic figures are rare. of recurrence.
with clusters of oval, polygo nal, or spin- Plasmacytoid cells and ductal structures
dled cells with uniform nuclei [440). are not encountered.

120 Tumours of the oral cavity and mobile tangue

Soft tissue and neural tumours

Granular ce// tumour

Allen C.M.
Gnepp D.R.
Ro J.Y.

Granular cell tumour is an uncommon
benign tumour of Schwann-cell differen-
tiation characterized by poorly demar-
cated accumulations of plump granular
cells (2458).

ICD-0 code 9580/0

Granular cell myoblastoma; granular cell
schwannoma; granular cell neurofibro-
ma; Abrikossoff tumour (ali obsolete)

Most granular cell tumours are diagnosed
duri ng the third to fifth decades of lite,
although they may occur in patients
of any age. Most reports describe a
female-to-male ratio of 2:1, anda higher Clinical features granular cell tumours have a significan!
incidence in Black populations has been Granular cell tumour presents as a non- degree of background fibrosis, with rela-
noted . tender, rubbery-firm, slow-growing, ses- tively few lesiona! cells. The cytoplasmic
sile, submucosal mass. On palpation, the granules give a diastase-resistant posi-
Localization tumour often feels demarcated, but not tive peri odic acid-Schiff (PAS) reaction.
Although granular cell tumour can affect encapsulated. lf the tumour is near the lmmunohistochemistry is positive for
any subcutaneous ar submucosal site, surface, a yellowish to creamy-white col- S100 protein, CD57, and SOX10 {72).
approximately 30-40% of cases occur our is afien apparent. Most granular cell CD68 antibodies also label th e cytoplas-
on the tangue. The buccal mucosa is the tumours are solitary, but multiple tumours mic granules . Pseudoepitheliomatous
second most common intraoral site. have infrequently been reported (2074). hyperp lasia overlies a substantial propor-
tion (30- 50%) of these lesions; therefore,
Macroscopy care should be taken when evaluating a
On cut surface, the tumour is a pale tan superficial biopsy sample to preven! an
to yellowish-white submucosal nodule. erroneous diagnosis of squamous cell
carcinoma. Rare cases of granular cell
Histopathology tumour with concurren! squamous cell
This unencapsulated submucosal tumour carcinoma have been reported, so care -
intermingles with the adjacent normal tis- ful and thorough evaluation of sections is
sue. The lesiona! cells usually appear po- necessary {1 68l. Rare examples of ma-
lygonal and exhibit abundan! eosinophil- lignant granular cell tumour (character-
ic granular cytoplasm . The tumur nuclei ized by pleomorphism , mitotic activity,
may be centrally or eccentrically located spindle-shaped lesiona! cells, and ne-
and are typically uniformly small, round, crosis) have also been described (2458).
Fig. 4.17 Granular cell tumour. Sessile nodule of the and pale-staining . The granular cells are
dorsal tangue showing intact surface mucosa that is often intimately associated with adja-
stretched by the underlying tumour. cent muscle fascicles or nerves. Sorne

Soft tissue and neuml tumours 121

Cell of origin space (affected in 36% of cases), larynx Genetic profile
lmmunohistochemical studies suggest (15%), submandibular (14%), paratrache- Aberrations of the PTCH1 locus have
differentiation consistent with an origin al region adjacent to the thyroid gland been reported in fetal rhabdomyomas
from Schwann cells {1976}. (12%), tangue (11 %), and floor of the {982\, which may be associated with
mouth (9%) {540). naevoid basal cell carcinoma syndrome.
Prognosis and predictive factors
Although recurrence is possible, the like- Clinical features Prognosis and predictive factors
lihood seems to be low, even when le- The tumours present as soft, painless Recurrences are uncommon after surgi-
siona! tissue appears to have been tran- and non-tender masses. cal excision. Malignant transformation
sected at the margins {2458}. does not occur.
Rhabdomyoma presents as a well-de-
Rhabdomyoms lineated, rounded or coarsely lobulated, Lymphangioma
sessile or pedunculated smooth submu-
Bullerdiek J. cosal mass that is greyish-yellow to red- Bullerdiek J.
Ro J .Y. dish-brown on cut surface. The tumours Flucke U.
Thompson L.D.R. can be 0.5-10 cm, with most examples
measuring 1-3 cm . There is no haemor-
rhage or necrosis. Definition
Definition Lymphangioma is a congenital malfor-
Rhabdomyoma is a benign tumour with Histopathology mation of lymphatic vessels.
skeletal muscle differentiation. The adult type is composed of variably
sized, deeply eosinophilic polygonal ICD-0 code 9170/0
ICD-0 code 8900/0 cells and cells with vacuolated cytoplasm
(spider cells). Rod-shaped cytoplasmic Synonyms
Epidemiology crystals (so-called jackstraws) or cross Lymphangioepithelioma (obsolete);
Rhabdomyoma is divided into fetal, ju- striations may be seen. Necrosis and mi- lymphangiomatous polyp
venile, and adult subtypes on the basis toses are absent. The fetal type is com-
of histology rather than patient age. For posed of an intimate, haphazard-looking Epidemiology
adult rhabdomyoma, patient age var- mixture of round or spindled mesen- Lymphangiomas are rel atively uncom-
es broadly (with a median age in the chymal cells and differentiated cells mon. They are usually diagnosed in in-
sixth decade of life {457)). Fetal rhabdo- with myofibrils within an occasionally fancy or early childhood.
myoma usually occurs in newborns and myxoid mucopolysaccharide-rich matrix .
during early childhood . There is a male There is a gradient of cellularity or matu- Localization
predominan ce. ration towards the periphery. Strap cells The skin and subcutaneous tissue of the
with eosinophilic cytoplasm, occasionally head and neck region is the most com-
Localization with cross striations, may be seen. 'here mon localization far lymphangiomas, but
Rh abdomyomas occur predominantly is immunopositivity for SMA, desmin, my- they are only occasionally re ported in
in the head and neck. About 15% of pa- oglobin, and MYOD1; fetal myosin may the oral cavity. lntraoral lymphan giomas
tients with adult rhabdomyoma present be seen in th e fetal type. S100 protein arise most commonly on the dorsum of
with multifocal disease (1427}. Common and GFAP may be focally expressed . the tangue, followed by the palate, buc-
localizations are the parapharyngeal ea! mucosa, gingiva, and lips {2450}.

122 Tumours of the oral cavity and mobile tongue

pericytes. The lumina may be subtle or
d ilated, especially in infantile haemangi-
omas {280,1 141). Cavernous haemangio-
mas show larger dilated vascular spaces
lined by endothelial cells. The endothe-
lial cells are positive for CD34, CD31 ,
and ERG {280,1611). GLUT1 is positive
in infantile haemangioma but negative
in pyogenic granuloma, vascular ecta-
sias, and congenital haemangioma {280,
1141,1746). Haemangiomas must be dis-
tinguished from pyogenic granulomas,
which are ulcerated reactive lesions fre-
quently arising on the g ingiva and char-
acterized by lobular accumulations of
maturing vascular granulation tissue.

Clinical features Haemangioma Genetic susceptibility

Clinical behaviour vares, with erratic Haemangiomas have been described
growth, progression, or even spontaneous Bullerdiek J. in carriers of various chromosomal ab-
regression during the first two decades Flucke U. normalities {39,2425,2484) and are fre-
of lile. Symptoms are related to size and quently associated with full or partial
perturbation of structure {280,2450). The polysomy 13 {108,1443,2007] .
lesions can be pedunculated or sessile. Definition
Oral haemangiomas are benign vascu lar Prognosis and predictiva factors
Histopathology hamartomas affecting the mucosa. They lnfantile haemangiomas initially grow rap-
The malformations consist of variably are distinct from vascular ectasias, vas- idly, but most subsequently involute and
sized, irregular, thin-walled fluid-fil led cu lar malformations, and s (also called require no intervention. Successful treat-
spaces lined by lymphatic endothe- lobular capillary haemangiomas). ment options are beta blockers, steroid
lium surrounded by a stroma of fibrous, injection, endovascular sclerotherapy,
smooth-muscle, and adipose tissue, ICD-0 code 9120/0 and surgery {15,1669,2577).
along with lymphocytes {280}. The vas-
cular endothelial cells are immunoposi- Epidemiology
tive for CD31 or CD34 {1186), podoplanin Haemangiomas are frequent childhood Schwannoma and neurofibroma
(as recognized by 0 2-40), PROX1, and tumours with a female predominance.
VEGFR3. Lymphatic endothelial cells They occur commonly in the head and Flucke U.
stain for LYVE1 {280,1163,1536}. The neck region in both children and adults, Wenig B.M.
wal ls of the lymphatic vessels stain posi- but only rarely in the oral cavity (including
tively for SMA (1186,1977}. the tangue) {11,235,1290). However,
haemangioma (infantile haemangioma) Definition
Genetic susceptibility is the most common benign tumour of Schwannoma and neurofibroma are be-
Like other vascular anomalies, malfor- the oral cavity and mobile tongue in the nign peripheral nerve sheath tumours.
mations of lymphatic vessels are com - paediatric population {1502,2080) Schwannoma consists of Schwann cells,
mon in Proteus syndrome {465}, wh ich is and neurofibroma consists of an admix-
caused by a somatic activating mutation Localization ture of Schwann cells, fibroblasts, peri-
in AKT1 {1437). Other genetic disorders In the oral cavity, haemangioma can neurial-like cells, and axons.
associated with lymphang ioma include arise in the tongue, lips, buccal mucosa,
Turner syndrome {45,X syndrome) and gingiva, and palate {1502,1669,2682}. ICD-0 codes
trisomy 21 {280}. Schwannoma 9560/0
Clinical features Neurofibroma 9540/0
Prognosis and predictiva factors The tumours present as smooth reddish-
Recurrences may occur alter surgical purple polypoid or pedunculated mass- Synonyms
resection {280}. es, often with increasing size and occa- Schwannoma: neurilemmoma;
sional bleeding. neurinoma

Histopathology Epidemiology
Capillary haemangiomas consist of Schwannomas usually occur in adults.
multilobular arrangements of proliferat- Neurofibromas are the most common
ing endothelial cells and capillaries of benign peripheral nerve sheath tumour
various shapes and sizes surrounded by affecting infants, ch ildren , adolescents,

Soft tissue and neural tumours 123

and adults {357,933,2005) . random rearrangement of spind le cells in a Kaposi sarcoma
collagenous to myxoid stroma. The nuclei
Etiology are wavy and the cytoplasm inconspicu- Thompson L.D.R.
Most lesions occur sporadically (933, ous. Mitotic figures are usually absent. The Ro J.Y.
2005). collagen bundles typically have a so-called Wenig B.M.
shredded-carrots appearance {2005}.
Localization Schwannomas show strong and diffuse
lntraorally, the tangue is the most corn- nuclear and cytoplasmic S100 protein Definition
mon site, followed by the palate, bucea! expression, as we ll as nuclear S0X10 Kaposi sarcoma is a locally aggressive
mucosa, floor of the mouth, lips, gingiva, reactivity. Scattered CD34-positive cells vascular neoplasm of intermediate type,
and jaws {656,933,1311,1440,1499}. may be seen. In contras!, neurofibromas uniform ly associated with HHV8.
show heterogeneous expression of these
Clinical features markers (357,952,1183,1797,2005}. ICD-0 code 9140/3
Patients present with a slow-growing,
sometimes painful, submucosal mass. Genetic profile Synonym
Multiple neurofibromas are associated Schwan nomas are characterized by loss Kaposi disease
with neurofibromatosis type 1 {357,933, of chromosome 22 and inactivating mu-
952). tations in NF2 {2267}. Neurofibromas Epidemiology
are characterized by inactivation of NF1 Kaposi sarcoma is separated into tour
Macroscopy {357}. distinct epidemiological categories (Ta-
Both lesions are nodular with a tan- ble 4. 06); of these, only the AIDS-related
white, glistening cut surface. An associ- Genetic susceptibility (HIV-1-related) type is associated with
ated nerve can occasionally be identified Neurofibroma is associated with neurofi- oral manifestations {697,1812,1897). As
{357,2005). bromatosis type 1 (357,2005}. many as 20% of individuals with HIV-1
infection develop oral Kaposi sarcoma,
Histopathology Prognosis and predictiva factors usuall y in the fou rth to fifth decades of
In mucosal sites, schwannomas are typi- Both tumours follow a benign clinical lite. In industrialized countries, it is most
cally submucosal and circumscribed but course. Neurofibromas have the potential common in horno- and bisexual HIV-1-
unencapsulated. They are composed of for malignan! transformation, especially infected men, whereas there is no sex
a spindle-cell proliferation arranged in al- in patients with neurofibromatosis type 1 difference in developing countries {1811,
ternating cellular Antoni A and hypocellu- (357,933,952,2005,2069}. 2538).
lar Antoni B areas. The spindle cells have
oval, tapered, or buckled nuclei with poorly Etiology
defined eosinophilic cytoplasm. Nuclear Kaposi sarcoma is always associated
palisading is a frequent feature, occasion- with the gamma-2 herpesvirus HHV8
ally with Verocay body formation. Degen- (also called Kaposi sarcoma- associ-
erative nuclear atypia and mitotic figures ated herpesvirus; KSHV). The neoplasm
should not be interpreted as ominous develops in a complex dynamic with
signs. Associated hyalinized blood vessels HIV-induced immunosuppression and
and foamy histiocytes are common. Haem- environmental and genetic factors alter
orrhage and lymphocytes may be present exposure to HHV8 in saliva or blood (122,
{952,2005). 1347}.
Neurofibromas are characterized by

124 Tumours of the oral cavity and mobile tangue

Table 4.06 Clinical and epidemiological forms of Kaposi sarcoma. Adapted from Barnes Letal. (146) and Fletcher CDM et al. {735} Myofibrob/astic sarcoma
Type Risk group Siles of involvement Clinical course
> 70% elderly men; Flucke U.
Classic Skin of lower extremities lndolent
Slavic, Jewish, ltalian Franchi A.
Skin of extremities; visceral
Endemic involvement common; lym- lndolent in adults;
Children and middle-aged men
(African) phadenopathic type common aggressive in children Definition
in children Mycfibroblastic sarcoma is a low-grade

Solid organ transplant recipients malignant infiltrative tumour of the deep

latrogenic/ Variable; may resolve
(0.5% of renal transplant patients}; Skin of extremities; may have soft tissue, with a predilection for the
transplant- upon cessation of im-
patients receiving immunosuppres- visceral involvement head and neck. lt has a variety of ap-
associated munosuppressanls
sive therapy pearances, from fasciitis-like or fibroma-
HIV-infected patients; more com- Skin of head and neck, tosis-like to fibrosarcoma-like.
mon in horno- and bisexual men extremities, genitals, mucosa
AIDS-related Aggressive
at younger age than classic Kaposi of upper aerodigestive tract; 1
ICD-0 code 8825/3
sarcoma lymph nodes
Localization mitoses {299,697,1811). Papillary tufting Myofibrosarcoma
The hard palate, followed by the gingiva within large dilated anastomosing ves-
and tongue, is the most common oral site. seis is seen in lymphang iomatous Kaposi Epidemiology
Up to 70% of patients with cutaneous Ka- sarcoma {1931}. The neoplastic cells are The tumours can occur in patients of any
posi sarcoma also have oral lesions. positive for HHV8, podoplanin (as recog- age, with a mean patient age of 40 years
nized by 02-40), LYVE1, VEGFR3, PROX1, !724,1591).
Clinical features CD34, CD31, FLl1 , and ERG, with HHV8
Patients present with multiple red to viola- positivity being most specific !1813). Localization
ceous macules or papules that progress The oral cavity, including the tongue, is
to plaques or nodules. Bleeding, ulcera- Cell of origin a preferred site. Rarely, these tumours
tion, and pain may be seen in advanced Phenotypically, the cells of orig1n are arise in the nasal cavity and paranasal
disease. Lymphoedema is uncommon lymphatic endothelial cells {322}. sinuses. Origin in bone, notably gnathic
!697,1812,1837). bone, can also occur. Low-grade myofi-
Prognosis and predictiva factors broblastic sarcoma can arise subcutane-
Histopathology Oral Kaposi sarcoma has a higher fatal- ously or in a submucosal localization but
The histopathological appearance devel- ity rate than does AIDS-related Kaposi is in most cases deep-seated {312,724,
ops with disease progression. The patch sarcoma of the skin, due to associated 1268,1591).
stage shows irregularly shaped, slit-like poor prognostic factors such as immune
vascular spaces dissecting collagen bun- status (e.g. CD4 count < 300 cells/ml), Clinical features
dles, often parallel to the epithelium, with ulceration, and nodular type {4.58,1545). Myoibroblastic sarcoma presents as a
extravasated erythrocytes and lympho- Kaposi sarcoma is often multifocal but painless swelling or enlarging mass !1591 ).
cytes: the plaque stage shows further spin- rarely metastasizes.
dle-cell proliferation associated with intra- Macroscopy
and extracellular hyaline globules; and The lesions are firm, with fibrous cut sur-
the nodular stage shows widely infiltrat- faces and typically poorly defined mar-
ing atypical spindled cells with increased gins {1591).

Soft tissue and neural tumours 125

desmin , calponin, and CD34. In rare
cases, h-caldesmon is detected , with only
focal expression {724,1591). Expression of
beta-catenin does not ru le out this tumour
type (335).
At the ultrastructural level, the neoplastic
cells are spindle-shaped, with oval, often
indented nuclei. The cytoplasm contains
numerous rough endoplasmic reticulum
cisternae (which often contain floccu lent
material) and subplasmalemmal bundles
of actin filaments, with or without focal
densities, sometimes associated with
subplasmalemmal attachment plaques
Pinocytotic vesicles and fibronexus junc-
tions are present in sorne cases {681,725).
Histopathology nuclei are atypical and show hyperchro-
The p attern is that of a rather ce llular, masia. Mitotic figu res are variably present. Genetic profile
fibromatosis-like or fibrosarcoma-like There are scant or moderate amounts of Complex genetic aberrations have been
lesion composed of fascicles or broad cytoplas m. The background can be col- identified (734).
sheets of cells, with or without focal lagenous or myxoid. Transformation into
herringbone or storiform arrangement. high-grade sarcoma has been reported Prognosis and predictiva factors
Checkerboard -like infiltration of the adja- {312,724,1591 ). lmmunohistochemistry Local recu rrences are common, but
cent voluntary muscle is a key diagnos- shows a myofibroblastic immunopheno- metastatic spread (to lung, soft tissue, or
tic feature. The tapered myofibroblastic type, with variable expression of SMA, bone) occurs rarely {1591}.

Oral mucosal melanoma Williams M.O.

Speight P.
Wenig B.M.

Definition Etiology
Oral mucosal melanoma is a malignant Mucosal melanomas, which are biologi-
neoplasm of melanocytes. cally distinct from lesions of cutaneous
origin, are caused by unknown factors . ,
ICD-0 code 8720/3
Epidemiology Most cases arise on the palate or gingiva
Oral mucosal melanoma is a rare en- {546,1958,2243,2338}.
tity, accounting fo r only about 0.5% of
melanomas. There is a slight male pre- Clinical features
dominance, and the median patient age The neoplasm, wh ich is often asymptomat-
at diagnosis is 55-66 years {385,1584, ic, presents as a 1.5 - 4 cm, blackish-
2238). grey, irregular, flat or nodular lesion , with

. .. ,..... .
~ .. :
.!--;. 1"'"'
..&-ll..1.....:.....t.-.. -' ~' ....., .... ... _,: .J,! --
Fig. 4.24 Oral mucosa! melanoma. Clinical presentation Fig. 4.25 Oral mucosa! melanoma. A Large epithelioid cells with ample eosinophilic cytoplasm are scattered within
shows an irregular, variably pigmented lesion on the hard the epithelial junction and submucosa. Pigmentation may not be identified. B S100 lmmunohistochemical staining
palate. highlights the melanocytic cells, showing both an in situ and an invasive pattern of growth.

126 Tumours of the oral cavity and mobile tang ue

ulceration present in one third of cases . invasive nests, and single cells infiltrate Prognosis and predictive factors
Lymph node metastases at presentation the submucosa. The cells are usually Cutaneous melanoma prognostic tactors
are common, present in about 30% of epithelioid, with prominent nucleoli, but (e.g . Clark leve! of invasion and Breslow
cases /984). spindled cells may be seen. tum our thickness) do not apply. The over-
all prognosis is poor, with a median sur-
Cytology Genetic profile vival of 2 years (11 31,1480,19 18,2238}.
Aspirates of metastatic oral melanoma are Associated mutations include alterations
identical to those of cutaneous melanoma. in KIT (occurring in 10- 30% of cases),
Preparations show malignan! epithelioid, RAS genes (in 10- 20%), and BRAF (in
spindled, or undifferentiated cells. < 10%) {343,1475,1996}.

Histopathology Genetic susceptibility

Atypical pigm ented melanocytes are lncidence vares among different ethnici-
present at the junction (in situ) and/or ties (1475,2243,2338}.

Salivary type tumours

Mucoepdermod carcinoma Macroscopy (678,1834,1900,2082}. PA with in the mo-
Many ap pear as bluish , domed swellings. bile tangue is uncommon {2355,2504).
lnagaki H.
Bell D. Histopathology and genetic profile Clinical features
Brandwein-Gensler M. See the Mucoepidermoid carcinoma The tumour presents as a slow-growing,
section (p. 163) in Chapter 7 (Tumours of painless, submucosal, fi xed (hard pal-
salivary glands) . ate), or mobile (bucea! mucosa) mass.
Definitlon Palatal PAs are located laterally and rare-
Mucoepidermoid carcinoma is a d is- Prognosis and predictive factors ly cross the midline. The tumour is typi-
tinctive salivary gland malignancy com - This tumour has a favourable outcome. Most cally detected early and rarely attains a
posed of mucinous, intermediate (clear- patients present with low-grade tumour and size > 1-2 cm.
cell), and squamoid tumour cells forming low-stage tumour (1700,1769}.
cystic and salid patterns. Macroscopy
See also the Mucoepidermoid carcinoma lntraoral PAs often lack encapsulation.
section (p. 163) in Chapter 7 (Tumours of Pleomorphc adenoma Palatal examples frequently involve the
salivary glands). periosteum or bone.
Bel! D.
ICD-0 code 8430/3 Brandwein-Gensler M. Histopathology
Chiosea S. PAs at these sites d isplay plasmacytoid
Synonym myoepithelial cytological features and
Mucoepidermoid tumour are often unencapsulated. Cutaneous
(not recommended) Definition adnexal d ifferentiation can be seen in
Pleomorphic adenoma (PA) is a benign palatal and lip PAs (i.e. tricholemmal, se-
Epidemiology tumour with variable cytomo rphological baceous, and infundibular cystic features
lt is a rare tumour (213} that most com- and architectural manifestations. The with trichohyalin granules) (2098] . Ec-
monly manifests as intraoral salivary gland identification of epithelial and myoepithe- tomesenchymal chondromyxoid tumour
carcinoma (in 37- 53% of cases), with a lial/stromal components is essential for is the main d ifferential diagnostic consid -
slight female predilection. A wide patient the diagnosis of PA. eration, especially in the tangue (52)
age has been reported, with the mean age See also the Pleomorphic adenoma sec-
in the sixth decade of lite [292,2402} . tion (p. 185) in Chapter 7 (Tumours of sa/i- Genetic profile
vary glands). See the Pleomorphic adenoma section
Localization (p. 185) in Chapter 7 (Tumours of salivary
The palate is the most common intraoral ICD-0 code 8940/0 glands).
site, accounting for > 50% of intraoral
cases {292,2402). Synonym Prognosis and predictive factors
Benign mixed tumour Prognosis of PA is generally good . PA
Clinical features does not recur alter adequate surgical
The tumou rs are often asymptomatic , but Localization excision. See also the P/eomorphic ade-
may cause symptoms, depend ing on the PAs ot the oral cavity most commonly noma section (p. 185) in Chapter 7 (Tu-
site and histological grade. arise in the palate, upper lip, and cheek mours of salivary glands) .

Salivary type tumours 127

Haematolymphoid tumours Ferry J.A.
Li X.-0.

Oral haematolymphoid tumours are neo-
plasms of lymphoid, plasma cell, histio-
cytic/dendritic, and myeloid origin arising
in the oral cavity.

Lymphoma accounts for 3.5% of oral cav-
ity malignancies (897). Approximately 2%
of extranodal lymphomas arise in the oral
cavity {761,2339). Among immunocom-
petent patients, lymphomas mainly af-
fect older adults, and only rarely children.
Th ere is a slight male preponderance
{897,909,1211 ,2464}. Almost ali HIV-pos-
itive patients are young to middle-aged
adult men {909}. The oral cavity is the
most common head and neck site for
involvement by myeloid sarcoma {2724).
Oral p lasmacytoma is rare, accounting
for 0-6% of head and neck extraosseous
plasmacytomas (116,2078). Histiocytic/ Macroscopy lymphoma (see Plasmablastic lympho-
dendritic cell neoplasms are rare (1810). Oral haematolymp hoid tumours p resent ma, p. 129), and Burkitt lymphoma (878,
as poorly defined or discrete masses, 909). Most immunodeficiency-associated
Etiology with or without ulceration. lymphomas are EBV-positive (560,909}.
Most lymphomas arise sporadically. A Lymphomas must be distinguished from
minority of patients are HIV-positive (878, Histopathology indolent and self-limited disorders, such
909,1211) or iatrogenically immunocom- Lymphomas occurring in immunocom- as primary mucosa! CD30-positive T-cell
promised (1387,1652). petent patients are heterogeneous. Dit- lymphoproliferative disorder (see below)
fuse large B-cell lymphoma is most com- {1000,2057) and EBV-positive mucocu-
Localization mon (909,1211}, with germinal-centre taneous ulcer (595). The latter presents
Lymphomas most often involve the pal- and non-germinal-centre B-cell pheno- as a circumscribed ulcerative lesion in
ate or gingiva (and may involve subja- types reported {1790). Others include the tangue or bucea! mucosa of immu-
cent bone), and less often involve the follicular lymphoma {909,1211); MALT nocompromised or elderly patients and
tangue, bucea! mucosa, floor of the lymphoma (909,1211); Burkitt lympho- is characterized by a polymorphous in-
mouth, or lips . One third to half of ali ma {1952}; mantle cell lymphoma {898, filtrate with atyp ical large B cells often
lymphomas arise from bone; the rest 2464}; rare B-lymphoblastic lymphoma resembling Reed-Stern berg cells. EBV-
arise from the mucosa {1211,1952, (2464); and high-grade B-cell lymphoma, positive mucocutaneous ulcer regresses
2464). Most patients have localized NOS {1790}. Burkitt lymphoma is among spontaneously or has a relapsing-remit-
(stage 1/1 L) disease (897). the most freq uent of the rare p aediatric ting course.
lymphomas (1952). T-cell and NK-cell
Clinical features lymphomas are rare in western popula- Prognosis and predictive factors
Non-tender swelling - is most common tions {1211 } but are not infrequent among Outcome depends on the type of lym-
(897,1211,1952,2464), followed by ulce- Asians {1952). HIV-positive patients fre- phoma, disease stage, and patient char-
ration (12 11}, pain, paraesthesia, and quently develop diffuse high-grade B- acteristics, including HIV status (878,897,
numbness (1211,2464}. Systemic symp- cell lymphomas, including diffuse large 909,2464).
toms are uncommon {2464). B-cell lymphoma (909), plasmablastic

128 Tumours of the oral cavity and mobile tangue

CD30-positive T-ce/1
/ymphoproliferative disorder
Feldman A. L.
Soy S.
Ferry J.A.
Ko Y.-H.
Li X.-0.
Pileri S.A.

CD30 -p ositive T-cell lymphoproliferative
disorder (TLPD) is a neo plastic prolifera-
tion of large, CD30-positive T cells aris-
ing in the oral cavity or occasionally other
Fig. 4.27 Primary CD30-positive T-cell lymphoproliferative disorder of the tongue. There is ulceration and infiltration
mucosal siles in the head and neck. This of the skeletal muscle.
entity constitutes a clinicopathological
spectrum of lymphoproliferative lesions,
analogous to the spectrum observed in
primary cutaneous CD30-positive TLPD.
This disorder must be distinguished from
reactive inflammatory conditions of the
oral cavity and from secondary involve-
ment by systemic anaplastic large cell

ICD-0 code 9718/3

There is a male predominance, with a
male-to-female ratio of 2:1. The d isorder cases show a diffuse or sheet-like g rowth observed in sorne primary cutaneous
primarily affects adults, with a mean pa- p attern. A mixed inflammatory back- cases of CD30-positive TLPD and ALK-
tient age in the sixth d ecade of lite {2108, ground may be present, including areas negative anaplastic large cell lympho-
2542). with prominent eosinophils or neutrophils mas {2108}.
{58,2108,2542]. So rne cases of !raumatic
Localization ulcerative granuloma with stromal eosin- Prognosis and predictive factors
The proliferation typically presents in the ophilia may represen! the indolent end Most cases show complete resolution
oral cavity or tongue, but similar lesions of the spectrum of CD30-positive TLPD with local therapy (excision with or with-
have been described in the nasophar- {1 00 0). out radiotherapy), with or without the
ynx, conjunctiva, and orbit {2013,2108, By definition, CD30 is positive, and stain- addition of systemic chemotherapy {23,
2339,2542) . ing is strong and uniform. The large lym- 2108,2542). Occasional cases show
p hoid cells typically show a T-cell phe- spontaneous regression.
Clinical features notype, but often demonstrate loss of
CD30-positive TLPD typically presents one or more pan-T-cell antigens. CD4 is
with a mass lesion, often with ulcera- expressed more frequently than CDS. Plasmablastic lymphoma
tion. Spontaneous regression may occur Cytotoxic markers (i.e. TIA1, g ranzyme B.
(716). Clinical history and staging are im- and perforin) are often expressed, and Boy S.
portan! for excluding secondary involve- EMA may be positive. CD56, ALK, and Ferry J.A.
ment by a systemic lymphoma. EBV are negative {2542). The EBV-pos-
itive cases that have been reported in
Histopathology children most likely represen! ch ro nic ac- Definition
Primary mucosal CD30-positive TLPD tive EBV infection instead {1019). Plasmablastic lymphoma (PBL) is a high-
demonstrates a morphological spectrum grade B-cell non-Hodgkin lymphoma with
similar to that observed in primary cutane- Genetic profile plasma cell immunophenotype and a pre-
ous cases . The neoplastic cells are large Clonal T-cell receptor gene rearrange- dilection for extranodal sites. Diagnosis is
atypical lymphoid cells with pleomorphic ments have been detected in most cases challenging due to the overlap with plasma
nuclei and abundan! cytoplasm. Cells re- {2108,2542). Occasional cases carry re- cell neoplasms and 8-cell lymphomas with
sembling the hallmark cells of anaplastic arrangements of the DUSP22- IRF4 locus plasmablastic differentiation. ALK-positive
large cell lymphoma often are seen. Most on 6p25.3, similar to the rearrangements large 8 -cell lymphoma is excluded.

Haematolymphoid tumours 129

Fig. 4.29 Plasmablastic lymphoma. Typical appearance
in a 39-year-old HIV-positive man; the palate and bucea!
vestibule are most commonly affected in oral mucosa!
plasmablastic lymphoma.

ICD-0 code 9735/3 of reactive T cells, mature plasma cells, Langerhans ce/1 histiocytosis
and pleomorphic giant cells. The neo-
Epidemiology plastic cells are negative far CD19, CD20, Pileri S.A.
PBL is strongly associated with HIV- PAX5, ALK, and HHVB, although there is Feldman A. L.
related immunosuppression , in the set- controversy regarding the allowance of Cheu k W.
ting of which it is AIDS-defining . lt also sorne positivity for B-cell markers (246). Slater L.
occurs in HIV-negative older adults and Variable expression of CD4b, CD10,
iatrogenically immunocompromised pa- CD79a, CD56, EMA, CD38, VS38c,
tients. HIV-associated PBL affects males, CD138, CD30, and cytoplasmic immu- Definition
usually with advanced-stage disease, al noglobulins has been described . MUM1/ Langerhans ce ll histiocytosis is a neo-
an average age of about 40 years. HIV- IRF4, PRDM1/BL1 MP1, and XBP1 typi- plastic proliferation of Langerhans cells
negative PBL more commonly affects cally show strong, diffuse positivity, and (1888).
females (aged > 60 years) with localized the Ki-67 index is usually > 80%. EBV is
disease. Post-transplant PBL, which is positive in > 70% of HIV-associated and ICD-0 code 9751 /3
rare, usually affects older patients with post-transplant cases and in 50% of HIV-
advanced-stage disease. negative cases. Synonyms
Histiocytosis X; eosinophilic granuloma;
Etiology Genetic profile Hand- Schller- Christian disease; Letter-
PBL is associated with EBV infection, MYC aberrations (translocations or gains) er- Siwe disease
which is known to cause a surge in occur in about half of ali cases (248,1652,
plasmablasts (720), and MYC deregula- 2455) Epidemiology
tion, which enhances cellular prolifera- This is a rare tumour, with an annual in-
tion {350,1235), but the exact molecular Prognosis and predictiva factors cidence of 5 cases p er 1 million pop-
pathogenesis is unknown. PBL is highly aggressive, with poor sur- ulation. The peak incidence is among
vival (6- 12 months) (349,350,1467,1652) . patients aged 3- 5 years and there is a
Localization Favourable prognostic factors include slight male predominance, with a male-
Head and neck siles, especially the oral EBV and CD45 positivity {1445,1652}. to-female ratio of 1.5-2:1 {914,977,1 729,
cavity (560}. oropharynx, nasopharynx, low stage, HIV negativity, younger pa- 2058).
and sinonasal trae!, are affected. Lymph tient age, and absence of MYC-IGH gene
nodes are occasionally involved, typi- fusion {350,351}. Localization
cally in HIV-negative patients. Head and neck involve ment occurs in

~-::~- -i"' _.ll. v -~ _

Clinical features
A mass in the mouth, nose, ar sinuses is
the most common clinical presentation,

g . ,~r ~Vi ..1

::M!a '~

i ,. t1tG,~~~. i~~-
.o. i,,u.

.... - 1'i!~i....-..
\j~ -

-~ -~
~ ~
. ~~ . ; , ~

:;;'1 .'
~ ,

with skin ar nada! involvement usually

seen in post-transplant PBL (350,1445,


. , ,. ~ ~ G I\ _. ~~ .~


' 11< 4:~ :
. ( 'IJ
~- ';JI
- ~~fi
/ ~f~ ,1
,-f ~ -
. , ~.:\. '",~
0 1
PBL exhibits a mixture of immunoblast-like ,l.'I..~
1' l.>rr '
~.u0 ?.''{a; ,:,
...,,... ~'(.; ~ t~ ~ J
~ ~~
- , , ~ ~~~t ~~"';e ~'*-,._ :a~h;::.
-"' . - ,; t ~ - ,,., ., !
cells and plasmablasts (medium-sized to
large cells with round nuclei, clumped
_ . . ., . ~..
Fig. 4.31 Langerhans cell histiocytosis. A Neoplastic cells show a large rim of acidophilic cytoplasm and grooved
chromatin, large nucleoli, and ampho- nuclei; in this case, mild atypia can be seen, as well as sorne eosinophils. B Neoplastic cells express CD207 (langerin),
philic cytoplasm) with varying numbers as shown by immunoperoxidase.

130 Tumours of the oral cavity and mobile tongue

60-80% of cases (287,1410,1730). of which not uncommon in head and neck tumou rs Clinical features
25% are part of multisystemic disease (287,1943}. The clinical presentation is often non-
{1730}. The most commonly involved specific.
sites are bone (skull vau lt, temporal bone,
orbit, and jawbone). scalp and peri auric- Extramedullary myeloid Histopathology
ular skin, cervical lymph nodes, parana- sarcoma The tumour mass consists of diffuse
sal sinuses. and oral mucosa (977,1093}. sheets of myeloblasts characterized by
Li X.-0. round to folded nuclei, fine chromatin,
Clinical features Gaulard P. small nucleoli, and scant to moderate
Depending on the site of involvement, amounts of eosinophilic cytoplasm, in-
the clinical presentation may include pain termingled with a variable number of
and swelling, orbi tal mass. skin rash, cer- Definition eosinophilic myelocytes. lmmunohisto-
vical lymphadenopathy, aura! discharge, Extramedullary myeloid sarcoma is a tu- chemically, the tumour cells express vari-
earache, vertigo, facial nerve palsy, and mour mass consisting of myeloid blasts ous myeloid or myelomonocytic mark-
oral ulcer or mass. with or without maturation. involving an ers, such as myeloperoxidase, CD68 (as
extramedullary anatomical site. lt occurs recognized by KP 1), lysozyme, CD33,
Histopathology de novo or can precede. coincide with. or C034 , KIT/C01 17, and CD163. CD43 is
The neoplastic cells have grooved nuclei follow the presentation of acule myeloid commonly positiva.
with minimal atypia {1888]. They are ad- leukaemia, or can constitute blastic trans-
mixed with a variable number of inflam- formation of a myelodysplastic syndrome Genetic profile
matory cells and express S100, CD1a, or myeloproliferative neoplasm {1887}. A variety of chromosomal aberrations,
and CD207 (langerin). Ultrastructurally, such as monosomy 7, trisomy 8, and
they contain Birbeck granules {1344, ICD-0 code 9930/3 inv(16), have been reportad [1887}. The
1888}. t(8;21)(q22;q22) translocation is more
Synonyms common ly observad in paediatric series
Genetic profile Granulocytic sarcoma; ch loroma [1887,2 107}. About 16% of cases har-
Clona! rearrangement of IGH and/or bour NPM1 mutations {688}.
T-cell receptor genes occurs in 30% of Epidemiology
cases (403}. sometimes signifying trans- Extramedullary myeloid sarcoma has Prognosis and predictiva factors
differentiation of a lymphoid malignancy been reported to occur in 3-8% of pa- The prognosis vares, but is often unfa-
(699,2596}. BRAFV600E mutations (or tients with acute myeloid leukaemia [319} . vourable. Patients without bone marrow
less commonly, MAP2K1 or ARAF muta- The median age of patients with head involvement and those who undergo al-
tions) occur in about half of ali cases [118, and neck involvement is 61 years (range: logeneic or autologous stem cell trans-
1719, 1720). 1-85 years), with a male-to-female ratio plantation seem to have a better out-
of 1.2-2.4:1 {2505,27241. come {1887.2505,27241.
Prognosis and predictiva factors
Patients without high-risk organ involve- Localization .
ment (e.g . of liver, spleen, bone marrow, Any head and neck site can be involved,
or lung) have a favourable prognosis, with the oral cavity being most frequently
with a mortality rate of < 10% {79 1,977]. affected {2724}. Rarely, the nasopharynx
However, permanent organ damage is involved {61,1957,2505}.
(e.g. permanent hearing loss. loss of
dentition) and disease reactivation are

Haematolymphoid tumours 131


Tumours of the oropharynx

(base of tongue, tonsils, adenoids)
Squamous cell carcinoma
Salivary gland tumours
Haematolymphoid tumours
WHO classification of tumours of the oropharynx
{base of tongue, tonsils, adenoids)
Squamous cell carcinoma Lymphocyte-rich classical Hodgkin lymphoma 9651 /3
Squamous cell carcinoma, HPV-positive 8085/3* Lymphocyte-depleted classical Hodgkin
Squamous cell carcinoma, HPV-negative 8086/3* lymphoma 9653/3
Burkitt lymphoma 9687/3
Salivary gland tumours Foll icular lymphoma 9690/3
Pleomorphic adenoma 8940/0 Mantle cell lymphoma 9673/3
Adenoid cystic carcinoma 8200/3 T-lymphoblastic leukaemia/lymphoma 9837/3
Polymorphous adenocarcinoma 8525/3 Follicular dendritic cell sarcoma 9758/3

Haematolymphoid tumours
The morphology codes are from the lnternational Classification of Diseases
Hodgkin lymphoma, nodular lymphocyte far Oncology (ICD-0) 1776A}. Behaviour is coded /0 far benign tumours;
predominan! 9659/3 /1 far unspecified, barderline, ar uncertain behaviour: /2 far carcinoma in
Classical Hodgkin lymphoma situ and grade 11 1 intraepithelial neoplasia; and /3 far malignan! tumours.
The classification is modified from the previous WHO classification, taking
Nodular sclerosis classical Hodgkin lymphoma9663/3 into account changes in our understanding of these lesions.
Mixed cellularity classical Hodgkin lymphoma 9652/3 'These new codes were approved by the IARC/WHO Committee for ICD-0.

TNM classification of carcinomas of the lip and oral cavity

TNM classification of carcinomas of the lip node, > 3 cm but::,; 6 cm in greatest dimension
and oral cavitya,b N2b Metastasis in multiple ipsilateral lymph
nodes, ali ~ 6 cm in greatest dimension
T - Primary tumour N2c Metastasis in bilateral or contralateral lymph
TX Primary tumour cannot be assessed nodes, all ::,; 6 cm in greatest dimension
TO No evidence of primary tumour N3 Metastasis in a lymph node > 6 cm in greatest
Tis Carcinoma in situ dimension
T1 Tumour ~ 2 cm in greatest dimension
T2 Tumour > 2 cm but ~ 4 cm in greatest dimension Note: Midline nodes are considered ipsilateral nodes .
T3 Tumour > 4 cm in greatest dimension
T4a (lip) M - Distarit metastasis
Tumour invades through cortical bone, inferior MO No distant metastasis
alveolar nerve, floor of mouth, or skin (of chin or M1 Distant metastasis
T4a (oral cavity) Stage grouping
Tumour invades through cortical bone, into deep/ Stage O Tis NO MO
extrinsic muscle of tongue (genioglossus, Stage 1 T1 NO MO
hyoglossus, palatoglossus, and styloglossus), Stage 11 T2 NO MO
maxillary sinus, or skin of face Stage 111 T1-2 N1 MO
T4b (lip and oral cavity) T3 N0-1 MO
Tumour invades masticator space, pterygoid Stage IVA T1 - 3 N2 MO
plates, or skull base; or encases interna! T4a N0-2 MO
carotid artery Stage IVB Any T N3 MO
Note: Superficial erosion alone of bone / tooth socket by T4b Any N MO
gingival primary is not sufficient to classify a tumour as T4. Stage IVC Any T Any N M1

N - Regional lymph nodes (i.e. the cervical nodes)

Adapted from Edge et al. {625A) - used with permission of the American
NX Regional lymph nodes cannot be assessed
Joint Committee on Cancer (AJCC), Chicago, lllinois; the original and prima-
NO No regional lymph node metastasis ry source far this information is the AJCC Cancer Staging Manual , Seventh
N1 Metastasis in a single ipsilateral lymph node, Edition (2010) publlshed by Sprlnger Science+Business Media - and Sobin
::,; 3 cm in greatest dimension et al. 12228A} .
N2 Metastasis as specified in N2a, N2b, or N2c below "A help desk for specific questions about TNM classification is available at
N2a Metastasis in a single ipsilateral lymph

134 Tumours of the oropharynx (base of tangue, tonsils, adenoids)

TNM classification of carcinomas of the oropharynx

TNM classifcation of carcinomas of the oropharynx,b N2b Metastasis in multiple ipsilateral lymph
nodes, all:::; 6 cm in greatest dimension
T - Primary tumour N2c Metastasis ih bilateral or contralateral
TX Primary tumour cannot be assessed lymph nodes, ali :::; 6 cm in greatest
TO No evidence of primary tumour dimension
Tis Carcinoma in situ N3 Metastasis in a lymph node > 6 cm in greatest
T1 Tumour :::; 2 cm in greatest dimension dimension
T2 Tumour > 2 cm but:::; 4 cm in greatest dimension
T3 Tumour > 4 cm in greatest dimension, or Note: Midline nodes are considered ipsilateral nodes.
extension to lingual surface of epiglottis
T4a Tumour invades any of the following: larynx, M - Distant metastasis
deep/extrinsic muscle of tongue (genioglossus, MO No distant metastasis
hyoglossus, palatoglossus, and styloglossus), M1 Distant metastasis
medial pterygoid, hard palate, mandible; note
that mucosal extension to lingual surface of Stage grouping
epiglottis from primary tumours of the base of the Stage O Tis NO MO
tongue and vallecula does not constitute invasion Stage 1 T1 NO MO
of the larynx Stage 11 T2 NO MO
T4b Tumour invades any of the following: lateral Stage 111 T1-2 N1 MO
pterygoid muscle, pterygoid plates, lateral T3 N0-1 MO
nasopharynx, skull base; or encases the carotid Stage IVA T1-3 N2 MO
artery T4a N0- 2 MO
Stage IVB T4b Any N MO
N - Regional lymph nodes (i.e. the cervical nades) AnyT N3 MO
NX Regional lymph nodes cannot be assessed Stage IVC AnyT Any N M1
NO No regional lymph node metastasis
N1 Metastasis in a single ipsilateral lymph node,
Adapted from Edge et al. {625AJ - used with permission of the American
:::; 3 cm in greatest dimension
Joint Committee on Cancer (AJCC), Chicago, lllinois; the original and prima-
N2 Metastasis as specified in N2a, N2b, or N2c below ry source for this information is the AJCC Cancer Staging Manual, Seventh
N2a Metastasis in a single ipsilateral lymph Edition (201 O) published by Springer Science+Business Media - and Sobin
node, > 3 cm but :::; 6 cm in greatest et al. {2228AJ.
dimension bA help ctesk for specific questions about TNM c lassification is available at

TNM classification of carcinomas of the oropharynx 135

Tumours of the oropharynx
(base of tongue, tonsils, adenoids)

1ntrod uction EI-Naggar A.f<.

Takata T.

Like the nasopharynx, th e orophar- and ethnic differences in the prevalence to the paren! Chapter 7 (Tumours ot sali-
ynx is characterized by lymphoid- of HPV-associated squamous cell car- vary glands, p. 159). Similarly, only hae-
based mucosa and is the target of cinoma, a separate entry for HPV-nega- matolymphoid disorders commonly en-
viral-associated carcinoma. The high tive oropharyngeal squamous cell carci- countered at th is location are presented
incidence of HPV-associated oro- noma has been included. and discussed.
pharyngeal carcinoma has been firmly To minimize redundancy and to maintain
validated and this carc inoma is now consistency, only selected salivary neo-
considered a distinct entity. Accordingly, plasms commonly reported in the oro-
a separate chapter on tumours of pharynx are briefly discussed in this
the oropharynx has been estab- chapter. For more detailed information on
lished. Because of the geographical these tumours, the readers are referred

Squamous cell carcinoma

Table 5.01 Comparison of HPV-positive and HPV-negative oropharyngeal squamous cell carcinoma (SCC)
Squamous ce// carcinoma,
HPV-positive Characteristics HPV-positive HPV-negative

Median age 50-56 years 60-70 years

Westra W.H. -- -
Boy S. Risk factors Sexual behaviour Smoking and alcohol use
1- -
EI-Mofty S.K. Lymph nade metastasis Frequently cystic Uncommonly cystic
Gillison M. -- Reticulated epithelium of
- --
Schwartz M.R. Postulated origin Surface epithelium
invaginated crypts
Syrjanen S. - ,- -
Yarb rough W.G . Dysplasia Rare Often present
Morphology Commonly non-keratinizing SCC Conventional SCC
Grading Not applicable Applicable
p16 immunostaining Positive Negative
Oropharyngeal squamous cell carcino-
ma (OPSCC) associated with high-risk Overall survival rate (3 years) 82% 57%
HPV (OPSCC-HPV) is an epidemiologi-
cally, pathologically, and clinically dis- Etiology Clinical features
tinct form of head and neck squamous OPSCC-HPV is caused by high-risk Unlike HPV-negative OPSCC, OPSCC-
cell carcinoma. HPV, with type 16 responsib le for > 90% HPV typically presents at an advanced
of all cases {507,841,2105). Oral sex is clinical stage, often as a small primary
ICD-0 code 8085/3 an established risk factor for oral HPV in- tumour with nodal involvement. Cervi-
fection. lndividuals with OPSCC-HPV are cal lymphadenopathy, which may be
Synonym less likely than patients with HPV-nega- cystic, is the most common clinical
Non-keratinizing squamous cell tive OPSCC to be smokers; yet tobacco presentation .
carcinoma smoking is associated with significantly
higher oral HPV prevalence and thus Macroscopy
Epidemiology may play sorne role in the progression Although primary tumours may be large,
The incidence of OPSCC-H PV has ris- from oral HPV infection to OPSC(_-;-HPV most are small and not apparent on
en over the past three decades {391 , (685). gross inspection. Nodal metastases are
392,1980). Patients w ith OPSCC-HPV often large and cystic {862}.
are typ ically male, Wh ite, and of higher Local izati on
socioeconomic status {392,841}. The OPSCC-HPV has a strong predilection Cytology
median patient age is 50-56 years (79, for the base of tangue and the palatine Aspirates of metastatic lesions are cel-
841), with a male-to-female ratio of 4:1. tonsils {169). lular, with tumour cells forming cohesive

136 Tumours of the oropharynx (base of tangue, tonsils, adenoids)

sheets and clusters and having hyper- The morphological spectrum of OPSCC- PCR-based assays) performed individu-
chromatic, pleomorphic, and overlap- HPV includes variants with papillary (635, ally or in combination (2598}. Oiffuse im-
ping nuclei {1115). The presence of 1580), adenosquamous {1553), lympho- munoreactivity for p16 is a reliable surro-
squamous differentiation and keratiniza- epithelioma-like (2187), sarcomatoid gate marker for the presence of high-risk
tion is uncommon. Demonstration of p16 (201), and small-cell features {204) . Tu- HPV in oropharyngeal carc inomas, and
or HPV in tumour cells strongly suggests mours resembling basaloid squamous may be sufficient as a standalone test
an oropharyngeal primary. cell carcinoma have also been described for HPV status in tumours with appropri-
{171), as have tumours with populations of ate morphology arising at this site {1401}.
Histopathology ciliated cells (206). The clinical behaviour The possibility of loss of p16 expression
OPSCC-HPV generally exhibits distinc- of the morphological variants (oth er than should also be considered (especially
tive non-keratinizing morphology; grad- the small -cell variant) is similar to that of in patients with traditional risk factors),
ing is not currently advocated . Unlike in OPSCC-HPV with typical morphology. and additional testing for high-risk virus
HPV-negative cases, dysplasia of the HPV-related small ce!! neuroendocri ne should be performed. Positive HPV test-
surface epithelium is rarely identified . carcinoma has an aggressive clinical ing may also point to the oropharynx as
OPSCC-HPV arises from crypt epithe- behaviour and is morphologically char- the most likely primary site for cervical
lium and grows b eneath the surface acterized by small anaplastic cells with lymph node metastasis of undetermined
epithelial lining as nests and lobules, o/- hyperchromatic moulded nuclei, numer- primary (170}.
ten with central necrosis {2599}. Tumour ous mitoses, and necrosis. Recognition When p16 or HPV testing is not available,
nests are o/ten embedded in lymphoid of the small-cell variant is facilitated by OPSCC can be diagnosed as "squa-
stroma, and may be penetrated by lym- an immunohistochemical profile that in- mous cell carcinoma, HPV status un-
phoid cells. Tumour cells display a high eludes weak expression of squamous known " or, if the tumour shows th e char-
N:C ratio anda high mitotic and/or apop- markers (e.g. p63, p40 , and CK5/6) and acteristic non-keratinizing morphology,
totic rate, which often imparts a b asaloid acquisition of neuroendocrine ,markers as "squamous cell carc inoma, HPV not
appearance. (e.g . synaptophysin, chromogranin, and tested, morphology highly suggestive of
Histological grading is not currently ad- CD56). HPV association".
vocated. Keratinization is absent or in-
consp icuous in most cases (414,8421, HPV detection Genetic profile
although a small subset of cases show HPV can be detected by molecular HPV oncoproteins E6 and E7 inacti-
keratin formation. assays (e.g. in situ hybrid ization and vate p53 and RB by targeting them for

Squamous cell carcinoma 137

protein degradation. Somatic mutations
in TRAF3, an immune regulator, are
unique to OPSCC- HPV.
Oncogenic PIK3CA mutation or gene
amplification is significantly more com-
f HPV Viral/ Viral
mon in OPSCC-HPV than in HPV-nega- lnfection lntegration Transcrlptlon
tive cases {1817,2375).

Prognosis and predictive factors

OPSCC-HPV is associated with signifi-
cantly better survival outcomes than is
HPV-negative OPSCC (79, 686,191 1}, but
this favourable prognosis may be tem-
pered by th e adverse effects of cigarette
smoking (79,843].
The risk of tumour recurrence and of the
d evelopment of second primary malig-
nancies is lower with HPV-positive OP-
SCCs than with HPV-negative cases, but
longer follow-up data are needed {79}.

Squamous ce// carcinoma,

HPV-negative Fig. 5.02 Pathogenetic pathway of HPV in oropharyngeal squamous cell carcinoma. Viral DNA is integrated into host
DNA. Transcription of HPV E6 and E7 mRNA leads to inactivation of p53 and RB proteins, and indirectly to accumulation
of p16. Curren! methods can detect HPV at the level of DNA (in situ hybridization or PCR), mRNA (in situ hybridization
Syrjanen S.
or RT-PCR), and protein (p16 immunohistochemistry as a surrogate marker). Reprinted from Bishop JA et al. {200).
Assaad A.
EI -Mofty S.K .
Katabi N. Clinical features cel l carcino ma al other head and neck
Schwartz M.R. Patients typically present with sore throat siles.
and diflculty in swallowing or a neck mass
{487). Genetic profile
Definition See the Squamous ce!! carcinoma sec-
HPV-negative oropharyngeal squamous Macroscopy tion (p. 109) in Chapter 4. The TP53gene
cell carcinoma (OPSCC) is a subset of See the Squamous ce!/ carcinoma sec- is commonly mutated, in contras! to the
OPSCC that lacks association with high- tion (p. 109) in Chapter 4. wildtype TP53 found in OPSCC-HPV.
risk HPV.
Cytology Prognosis and predictive factors
ICD-0 code 8086/3 Aspirates of metastatic lesions usually See Table 5.01 (p. 136).
show featu res of keratinizing squamous
Synonym cell carcinoma, with sheets and small
Keratin izing squamous cell carcinoma clusters of malignan! squamous cells
with intracellular and extracellular kerati-
Epidemiology nization. Occasional cases have cyto-
Patients with HPV-negative OPSCC are logical features identical to those of HPV-
older on average than patients with HPV- positive tumours (i.e. non-keratinizing
related OPSCC (OPSCC -H PV; see Tab le squamous cel l carc inoma) (241,637}.
5.01, p. 136) (247 1\.
Etiology Unlike OPSCC-HPV, HPV-negative OPSCC
See the Squamous ce// carcinoma sec- typically exhibits differentiated squamous
tion (p . 109) in Chapter 4. features (i.e. kerati nization, desmoplastic
stromal reaction, and surface dysplasia)
Localization identical to !hose of squamous cell 9arcino-
Whereas most examples of OPSCC- mas at other head and neck mucosal sites
HPV target the base of tongue and the {1 405). HPV status is negative (by p16
palataine tonsils, HPV-negative OP- immunohistochemistry and/or molecular
SCC more commonly involves the soft detection of HPV). The histological grad-
palatine. ing is similar to that used for squamous

138 Tumours of the oropharynx (base of tongue, tonsils, adenoids)

Salivary gland tumours

Pleomorphic adenoma Localization Adenoid cystic carcinoma

Pleomorphic adenoma of the base of
Bell D. tangue, tonsils, and adenoids is rare (179, Stenman G.
Bullerdiek J . 1710,2687). Bel! D.
Katabi N. Gnepp D.R .
Clinical features
Presenting symptoms include a slow-
Definition growing mass and mild dysphagia (1710}. Definition
Pleomorphic adenoma is a benign tu- Adenoid cystic carcinoma is a slow-
mour with variable cytomorphological Histopathology growing and relentless salivary gland
and architectural manifestations. The Pleomorphic adenomas of the minar malignancy composed of epithelial and
identification of epithelial and myoepi- salivary glands, compared with those myoepithelial neoplastic cells that form
thelial and stromal components is es- occurring in majar glands, are typically various patterns, including tubular, cribri-
sential fa r the diagnosis. See also the more cellular, with a less predominan! form, and salid forms.
Pleomorphic adenoma section (p. 185) stromal componen! (930,2123}. Both epi- See also the Adenoid cystic carcinoma
in Chapter 7. thelial and myoepithelial components are section (p. 164) in Chapter 7.
found, in varying compositions (2082}.
ICD-0 code 8940/0 ICD-0 code 8200/3
Prognosis and predictive factors
Synonym Complete excision is generally curative. Re- Epidemiology and clinical features
Benign mixed tumour currence is not uncommon, due to micro- See the Adenoid cystic carcinoma sec-
scopic satellite extension. The myxoid variant tion (p. 164) in Chapter 7.
may have a higher recurrence rate (2082).
The histology is identical to adenoid
cystic carcinomas of majar and other
minar salivary gland sites; see the Ade-
noid cystic carcinoma section (p. 164) in
Chapter 7 (Tumours of sa/ivary glands).

Genetic profile
See the Adenoid cystic carcinoma sec-
tion (p. 164) in Chapter 7.

Prognosis and predictive factors

The prognosis is similar to that of ad-
enoid cystic carcinomas from the majar
and other minar salivary gland siles (22,
1104); see the Adenoid cystic carcinoma
section (p. 164) in Chapter 7.

._,.,. ' ~ ..mi~ :11:iia:.':i~,;t; .
Fig. 5.03 A Unencapsulated submucosal pleomorphic adenoma of soft palate. B Pleomorphic adenoma. Myoepithelial
cell nests in fibromyxoid and hyalinized stroma.

Salivary gland tumours 139

,J n

)J n
uil (u ni

g it

ol. J'f[ 1
t,1 ~;
ti tt
~ ~t

UAJ'~) n

., 10 11

}i ( ,
' ,..

rJ t\
13 14
" "16
, , r1
17 18

?! ,._ . . ..'\ )
B . 20
,\ f.
t"i G
22 X

B Karyotype of the same case shown in Fig. A, with a 1(6;14)

Polymorphous adenocarcinoma Localization Cytology

Polymorphous adenocarcinoma occurs The cytological features are not specific
Fonseca l. predominantly at th e junction of the hard far the diagnosis.
Bell D. and soft palate {239,461,1915,2198).
Gnepp D.R. H istopathology
Seethala R. Clinical features See the Polymorphous adenocarcinoma
Weinreb l. The tumours presentas pain less masses section (p. 167) in Chapter 7.
Genetic profile
Definition Macroscopy The genetic profile {2569,2574) is dis-
Polymorphous adenocarcinoma is a Polymorphous adenocarcinoma pre- cussed in the Polymorphous adenocarci-
malignant neoplasm characterized by sents as a firm, circumscribed, unencap- noma section (p. 167) in Chapter 7.
cytological uniformity, morphological di- sulated, yellowish-tan tumour {1832).
versity, and an infiltrative growth pattern. Prognosis and predictive factors
See also the Polymorphous adenocarci- The overall survival rate is excellent (352,
noma section (p. 167) in Chapter 7. 671 ,1231,1832). but aggressive behav-
iour can occur. See the Polymorphous
ICD-0 code 8525/3 adenocarcinoma section (p. 167) in
Chapter 7.
Polymorphous low-grade adenocarci-
noma; terminal duct carcinoma; cribriform

The female-to-male ratio is 2:1, and Fig. 5.05 Polymorphous adenocarcinoma. The cribriform
> 70% of patients are aged 50- 70 years variant is frequently characterized by the presence of
{239,1832,1915,2198). optically clear nuclei.

140 Tumours of the oropharynx (base of tang ue, tonsils, adenoids)

Haematolymphoid tumours

/ntroduction Localization excluded befare diagnosing lymphoma.

Within the Waldeyer ring, lymphoma EBV-positive mucocutaneous ulcer is also
Ferry J.A. most common ly involves tonsil, followed an importan! differential diagnosis far cir-
Ko Y. -H. by nasopharynx, with the base of tangue cumscribed ulcers {595}. MALT lymphoma
leas! o/ten affected [37,682,1338,1 372} . should be distinguished from atypical mar-
Most lymphomas are localized (stage 1/11) ginal zone hyperplasia of mucosa-associ-
Definition {37,905,1338,1372}. ated lymphoi d tissue - a rare monotypic,
Oropharyngeal haematolymphoid tu- polyclonal lymphoproliferative disorder in-
mours are neoplasms of lymphoid, plas- Clinical features volving the tonsils of children (101}.
ma-cell, histiocytic/dendritic, or myeloid Dysphagia, odynophagia, and cervical
origin arising in the oropharynx. lymphadenopathy are common (934, Prognosis and predictive factors
1260,1338,2183}. The prognosis is relatively favourable.
Epidemiology Outcome is worse with older patient age
The Waldeyer ring (pharyngeal lymphoid Macroscopy (682,1372}, T-cell phenotype {1372}, non-
ring) is the most common extranodal head Tonsillar ar base-of-tongue swelling, with tonsil primary, and high levels of lactate
and neck site for development of lympho- or without ulceration, is apparent macro- dehydrogenase (682}.
ma {100}, affected in 36% {666,934} to scopically (905,934}.
67% (37,682} of cases. Patients can be
affected in childhood (905} through ad - Histopathology Hodgkin /ymphoma
vanced age {1338,1372,1429,1790}, with Diffuse large B-cell lymphoma is most
mean and median palien! ages in the common by far {37,682,1372), with ger- Jaffe E.S.
sixth (37,682,1372} and seventh (1790} minal-centre and non- germinal-cen tre Ott G.
decades of life. The male-to-female ratio B-cell phenotypes reparted (1790,1968).
is about 1-2:1 (905,1338 ,1 372,1790}, al- Others include MALT lymphoma {333,
though MALT lymphomas show a slight 1260,1372,2239}; extranodal NK/T-cell Definition
female preponderance (1260}. lymphoma (1372); mantle cell lymphoma Hodgkin lymphoma is a B-cell-derived
Oropharyngeal p lasmacytoma accounts {1260,1372, 1790); fol licular lymphoma neoplasm in which relatively few neo-
far 13-19% of all head and neck extra- (1260,1372}; peripheral T-cell lymphoma, plastic cells are seen, in a background
osseous p lasmacytomas {11 6,494,2078}. NOS (1372}; and rare classical Hodgkin rich in inflammatory cells. Th e two major
Myeloid sarcoma {2724} and histiocytic/ lymphoma (1939). Burkitt lymphoma is forms are classical Hodgkin lymphoma
dendritic cell neoplasms {1810} are rare. rare in adults (1372) but common among and nodular lymphocyte-predominant
children (905}. Hodg kin lymphoma . The characteri stics
Etiology lnfectious mononucleosis can mimic dif- of the neoplastic cells and the nature of
A few patients are immunocompromised; fuse large B-cell lymphoma and classical the infl ammatory background differ in
their lymphomas may be EBV-positive (1790}. Hodgkin lymphoma (1479}, and should be these two majar subtypes (1524) .

Q .


Haematolymphoid tumours 141

cells have lobulated nuclear contours, Epidemiology
basophilic nucleoli, anda thin rim of pale BL accounts for < 1% of ali peripheral B-
cytoplasm. The neop lastic cel ls (i .e . ce ll lymphoma cases {2377). Three vari-
lymphocyte-predominant [LP] cells) re- ants are recognized: endemic (occurring
tain expression of most B-cell antigens, in malaria-endemic reg ions of the world),
including CD20, CD79a, PAX5, and sporadic (occurring where malaria is not
OCT2, and are posit ive for BCL6. A nod- endem ic) , an d im munodefic iency-as-
ular growth pattern is usually evident, sociated (occurring in immunocompro-
with the B cells often distributed within mised, typical ly HIV-positive, patients)
the remnants of primary follicles. Nor- [1639). Despite their common morphol-
mal small B cells are frequent, particu- ogy and phenotype, these variants differ
larly early in the course of the disease. in terms of patient age and pathobiology.
The LP cells are rosetted by T cel ls Endemic BL occurs in children and ado-
with the phenotype of T follicular helper lescents, whereas sporadic and immu-
(TFH) cells, expressing CD4 and PD1 nodeficiency-associated Bls typically

Fig. 5.07 Classical Hodgkin lymphoma of the tonsil. (CD279), and T cel ls usually become occur in adults {1639].
High-power view shows classic Reed-Sternberg cells more numerous over time. Overlap with
and variants in a background of small lymphocytes. T-ce ll lymphoma or histiocyte-rich large Etiology
B-cell lymphoma may be seen {949} . In endemic BL, the neoplastic cells invari-
ICD-0 codes Primary nodular lymphocyte-predomi- ably contain EBV {1639). However, recent
Hodgkin lymphoma, nodular lymphocyte nant Hodgkin lymphoma in the Waldeyer data suggest that the pathogenesis of this
p redominan! 9659/3 ring is rare. variant may be polymicrobial {3,2460).
Classical Hodgkin lymphoma EBV infection is detected in about 30% ot
Nodular sclerosis classical Hodgkin sporadic cases and 25-40% of immuno-
lymphoma 9663/3 Burkitt lymphoma deficiency-associated cases {1639).
Mixed cellularity classical Hodgkin
lymphoma 9652/3 Pileri S.A. Localization
Lymphocyte-rich classical Hodgkin Nakamura S. lnvolvement of the head and neck (espe-
lymphoma 9651/3 cial ly the jawbones) is frequent in endem-
Lymphocyte-depleted c lassical ic BL but rare in the other variants {1639).
Hodgkin lymphoma 9653/3 Definition
Burkitt lymphoma (BL) is a peripheral B- Clinical features
Synonym cell lymphoma that has an extremely high Patients often present with bulky disease
Hodgkin disease proliferation rate and often presents in and a high tumour burden, sometimes
extranodal sites. lt is composed of mono- with leukaemic spread [2244). A pure
Localization morphic medium-sized cells. Transloca- leukaemic presentation, which is exceed-
Both form s of Hodgkin lymphoma pre- tion involving MYC is highly characteristic ingly rare, is usually associated with CNS
sent most often in lymph nades. Primary but not specific. The diagnosis requires involvement {2244).
presentations in oropharyngeal lymphoid the combination of morphology, pheno-
tissue are rare {1103,1 175). type, and genetics. Histopathology
The neoplastic cells tend to be cohesive
Histopathology ICD-0 code 9687/3 and undergo apoptosis [1639,2434).
In classical Hodgkin lymphoma, the neo-
plastic cells (i.e. Reed-Sternberg cells
and variants) frequently show downregu-
lation of the B-cell programme. They are
positive for PAX5 but most often negative
for CD20 and CD79a. There is positivity
for CD30 in virtually all cases and forCD15
in most. The inflammatory background is
composed mainly of T cells, with variable
numbers of plasma cells, histiocytes,
and eosi nophils. EBV sequences are
found in 15- 25% of cases overall, but the
incidence of EBV positivity in classical
Hodgkin lymphoma involving the Wal-
deyer ring (pharyngeal lymphoid ri ng) is
higher: approximately 65% in one study
{11 75). In nodular lymphocyte-predomi-
nant Hodgkin lymphoma, the neoplastic

142 Tumours of the oropharynx (base of tang ue, tonsils, adenoids)

Follcular /ymphoma
Ott G .
Nakamura S.

Follicular lymphoma is a malig nan! lym-
phoma composed of centroblasts and
centrocytes, with at least a partially fol-
licular pattern.

ICD-0 code 9690/3

Cases involving the Waldeyer ring (pha-
Fig. 5.09 Burkitt lymphoma. MYC gene rearrangement, as shown by a dual-colour break-apart probe (in situ
hybridization, DAPI nuclear staining).
ryngeal lymphoid ring) typically con-
stitute secondary tonsillar extension in
They are intermingled with phagocytizing infection within the non-neoplastic tissue individuals with widespread nada! dis-
macrophages, which contribute to the in > 50% of cases; expression of EBV lyt- ease (95}. lsolated manifestation in the
characteristic starry-sky pattern (1639, ic genes, inversely associated with TCF3 oropharynx, wh ich is rare, is more often
2434). The number of mitotic figures is ex- activity; recurren! alterations in genes seen in children and young adults.
ceed ingly high. Features of plasma-ce!! rarely mutated in the sporadic variant
differentiation can be seen, especially in (AR/01A, CCNF, and RHOA) ; and fewer Histopathology
the immunodeficiency-associated var- mutations in genes commonly altered in The cytomorphology of fallicular lympho-
an! {2434). On immunophenotyping, the sporadic cases (MYC. /03, TCF3, and ma in the tonsil is the same as that of its
neoplastic cells are positive far CD20, TP53) {3, 2099). counterpart in the lymph nade. Crowded
CD1 0, and BCL6; negative far BCL2; and atypical follicles that consist of centro-
positive for MYC and Ki-67 (with a Ki-67 Prognosis and predictiva factors blasts and centrocytes efface the normal
proliferation index of 100%) {2434}. In Both endemic BL and sporadic BL are architecture. The follicles are uniform in
situ hybridization for EBV-encoded small highly aggressive but potentially curable. size and poorly demarcated; the starry-
RNA (EBER) reveals a variable preva- Staging is perfarmed according to the sky pattern is usually absent. Large
lence of EBV infection, depending on the system developed by Murphy and Hustu B-cell lymphoma with or without a follicu-
BL variant {1639,2434}. {1677} and modified by Magrath (1511). lar componen! in Waldeyer ring arising in
lntensive chemotherapy regimens are children or young adults more often fea-
Genetic profile associated with cure rates of 90% and tures large, expansile follicles composed
The tumours cells carry clona! rearrange- 60- 80% far patients with low- and high- of centroblasts or intermediate-sized
ments of the IG gene family, with somatic stage disease. respectively {1639}. with blastoid cells exclusive ly, as well as at-
hypermutation. FISH shows MYC translo- particularly excellent results in childhood tenuated mantle zones (1446,1 477,1785,
cation at band 8q24 to the IG H region at [1639}. 1942).
14q32 or less frequently to IGL at 22q11 Classic follicular lymphoma expresses
or IGK at 2p12 (178,1844). In about 10% CD20 and germinal centre markers (e.g.
of cases, FISH fails to demonstrate MYC
translocation, but mostly due to techni-
cal limitations {1639}. The few BL cases
that actually lack MYC translocation are
characterized by deregulation of genes
on 11q {2050}. Gene expression profil-
ing studies have shown that the endemic
and immunodeficiency-associated BL
variants have almost identical signatures,
whereas the endemic and sporadic vari -
ants have been found to diverge in their
expression of 124 genes dependen! on
RBL2 activity {531,1884). Next-genera-
tion sequenc ing has highlighted differ-
ences between endemic BL and sporadic
BL (3}. The endemic variant shows cyto- ,;j_,!"..4.};
megalovirus and HHV8 (also called Ka- Fig. 5.10 Follicular lymphoma of the tonsil. The tonsillar parenchyma shows infiltration by crowded atypical follicles
posi sarcoma- associated herpesvirus) that efface the normal architecture.

Haematolymphoid tumours 143

CD10, BCL6, and HGAL), and is BCL2-
positive in 85- 90% of cases. In contras!,
large B-cell lymphoma with IRF4 re-
arrangement of the tonsil, which has a fol-
licular growth pattern in many cases and
arises in children and young adults, con-
sistently and strongly expresses MUM1/
IRF4 in addition to germinal centre mark-
ers. lt variab ly expresses BCL2, and has a
high proliferation index {1446,1942,2051).

Genetic profile
Typical follicular lymphoma involving the
tonsil in the setting of widespread disease
usually harbours the t(14;18)(q32;q21)
translocation. In contras!, MUM1/IRF4 -
positive large cell lymphomas occurring
in chi ldren and young adults lack the
1(14;18) translocation, and a MUM1/IRF4 most common extranodal site, involved 2623). Mutations involving ATM and TP53
translocation can be demonstrated in in 6.2% of MCLs [68). MCL accounts for are common, occurring in 41% and 28%
about 50% of cases [1446,2051). In the 2.6% of al! Waldeyer ring (pharyngeal of cases, respectively (165,1116).
4th edition update of the WHO classifi- lymphoid ring) non-Hodgkin lymphoma
cation of tumours of haematopoietic and cases, occurring most often in the tonsi l Prognosis and predictive factors
lymphoid tissues, MUM1/IRF4+ lympho- [1372,2217). MCL is an aggressive non-Hodgkin lym-
ma in children and young adults is classi- phoma, with a median overa!! survival of
fied as "large B-cell lymphoma with IRF4 Clinical features < 4 years (1393,2064}. The Mantle Ce!!
rearrangement" instead of a form of follic- Patients typically have a mass causing Lymphoma lnternational Prognostic ln-
ular lymphoma. odynophagia and dysphagia. MCL of the dex correlates well with prognosis [2513}.
head and neck presents with advanced Adverse prognostic factors include blas-
Prognosis and predictiva factors disease at diagnosis less commonly (in toid or pleomorphic morphology, diffuse
MUM1/ IRF4 expression and/or MUM1/ 41% of cases) than does lymphoma of p attern, high proliferation index, high
IRF4 translocation in follicular lymphoma the lymph nades (in 87%) {68}. expression of p53 protein , and MYC ab-
of the tonsil is associated with favourable errations with overexpression (182,434,
outcome. Histopathology 2403}. Patients with primary extranodal
MCL shows a diffuse, vaguely nodular disease (including in the head and neck)
or mantle-zone pattern, with proliferation have better survival than do those with
Mantle ce// lymphoma of small to medium-sized lymphoid cells nodal disease [68).
with slight nuclear irregularity. Epithe-
Ko Y.-H . lioid histiocytes may be evenly scattered
Ferry J.A. throughout the tumour. T-lymphoblastic
Sorne cases have blastoid or pleomor-
phic morphology [27,2674). In rare cas-
Detinition es, cyc lin D1- positive lymphocytes are Ferry J.A.
Mantle cell lymphoma (mantle cell neopla- localized within mantles of hyperplastic Gaulard P.
sia) is a mature B-cell neoplasm of small lymphoid follicles (with in situ mantle ce!!
to medium-sized lymphoid cells, usually neoplasia) {1264). The neoplastic cells
characterized by CCND1 trans location are positive for slgM, lgD, CD20, and Definition
leading to cyclin D1 overexpression . CD5 and negative for CD10, CD23, and T-lymphoblastic leukaemia/lymphoma
BCL6. Cyclin 0 1 is expressed in virtually (T-LBL/L) is a neoplasm of lymphoblasts
!CD-O code 9673/3 al! cases. SOX11 is useful for identifying committed to T-cell lineage.
rare cyclin 01- negative MCL {310,1693].
Epidemiology Aberran! immunophenotypes (e.g. with !CD-O code 9837/3
The overall incidence of MCL is ap- CD5 negativity, CD10 positivity, or CD23
proximately 0.5 cases per 100 000 per- positivity) may occur (34,2258,2479, Epidemiology
son-years. The male-to -female ratio is 2723). . lnvolvement of head and neck by
2.3- 2.5:1. The median patient age al di- T-LBL/L is rare. Among 109 reported
agnosis is 70 years {1393, 2216,2725). Genetic profile cases of nasopharyngeal lymphoma,
Most cases have CCND1- /GH transloca- only one (0 .9%) was T-LBL/L (1054}. In
Localization tion. Cyclin 01-negative MCL may have a large series of chi ldhood non-Hodgkin
The head and neck region is the second CCND2 translocation {1597,2052,2164, lymphomas, 1% of al! lymphomas and

144 Tumours of the oropharynx (base of tongue, tonsils, adenoids)

have clonal IGH . Cytogenetic and mo-
lecular genetic changes are heteroge-
neous. Many cases have an abnormal
karyotype; translocations involving T-cell
receptor genes are common {884,1889,
2329}. Activation of Notch signalling and
loss of CDKN2A (also called P16/NK4a
and P14ARF), which codes far the tumour
suppressor proteins p16 (p161NK4a) and
p14ARF, are also common (2476) .

Prognosis and predictive factors

The outcome appears to be similar to that
of T-LBL/L in other siles.

Follicular dendritic
ce// sarcoma
Cheuk W.
11: Pileri S.A.

Fig. 5.1 2 A,B lndolent T-lymphoblastic proliferation. A The interfollicular compartment is filled and expanded by
Follicular dendritic cell (FDC) sarcoma is
a proliferation of TdT-positive T cells. B High-power view shows a population of relatively small, uniform cells,
sorne with minimally enlarged nuclei and fine chromatin. C T-lymphoblastic lymphoma involving the tonsils. a tumour of nodal and extranodal sites
In contras! with indolent T-lymphoblastic proliferation, there is a monotonous infiltrate containing medium-sized bias! that exhibits phenotypic featu res of FDCs.
cells with convoluted nuclei and fine chromatin.
ICD-0 code 9758/3
5% of all T-LBUL cases were T-LBL/L of disorder characterized by a prolifera-
the head and neck (2642] . Patient age tion of immature T cells in lymphoid tis- Epidemiology
ranges from childhood to advanced age sue. Patients present with sore throat, FDC sarcoma accounts far < 1% of all
(771,2642}. hoarseness, or airway obstruction . Ex- head and neck tumours, although the
amination reveals prominent hypertrophy head and neck region is the most com-
Localization of oropharyngeal and nasopharyngeal mon anatomical site of occurrence of this
T-LBL/L cases have been reported in- lymphoid tissue, sometimes with cervi- tumour. lt typically affects patients in mid-
volving the oropharynx {2642). nasophar- cal lymphadenopathy {2290,24'89}. Mi- adulthood (mean patient age: 42 years).
ynx (1054,2642). salivary gland {2642). croscopic examination reveals sheets or Although the patient age range is wide
tangue (771}. and larynx (1541}. Staging c lusters of small to medium-sized ce lls (9- 80 years), only 6% of al i cases occur
may reveal widespread disease involving with fine chromatin, inconspicuous nu- in children (1187}. There is no sex predi-
lymph nodes, mediastinum, and/or bone cleoli, and a high mitotic rate, but with no lection (1488,1810).
marrow (771,1541]. significan! cytological atypia and sparing
fallicles. The cells are positive for CD3 Etiology
Clinical features and TdT, and have a high proliferation A minority (15%) of FDC sarcomas arise
The symptoms are related to the pres- index. T-cell receptor genes are not clon- in the setting of hyaline-vascular Castle-
ence of a mass. ally rearranged. The appearance resem- man disease, and a hyperplasia-dyspla-
bles that of the normal thymic cortex, sia- neoplasia model of FDC proliferation
Histopathology although without thymic epithelium. After has been proposed (373,379,412]. Sorne
Evaluation reveals a diffuse infi ltrate of therapy (surgical excision or chemo-
small to medium-sized cells with oval or therapy) indolent T-lymphoblastic proli-
slightly to prominently irregular nuclei , feration may rep eatedly recur, although
dispersed to finely stippled chromatin, without progression to bone marrow or
variably conspicuous nucleoli, and scant peripheral blood involvement {1764,1765,
cytoplasm . Mitoses are frequent. T-LBL/L 2290,2489}.
is typically positive for CD3, TdT, CD?,
and CD1a; variably positive for CD10; Genetic profile
and either double-positive or double- Limited information is available about
negative for CD4 and CD8. head and neck cases, but T-LBL/L in Fig. 5.13 Follicular dendritic cell sarcoma of the tonsil.
The differential diagnosis inc ludes indo- general has clonally rearranged T-cell The surface epithelium is intact; this tumour shows partial
lent T-lymphoblastic proliferation; a rare receptor genes, and a minority of cases involvement of !he tonsil (left field) and exhibits pushing borders.

Haematolymphoid tumours 145

studies have found clona! abnormalities in Macroscopy The tumour cells are positive for FDC
FDCs in hyaline-vascular Castleman dis- The mean size of FDC sarcomas in the head markers such as CD21, CD23, CD35,
ease, which may precede FDC sarcoma and neck is 4.5 cm (1810). The tumours clusterin , CXCL13, and podoplanin (as
overgrowth (469, 1840). Overexpression are solitary, round to ovoid circumscribed recognized by 02-40). Cytokeratin is
of EGFR has been demonstrated in FDC masses with a fleshy cut surface. Areas of negative and EMA is often positive. Ex-
sarcomas and dysplastic FDCs in hyaline- haemorrhage and necrosis may be present. ceptionally, the cells can be positive for
vascular Castleman disease , providing cytokeratin and TTF1 (11 05,2452).
a further link between the two conditions Histopathology
{2311). Ligand-dependent EGFR activation, The morphological features are 'Similar Prognosis and predictive factors
which may be importan! for the survival and to !hose of FDC sarcoma in other parts FDC sarcoma is a low- to intermediate-
proliferation of neoplastic FDCs, could be a of the body. The tumours, which tend to grade malignan! tumour with a recurrence
potential therapeutic target {2496). have pushing invasive fronts, are com- rate of ;::: 40% and a distan! metastasis
posed of spindle to ovoid cells arranged rate of;::: 25% {377,1810}. The overall and
Localization in fascicular, whorled, or storiform pat- disease-specific survival rates, respec-
In the head and neck region, the most terns, accompanied by an admixture tively, are 91% and 64% at 2 years and
frequently affected siles are the cervi- of small lymphocytes or lymphoid ag- 81% and 34% at 5 years. Surgery is po-
cal lymph nodes (involved in 40-50% gregates around blood vessels. The tentially curative for early-stage disease,
of cases), followed by the Waldeyer ring tumour cells have a moderate amount but late recurrence and metastasis can
(pharyngeal lymphoid ring; in 24-40%) of pale eosinophilic cytoplasm and in- occur many years after initial presentation
and the soft tissue of the neck (in 10%) distinct cell bord ers, imparting a syn - {438). The most common metastatic sites
{11 87,1810). Other head and neck mu- cytial appearance. The nuclei are oval are lung, liver, and lymph nodes. Large
cosa! sites can also be affected. or elongated, with vesicular or granular tumour size (> 4- 6 cm) has consistently
fine ly dispersed chromatin, small dis- been shown to co rrelate with poor prog-
Clinical features tinct nucleoli, and a smooth nuclear nosis {1810,2088}. Other proposed poor
Cases with lymph node involvement membrane. Nuclear pseudoinclusions, prognostic factors include disseminated
present with a neck mass. Tumours binucleated tumour cells, and multinu- disease, extensive necrosis, high mi-
arising in the Waldeyer ring present with cleated tumour cells are often seen. The totic rate (> 5 mitoses per 10 high-power
intraoral swelling or dysphagia. Sys- mitotic rate is usually 0- 1O mitoses per fields), and significan! nuclear atypia (377,
temic symptoms are rare. Most p atients 10 high-power fields. High-grade nucle- 521,1856).
(80- 90%) have localized disease at ar pleomorphism, atypical mitoses, and
presentation. coagulative necrosis are uncommon.

146 Tumours of the oropharynx (base of tangue, tonsils, adenoids)


Tumours and tumour-like lesions of

the neck and lymph nodes
Tumours of unknown origin
Haematolymphoid tumours
Cysts and cyst-like lesions
WHO classification of tumours and tumour-like lesions of the
neck and lymph nodes

Tumours of unknown origin

Carcinoma of unknown primary The morphology codes are from the lnternational Classification of Diseases
for Oncology (ICD-0) {776A}. Behaviour is coded /0 for benign tumours;
Merkel cell carcinoma 8247/3 /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in
Heterotopia-associated carcinoma 8010/3 situ and grade 111 intraepithelial neoplasia; and /3 far malignan! tumours.
The classification is modified from the previous WHO classification, taking
into account changes in our understanding ot these lesions.
Haematolymphoid tumours

Cysts and cyst-like lesions

Branchial cleft cyst
Thyroglossal duct cyst
Dermoid and teratoid cysts

lntroduction Schwartz M.R .

Vielh P.

The neck contains lymph nodes, soft small size of samples obtained, adjunc - lymphoid lesions), gene rearrangements,
tissue, fascia, skeletal muscle, nerves, tive tests are useful in the evaluation of in situ hybridization, cytogenetics. and
blood vessels, lymphatic vessels, carti- cytological and tissue specimens. These PCR.
lage, bone, and paraganglia. Tumours tests include immunohistochemistry,
and tumour-like lesions can arise in any flow cytometry (for haematopoietic and Lymph nodes
of these components. An understanding The lymph nodes are the most frequent
of anatomy is critica! in the evaluation of site of tumours in the neck. Lymph nodes
lesions in the neck. Table Fig. 6.0 1 sum- can be involved by metastatic tumours,
marizes the levels used to classify the lo- la - Submental tJiangle haematolymphoid tumours, and benign
lb - Submandibular triangle
cation of lymph nodes in the neck. , Ita Anterior-inferior to spinal accessory
llb Posterior-superior to spinal accessory
Table 6.01 Systematic approach to the evaluation of
The general diagnostic approach to le- fine-needle aspirations from the neck
......_ 111 - Middle 113 of interna! jugular vein
sions of the neck includes identification IV- Lower 1/3 of Interna! jugular vein
v - Postenor tnangle Is the asprate satisfactory for evaluation?
of where in the neck the lesion is, as well VI - Antenor cen~al cornpanment
as clinical features such as patient age, What is the cellularity?
sex, and cl inical presentation. Correlation
with rad iographical fin dings, including
d) Is the lesion viable?
Is the lesion salid or cystic?
determination of location, adjacent struc-
tures, size, solid versus cystic nature, What type of general process is it - neoplastic, infec-
tious, or other?
and whether the lesion is circumscribed
or infiltrative, is helpful. Is it a haematopoietic, epithelial, mesenchymal, or
Given the close proximity of vital struc- neurogenic process?
tures in the neck, core needle. biop- Is it a polymorphous or monomorphous population?
sies are generally performed only by Are the cells cohesiva (favours epithelial lesion) or
experienced c linicians. Fine-needle dyshesive (favours haematopoietic, neuroendocrina)?
aspiration and excision are more fre- What sized cell groups are present?
quently employed. Table 6.01 p resents
What is in the background (e.g. necrosis, mucn,
a systematic approach to the evalua-
clean background, lymphoglandular bodies)?
tion of fine-needle aspirations from the Fig. 6.01 Schematic anatomy of relevan! siles for the
neck. Given the complexity and the recording of tumours in neck lymph nades. Is the lesion benign, malignan!, or indetermnate?

148 Tumours and tumour-lke lesions of the neck and lymph nodes
Table 6.02 Lymph nodes most commonly involved by head and neck carcinoma the most common malignancy in neck
Slte Most commonly involved nodes (in descendlng order of frequency) nades. Table 6.02 summarizes the most
oral tongue ] Subdigastric, submandibular, midjugular common sites of metastases from key

Retromotar trigone IAngle of mandible, midjugular primary sites in the head and neck {47,
floor of mouth Jugulodigastric, submandibular The evaluation of cervical nodal metas-
Angte of mandible, midjugular, lower jugular, ipsilateral and contralateral posterior tases of unknown primary has changad
Tonsils cervical, parapharyngeal dramatical ly over the past decade (1934,
Base of tangue 1 Midjugular, lower jugular; bilateral involvement common 2189,2292). This is due largely to the
marked increase in incidence of HPV-re-
Pharyngeal wall Subdigastric, midjugular, posterior cervical, parapharyngeal, retropharyngeal
lated oropharyngeal squamous cell car-
Supraglottic larynx Subdigastric, midjugular cinomas. Many carcinomas previously
Glottis Typically no nodal metastases diagnosed as cervical nodal metastases
Hypopharynx Upper, mid-, and lower jugular of unknown primary are now identified as
being from occult oropharyngeal prima-
Jugular, posterior cervical, supraclavicular; bilateral involvement common; wide
distribution common
ries (2491, 2672). These cases often pre-
sent with small primaries and large bulky
Paranasal sinuses Subdigastric, submandibular cervical nodal metastases (80,392,862}.
Ala nasi and nasal vestibule Submandibular Evaluation of nodal metastases far p16
Skin; upper/midface, temporal Preauricular, intraparotid, periparotid expression (a surrogate marker for high-
risk HPV intection) and/or for high-risk
Skin; posterior scalp, neck 1 Postauricular, occipital, posterior triangle
HPV by molecular tests helps in the iden-
tification of likely HPV-related primaries.
processes. commonly from primaries outside the Although rare, ectopic thymic tissue and
The most common malignancies in neck head and neck) and metastatic mela- thymic tumours may be encountered and
nodes are metastatic carcinoma from noma. Metastatic squamous cell carci- should be considered in the differential
primaries in the head and neck (and less noma from a head and neck primary is diagnosis {200,637,1 277,20221.

lntroduction 149
Tumours of unknown origin

Carcinoma of unknown primary cervical nodal CUPs, constitute only

1-2% of head and neck malignancies
LewisJ.S. (911,2293}. The literature contains only
Richardson M. limited data addressing squamous cell
Syrjanen S. carcinoma (SCC) versus undifferentiated
Westra W.H. carcinomas as cervical CUPs; most se
ries group the two tumour types. SCCs
constitute 75-80% of cases and undif
Definition ferentiated carcinomas 2-20% {883,911,
Metastatic carci,oma of unknown prima 1129,2293,2412}, depending on geo
ry (CUP) is usually squamous or undif graphical location. For example, in areas Fig. 6.03 Lymph node with metastatic non-keratinizing
ferentiated and metastatic to neck lymph of endemic EBV infection such as south squamous cell carcinoma of unknown primary mimicking
nades with no known primary tumour eastern Asia, the proportion of CUPs that branchial cleft cyst. A primary oropharyngeal carcinoma
identified at initial presentation or after a are undifferentiated carcinomas may be was subsequently identified.
thorough clinical work-up. higher {2412}.

ICD-0 codes Localization

Coding should be according to the CUPs occur most commonly in level 11
morphology type. nades, followed by level 111 nodes, and
< 10% of patients have bilateral neck
Synonym involvement (883,2293). Approximately
Cancer of unknown primary 50% of cases involve a single lymph
nade. Most are of N stage N2a, b, or e
Epidemiology (2412). In patients with CUP, the distribu
Although the reported figures have var tion of lymph node involvement may pro
ied over time and by study type, in gen vide clues as to the site of tumour origin Fig. 6.04 Metastatic non-keratinizing squamous cell
eral, cervical metastatic carcinomas with [1670l. EBV-related undifferentiated car carcinoma of unknown primary. lmmunostaining for p16
no primary tumcur immediately apparent cinomas of the nasopharynx initially me shows strong, diffuse nuclear and cytoplasmic positivity.
al initial presentation (i.e. CUP) constitute tastasize to retropharyngeal lymphnodes
about 5% of all head and neck malig and level 11 and V nades. HPV-related lymph nades. Supraclavicular metasta
nancies (911,1842}. However, extensive oropharyngeal carcinomas typically me ses are more suggestive of a primary ori
clinical and radiographical work-up will tastasize to levels 11 and 111 f448,1670). gin outside the head and neck.
identify primary tumour in most patients, Carcinomas of the facial skin and scalp
and the remaining cases, so-called true frequently metastasize to intraparotid

A ~~~l~~ ~~~~J~ .~
~~_S!~:&r _ _ _ ,'!;_~ _L _ ., _
Fig. 6.02 Metastatic non-keratinizing squamous cell carcinoma of unknown primary with cystic change. A Low-power view displaying multiple cystic spaces with eosinophilie,
proteinaceous contents and lined by a thin layer of tumour cells. B Tumour cells lining the cystic spaces show prominent mitotic activity and no obvious squamous maturalion; these
are typical features o (although not completely specific far) HPV-related carcinomas.

150 Tumours and tumour-like lesions of the neck and lymph nades
Clinical features cells or be lymphoepithe lial. In lympho- Merkel cell carcinoma
CUP most commonly occurs in patients epithelial cases, the tumour cells have
in their fifth or sixth decade of lite, and a syncytial appearance, with poorly de- Perez-Ordonez B.
frequently occurs in current or former fined cell borders, modest eosinophilic Gnepp D.R.
smokers. The male-to-female ratio is cytoplasm, and large round vesicular Thompson L.O.R.
2. 4:1 [1100,2540). The tumours present nuclei with prominent nucleoli. Most tu- Williams M.O.
with symptoms of a neck mass and less mours, despite being histologically undif-
often with pain, weight loss, and/or dys- ferentiated, show immunohistochemical
phagia {883). evidence of squamous differentiation, Definition
being positive for p63, p40, and CK5/6 Merkel cell carcinoma (MCC) is a prima-
Cytology {1 202,2186}. ry neuroendocrine carcinoma of lymph
The cyto logy of aspirates of metastatic Neuroendocrine carcinomas and ad- nodes with microscopic, immunohisto-
lesions may be helpful in determining enocarcinomas arising in head and neck chemical, and genetic teatures similar to
possible primary sites. Far SCC, see Ta- sites occasionally present with nodal those of cutaneous MCC.
ble 5.01 (p. 136), Chapter 5. Many CUPs disease, but the primary site is usually
are associated with HPV or EBV. Oetec- evident on microscopic examination and ICD-0 code 8247/3
tion of HPV ONA or p16 immunopositivity clinical evaluation.
suggests the oropharynx as a likely pri- Synonyms
mary site, whereas identification of EBV Prognosis and predictive factors Extracutaneous Merkel cell carcinoma;
suggests a nasopharyngeal origin. The survival rates vary with clinical stage Merkel cell carci noma of lymph node;
and tumour type, and are better for CUP nodal Merkel cell carc inoma; unknown
Histopathology related to high-risk HPV {1128,2189,2421 , primary Merkel cell carcinoma; Merkel
The morphology of CUPs mirrors that 2576]. cell carcinoma of unknown primary
of tumours of known primary site. A
large proportion of the tumours are non-
keratinizing , consisting of large, round ed
nests or ribbons of cells with a high N:C
ratio, hyperchromatic ovoid nuclei with
inconspicuous nucleoli, brisk mitotic ac-
tivity, frequent apoptosis, and numerous
foci of necrosis {1405]. Cystic change is
particularly common in non-keratinizing
SCC metastases {862); these features
are strongly associated with HPV-related
oropharyngeal carcinoma. More rarely,
cystic tumours have gland formation and
even ciliated lining cells; these cases
should not be misinterpreted as carcino-
ma arising in a branchial cleft cyst (206,
1946). Other tumours are conventional
keratinizing SCC.
Undifferentiated carcinomas can either con-
sist of nondescript sheets of pleomorphic

Tumours of unknown origin 151

- -
Fig. 6.07 Merkel cell carcinoma of lymph node. A Tumour composed of small cells with inconspicuous cytoplasm and largely round to oval nuclei with dense chromatin; note the
absence of nucleoli. B Perinuclear CK2D staining.

Epidemiology Cytology a 2-year disease-specific survival of

Nodal MCCs are extremely rare, ac- Aspirates of metastatic lesions show 76.9% and can metastasize to brain.
counting for only 0.05% of all MCCs cytological find ings identical to those of liver, bone, and non-regional lymph
{237l, They may represent metastasis small cell neuroendocrine carcinomas nodes {1807,2358). The only prognoslic
from a regressed dermal primary. from other sites {491). factor is high-stage disease.

Etiology Histopathology
Origin va malignant transformation of The pathological and immunohistochem-
pre-existing intranodal epithelial rests or ical features are similar to those of cuta- Heterotopa-assocated
pluripotent stem cells has been postu- neous MCCs. Tumours grow in sheets, carcinoma
lated {670}. Merkel cell polyomavirus has with geographical necrosis, solid and
been detected in 31% of nodal MCCs organoid nests, trabecu lae. and cords, Ro J.Y.
{543,1807). An association with other often separated by fibrovascular septa. Brandwein-Gensler M.
malignancies, particularly small lympho- Tumour cells are medium-sized and Schwartz M.R.
cytic lymphoma and chronic lymphocytic have scant cytoplasm, a high N:C ratio,
leukaemia, has been noted in as many as and round to ovoid nuclei with finely dis-
36% of cases {1807,2358}. persed salt-and-pepper chromatin with Definition
inconspicuous or small nucleoli. Rare Heterotopia-associated carcinoma is a
Localization cases have moderate amounts of cyto- carcinoma arising from heterotopic tissue
The head and neck lymph nodes are plasm with dense chromatin and visible elements (i.e. histologically normal tissue
one of the most common sites of nodal nucleoli {670,18071. of a particular type that is present at an
MCC (affected in 21% of cases), second MCCs show diffuse expression of abnormal anatomical site). In the neck,
only to the ing uinal nodes (affected in pancytokeratins. low-molecular-weight most heterotopias consist of salivary or
56%) {1807,2358). lt is unclear whether cytokeratins, and CK20, usually in peri- thyroid tissue, but heterotopic gastric and
a subset of parotid gland small cell neu- nuclear dots. Synaptophysin, chromogra- colonic tissues have also been (rarely)
roendocrine carcinomas may be nodal nin A, and CD56 are also positive. TdT reported. Most carcinomas arising from
MCCs. and PAX5 are expressed in two th irds of heterotopic tissue are of salivary gland or
cases. TTF1 and CK7 are usually nega- thyroid origin.
Clinical features tive {1807). Merkel cell polyomavirus large
Nodal MCC presents as an enlarged T antigen and DNA are detected by im- ICD-0 code 8010/3
lymph node. lt is most common in Cau- munohistochemistry and PCR in 31% of
casian males (male-to-female ratio: cases {543,1807}. Ultrastructurally, tu- Synonyms
4.5:1). The reported patient age range mour cells contain perinuclear globular Choristoma; ectopia; accessory tissue-
is 48- 92 years (mean: 65 years) {1807, aggregates of intermediate filaments and associated carcinoma
2358). Clinical history, physical examina- neurosecretory granules 1670).
tion, imaging, and follow-up are negative Epidemiology
for cutaneous MCC. Prognosis and predictive factor~ Carcinomas arising from ectopic thyroid
Nodal MCCs are classified as stage IIIB tissue or ectopic salivary tissue are rare,
Macroscopy or IV disease and have a lower and < 1% of carcinomas arise in hetero-
Nodal MCCs replace most of the in- recurrence rate and better survival (me- topic thyroid or salivary tissue. Of the tew
volved lymph nodes, display central dian: 104 months) than do known cu- reported heterotopia-associated carcino-
necrosis, and range in size from 1.5 to taneous MCCs of similar stage (567, ma cases, most thyroid and salivary can-
27 cm (mean: 6 cm) {1807,2358). 2358). Stage III B nodal MCCs have cers presented during the third and sixth

152 Tumours and turnour-like lesions of the neck and lymph nodes
ctecades of lile, respectively {523,1555).
They occur more commonly in women.

Heterotopia-associated salivary carcino-
ma is usually seen in periparotid lymph
nodes or along low anterior sternocleido-
rnastoid muscle, with a right-side pre-
dilection {920). Heterotopia-associated
thyroid carcinoma has been reported in
lingual thyroid, thyroglossal duct cysts.
ectopic intratracheal thyroid, midline
ectopic thyroid , lateral neck, and branchi-
al cleft cysts (706,1251).

Clinical features
Heterotopia-associated carcinoma usu-
ally presents as a mass, but may be de-
~-~ ---~....... ---""--'---~--- , _
,__._...._. _....._'"' ~

~ ~~
_-..,'!_... ,_
Fig. 6.08 Heterotopia-associated carcinoma. A Primary mucoepidermoid carcinoma in periparotid lymph node.
B Primary mucoepidermoid carcinoma in periparotid lymph node with mucinous carcinoma component.
tected incidentally.

The lesions are usually 1.5-3.0 cm, but
may reach > 4 cm.

Aspirates show cytological features
identical to those of aspirates of the same
lesions arising in their typical primary

Papillary thyroid carcinoma is by far the
most common thyroid malignancy in het-
erotopic siles. followed by follicular carci- -:.-....;
noma, squamous cell carcinoma, Hurthle Fig. 6.09 Papillary thyroid carcinoma arising in association with thyroglossal duct cyst. Papillary structures and
cell carcinoma, anaplastic carc inoma, occasional psammoma bodies are seen; at the right, a respiratory epithelium-lined cyst and skeletal muscle fibres are
and medullary carcinoma (1251}. seen; also seen are scattered benign thyroicl follicles.
Tumours arising in heterotopic salivary
gland tissue are rare, and about 80% The major differential diagnosis is metas- Prognosis and predictive factors
are benign. Mucoepidermoid carcino- tasis to lymph node. Most cases of carci- The most importan! prognostic factors
ma is the most common carcinoma in noma in lateral neck ectopic thyroid are are tumour size, stage, and grade. With
this setting, followed by acinic cell car- thought to constitute nodal metastasis reported follow-up ranging from 1 month
cinoma; adenocarcinoma, NOS; and trom an undetected primary in the thyroid to 17 years , most patients are alive and
cystadenocarcinoma. Other types of gland. Most alleged carcinomas aris- disease-free {523 ,1251}.
carcinoma have also been reported, ing in branchial cleft cysts are thought
but unlike among eutopic salivary gland to be metastatic squamous cell carci-
carcinomas, adenoid cystic carcinoma is noma from an undetected oropharyngeal
particularly rare {1725). carcinoma.

Tumours of unl<nown origin 153

Haematolymphoid tumours Wakely P.E.
Li X.-0.
Schwartz M.R.

Definition various extranodal siles in the head and {2522}. Accurate distinction of lymphoma
Lymphomas are neoplastic clonal prolif- neck [2373}. from other non-lymphoid neoplasms and
erations of lymphoid cells. This category from reactive conditions is possible when
is subdivided into Hodgkin lymphoma Clinical features cytology is coupled with appropriate an-
(HL) and non-Hodgkin lymphoma (NHL). Lymphomas commonly present as a cillary tests such as flow cytometry, im-
painless nodal swelling in the neck. In munohistochemistry, in situ hybridization
Epidemiology sorne lymphomas, a concomitant anterior FISH, cytogenetics , and/or assessment
Both HL and NHL are more common in mediastinal mass is present. Non-specif- of gene rearrangements. A variety of
developed countries. There is a slight ic constitutional symptoms include weak- NHLs can be subclassif ied in this man-
male predominance. Caucasians have ness and fatigue. Lymphomas may be ner. Fine-needle aspiration is particularly
the highest incidence of NHL, whereas associated with so-called B symptoms: applicable in cases where recurrent lym-
the indigenous peoples of North Amer- fever, weight loss, and night sweats. phoma is suspected.
ica are leas! affected. After the age of
10 years, the incidence of NHL increases Macroscopy Histopathology
with each passing decade. The incidence Enlarged neck nodes may be single or The characteristic low-power appearance
of HL spikes in the second to fourth dec- matted together as a group. The cut sur- of ali nodal-based NHLs is partial or com-
ades of lite. NHLs are subdivided into face shows a homogeneous pale-tan to plete alteration of the normal architecture
B-cell, T-cell, and NK-cell types, with off-white, soft or firm, bulging mass. Yel - of the lymph node by a proliferation of ab-
80- 85% of being B-cell neoplasms. Fol- lowish necrotic foci may exist in sorne normal lymphoid cells. This proliferation
licular lymphoma and diffuse large B-cell high-grade lymphomas. Sorne HL sub- may show a follicular, sinusoidal, mantle-
lymphoma are the most common NHLs types display a nodular cut surface zone, or diffuse confluent pattern of ef-
encountered in neck nades. HL has two showing a variable amount of fibrosis that facement. Higher-grade lymphomas are
major subtypes: classical and nodular manifests as strands of connective tissue associated with increased mitotic figures,
lymphocyte-predominant, with the classi- arborizing throughout the node. tingible body macrophages, and necro-
cal variant constituting 95% of ali cases. sis (manifesting as individual cell apop-
Cytology tosis or geographical zones of necrosis).
Localization The use of cytopathology in the diagno- The cells of large cell lymphoma have a
Lymphomas typically arise from lymph sis of haematolymphoid neoplasms has diameter 2- 4 times that of small resting
nodes in the anterior or posterior cer- evolved over the past three decad'es . Al- lymphocytes, rou nd to ovoid nuclei with a
vical, postauricular, occipital, or su- though the diagnostic standard for newly vesicular appearance, coarsely granular
praclavicular reg ions. HL may arise in diagnosed patients remains histopathol- chromatin, and discrete nucleoli. The cyto-
a single node or a chain of nodes, but ogy in many centres, fine-needle aspi- plasm is modest in amount and basophilic.
only rarely in extranodal siles. Although ration cytopathology has proven useful More anaplastic forms of large cell lym-
typically nodal, NHL may develop in in centres that use ancillary techniques phoma display multinucleation, irregular

:, .. --
.. e

' .;


~ ......- """""~- _ _::.a .._ B ! :
Fig. 6.10 A Mantle cell lymphoma. An isomorphic population of small lymphocytes displays irregular nuclear contours, evenly dispersed chromatin, absent nucleoli, and minimal
cytoplasm (Romanowsky stain). B Hodgkin lymphoma. A classic Reed- Sternberg cell dwarfs surrounding lymphocytes and neutrophi/s; huge nuclei mirroring one another contain
enlarged misshapen nucleoli (Papanicolaou stain).

154 Tumours and tumour-like lesions of the neck and lymph nodes
nuclear contours, and large acidophilic lacunar-type Reed-Sternberg cells, which Prognosis and predictiva factors
nucleoli. Small cell subtypes of NHL have have polylobated nuclei and a retracted The prognosis of NHL is highly vari-
a monotonous population of lymphocytes cytoplasm in formalin-fixed tissue. Positive able, depending on histological type
that are slightly larger than mature resting CD30, CD15, and PAX5 staining is helpful and the lnternational Prognostic lndex,
lymphocytes. Depending on the subtype, for recognizing these cells. which consists of cl inical stage, serum
nuclei are rounded or angulated with finely lactate dehydrogenase, patient age,
granular or clumped chromatin. Nucleoli, if Genetic profil e performance status, and involvement
visible, are small. Most NHLs show clonal rearrangements of extranodal sites {2732). HL is curable
Reed- Sternberg cells and variants are a of either IG genes (in 8-cell lympho- by rad iation and chemotherapy in about
minor componen! of the polymorphous mas) or T-cell receptor genes (in T-cell 85% of cases. Clinical stage is the prin-
population of lymphocytes, eosinophils, lymphomas). Severa! B-cell lympho- cipal prognostic factor in determining
plasma cells, and neutrophils in classical mas have characteristic genetic abnor- survival.
HL. The common nodular sclerosis variant malities that can be used in differential
of classical HL typically contains so-called diagnosis.

Cysts and cyst-like lesions

Branchial cleft cyst for 20% of cases) and 20- 40 years (ac- Clinical features
counting for 75%). Males and females are Patients present with painless cervical
Ro J.Y. equally affected {599,906}. swelling. Bilateral lesions suggest syn-
Bell D. dromic or famil ia! association. Dyspha-
Gnepp D.R. Etiology gia, dysphonia, dyspnoea, and stridor
Wenig B.M . Branchial cleft cysts were previously de- may occur. Spontaneous rupture of an
scribed as congenital malformations re - infected cyst may occur, resulting in a
sulting from imperfect obliteration of the purulent draining sinus to the skin or
Definition branchial clefts, arches, and pouches. pharynx.
A branchial cleft cyst is a lateral neck cyst, Other theories of their etiology include
derived most often (approximately 90% cervical lymph node cystic transforma- Macroscopy
of ali cases) from remnants of the sec- tion and incomplete obliteration of cervi- The cysts are unilocular and contain
ond branchial apparatus. First, third, and cal sinus or thymopharyngeal ducts {251, clear to grumous material. They have a
fourth branchial cleft anomalies are rare. 594,866,2173). wide size range, and can reach 10 cm .

Synonyms Localization Cytology

Lateral neck cyst; cervical lymphoepithe- The typical localization is the lateral neck Preparations show neutrophils, lympho-
lial cyst near the mandibular ang le, along the an- cytes, and debris admixed with mature
terior border of sternocleidomastoid mus- squamous cells, including degenerate
Epidemiology cle, but these cysts can occur anywhere forms {906,2378).
Branchial cleft cyst accounts for about from the hyoid bone to the suprasternal
20% of cervical cysts and 90% of lateral notch. They are equally distributed on the Histopathology
cervical cysts (879). lt has bimodal pa- left and right sides of the neck, with rare Branchial cleft cysts are usually unilocu-
tient age peaks at < 5 years (accounting bilateral occurrence {599,906}. lar. They are lined by stratified squamous

Fig. 6.11 Branchial cleft cyst. A Scattered mature squamous epithelial cells are seen admixed with neutrophils, lymphocytes, histiocytes, and necrotic debris (Diff-Quik stain).
B A unilocular cyst, lined by stratified squamous epithelium. Under the epithelial lining, lymphoid tissue with germinal centres is present. CThe cyst is lined by respiratory epithelium,
with scattered goblet cells; beneath the cyst, only a few lymphocytes and eosinophils are present.

Cysts and cyst-like lesions 155

( ;;
', .'\, tl1.c\
~~: \' "'t1ff
tf ,\ ~\ f
~ , : ~ ,) ... i .,.~ \~
1 ,1\\'' ~ I
. : '
. ---. - -.., ...
~ . . .,,_
. ... ..,:
\ ..\
' ,..., .
' ; ,\.'

., . r .\..~-._\\~ . ;:~ :\. . .-..

~ ' ....

,.:_ < '/ \' , ~-'~ t- :;~ -

:::~ )~:-.~ "- . ...-;.:. 'Si~ :f... .
... .
, . ; . ... ?' ' _, . ... ,
,~ ')~\.~.... ~ ,.~ .
' .. /'".i, ,.-, ~~~~.'N'' )..;.~,....,.,"" . . ., ' --?"'e,
' ' ,. .)t;~ .,.: . ~:,,\ -'~';,:~:.z..,.:.:.}~~~~,r.~/!'!';-;: ~~.-/
,. f .. '. ~<~-i{. .::,~"\.) \: ;--:~~,~~i::'";:P:~\-,-.;,"':_i}:::~~-/'
. ~.-'
. . . .-- , ~."'
J ,:
. , . .
_:, .... , ~
.... ........, , ,\ . - ..:-,~----~:<.~"'
_\,. "' ....
l> '
t,' '1,,;-,..:_~ ' ~-,
.. ......~ .. , . . .. ...... -
, . .
.,. . j--~. - :!- :~ ! ' " ~ ....... -~ ', ~.,/ ; :..:. ..::~ . . 1
i<.i! .,. . 1,\ -- ?-. , V \ ~.:.:,. 4 . .. ...,.. ~, . , . .
;/,t:;1f '~'t::__'r_.',:.' ,1 -.,::\,\._,~,.,,~ ~L\'
-~~~\ , '- ~........ ~:-- . ,~.; ~ '
""' ~ . -:~ ~ ~
,',. ' .. !... .

..~~:_\_:_~;-~ :~-:~::
)-: :,~ . . . ; .
~-'i:~ ~ ~ \i;~,< ' ' , , , -..., A<
-~ ~- ~ ' ":,:,.. ~ ~,._',",,.... H.:..:.... ' .,.,,. , _ _ -
Fig. 6.12 Thyroglossal duct cyst. A The cyst is lined by benign epithelium that is variable, even within the same cyst, and consists of columnar, cuboidal, and flat cells; the cyst
contents are thin and mucinous, unless infected; thyroid follicles {al lower left) are seen in 31-62% of cases (1454,2560}. B The cyst is lined by ciliated pseudostratified respiratory
and squamous epithelium and cuboidal cells; a subepithelial lymphoid infiltrate is present.

epithelium in 90% of cases and less com Epidemiology cells or ci liated columnar cells . Thyroid
monly by respiratory epithelium, with oc- TGD cyst is the most common congenital follicular epithelium is sometimes seen.
casional goblet cells and transitional areas mass in the neck, presenting in patients
in both epithelial types. The lumen is fi lled of any age, with no sex predilection (277, Histopathology
with keratin debris. Lymphoid tissue with 547,1334,1434). Thyroglossal tract rem- TGD cyst is lined by benign epithe lium,
germinal centres is present in the wall. Car- nants are found in 7% of autopsies (651, usually respiratory or squamous in type,
cinoma either does not occur in branchial 1310}. and may show thyroid follicles and mu-
cleft cysts or is vanishingly rare (251) . cous glands in the wall. Severe inflam-
Presumed branchial clefl cysts with cyto- Etiology mation, abscess , and granulomatous
logical atypia in patients aged > 40 years The TGD arises from the endoderm at reaction with choleste rol granulomas
should raise the possibility of metastatic the base of tangue and descends in the may obliterate the cyst lining . Malignancy
carcinoma from the oropharynx. In this set midline of neck to form the thyroid gland. (most often papillary thyroid carcinoma)
ting, the value of p16 immunostaining for Persistence of TGD with accumulation of can infreq uently supervene.
differential diagnosis is limited, because secretions from its epithelium may lead to
p1 6 is overexpressed in almost 50% of cyst formation (51). Genetic susceptibility
branchial cleft cysts (326,2663}. TGD cyst may rare ly be inherited in an
Localization autosomal dominan! manner (2089}.
Prognosis and predictive factors The typical localization is th e midline of
Branchial cleft cysts are benign. After the neck or within 2 cm of it, at the l'evel of Prognosis and predictive factors
complete surgical excision, there is only the hyoid, infrahyoid, or suprahyoid (sub- Recu rrences may occu r after inadequate
a low risk of recurrence (< 3%) without mental). Uncommon locations include excision (547). The p rog nosis of papillary
infection befare surgery, but the risk in- intralingual, intrahyoid, an d intrathyroidal thyroid carcinoma complicating a TGD
creases to nearly 20% if the cyst is in- {1334,2240). cyst is excellent [439,948 ,1827).
fected or previously incised, drained, or
incompletely removed . Clinical features
TGD cysts may present as an asymp- Ranula
tomatic mass, draining sinus, fistula, or
Thyroglossal duct cyst recurren! swelling that moves with swal- Katabi N.
lowing. Ultraso nography confirms the Gnepp D.R.
Prasad M.L. presence of thyroid gland and detects Wen ig B.M.
Bell D. any associated malignancy [439).
Gnepp D.R.
Richardson M. Macroscopy Definition
The cysts are generally < 2 cm in size Extravasation of mucus with in an intraoral
(range: 0.5-10 cm) (51,790). The cyst cystic cavity, usually associated with the
Definition contents are thin and mucoid, unless sublingual gland {647).
A thyrog lossal duct (TGD) cyst is a cystic infected. Solid areas should raise suspi-
dilatation of a persisten! TGD. c ion for malignancy {439). Synonyms
Mucocoe le; retention cyst; mucus
Synonyms Cytology extravasation
Thyroglossal duct remnant; thyroglossal Asp irates show inflammatory cells and
cyst (1640) debri s admixed with mature squamous

156 Tumours and tumour-like lesions of the neck and lymph nodes
by epithelium, which can be squamous,
cuboidal, or columnar. A plunging ranula
is a pool of mucin surrounded by fibrous
tissue and inflammatory cells (frequently
histiocytes), without an epithelial lining.
Mucicarmine staining or periodic acid-
Schiff (PAS) with diastase may be helpfu l
in identifying extravasated mucin.

Prognosis and predictive factors

Complete excision, including removal of Fig. 6.14 Dermoid cyst. Cut surface of a midline neck
the traumatized salivary duct, is the treat- dermoid cyst; the cyst is unilocular and filled with keratin.
ment of choice {2720}. lnadequate exci-
sion can result in recurrence.

Dermoid and teratoid cysts

Epidemiology Chiosea S.
These are rare lesions. There is no sex Gnepp D.R .
predilection, and they can affect patients Wenig B.M.
of any age (2592) .

Etiology Definition
Trauma to an excretory duct is the most A dermoid cyst is a cyst containing ec-
common etiology. toderm- and mesoderm-derived tissues.
The additional presence of endodermal
Localization derivatives defines a teratoid cyst. or fistula. Midline nasal dermoid cysts
Simple ranulas occur in the (lateral) !loor must be assessed (by imaging studies)
of the mouth in association with the ex- Synonyms for intracran ial or deeper soft tissue and/
cretory duct of the sublingual gland Nasal dermoid sinus cyst; cystic der- or bony extension.
{2592). In plunging ranula, extravasated moid; cystic teratoma
mucin dissects through the muscle of the Macroscopy
floor of the mouth into the neck {2720). Epidemiology The cysts can reach 12 cm in size
Dermoid cysts of the head and neck ac- and have keratinous (yellowish-white)
Clinical features count for as many as 7% of ali dermoid contents.
There are two types of ranulas: simple cysts {1929}. There is no cleaf sex pre-
and plunging (deep) {2592,2720}. Simple dilection [1815}. About two thirds of der- H istopathology
ranulas presentas a painless mass in the moid cysts are recognized in patients Dermoid cysts are lined by squamous
oral cavity floor. Plunging ranulas present aged < 5 years. epithelium with mature cutaneous ad-
as a painless neck mass. Ranulas are nexal structures (e.g. sebaceous glands
usually unilateral and unifocal, but may Localization and hair follicles). The absence of cuta-
be bilateral or multiple {2592). The cysts are predominantly subcuta- neous adnexal structures is indicative of
neous. The most common sites are the epidermoid cyst. ldentification of endo-
Macroscopy midline neck or nose, nasolabial fold, and dermal derivatives (e.g. gastrointestinal
Ranulas usually present as blue, fluctu- lateral third of the eyebrow (i.e . embryo- or respiratory mucosa or smooth muscle)
ant, painless masses, and can reach sev- logical fusion lines) (1780}. Lateral der- is diagnostic of a teratoid cyst.
era! centimetres in size {142}. moid cysts are rare {2372).
Prognosis and predictive factors
Histopathology Clinical features Complete surgical excision is the primary
A simple ranula is a pseudocyst that Dermoid cysts present as a non-pulsatile treatment {1780). Recurrence is rare.
contains mucin and may be focally lined painless mass, pit (with protruding hair),

Cysts and cyst-like lesions 157


Tumours of salivary glands

Malignant tumours
Benign tumours
Non-neoplastic epithelial lesions
Benign soft tissue lesions
Haematolymphoid turnours
WHO classification of tumours of salivary glands

Malignant tumours Lymphadenoma 8563/0*

Mucoepidermoid carcinoma 8430/3 Cystadenoma 8440/0
Adenoid cystic carcinoma 8200/3 Sialadenoma papilliferum 8406/0
Acinic cell carcinoma 8550/3 Ouctal papillomas 8503/0
Polymorphous adenocarcinoma 8525/3 Sebaceous adenoma 8410/0
Clear cell carcinoma 8310/3 Canalicular adenoma and other
Basal cell adenocarcinoma 81 47/3 ductal adenomas 8149/0
lntraductal carcinoma 8500/2
Adenocarcinoma, NOS 8140/3 Non-neoplastic epithelial lesions
Salivary duct carcinoma 8500/3 Sclerosing polycystic adenosis
Myoepithelial carcinoma 8982/3 Nodular oncocytic hyperplasia
Epithelial- myoepithelial carcinoma 8562/3 Lymphoepithelial sialadenitis
Carcinoma ex pleomorphic adenoma 8941/3 lntercalated duct hyperplasia
Secretory carcinoma 8502/3*
Sebaceous adenocarcinoma 8410/3 Benign soft tissue lesions
Carcinosarcoma 8980/3 Haemangioma 9 120/0
Poorly differentiated carcinoma Lipoma/sialolipoma 8850/0
Undifferentiated carcinoma 8020/3 Nodular fasciitis 8828/0
Large ce ll neuroendocrine carcinoma 80 13/3
Small cell neuroendocrine carcinoma 8041/3 Haematolymphoid tumours
Lymphoepithelial carcinoma 8082/3 Extranodal marginal zone lymphoma of
Squamous cell carcinoma 8070/3 mucosa-associated lymphoid tissue
Oncocytic carcinoma 8290/3 (MALT lymphoma) 9699/3
Uncertain malignant potential
Sialoblastoma 8974/1

Benign tumours
Pleomorphic adenoma 8940/0 The morphology codes are from the lnternational Classification of Diseases
for Oncology (ICD-0) !776AJ. Behaviour is coded /O for benign tumours;
Myoepithelioma 8982/0 /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma In
Basal cell adenoma 8147/0 situ and grade 111 intraepithelial neoplasia; and /3 for malignant tumours.
Warthin tumour 8561/0 The c lassification is modified from the previous WHO classification, taking
into account changes in our understanding of these lesions.
Oncocytoma 8290/0 *These new codes were approved by the IARC/WHO Committee for ICD-0.

160 Tumours of salivary glands

TNM classification of carcinomas of the
major salivary glands

TNM classificationb,c M - Distant metastasis

MO No distan! metastasis
T - Primary tumour M1 Distan! metastasis
TX Primary tumour cannot be assessed
TO No evidence of primary tumour Stage grouping
T1 Tumour 5 2 cm in greatest dimension, without Stage 1 T1 NO MO
extraparenchymal extension Stage 11 T2 NO MO
T2 Tumour > 2 cm but 5 4 cm in greatest dimension, Stage 111 T3 NO MO
without extraparenchymal extension T1- 3 N1 MO
T3 Tumour > 4 cm and/or with extraparenchymal extension Stage IVA T1 - 3 N2 MO
T4a Tumour invades skin, mandible, ear canal, or facial nerve T4a N0- 2 MO
T4b Tumour invades base of skull or pterygoid plates, or Stage IV B T4b Any N MO
encases carotid artery Any T N3 MO
Stage IVC Any T Any N M1
Note: Extraparenchymal extension is clinical or macroscopic evi-
dence of invasion of soft tissues or nerve, except !hose tissues/
nerves listed under T4a and 4b. Microscopic evidence alone
This classification applies to carcinomas of the majar salivary glands: pa-
does not constitute extraparenchymal extension for classification
rotid, submandibular (submaxillary), and sublingual; carcinomas arising in
purposes. minar salivary glands (i.e. the mucus-secreting glands in the lining mem-
brane of the upper aerodigestive tract) are not included in this classification,
N - Regional lymph nades (i.e. the cervical nades) but instead at their anatomical site of origin (e.g. the lip).
NX Regional lymph nades cannot be assessed bAdapted from Edge e t al. {625AJ - used with permission o f the American
Joint Committee on Cancer (AJCC), Chicago, lllinois; the original and prima-
NO No regional lymph node metastasis ry source far this information is the AJCC Cancer Staging Manual, Seventh
N1 Metastasis in a single ipsilateral lymph node, 5 3 cm in Edition (2010) published by Springer Science+Business Media - and Sobin
greatest dimension et al. {2228A).
N2 Metastasis as specified in N2a, N2b, or N2c below A help desk far specific questions about TNM classification is available at
N2a Metastasis in a single ipsilateral lymph nade, > 3 cm but
5 6 cm in greatest dimension
N2b Metastasis in multiple ipsilateral lymph nades, all 5 6 cm
in greatest dimension
N2c Metastasis in bilateral or contralateral lymph nades, ali
5 6 cm in greatest dimension
N3 Metastasis in a lymph node > 6 cm in greatest dimension

Note: Midline nades are considered ipsilateral nades.

TNM c lassification of carcinomas of the majar salivary glands 161

lntroduction EI- Naggar A.K .

In this volume, Chapter 7 is the main multtude of existing entites and the re- the biological and therapeutc stratifica-
reference on ali salivary gland tumours markable overlap of cellular and pheno- tion of certain salivary carcinomas is in-
occurrng throughout the head and neck. typic features wthin and between sali- evitable, none of the reported markers
In recognition of cytology as an initial vary gland carcinomas, only thoroughly are yet clnically applicable.
tool in assessing salivary gland masses, documented new phenotypes were con- As in other chapters of this 4th edtion
it has been included, when appropriate, sidered . This approach led to the inclu- volume, poorly dfferentiated carcino-
in most malignan! and selected benign sion of secretory carcinoma as the only mas (small cell and large cell) have
entities. new entity in this edtion. Reported ent- been renamed poorly differentiated neu-
To allow flexbility in grading and the ties and subentities lacking consensus roendocrne and non-neuroendocrine
enrolment of patients n clnica! Irais support and/or validaton by independent carcinomas far consistency. Lastly, sialo-
the term "low-grade" has been omitted investigators have not been included in blastoma and paragangloma have been
across entities. ths editon. reclassif ied from indeterminate to malig-
Another notable modification in this edi- In this chapter, efforts were made to limt nan! and coded accordingly.
ton is the grouping of rare epithelial the hstomorphological, lineage, and bo-
carcinoma subtypes that share similar log cal features discussed to those con-
patholog ical and clinical characteristics sidered to be validated and re levan! to
under "adenocarcinoma, NOS", includ- curren! diagnostc and clinical practice.
ng cystadenocarcinoma, mucinous ade- Similarly, only molecular and cytogenetic
nocarcinoma, and intestinal adenocarcno- fndings that have been dentified by n-
ma. Similarly, ductal papilloma subtypes dependent authors and in large series
(intraductal and inverted) are discussed are dscussed. Although the future nte-
together in a single section. Given the gration of molecular genetc findings into

162 Tumours of salivary glands

Malig nant tumours

Mucoepidermoid carcinoma bular gland, and other intraoral minar sal- demonstrate intracytoplasmic staining in
ivary gland sites (309,1899). Primary in- mucinous cells.
Brandwein-Gensler M. traosseous (central) MECs are rare (275, The rare oncocytic variant is composed
Bell D. 1425) mainly of polygonal/columnar oncocytic
lnagaki H. cells with scattered mucocytes, and few
Katabi N. Clinical features if any squamoid cells [782). The scleros-
Leivo l. The clinical presentation vares depend- ing variant is characterized by dense
Seethala R. ing on tumour site, size, and grade. Cyst- hyalinizing fibrosis {1585,2360). Salid
Triantafyllou A. ic intraoral MEC can mimic a mucocoele. MECs tend to demonstrate predominan!
Mucinous MEC may fluctuate in size due squamoid and intermediate cells, with
to cyst rupture and may present as a mu- a subtle transition between these two
Definition cin-draining cutaneous fistula. components.
Mucoepidermoid carcinoma (MEC) is Low-grade MEC is cystic, mucous cell-
a distinctive salivary gland malignancy Macroscopy rich, and well circumscribed . lntermedi-
composed of mucinous, intermediate MECs typically present as a soft or firm ate gmdc MECs are generally more salid
(clear-cell), and squamoid tumour cells circumscribed or infiltrative mass, com- and less circumscribed and show a di-
formi ng cystic and salid patterns . monly with a cystic component. versity of appearances, including mucin
extravasation. High-grade MEC displays
ICD-0 code 8430/3 Cytology one or more of the following features: nu-
Aspirates of low-grade, mostly cystic le- clear anaplasia; necrosis; increased mi-
Synonym sions show predominately mucus and totic rate; and perineural, lymphovascular,
Mucoepidermoid tumour macrophages. Occasional bland epi- or bony invasion {105,124,255,876}. The
thelial cells may be seen. Aspirates of diagnosis of high-grade MEC requires al
Epidemiology higher-grade lesions are more cellular, least focal intracellular mucin positivity;
MEC occurs overa wide age distribution, showing an admixture of epithelial cell the tumours typically contain foci of low or
and is the most common salivary gland types typical of the lesions. Cytological intermediate MEC. The diagnosis should
malignancy in children and young adults, pleomorphism, mitotic activity, and ne- be reconsidered in the presence of kera-
with a peak incidence in the second dec- c rosis may be seen {1248). tin pearls, extreme nuclear pleomorphism,
ade of life {1995). or a history of skin cancer. Necrotizing
Histopathology sialometaplasia, pleomorphic adenoma
Etiology MEC is characterized by variable com- with squamous metaplasia, and scleros-
MEC may develop secondary to radiation ponents of squamoid, mucin-producing, ing polycystic adenosis can be misclas-
or chemotherapy during childhood, with a and intermediate-type cells, with a cystic sified as MEC. Cystic oncocytic MEC with
median latency period of 8 years {2495). and salid growth pattern. Overt keratini- lymphoid componen! can mimic Warthin
zation is rare. Oncocytic, clear-cell, and tumour (MEC may develop in Warthin tu-
Localization sclerosing variants have been described . mour) . The sclerosing variant can be mis-
The parotid is the most common site far Mucicarmine staining and periodic taken far sclerosing sialadenitis.
MEC, followed by the palate, submandi- acid-Schiff (PAS) stain with diastase

, ~ -
Fig. 7.01 Mucoepidermoid carcinoma. A Circumscribed tumour with dominan! clear-cell composition. B Oncocytic variant. The finding of larger intermediate cells with clear
cytoplasm guides this diagnosis to mucoepidermoid carcinoma; intracytoplasmic mucin is also present. C lntracytoplasmic mucin is a requisite finding.

Malignan! tumours 163


L, '
wJ Y. ,
.~. 1~1
, . .
Ji.: ,'"''.
tAJ. 1 ; .'~ /

Genetic profile Epidemiology finding of necrosis and/or haemorrhage

Most MECs are characterized by a The annual incidence of ACC is about may indicate the presence of high-grade
t(11;19)(q21;p13) translocation and 2 cases per 100 000 population in the tumour {2117).
CRTC1-MAML2 gene fusion (1 122,2116), USA {646}, and the median patient age
whereas a small subset show a 1(11;15) at diagnosis is 57 years. There is no eth- Cytology
(q21 ;q26) translocation and CRTC3- nic predilection, and the female-to-male Aspirates are composed of groups of
MAML2gene fusion (1700\. Tumours with ratio is about 1.5:1 {244,646}. ACC ac- compact uniform basaloid cells, usually
translocation and gene fusion tend to be counts for < 1% of ali head and neck associated with metachromatic spheres
of low to intermediate grade (1122,2116) cancers and < 10% of ali salivary gland or cylinders of acellular hyaline stroma
and reported in younger patients {1700), neoplasms. {1247,1671,1690\. Neither the cytological
but high-grade MEC can also be fusion- features of a high-grade malignancy nor
positive. Rare cases with t(6;22)(p21 ;q12) Localization keratinization is seen.
translocation and EWSR1-POU5F1 gene ACC occurs most frequently in the major
fusion have been reported (1638). Al- salivary glands, but more than one third Histopathology
though these fusion find ings have been of cases occur in minor glands in the oral ACCs can manifest a variety of tubular
validated, their diagnostic and c linical cavity, sinonasal trae!, or (rarely) other and cribriform structures with variably
implications in the pathological evalua- siles {244,646}. solid components. The most recogniz-
tion of these tumours remain uncertain. able architectural form is the cribriform
Clinical features pattern, characterized by nests of tumour
Prognosis and predictive factors Patients usually present with swelling cells interrupted by sharply punched-out
Low- and intermediate-grade MECs are or masses, and may have numbness, spaces fi lled with basophilic matrix. The
less aggressive and are generally cured paraesthesia, or pain. lnvolvement of tubular pattern is composed of bilayered
by complete surgical excision {1 195, motor nerves can cause facial or tongue tubu les with true lumina. The tumour
1569}. The 10-year overa!! survival rates weakness (517,2253). cells show scant cytoplasm and typically
for low-, intermediate-, and high-grade have small angulated and hyperchro-
MECs are approximately 90%, 70%, and Macroscopy matic nuclei. The solid growth pattern is
25% , respectively (1899). ACC typically presents as a firm, grey- characterized by sheets of tumour cells
ish-white, unencapsulated and infiltrative without lumen formation and may consist
mass of variable size (2251). The rare of epithelial or myoepithelial elements.
Adenoid cystic carcinoma
Stenman G.
Licitra L.
Said-AI -Naief N.
van Zante A.
Yarbrough W.G .

Adenoid cysti c carcinoma (ACC) is a
slow-growing and relentless salivary
gland malignancy composed of epithelial
and myoepithelial neoplastic cells that
form various patterns, including tubular,
cribriform, and solid forms.
Fig. 7.03 Adenoid cystic carcinoma. Spectral karyotype of a MYB-NFIB fusion-positive tumour with a t(6;9)(q22
ICD-0 code 8200/3 23;p23-24) chromosomal translocation as the sole cytogenetic anomaly.

164 Tumours of salivary glands

Perineural invasion is virtually ubiquitous. prognosis, whereas losses of 14q are common ly to the lungs , tollowed by
Rarely, ACC can undergo high-grade exclusively seen in mainly tubular and bone, liver, and brain (2185}. Factors
transformation or dedifferentiation; this cribriform pattern tumours (1862,1955}. that influence survival include tumour
diagnosis should not be made in the ab- Whole-exome sequencing of ACCs has stage, node status, patient age, tumour
sence of conventional ACC (1681 ,2117). revealed a wide mutational diversity and site, large nerve perineural invasion, and
lmmunohistochemical stain ing for KIT a low exonic somatic mutation rate, with surgical margins (71,449,1981). Gener-
(CD117) is typical ly restricted to inner mutations in genes involving a wide va- ally, tumours with tubular and cribriform
epithelial cells and p63 and SMA to pe- riety of pathways, including f ibroblast growth patterns have a less aggressive
ripheral myoep ithelial ce lls {78}. MYB and growth factor, insulin-like growth factor, clinical course than do tumours with a
MYB-NFIB antibodies are currently being Pl3K and NOTCH signalling (PIK3CA, salid componen! constituting more than
evaluated {270,2597). FOX03, INSRR, NOTCH1, and NOTCH2) one third of the tu mour {509,2328].
The majar entities to be distinguished (1002,2277}. KIT and EGFR, which are Radical surgical excision, with or without
from ACC are pleomorphic adenoma, frequently overexpressed in ACC, are postoperative radiation, is the treatment
polymorphous adenocarcinoma, epithe- only rarely mutated or amplified (516, of choice; overall survival is poorer with
lial-myoepithelial carcinoma, and basal 1002,1625,2277}. a single-modality approach {1981}. lnten-
cell adenocarcinoma. sity-modulated rad iotherapy plus carbon
Genetic susceptibility ion boost has recently been shown to im-
Genetic profile Germline BRCA mutations and genetic prove locoregional control and progres-
The key genomic alterations are a t(6;9) variants in DNA double-strand break re- sion -free and overall survival {1 126,1 127,
chromosomal t rans location or more pair genes have been associated with an 1348).
rarely a t(8;9) translocation, resulting increased risk of salivary gland cancers,
in fusions involving the MYB or MYBL1 including ACC (2157,2658}.
oncogenes and the transcription fac-
tor gene NFIB (266,1629,1745,1861 }. Prognosis and predictive factors
MYB/MYBL 1 activations due to gene fu- The 10-year survival rate is 50- 70% (459,
sion or other mechanisms are foun d in 1535,1981 }, and the local recu rrence rate
> 80% of ACCs and may be useful po- is highly variable. Lymph node involve-
tential therapeutic targets {270,1630, ment is uncommon, but is more frequent
2271 }. Losses of 1p and 6q are associ- in solid variants (2477}. Distan! metasta-
ated with salid form tumours with poor sis is reported in > 50% of cases, most

Malignant tumours 165

Acinic ce// carcinoma
Simpson R.H.W.
Chiosea S.
Katabi N.
Leivo l.
Vielh P.
Williams M.O.

Acinic cell carcinoma is a malignant sali-
vary gland neoplasm composed of can-
cer cells with acinar features. A subset of
this entity has been reclassified as secre-
tory carcinoma (208}.

ICD-0 code 8550/3

Acinic cell adenocarcinoma; acinar cell

The mean patient age at presentation is Macroscopy
approximately 50 years, with a female-to- Most tumours are circumscribed (occa-
male ratio of 1.5:1 {430,1826}. About 35% sionally cystic) solitary nodules of varying
of patients are aged > 60 years, and 4% size, but sorne are poorly defined.
are aged < 20 years. Acinic cell carcino-
ma is the second most common salivary Cytology
gland malignancy in ch ildren. Aspirates are usually cellular, and com-
posed of sheets, microcystic structures,
Localization or follicles of serous acinar cells. The
More than 90-95% of acinic cell carcino- cells typically display granular cyto- 1 .;. '

mas occur in the parotid glands. plasm encasing hyperchromatic, round, Fig. 7.08 Acinic cell carcinoma. D0G1 stains most acinic
relatively monomorp hic nuclei. Admixed cell carcinomas.
Clinical features capillaries are often seen {48,1245!.
The tumours typically present as slow- A subset of tumours may display an un-
growing, solitary, unfixed masses, but Histopathology differentiated componen!, predominantly
sorne are multinodular and/or fixed to Acinar and ductal cells with variable salid or cribriform with glandular patterns
skin. One third of patients experience vacuolated, clear, oncocytic, and hobnail and areas of necrosis (poorly differenti-
pain and 5-10% develop facial paralysis. features forming salid, microcystic, and ated transformation ar dedifferentiation)
follicular patterns are present. The pap- \430,2199,2384}.
illary cystic component, if present, has Although non-specific, DOG1 and
macrocystic spaces with papillary prolif- SOX1 O are immunopositive in acinar and
erations. A prominent lymphoid infiltrate intercalated duct cells {408,1767). Acinic
can be seen \103,1604). The acinar cells cell carcinoma is usually immunonega-
are large and polygonal, with basophilic tive for mammaglobin, which is useful in
granular cytoplasm and round, eccentric its distinction from secretory carcinoma.
nuclei. The granules give a diastase-re-
sistant positive periodic acid-Schiff (PAS) Genetic profile
reaction, which may be focal, but the test Pl3K pathway alterations have been
is not necessary far diagnosis. Acinic cell reported (581}, but the biological and
carcinomas rarely show mitoses, .!1ecro- therapeutic significance of these findi ngs
sis, or significant pleomorphism, and can remains unknown (669}.
be considered low-/intermediate-grade
malignancies. The presence of neural in- Prognosis and predictive factors
vasion and stromal hyalinization is associ- Although acinic cell carcinoma is general
ated with aggressive behaviour (152,641, ly not aggressive, a proportion can metas
649,2255). tasize to cervical lymph nades and lung.

166 Tumours of salivary glands

A recurrence rate as high as 35% has Macroscopy
been reported {649,928,973,1013,1400, PACs typically present as firm , c ircum-
1703,2405}. The 20-year survival rate is scrib ed, unencapsulated, yellowish-tan
approximately 90%, with a slightly better lobulated nodules of variable size (aver-
rate for females {1826}. age: 2.1 c m) {1832}.
Poor prognostic factors include large tu -
rnour size, involvement of the deep lobe Cytology
of the parotid gland , and incomplete re- Due to their locations, PACs are rarely
section. Multiple recurrences and cervi- sampled by aspiration. lf accessible,
cal lymph node and distan! metastases smears show sheets and clusters of
predict poor prognosis. Compared with Fig. 7.10 Polymorphous adenocarcinoma. Note the
epithelial cells, with papillary formations.
conventional acinic cell carcinomas, cas- multinodular surface and the haemorrhage. The cytological features ot high-grade
es with high-grade transformation have malignancy and squamous d itterentia-
been reported to be associated with a Epidemiology tion are not seen unless dedifferentiation
shorter mean overall survival (40 months PAC is the second most common is present {1250).
versus 125 months) {430}. intraoral malignan! salivary gland tumour,
accounting for 26% of ali carcinomas al Histopathology
this site (2524). The female-to-male ratio PAC is typically submucosal in location
Polymorphous adenocarcinoma is about 2:1. The patient age ranges from and unencapsulated. The tumour histo-
16 to 94 years, with a mean of 59 years pathology is characterized by cytolog i-
Fonseca l. {1832). More than 70% of patients are cal unitormity, histological d iversity, and
Assaad A. aged 50- 70 years {1832). Few examples an infiltrative growth pattern. Due to the
Katabi N. of PAC have been reported in chi ldren aggressive clinical behaviour of sorne ot
Seethala R. {1 231,1832,2430). these tumours, the term "low-grade" is
Weinreb l. omitted but can be used on a case-by-
Wen ig B.M . Local ization case basis. Neoplastic cells are small to
App roximately 60% of PAC cases involve medium-sized and uniform in shape, with
the palate. Other intraoral locations are bl and, minimally hyperchromatic, oval nu-
Definition the bucea! mucosa, retromolar region, clei and only occasional nucleoli. Mitoses
Polymorphous adenocarcinoma (PAC) is upper lip, and base of tangue {1231, are uncornmon and necrosis is seen in
a malignan! epithelial tumo ur character- 1832). Uncommon locations include the high-grade transfo rmation. A salient and
ized by cytological uniformity, morpho- majar salivary and lacrimal glands, naso- prominent teature is the wide variation
logical diversity, and an infiltrative growth pharynx, and nasal cavity (1231,1832, of morphological configurations within
pattern. 2587}. and between tumours. The main micro-
scopic architectural patterns are lobular,
ICD-0 code 8525/3 Clinical features trabecular, microcystic or cribriform (as
PACs typically present as a painless in adenoid cystic carcinoma), salid, and
Synonyms mass ot variable duration (from a few papillary-cystic. An eddy-like pattern can
Polymorp hous low-grade adenocarci- weeks to 40 years) {352) . Bleeding, telan- be observed al the peripheral boundaries
noma; terminal duct carcinoma ; lobular g iectasia, and ulceration of the overlying of tumour. Foci ot oncocytic, clear, squa-
carcinoma; cribriform adenocarcinoma mucosa may occasionally be found. mous, or mucous cells can be observed .
of tongue/minor salivary glands Tumour stroma can be mucinous or hya-
linized. Perineural involvement is common.

-A , . >
.. .1. ... .:.!.;.,,. \, -
~-11..J..W:.u.i<- r l -
,Ir/ J.
~ -._... ' -
Fig. 7.09 Polymorphous adenocarcinoma. A Tumour of minor salivary gland presenting as submucosal, well-circumscribed nodule. B A storiform pattern may be present in the
periphery; neurotropism is common.

Malignan! tumours 167

lnvasion into adjacent bone may be seen Prognosis and predictive factors in the fifth to eighth decades of life. CCC
in tumours of the palate or mandible. A cri- The overall survival of patients with PAC is rare in chi ldren.
briform variant {1604A), initially reported is generally good {352,671,1231 ,1832,
at the base of tangue and later in other 2118). A review of larg e series with long- Localization
minor salivary gland siles, is considered term follow-up found local recurrence CCCs most frequently occur in intraoral
by sorne authors to constitute a separate rates of 10- 33% (average: 19%) {1231 , salivary gland sites (p alate and base of
entity {1604A,2198}; however, this phe- 1832). Of these, 50% occurred 5 years tangue) {1 614,2 137,2182,2530) but may
notype is considered a feature within the after initial diagnosis {1231,1832). The also occur in other siles {361,659,783,
PAC morphological spectrum by others. range of reported regional metastasis 784,951,988 ,1694,1755,1993,2053,2231,
According ly, this variant is considered an rates is 9-1 5% {352,1231 ,1832). Distant 2308,2719}.
emerging entity pending further evidence metastases have seldom been reported
to justify a separate classification {2655A}. {352,1231 ,1832,2118}. Deaths have oc- Clinical features
The tumour cells are immunoreactive for curred after prolonged periods {352,1231, CCC most commonly presents as swell-
cytokeratins (e.g. CK7, in 100% of cases) 1832). High-grade transformation of PAC ing and may be ulcerated or associated
11577), S100 protein (in 97%), CEA (54%), has been reported and is associated with with p ain, bone invasion , and soft tissue
GFAP (15%), MSA (13%), and EMA (12%) an unfavourable prognosis {1681,2180}. fixation .
{1855,1916,2587). Expression of galec-
tin 3 has been reported to be significan! Macroscopy
in PACs {1850}. BCL2 is overexpressed in Clear ce// carcinoma Tumours present as a poorly circum-
most cases {185 5), and mammaglobin is scribed, solid, greyish-white mass.
positive in 67- 100% of tumours 1207,1927). Wenig B.M . Prominent hyalinization may be grossly
Staining for p63 is reported in 100% of Bell D. apparent.
cases, whereas p40 is consistently nega- Chiosea S.
tive; this pattern is helpful (although not in- lnagaki H. Cytology
fallible) in the differential diagnosis {2011}. Seethala R. As pirates comprise groups (often sheets)
KI T (CD117) positivity has been described of cohesive small and large epithelial
in about 60% of tumours {1 850). cells with prominent cell borders and uni-
Definition form, round to ovoid nuclei with granular-
Genetic profile Clear cell carcinoma (CCC) is a low-grade looking chromatin, small nucleoli, and
A variety of molecular and genetic find- salivary gland carcinoma composed of abundan! clear cytoplasm.
ings have been reported in PAC, among malignan! cells with clear cytoplasm, with
these are HRAS mutations {2569]. in- or without hyalinization. lt has a squamoid Histopathology
c luding alterations of th e PRKD gene phenotype and lacks features of other CCCs are unencapsulated and infiltrative
family {2574): rearrangements of PRKD1, clear cell-rich salivary gland carcinomas. with salid sheets, nests, cords, trabecu-
PRKD2, and PRKD3 {2574} and activat- lae, and single-cell growth patterns. Peri-
ing mutation of PRKD1 (p.Glu710Asp, ICD-0 code 8310/3 neural and bone invasion are common.
exon 15). This activating mutation has Ducts and gland-like spaces can be
also been rarely detected in other sali- Synonym seen. Most cases are characterized by
vary gland tumours {2569). PRKD1 and Hyalinizing clear cell carcinoma sclerotic or hyalinized strorna surround-
PRKD3 rearrangements have also been ing tumour nests juxtaposed to variable
found in clinically aggressive tumours. Epidemiology fibrocellular myxoid stroma {1614}. The
The diagnostic and biological signifi- CCC is more common in women {1614, tumo ur cells are polygonal, with distinct
cance of these findings is unknown. 1755,2137,2231} and typically presents cell borders and lightly eosinophilic to

168 Tumours of salivary glands

clear cytoplasm /1614). CCC may also Basal ce// adenocarcinoma Localization
show overt squamous and even muci- Most BACs occur in the parotid gland
nous differentiation. Fonseca l. /502,650,745,1816}.
lntracytoplasmic glycogen that gives Gnepp D.R.
a diastase-sensitive positive period ic Seethala R. Clinical features
acid- Schiff (PAS) reaction is present in Simpson R.H .W. BAC usually presents as a slow-growing
CCC. The tumour may also show pune - Vielh P. nodule. A subset of basal cell adenocar-
tate or even overt intracytoplasmic muci- Williams M.O. cinomas may be associated with multiple
carm ine staining. CCCs are positive for skin adnexal tumours (650,1069,2111,
cytokeratins and p63, and negative for 2691).
other myoepithelial markers /361,1326, Definition
1614, 2137,2182,2530). Basal cell adenocarc inoma (BAC) is a Macroscopy
salivary gland malignancy with variable BAC presents as an unencapsulated,
Genetic profile basal and myoepithelial neoplastic cells firm, light-tan mass .
CCC shows consistent EWSR1-ATF1 forming nests and glandular structures.
gene fusion (84,2137,2354,2566}. Cytology
ICD-0 code 8147/3 Aspirate smears are cellular and show
Prognosis and predictiva factors basaloid clusters of monomorphic small
CCCs are low-grade malignancies as- Synonyms cells, with sean! cytoplasm and frequent
sociated with a good prognosis after Basal ce ll adenocarcinoma ex monomor- naked nuclei (1241,24321. Stroma is sean!
complete surgical excision. Local recur- phic adenoma; malignant dermal ana- to absent; in the membranous type, it con-
rence and nodal metastases may occur logue tumour sists mainly of hyaline matrix that ranges
{2231}. Distant metastasis and death due from interdigitating strands to small cylin-
to disease occur rarely {1754). lnstances Epidemiology . droma-like droplets . Squamoid and seba-
of high-grade transformation of CCC with BAC is rare {502,745,1816,2709}. Most ceous features may be noted /2262).
EWSR1 rearrangement have been re- patients are in th eir sixth or seventh dec-
ported {1135). ade of lile {502,745,1816,2709}. There is Histopathology
no sex predilection {650,2709). Tumours may exhibit solid, tubular, tra-
becular, and membranous patterns with
infiltrative borders . Tumour cells typically

Malignan! tumours 169

display peripheral palisading of basal Genetic profile lntraductal carcinoma
cells with occasional inner lighter epithe- A subset of these tumours, mainly of
lial cells wit