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World Health Organization Classification of Tumours

WHO
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OMS

International Agency for Research on Cancer (IARC)

4th Edition

WHO Classification of
Head and Neck Tumours

ERRNVPHGLFRVRUJ Edited by

Adel K. EI-Naggar
John K.C. Chan
Jennifer R. Grandis
Takashi Takata
Pieter J. Slootweg

International Agency for Research on Cancer

Lyon l 2017
 Published by the International Agency for Research on Cancer (IARC),
150 Cours Albert Thomas, 69372 Lyon Cedex 08, France

© International Agency for Research on Cancer, 2017

Distributed by
WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland
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distinguished by initial capital letters.

The authors alone are responsible for the views expressed in this publication.

The copyright of figures and tables remains with the authors.

(See Sources of figures and tables, pages 294-297.)

First print run (10 000 copies)

Format for bibliographic citations:

EI-Naggar AK.,Chan J.K.C.,G randis J..
R , Takata T., Slootweg P. J.(Eds):
WHOClassification of Head and Neck Tumours (4th edition).
IA C
R : Lyon 2017

IARC Library Cataloguing in Publication Data

WH� classificatio� of head �nd neck t_umours / edited by AdelK.

EI-Naggar, o
J hn
KC· ·Chan '
enni
J fer R . G rand1s, Takash1 Takata, Pieter .J Slootweg. - 4th edition
.
(World Health Organization classification of tumours)

1. Head and neck neoplasms - genetics 2. Head and neck neoplasms -

3. Odontogenic tumours - genetics pathology
4. Odontogenic tumours _ patho
logy
I. EI-Naggar, AdelK. II. Series

ISBN 978-92-832-2438-9 (NLMClassification: WE 707

)
 Contents
Tumours of the nasal cavity, paranasal sinuses and 11 Introduction
Nasopharyngeal carcinoma 65
skull base 65
WHO and TNM classifications 12 Nasopharyngeal papillary adenocarcinoma
Salivary gland tumours 70
Introduction 14
Adenoid cystic carcinoma 71
Carcinomas 14
Salivary gland anlage tumour 71
K eratinizing squamous cell carcinoma 14
Benign and borderline lesions 71
Non-keratinizing squamous cell carcinoma 15 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
Intestinal-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
Sinonasal papilloma, inverted type 28 parapharyngeal space
Sinonasal papilloma, oncocytic type 29 WHO and TNM classifications 78
Sinonasal papilloma, exophytic type 30 Introduction 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 sinonasal 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
Leiomyoma 47 Granular cell tumour 1()0
Haemangioma 47 Liposarcoma 1()0
Schwannoma 48 Inflammatory myofibroblastic tumour 101
Neurofibroma 49 Cartilage tumours 102
Other tumours 50 102
Chondroma and chondrosarcoma
Meningioma 50 104
Haematolymphoid tumours
Sinonasal ameloblastoma 51
Chondromesenchymal hamartoma 51 105
4 Tumours of the oral cavity and mobile tongue
Haematolymphoid tumours 52 106
WHO and TNM classifications
Overview 52 108
Introduction
Extranodal NK/f-cell lymphoma 52 109
Malignant surface epithelial tumours
Extraosseous plasmacytoma 54 109
Squamous cell carcinoma
Neuroectodermal/ melanocytic tumours . 1 12
56 Oral potentially malignant disorders & oral epithelial dysplasia
Ewing sarcoma/primitive neuroectodermal tumours 12
56 Oral po�entially malignant disorders
Olfactory neuroblastoma _ ; 12
57 Ora� ep1t�ellal dysplasia
Mucosa! melanoma 60 1 13
Prol1ferat1ve verrucous leukoplakia
115
Papillomas
2 Tumours of the nasopharynx 63 1 15
Squamous cell papilloma
WHO and TNM classifications 64 116
Condyloma acuminatum
 Verruca vulgarls 117 Introduction 162
Multifocal epithelial hyperplasia 117 Malignant tumours 163
Tumours of uncertain histogenesls 119 Mucoepldermold carcinoma 163
Congenital granular cell epulis 119 Adenoid cystic carcinoma 164
Ectomesenchymal chondromyxoid tumour 119 Aclnlc cell carcinoma 166
Soft tissue and neural tumours 121 Polymorphous adenocarclnoma 167
Granular cell tumour 121 Clear cell carcinoma 168
Rhabdomyoma 122 Basal cell adenocarclnoma 169
Lymphangioma 122 lntraductal carcinoma 170
Haemangioma 123 Adenocarclnoma, NOS 171
Schwannoma and neurofibroma 123 Salivary duct carcinoma 173
Kaposi sarcoma 124 Myoeplthelial carcinoma 174
Myofibroblastic sarcoma 125 Eplthelial-myoeplthellal carcinoma 175
Oral mucosa! melanoma 126 Carcinoma ex pleomorphlc adenoma 176
Salivary type tumours 127 Secretory carcinoma 177
Mucoepidermoid carcinoma 127 Sebaceous adenocarclnoma 178
Pleomorphic adenoma 127 Carcinosarcoma 179
Haematolymphoid tumours 128 Poorly differentiated carcinoma 180
Overview 128 Lymphoeplthellal carcinoma 181
CD30-positive T-cell lymphoproliferative dis.order 129 Squamous cell carcinoma 182
Plasmablastic lymphoma 129 Oncocytic carcinoma 182
Langerhans cell histiocytosis 130 Slaloblastoma 183
Extramedullary myeloid sarcoma 131 Benign tumours 185
Pleomorphic adenoma 185
5 Tumours of the oropharynx 133 Myoepithelioma 186
(base of tongue, tonsils, adenoids) Basal cell adenoma 187
WHO and TNM classifications 134 Warthin tumour 188
Introduction 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 adenosls 195
Introduction 141 Nodular oncocytic hyperplasia 195
Hodgkin lymphoma 141 Lymphoeplthelial sialadenltls 196
Burkitt lymphoma 142 Intercalated duct hyperplasia 197
Follicular lymphoma 143 Benign soft tissue lesions 198
Mantle cell lymphoma 144 Haemangloma 198
T-lymphoblastic leukaemia/lymphoma 144 Llpoma/sialolipoma 198
Follicular dendritic cell sarcoma 145 Nodular fasclltls 199
Haematolymphold tumours 200
6 Tumours and tumour-like lesions 147 Extranodal marginal zone lymphoma of mucosa-
of the neck and lymph nodes associated lymphoid tissue (MALT lymphoma) 201
WHO classification 148
Introduction 148 8 Odontogenlc and maxlllofaclal bone tumours 203
Tumours of unknown origin 150 WHO classlf icatlon 204
Carcinoma of unknown primary 150 Introduction 205
Merkel cell carcinoma 151 Odontogenlc carcinomas 206
Heterotopia-associated carcinoma 152 Ameloblastic carcinoma 206
Haematolymphoid tumours 154 Primary lntraosseous carcinoma, NOS 207
Cysts and cyst-like lesions 155 Scleroslng odontogenlc carcinoma 209
Branchial cleft cyst 155 Clear cell odontogenlc carcinoma 210
Thyroglossal duct cyst 156 Ghost cell odontogenlc carcinoma 211
Ranula 156 Odontogenlc carclnosarcoma 213
Dermoid and teratoid cysts 157 Odontogenlc sarcomas 214
Benign epithelial odontogenlc tumours 215
7 Tumours of salivary glands 159 Ameloblastoma 215
WHO and TNM classifications 160 Ameloblastoma, unlcystlc type 217
 Ameloblastoma, extraosseous/peripheral type 218 9 Tumours of the ear 26 1
Metastasizing ameloblastoma 218 WHO classification 262
Squamous odontogenlc tumour 219 Introduction 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 Cerumlnous adenoma 265
Primordial odontogenic tumour 223 Tumours of the middle and inner ear 266
Odontoma 224 Squamous cell carcinoma 26 6
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
Inflammatory collateral cysts 233 10 Paraganglion tumours 275
Odontogenic and non-odontogenic developmental cysts 234 WHO classification 276

I
Dentigerous cyst 234 Introduction 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

'
f Calcifying odontogenic cyst 239
Orthokeratinized odontogenic cyst 241 Contributors 285

I
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

I
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
l1- Chondromyxoid fibroma 249
Osteoid osteoma 249
Osteoblastoma 249
Desmoplastic fibroma 250
Fibro-osseous and osteochondromatous lesions 251
Ossifying fibroma 251
Familial 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
 CHAPTER 1

Tumours of the nasal cavity, paranasal

sinuses and skull base
Squamous cell carcinomas
Lymphoepithelial carcinoma
NUT carcinoma
Neuroendocrine carcinomas
Adenocarcinomas
Teratocarci nosarcoma
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 Oesmoid-type fibromatosis 8821/1
Non-keratinizing squamous cell carcinoma 8072/3 Sinonasal glomangiopericytoma 9150/1
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
Intestinal-type adenocarcinoma 8144/3
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
U ndifferentiated pleomorphic sarcoma 8802/3
Leiomyosarcoma 8890/3
Rhabdomyosarcoma, NOS 8900/3
Embryonal rhabdomyosarcoma 8910/3
The morphology codes are from the International Classification of Diseases
Alveolar rhabdomyosarcoma 8920/3
for Oncology (ICD-0) 1776A). Behaviour is coded /0 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 Ill intraepithelial neoplasia; and /3 for malignant tumours.
Angiosarcoma 9120/3 The classification is modified from the previous WHO classification, taking
into account changes in our understanding of these lesions.
Malignant 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 classificati on of carcinomas of the nasal cavity and
paranasal sinuses

"NM classification a.b N - Regional lymph nodes (I.e. the cervical nodes)
P 1mary tumour NX Regional lymph nodes cannot be assessed
Primary tumour cannot be assessed NO No regional lymph node metastasis
O No evidence of primary tumour N1 Metastasis in a single ipsilateral lymph node,� 3 cm in
T" s Carcinoma in situ greatest dimension
N2 Metastasis as specified in N2a, N2b, or N2c below
Maxlllary sinus N2a Metastasis in a single ipsilateral lymph node, > 3 cm but
T1 Tumour limited to the antral mucosa, with no erosion or :S 6 cm in greatest dimensfon
destruction of bone N2b Metastasis in multiple ipsilateral lymph nodes, all :S 9 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 nodes, all
except extension to posterior wall of maxillary sinus and � 6 cm in greatest dimension
pterygoid plates N3 Metastasis in a lymph node > 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, floor or
medial wall of orbit, pterygoid fossa, ethmoid sinuses
T4a Tumour invades any of the following: anterior orbital M - Distant metastasis
contents, skin of cheek, pterygoid plates, infratemporal MO No distant metastasis
fossa, cribriform plate, sphenoid or frontal sinuses M1 Distant 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 I T1 NO MO
Nasal cavity and ethmoid sinus Stage II T2 NO MO
T1 Tumour limited to one subsite of nasal cavity or ethmoid Stage Ill 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 IVS T4b Any N MO
T3 Tumour extends to invade the medial wall or floor 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. l625Al - used with permission of the American
anterior cranial Iossa, pterygoid plates, sphenoid or
Joint Committee on Cancer (AJCC). Chicago, Illinois; 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. {2228Al.
0
A help desk for specific questions about TNM classification is available at
nasopharynx, clivus
http://www.uicc.org/resources/tnm/helpdesk.

TNM classification of carcinomas of the nasal cavity and paranasal sinuses 13

Tu mou rs of the nasal cavity, para na s al
s i n uses and sku l l base
Introduction
S lootweg P.J .
C han J . K . C .
Stelow E . B .
Thompson L . D . R .
T h e si nonasal tract (i.e. the nasal cav­
ity and . associated paranasal sinuses)
is the site of origin for a wide variety of
neoplasms. The entities included in this
chapter meet one of three inclusion crite­
ria: ( 1 ) they occ ur exclusively in the si no­
nasal tract, (2) they occur at other head
and neck sites but show a predilection
for the si nonasal tract, or (3) they are im­
portant i n the si nonasal ract for differen­
tial diagnostic reasons. The first group is
discussed extensively and the other two
more concisely, with the reader referred
to other chapters for ad ditional i nforma­
tion. This edition includes N UT carcino­
ma and bip henotypic sinonasal sarcoma
as well-defined new entities. H PV- related
Carci nomas
Keratinizing squamous cell
carcinoma
Bi shop J . A .
Bell D.
Westra W. H .
Definition
Si nonasal keratinizing squamous cell
carc inoma ( KSCC) is a malig nant epi­
thelial neoplasm arising from the su rface
epithelium l i ning the nasal cavity and
paranasal si nuses and exhibiting squa­
mous differentiation.
ICD-0 code 8071 /3
14 Tumours of the nasal cavity, paranasal sinuses and sku l l base
carci noma with adenoid cystic-li ke fea­
tures is provi sionally listed as a su btyp e
of non-kerati nizing squamous cell carci­
noma , with additional data needed to jus­
tify fu ll recognition as a unique entity. Tu­
mours of bone and carti lage, which were
incl uded in both the jaw and si nonasal
tract chapters in the previous edition , are
in this edition d iscussed exclu sively in
Chapter 8 ( Odontogenic and maxillofacial
bone tumours, p. 203) - a more appropri­
ate approach given their morpholog ical
overlap with some odontogenic tumours.
The role of im mu nohistochemical and
genetic features in tumour c haracteriza­
tion is reported with a balance between
worldwide global application and the use
of more expensive diagnostic methods
not everywhere avai lable, in an effort to
ensure a more universal applicabil ity of
the classification.
It is noted that some tumours may consti ­
tute a spectrum of entities, such as high­
grade non-i ntestinal -type adenocar­
ci noma and si nonasal undifferentiated
Synonym
Epidermoid carc inoma
Epidemiology
Sinonasal KSCCs are rare , and the sino­
nasal tract is the least common head and
neck su bsite involved by squamous cell
carcinoma (SCC) (82). KSCC most often
affects patients in their sixth to seventh
decades of life, and men are affected
twice as often as women (82,2065 ,2438}.
Etiology
Cigarette smoking increases risk, al­
though less dramatically than in other
head and neck sites {271 ,960,1 458 ,
2688 ) . Wood d ust, leather dust, and other
carc inom a , and that there may be som e
over lap betw een tumo urs, such as be­
twee n som e si nona sal u n d ifferenti ated
carc inom as and h i g h - g rade neuroen do­
crine carc i noma s. M ore d ata are neede d
befor e recom mend ation s can be made
on how best to classif y tumou rs within
these categ ories. I n the mean ti me, we
have tried to remai n consis tent with p re­
vious classif ication system s of tumo urs
both at this site and at others (e.g . the
class ification of high-grade neuroendo­
crine carc i nomas of the l u ng).
Withi n the si nonasal tract, CT is prim arily
used to evaluate mass effect on adjacent
osseous structu res, whereas M R I is bet­
ter for d isti nguishing mucosa! thickening
and f l u i d res ulting from a pathological
mass process. Thus, these i maging mo­
dalities are complementary tec hniques.
However, in gen eral , cross-sectional im­
aging f i n d i n g s are not unique or tumour­
specific; therefore, i nformation reg ard ing
imaging findings i s included only when it
is of specific diagnostic value.
industrial exposures are linked to sinona­
sal KSCC , although the association is
not as �trong as with intestinal-type ade­
noca �c1noma 1940, 1 490, 1 627). High-risk
HPV 1s most frequently associated with
non-keratinizing squamous cell carci­
noma (see Non-keratinizing squamous
cell ca :cinoma, p. 1 5) 1 1 99,636,1335).
Some s1no nasal papillomas (2- 1 0%) un­
_
� ergo malignant transformation, usually
into KSCC and less frequently into non­
kerati nizing squamous cell carcinoma
{ 1 750).

Localization
The maxillary sinus is most frequently af­
fected, followed by the nasal cavity and
ethmoid sinus. Primary carcinomas of the
sphenoid and frontal sinuses are rare 182,
1 999, 2065 ,2342,2438}.

C l i nical features
Presenting symptoms are generally non­
specific and include nasal obstruction,
epistaxis, and rhinorrhoea. Facial pain
and/or paralysis, d iplopia, and proptosis
are indicative of more-advanced tumour
growth 1 1 458}. Imaging determines ex­
tent of disease.

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

Cytology
Aspirates of metastases are cellular, with
sheets and small clusters of malig nant
Fi g . 1 .02 Sinonasal non-keratinizing squamous cell carcinoma. A Interconnecting squamous ribbons invading the
squamous cells with intracellular and stroma with a broad, pushing border. B Invasion 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-keratinlzing 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
tical to those of conventional squamous
cell carcinoma of other head and neck
sites, with irreg ular nests and cords of
eosinophilic cells demonstrating kerati­
nization and inducing a desmoplastic
stromal reaction. Grades include well,
moderately, and poorly differentiated.
See Chapter 3 ( Tumours of the hypophar­
ynx, larynx, trachea and parapharyngeal
space, p. 77) for further detail.
Genetic profile
The genetic profile is similar to that of
KSCC of other upper aerodigestive tract
sites, whereas the genetic profile of non­
keratinizing squamous cell carcinoma is
pharynx 1447, 1 458, 1 474}. cell carcinoma
Prognosis a n d predictive factors Bishop J . A .
The 5-year overall survival rate for sino­ Brandwein-Gensler M .
nasal squamous cell carcinoma is approx­ Nicolai P.
imately 50-60%, and is stage-depend­ Steens S.
ent {2065,2397,2438}. Carcinomas of Syrjanen S.
the nasal cavity have a better prognosis Westra W. H .
than carcinomas arising in the paranasal
sinuses 182,6 1 7,2397, 2438). This differ­
ence is likely in part because sinus carci­ Definition
nomas present later and at higher stage; Non-keratinizing squamous cell carcino­
it is unclear whether there is a stage-for­ ma (NKSCC) is a squamous cell carcino­
stage survival difference. Regional lymph ma (SCC) characterized by a distinctive
node metastasis is uncommon 11 458). ribbon-like growth pattern with absent to
limited maturation.

Carcinomas 15
I C D-0 code 8072/3
Synonyms
Schneiderian carcinoma; transitional cell
carcinoma; cylind rical cell carcinoma
Epidemiology
NKSCC accounts for approximately 1 0 -
27% of sinonasal sec. It affects adults in
their sixth to seventh decades of life, and
men more frequently than women { 1 99,
636 , 1 78 .1 999}.
Etiology
In general, NKSCC has similar risk fac­
tors to keratinizing squamous cell car­
cinoma, but 30-50% of cases harbour
transcriptionally active high-risk H PV
{ 1 99 , 636,1335}. Some sinonasal papil­
lomas (2-1 0%) undergo malignant trans­
formation, usually into keratinizing squa­
mous cell carcinoma and less frequently
into N KSCC 1 1 750}.
Local ization
N KSCC arises most frequently from the
maxillary sinus or nasal cavity 182,1 402,
2065 , 2438 } .
Fig . 1 .04 HPV-relat�d � rcinoma wi� adenoid cystic-:-li �e features. A Many examples demonstrate foci of squamous dysplasia in the overlying surface epithelium.
. _ _
B Transcnpt1onally active h1gh-nsk HPV 1s demonstrated within the neoplasm by RNA in situ hybridization.
16 Tumours o the nasal cavity, paranasal sinuses and skull base
Clinical features
Presenting signs and symptoms include
nasal obstruction, discharge, epistaxis,
facial pain or fullness, nasal mass or
ulcer, and eye-related symptoms in ad­
vanced cases 1 1 4 58}. Patients with para­
nasal sinus neoplasms present later and
at a higher stage than do patients with
nasal cavity carcinomas 182, 2438). Im­
aging determines extent of disease.
Macroscopy
The tumours are variably exophytic and/
or inverted in growth, and often friable,
with necrosis and/or haemorrhage.
Cytology
Aspirates of metastases are cellular, with
clusters of basaloid cells showing cyto­
logical features typical of malignancy,
with nuclear atypia and increased mitotic
figures. Mixed inflammation and necrosis
can be present.
Histopathology
NKSCC characteristically grows as ex­
panding nests or anastomosing ribbons
of cells in the submucosa, with a smooth
stromal interface and a pushing border
eliciting minimal or no desmoplasia. This
pattern is reminiscent of urothelial carci­
noma (hence the synonym "transitional
cell carcinoma") and may be difficult
to recognize as invasive, particularly in
small biopsies. Papillary features can
be seen within the tumour or at the mu­
cosa! surface. N KSCC has an immature
appearance, with minimal or no kerati­
nization; tumour nuclei are oval and the
N : C ratio is high. Basal/superficial cel­
lular polarity is often apparent: basal­
type cells often demonstrate peripheral
palisading , whereas superficial cells are
more flattened . Scattered mucinous cells
are occasionally present. The degree of
nuclear atypia varies, but mitotic figures
are typically numerous, and necrosis is
common. There is no established role for
tumour g rading in this variant.
There is a broad differential diagnosis;
the g rowth pattern of N KSCC can mimic
that of a sinonasal papilloma with malig­
nant transformation. However, this would
require confirmation of metachronous
or synchronous sinonasal papilloma.
Sinonasal undifferentiated carcinoma,
neuroendocrine carcinoma, the solid
variant of adenoid cystic carcinoma,
and SMA R C B 1 -deficient carcinomas
should be considered in the differential
. ... .
, •l -
diagnosis. The pres ence of so-c alle d
abrupt kerat i nizat ion shou ld raise the
ossibility of NUT carcino m a .
KSCC is d iffus ely posi tive for cyto kera t­
ins (includ ing hig h-mo lecu lar-wei ght
forms such as CK5/6 ) and for p63 and
p40 . It retai ns n uclea r expr essio n of
S RCB1 ( I N l 1 ) and is negative for neu­
roe ""' docri ne mark ers, S 1 00, and NUT1 .
' P '-relate d secs are d iffusel y p1 6-
o� · e by immu nohistochem istry and
oos • e for H PV by in situ hybridi zation
a a ?CR.
Genetic profi le
The disti nctive m utational profiles of
HPV- positive and H PV-negative si nona­
sal SCC are similar to those of their coun­
erpar s in other head and neck sites ,
such as the oropharynx {447,1 458,1 474}.
Prog nosis and pred ictive factors
The 5-year overal l survival rate of si no­
nasal SCCs as a group is approxi mately
60%; it is unclear whether the survival rate
of N KSCC differs from that of kerati niz­
ing squamous cell carcinoma {82,1 999,
2065, 2397, 2438). H PV positivity may be
associated with improved survival, al­
though the prog nostic significance is not
as clearly defined as it is in the oropha­
rynx { 1 99,1 335}. Some studies have dem­
onstrated improved survival in si nonasal
SCC harbouri ng high-risk H PV or overex­
pressing EGFR { 1 99,1 335 , 2342}.
The newly recognized si nonasal tract
H PV-related carcinoma with adenoid
cystic-l ike features is a di stinctive H PV­
related carcinoma of the sinonasal tract,
with histo logical and immu nophenotypic
features of both surface-derived and sali­
vary gland carcinoma - the latter show­
ing the appearance of a high-grade ad ­
enoid cystic carcinoma. Among the few
cases of H PV-related carcinoma with ad­
enoid cystic-l i ke features that have been
reported to date, the female-to-male ratio
is 7:2 and the patient age range is 40-
75 years { 1 99,202,1 065}. The presence
of a high-risk H PV type sug gests a viral
etiology {202,1 065}. Most cases present
with nasal obstruction and/or epi staxi s,
with a tan-white, fleshy mass u ndermin­
ing normal-looking mucosa. The tumour
consists of highly cellu lar prol iferations of
basaloid cells growing in various sizes,
separated by thin collagenized fibrous
bands . The growth pattern is predomi­
nantly solid, but cribriform structures are
frequently encountered. The basaloid
cells align around cylindromatous micro­
cystic spaces and have hyperchromatic
and slightly angulated nuclei with a high
N:C ratio. I n contrast to typical N KSCC,
true ductal cells are also present (al­
thoug h less conspicuous), often sur­
rounded by a peripheral layer of basaloid
to clear myoepithelial cells. When this
bilayered pattern is well developed , it im­
parts an ap pearance like that of epithe­
lial-myoe pithelial carcinoma. Although
overt squamous differentiation is not typi­
cally present in the invasive component,
the surface epithelium may show various
degrees of dysplasia. Mitotic rates are
usually high, and necrosis may be seen. Etiology
The basaloid cells show myoepithelial SCSCC is assoc iated with smoki ng and
differentiation (e. g . S 1 00, calponi n, p63, radiation expos ure ( 1 398 , 2396). H PV has
and actin), and the ductal cells are KIT­ been negative in the few c ases tested
positive. Cytokerati ns tend to be more 1 1 99}.
strongly expressed in the ductal rather
than myoepithelial cells. Both cell types Localization
are p1 6-positive and harbour hig h-risk SCSCC arises in the nasal c avity and/
H PV as detected by in situ hybrid ization . or maxillary or frontal sinuses ( 787, 9 1 2 ,
No MYB translocations (typ ically seen in 1 032 ,1 035).
about 50% of adenoid cystic carcinomas)
have been identified {202}. To date, with Clinical features
only a lim ited num ber of cases reported , Patients present with nasal obstruction,
local recurrence has been seen, but no epistaxis, and/or facial swelling, with
reg ional or distant metastases or tumour­ masses apparent on CT or MRI {787,896,
related deaths {202}. 9 1 2,1 032,1 035).
Macroscopy
Spmd� cell �arcomaroid) Some SCSCCs grow as a polypoid mass
squamous cell carcinoma with an ulcerated surface, simi lar to the
more common laryngeal examples {896,
Bi shop J . A . 9 1 2}.
Lewis J . S .
Cytology
See Spindle cell squamous cell carcino­
Definition ma section (p. 87) in C hapter 3 .
Spindle cell sq uamous cell carcinoma
(SCSCC) is a vari ant of sq uamous cell Histopathology
carcinoma characterized by predomi­ For histology and d ifferential diagnosis,
nant malignant spindle and/or pleomor­ see Spindle cell squamous cell carcino­
phic cells. ma section (p. 87) i n Chapter 3 .
ICD-0 code 8074/3 Prognosis and pred ictive factors
No specific features are described for
Synonym the sinonasal tract region.
Sarcomatoid carcinoma
Epidemiology
SCSCC presents most commonly in el­
derly men { 1 56,1 330,2396}. This variant
is rare in the sinonasal tract, accounti ng
for < 5% of si nonasal sq uamous cell car­
cinomas { 1 99,787,896,912,1 032,1 035}.
Carcino mas 17
Lymphoepithelial carcinoma
Bishop J . A .
Gau lard P.
G i l l i son M .
Definition
Lymphoepithelial carcinoma (LEC) is a
squamous cell carcinoma morpholog i­
cally similar to non-keratinizing naso­
pharyngeal carcinoma, und ifferentiated
subtype.
ICD-0 code 8082/3
Synonym
Lymphoepithe lioma- like carcinoma
Epidemiology
Sinonasal LEC is rare, with only about 40
reported cases {1 1 25 , 2034, 2584 , 2733) .
I t most freq uently affects men i n the ir
fifth to seventh decades of life (median
patient age: 58 years) (381 , 1 1 25,2034,
2584, 2733). Most reported cases have
been in patients from Asia, where EBV­
related malignancies are endemic.
Etiology
In the sinonasal tract, most cases
(> 90%) of LEC harbour EBV { 1 1 25,1 392,
2034,2584 , 2733 ).
Localization
Sinonasal LEC arises in the nasal cav­
ity more freq uently than in the paranasal
sinuses {2034 ,2584, 2733). For an LEC
to be considered truly primary to the
sinonasal region, spread from a nearby
nasopharyngeal carcinoma must be ex­
cluded on cli nical, rad iographical , and/or
pathological grounds.
18 Tumours of the nasal cavity, paranasal sinuses and sku ll base
Clin ical features
Patients present with nasal obstruction,
nasal discharge, and/or epistaxis. Pa­
tients may also have eye symptoms or
cranial nerve palsies as a result of local
tumour invasion 1 1 1 25,2034, 2584 , 2733 } .
Macroscopy
The tumours are irreg ular or polypoid,
tan-white, bulky masses that may be
haemorrhagic { 1 1 55,2034 , 2347).
Cytology
The cytolog.ical findi ngs are the same as
those for non-keratinizing nasopharyn­
geal carcinoma, undifferentiated subtype
(see Nasopharyngeal carcinoma, p. 65.)
Histopathology
LEC is defined by its resemblance to
non-keratinizing nasopharyngeal carci­
noma, undifferentiated subtype (see Na­
sopharyngeal carcinoma, p. 65).
By immunohistochemistry, L EC is dif­
fusely positive for pancytokerati n, CK5/6 ,
p63, and p40, and is negative for lym­
phoid and melanocytic markers. Sino­
nasal LEC is usually pos itive for EBV­
encoded small R NA (EB ER) by in situ
hybrid ization.
Si nonasal LEC must be disti nguished
from lymp homa and melanoma (potential
mimics), as well as from si nonasal und if­
ferentiated carcinoma, a neoplasm that
lacks the syncytial growth pattern of LEC,
is consistently EBER-negative, and lacks
C K5/6 , with lim ited to absent p63.
Prognosis and predictive factors
According to the SEER database, si non­
asal LEC has a 5-year disease-specific
survival rate of approximately 50%;
patients with local ized disease, aged
< 60 years, and of White ethnicity have
significantly improved survival {381 ).
Si nonasal LEC metastasizes to regional
lymph nodes less freq uently than does
nasop haryngeal carcinoma, and tends
to be rad iosensitive even in the presence
of nodal disease {381 ,1 1 25, 2034, 2584,
2733).
Sinonasal undifferentiated
carcinoma
Lewis J . S .
Bishop J . A .
Gil lison M .
Westra W. H .
Yarbrough W.G .
Definition
Si nonasal undifferentiated carci noma
(SN UC) is undifferentiated carcinoma of
the sinonasal tract without g landu lar or
squamous features and not otherwise
classifiable.
Table 1 .01 Differential diagnosis of sinonasal
undifferentiated carcinoma
Lymphoma
Non-keratinizing squamous cell carcinoma (including
HPV-related carcinoma with adenoid cystic-like
features)
Basaloid squamous cell carcinoma
High-grade neuroendocrine carcinoma
Olfactory neuroblastoma
NUT carcinoma
Alveolar rhabdomyosarcoma
Ewing sarcoma / primitive neuroectodermal tumour
Adenoid cystic carcinoma, solid-type (grade 10)
Melanoma

ICD-0 code 8020/3
Epidemiology
SNUC is rare, with about 0.02 cases
per 1 00 000 people, accounting for only
about 3-5% of all sinonasal carcinomas
/ 1 458). It occurs in patients of a wide
range of ages, from teenagers to the el­
derly (average patient age: 50-60 years).
Approxi mately 60-70% of patients are
Caucasian males /371 ,1 974).
Etiology
No consistent etiology of S N U C has been
identified . Some patients are smokers
but many are not {365). If EBV or H PV is
detected, the diagnosis of S N U C should
be qu estioned ( 1 99,365,885 ,2518}.
Localization
Tumours arise most freq uently in the na­
sal cavity and ethmoid sinuses, and most
present as very large masses involving
multiple sites. As many as 60% of cases
have spread beyond the sinonasal tract
to adjacent sites such as the orbital apex,
skull base, and brai n / 1 974). Nodal me­
tastases are relatively uncommon (occur­
ring in 1 0-15% of cases) despite large
primary tumour size (416,885,1 974).
Clin ical features
Patients present with nasal obstruction,
epistaxis, headache, and diplopia or
of supporting histological features. The
The differential diagnosis is lengthy
(Table 1 .1 ), but most importantly includes
lymphoma, non-keratinizing squamous
cell carcinoma, basaloid squamous cell
o her visual symp oms {2656). Prop osis
and periorbi al s elling can be seen as
well. tea ures re lee ·ng reque o bi aJ
involvemen .
Macroscopy
Tumours are usually large (> 4 cm) a
presenta ion, wi h a funga ing endoscop­
ic appearance and poorty de ined mar­
gins radiographicaJly { 1 883}.
Cytology
Aspira es of me as atic S UC are cel­
lular, with cohesive groups, single large
malig nant cells, and background necrotic
debris. Numerous mi o ic figures and ap­
optotic bodies can be seen. euroendo­
crine features are typically not prominent,
and squamous or glandular fea ures are
not seen.
Histopathology
SNUC consists of sheets lobules, and
trabeculae of overtly maJignan 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
open chromatin with prominent n ucleoli.
Apoptosis, mitoses, and necrosis are
frequent. Despite their high-grade ap­
pearance, SN UCs characteristically have
tumour nuclei of relatively consistent size
and lack of pleomorphism. By defin ition,
there is no squamous or g landular differ­
entiation, although adjacent carcinoma i n
situ has been described .
By immunohistochemistry, the tumour
is positive for pancytokeratin (AE1/AE3}
and simple cytokeratins such as CK7,
CK8 , and CK1 8, but is negative for
CK5/6. The tumour cells are variably pos­
itive for p63, but consistently negative for
its more squamous-specific isoform, p40
{21 86}. The cells are consistently positive
for neuron-specific enolase. Very focal,
patchy staining for chromogranin and
synaptophysin may be seen {365,41 6},
but does not qualify a tumour as a neu­
roendocrine carcinoma in the absence
tumours are negative for carcinoembry­
onic antigen, S 1 00, CD45. and calretinin
{2635}. The tumours are consistently
p1 6-positive, regardless of H PV status
{885,2518).
Cardnomas 19
carcinoma, and neuroendocrine carcino­
ma. Squamous cell carcinoma has areas
of histological sq uamous differentiation
an is consistently positive for Cf 5/6 ,
p63, and p40. Neuroendocri ne carcino­
mas have speckled chromati n and other
histological featu res such as rosette
formation and palisad ing, and are con­
sistently reactive with neuroendocrine
markers. NUT carci noma has evidence
of squamous dif ferentiation (at least fo­
cally) , is consistently diffusely positive
for p63 and p40, and strongly exp resses
the N UT protein by immunoh istochemis­
try. Recently, a subset of undifferentiated
carci nomas with rhabdoid features and a
lack of SMARCB1 ( I N 1 1 ) protein by immu­
nohistochemistry has been reported. It is
unclear whether these tumours constitute
a distinct entity { 1 98).
Genetic profile
No specific genetic alterations have been
identified in SNUC \819). The S0X2 gene is
amplified in one third of tumours {2102). I IT
(CD1 1 7 ) is frequently strongly expressed,
but no activating mutations or gene amplifi­
cations have been identified \416}.
Prognosis and predictive factors
The prognosis of S N U C is poor, although
it seems to have im proved in recent
years , likely due to the use of agg ressive
trimodality therapy \371 ). Systemic che­
motherapy is associated with particul arly
high response rates {243). A large analy­
sis of SEER data showed a median over­
all su rvival of 22.1 months and 3-, 5-, and
1 0-year su rvival rates of 44.3%, 34.9%,
and 3 1 .3%, res pectively {371 j. A recent
meta-analysis had similar findings { 1 974).
Patient survival is significantly better with
primary surg ical resection { 1 974 , 2685) .
NUT carcinoma
French C . A .
Bishop J . A .
Lewis J .S .
Mu ller S.
Westra W. H .
Definition
N U T carcinoma is a poorly d ifferentiated
carcinoma (often with evidence of squa­
mous d ifferentiation) defined by the pres­
ence of nuclear protein in testis (NUT)
gene (NUTM1) rearrangement.
20 Tu mours of the nasal cavity, paranasal sin uses and s ull base
-
Fig. 1 .09 NUT carcinoma. A Sheets of moderate-sized monomorphic poorly differentiated epithelioid cells have pale
to clear glycogenated cytoplasm; tl1e intervening stroma is scant, and necrosis and mitoses are invariably present.
B Abrupt keratinization can appear as a discrete island within a sea of poorly differentiated cells. C FISH demonstrates
NUT rearrangement when red and green probes flanking the NUT locus are split apart; the red and green signals
together are the nom1al NUT allele. D Diffuse, nuclear immunohistochemical staining with the NUT antibody is
diagnostic of NUT carcinoma; the speckled pattern is characteristic but not always this distinct.
IC D-0 code 8023/3 Clinical features
NUT carcinoma p resents with non­
Synonyms specific symptoms caused by a rapidly
NU T midline carcinoma; t( 1 5 ; 1 9) carci­ g rowing mass. In the si nonasal tract,
noma; midline carcinoma of children and this man ifests as nasal obstruction, pain,
young adults with NUT rearrangement epista is, nasal di scharge, and frequent­
ly eye-rel ated symptoms such as prop­
Epidemiology tosis {205,692 ) . I maging studies reveal
NUT carcinoma is a rare tumour in the extensive local invas ion into neig hbour­
upper aerodigestive tract { 1 59 , 393, ing structures such as the orbit or brain
2234). Due to its rari ty, the true incidence {205,692). In approximately 50% of cas­
is unknown . In the largest series report­ es, N UT carcinoma presents with lymph
ed (n = 40), the med ian patient age was node involvement or distant metastatic
2 1 . 9 years , but people of all ages were di sease { 1 59).
affected (range: 0.1 -82 years). A slight
predominance of females was see n , with Macroscopy
55% of the cases occ urring in females Few tumours are resecte d , due to early
{393). d isease spread . No consistent macro­
scopic featu res h ave been described.
Etiology
The etiology is un known . There is no as­ Cytology
sociation with H PV, E BV, other viral i n ­ Aspirates of metastases are cellular . with
fection; smoking; or other environmental variably sized clusters of malign ant cells
factors. and single malignant cel ls. Mitotic figures
and apoptotic bodies are seen. Squa­
Localization mous d ifferentiation may be observed .
Most cases (65%) in the head and neck
are in the nasal cavity and paranasal si­ Histopath ology
nuses, but rare cases involve the orbital The d iagnosis of N U T carcinoma is es­
region , nasopharynx, oropharynx, lar­ tablished by demonstration of NUT re­
ynx, epiglottis, and major salivary glands arrangement, rather than by hi stology.
\ 1 59 ,508 ,763 , 2032} . The tumours are An unequivocal diagnosis can be made
generally midline. by demonstration of d iffuse ( > 50% )
 N UT
N
BRD3 N ....._._....___ -J_U.../,.__.
N SD3
N W.iiiiiiili liiiiiiiliiiiii
iilliiiliiiiilai&a&llliiliiiiiiiiiiii,
- -
PWWP
I PHO
SfT
C/Hrlch
It
Acidic domain 1
Fig. 1 - 1 0 NUT carcinoma . Schematic illustration of the various
NUT genes an � BRD4, BRO�, and WHSC1 L 1 (also called NS03); the arrows indicate breakpoints Nearly the
NUT transcript 1s preserved 1n every known translocation . PWWP PWWP domain· PHO plant homeodomain·
. .
SET d om � in,· C/H nch , Cys/H1·�-nch
· domain;
· NLS, nuclear localization signal sequence; NES, nuclear export signal
sequence , Bromo, bromodom am; ET, extraterminal domain
.
nuclear stai n i n g with the N U T monoclo­
nal anti body C52, which has a sensitiv­
ity of 8 7 % 1 9 1 6 ) . Other diag nostic tools
i n c l u d e F I S H , RT- P C R , conventional cy­
tog e netics, and targeted next-generation
se quencing approaches.
The h istology is that of an und ifferenti­
ated carcinoma or poorly differentiated
squamous cell carcinoma. N UT carcino­
ma consists of s heets of cells with mod­
erately l arge, rou n d to oval nuclei . The
chromatin i s vesicular with distinct nucle­
oli. Cytoplasm varies from scant to mod­
erate, and can be clear. M itotic activity is
brisk and necrosis is often present. Hall­
mark features i n c l u de monomorphism
and the presence of so-called abrupt
foci of ke rati nization. Occasional tumours
have more extensive sq uamous d ifferen­
tiation { 764). l ntratumoural acute inflam­
mation can be brisk and is freq uently
present. G landular and mesenchymal
differentiatio n , although described , is in­
frequent {566}. Markers other than N U T
that are commonly positive include p63,
p40, and cytokeratins 12265). N UT carci­
noma occasionally (in 55% of cases) ex­
presses CD34 { 764). Occasional positiv­
ity for neuroendocrine markers, p1 6, and
TTF1 has also been described.
Due to the non-specific, poorly d ifferenti­
ated nature of N UT carcinoma, it is often
confused with poorly d iffere ntiated sq ua­
mous cell carcinoma, Ewi ng sarcoma,
si nonasal u n d ifferentiated carci noma,
leukaem i a , germ cell tumour, and even
olfactory neuroblastoma 1763) . A pro� i­
. survival than do B R O - N UT carcinoma
sionally defined entity included i n th e dif­
. .
ferential d iagnosis is S M A R C B 1 - def1c1ent
Chromosome 15q14
Chromosome 19p1 3.1
Chromosome 9q34.2
Chromosome Bpll.23
---iiiiiiiiii,lii,:l.i.ia1
Acidic domain 2
NLS
NES
Bromo
fT
translocations that occur in NUT carcinoma between
entire
.
' ' ' ' SET'
carcinoma. However, unlike NUT carci­
nomas , SMARCB1 -deficient si nonasal
carci nomas do not exhibit focal kerati­
nization . Instead, the basaloid cells
demonstrate various degrees of rhab­
doid or plasmacytoid features. Be­
cause SMARCB 1 -deficient si nonasal
carcinomas have biallelic inactivation of
SMARCB 1 (/N/1), immunohistoc hemi­
cal staining for SMARCB1 consistently
demonstrates loss of nuclear expres­
sion , an im portant finding fo r distinguish­
ing SMARC B1 -deficient carc inoma from
N U T carcinoma.
Genetic profile
N U T carcinoma is genetically defined by
rearrangements of the nuclear prote in
in testis ( N U T) gene (NUTM1). In most
N U T carci nomas , most of the coding
sequence of NUTM1 on chromosome
1 5q 1 4 is fused with BRD4 (in 70% of
cases). BR03 (in 6%), or WHSC 1L1 (also
called NS03), creating chimeric genes
that encode N UT fusion proteins { 1 59,
764, 765 ,766 ,767, 23 1 8 ). In the remaining
cases, referred to as NUT-variant carci­
noma, NUTM1 is fused to an un known part­
ner gene. To date. no other oncogenic
mutations have been identified in N U T
carcinoma.
Prognosis and predictive factors
Prognosis is poor, with a median overall
survival of 9.8 months /393). Some evi­
dence suggests that patients with N UT­
variant carcinoma may have a longer
patients / 1 59.763}.
Neuroendocrine carcinomas
Thompson L . D. R .
Bell D.
Bishop J . A .
Defin ition
Si nonasal neuroendocrine carci noma is
a high-grade carcinoma with morpholog­
ical and immunohistochemical features
of neuroendocrine d ifferentiation .
ICD-0 codes
Small cell neuroendocrine
carcinoma (SmCC) 8041/3
Large cell neuroendocrine
carcinoma (LCN EC) 801 3/3
Synonyms
Poorly differentiated neuroendocrine
carcinoma; high-grade neuroendocrine
carcinoma
Epidem iology
Sinonasal neuroendocrine carcinomas
are rare , accounting for about 3% of
si nonasal tumou rs, but are more com­
mon in middle-aged to older men. The
mean patient ages are 49-65 years for
LC N EC and 40-55 years for SmCC {370,
1 83 1 ,1 853 , 2222}.
Etiology
There is rare assoc iation with transcrip­
tionally active high-risk HPV { 1 99 , 1 323}
and previous irradiation {2535} , but no
strong smoking association {2296}.
Localization
The most common location is the ethmoid
sinus, followed by the nasal cavity and
the maxil lary and sphenoid sinuses
( 1 63 1 , 2222 ,2296).
Clin ical features
Many patients present with non-spe­
cific symptoms (e.g. nasal obstruction,
discharge, and sinusitis) and have ad­
vanced local d isease (pT3 or T4), with re­
gional or d istant metastases (to lung, l iv­
er, or bone) { 1 1 4 , 1 428 , 1 63 1 ,1 853). Rarely,
paraneoplastic syndromes are reported
{ 1 1 4 , 1 207, 2 0 1 8 , 2482}.
Macroscopy
The tumours are large and destructive,
with haemorrhage and necrosis.
Carcinomas 21
Cytology
Aspirates of metastases are identical to
those of Smee and Le N Ee sampled
elsewhere. Malignant cells show less co­
hesion than seen in other epithelial malig­
nancies and are more fragile, displaying
more crush artefact. Mitotic figures and
apoptotic bodies are frequent.
Histopathology
Sinonasal neuroendocrine carcinoma is
histolog ically identical to its counterparts
in lung and other head and neck sites;
for a detailed description , see Poorly dif­
ferentiated neuroendocrine carcinoma
(p. 97). The tumours are highly infiltrative,
with freq uent perineural and lymp hovas­
cular i nvasion { 1 853, 2222}.
Le N Ee contains large cells that show
light microscopic neuroendocrine fea­
tures; for a detai led description of these
features, see Poorly differentiated neuro­
endocrine carcinoma (p. 97).
Smee and Le N Ee are strongly immu­
nopositive for cytokeratins (e .g. eAM5.2
and AE1/A E3) and EMA, freq uently
showing a perinuclear or dot- like pattern
{ 1 587). Neuroendocrine d ifferentiation
can be confirmed by staining with at least
one neuroendocrine marker, such as syn­
aptophysin (most sensitive and specific),
22 Tumours of the nasal cavity, paranasal sinuses and sku ll base
chromogranin, neuron-specific enolase,
or e 056 (least specific) 14861, although
neuron-specific enolase is less common
in Le NEe { 1 1 4 , 2568}. In Smee, S 1 00
protein stai ning (when positive) is diffuse
rather than sustentacular {2222). Smee
and Le N Ee are positive for p16 (which
is negative in si nonasal und ifferentiated
carcinoma); focal ly, they may be weakly
positive for p63. The tumours are rarely
reactive with calretinin and are consist­
ently negative for eK5/6 , EBV-encoded
small RNA (E BER), and eK 20 (378,390,
2635} . ASCL 1 (also called hASH 1), which
is a master gene for neuroendocrine dif­
ferentiation, shows a hig her degree of
expression in Smee and Le N Ee than
in olfactory neuroblastoma or rhabdo­
myosarcoma (486, 233 1 ) . N ucl ear immu­
nohi stochemistry for p53 correlates with
TP53 mutations (758}.
Rare examples of si nonasal neuroendo­
crine carcinoma combined with either
squamous cell carci noma (in situ or in­
vasive) or adenocarcinoma have been
reported ( 1 1 4,758,1 320}. However, squa­
mous cell carcinoma or adenocarcinoma
should not be regarded as si nonasal
neuroendocrine carcinoma based solely
on the presence of focal neuroendo­
crine immunoreactivity in the absence of
light- microscopic featu res of neuroendo­
crine differentiation.
The differential diagnosis frequently in­
cludes olfactory neuroblastoma, si nona­
sal und ifferentiated carcinoma, and N U T
carcinoma. High-grade olfactory neu­
roblastoma may retai n a focal lobular
architecture with a variable presence of
peri pheral sustentacular cells demon­
strated by immunoh istochemistry; cy­
tokeratins, if expressed , tend to be focal
rather than d iffuse. Sinonasal u n differen­
tiated carcinomas occasionally express
neuroendocrine markers , but lack the
morphological features of Le N EC {773,
1 034, 2568}. N UT carcinoma does not
show neuroendocrine d ifferentiation , and
typically shows diffuse expression of
e K5/6 and p63 {692}.
Prognosis and predictive factors
The 5-year d isease-free survival rate is
about 50-65% overall, and is better for
sphenoid sinus tumours (-80%) than
for maxil lary or ethmoid sinus tumours
(-33%), i n particular when managed by
com bination surgery and/or neoadjuvant,
concurrent, or adj uvant chemoradiother­
apy, with neoadjuvant therapy possibly
yielding a better outcome (especially
for LeN EC) ( 7 70 , 1 428 , 1 63 1 ,1 83 1 ,2462}.
D ata are limited , but LCN EC s ten d to
Epi demiology
h ave a better progno sis than do SmC Cs
Sino nasal ITACs are uncommon , with
( 1 587, 1 6 � 1 , 20 1 6 , �4 6 2 ) . Adv anc e d-st age
_ an overall incidence of < 1 case per
disease 1s associated with poo r prog no­
1 mil lion person-years. However, inci­
sis ( 1 831 } .
dence varies drastically across popula­
tions, and the tumours are as much as
5 00 times as prevalent among people
Intestinal-type adenocarcinoma who work for prolonged periods in wood
or leather-working industries as they are
Stelow E . B . in the general population (9J. Men are
Franchi A.
3-4 times as likely to develop these tu­
Wenig B . M . mours as women , which is thought to be
due to differences in occupational ex­
posure rates { 1 39, 1 2 38, 2 0 6 3). Although
Definition the patient age range is reportedly wide,
Sinonasal i ntestinal-type adenocarci­ most patients are older, with mean and
noma (ITAC) is an adenocarcinoma of median reported patient ages at diagno­
he sinonasal tract morphologically simi­ sis in the sixth to seventh decades of life.
lar to adenocarcinomas primary to the
intestines. Etiology
Many ITACs are secondary to wood dust
I CD-0 code 8 1 44/3 or leather dust exposure (9,1 0 ,9 1 8,1 2 38).
Formaldehyde and textile dust exposu res
may also increase the risk of these tu­
Synonyms mours ( 1 490).
Colloid-type adenocarcinoma; colonic­
type adenocarcinoma; enteric-type Localization
adenocarcinoma ITACs typically develop near the lateral
Fig. 1 .1 2 Sinonasal intestinal-type adenocarcinoma. A This wel (-differen�iated tu �our 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 1s composed of abundant extracellular mucus with occasional strips of malignant epithelium.
D Some tumours are composed of signet-ring cells.
nasal wall, near the middle turbinate { 1 39,
2063). It is estimated that 40% of cases
develop in the ethmoid sinuses, 28% in the
nasal cavity, and 23% in the maxillary sinus.
Clinical features
Patients with ITACs typically p resent with
unilateral nasal obstruction, epistaxis,
and/or rhinorrhoea { 1 39, 2 0 6 3). Less
common symptoms include pain, facial
contour changes, and d iplopia. The tu­
mours present as soft tissue densities
within the sinonasal tract { 1 39). Destruc­
tion of surrounding bone occurs in nearly
half of all patients. Patients most often
present with multiple sites of i nvolvement
{ 1 39). Osseous destruction with local
spread into surrou nding tissues, includ­
ing the orbit and brain, is frequently seen.
Macroscopy
In vivo, ITACs are polypoid, papilla ry,
nodular, and fungating ( 1 39, 2 0 6 3}. They
are usually friable, sometimes ulcerated
or haemorrhagic, and uncommonly ge­
latinous or mucoid.
.,. _
Carcino mas 23

Cytology
Aspirates of rare rnetastatic lesions show
findings identica l to those seen with colo­
rectal adenocarc inomas.
Histopathology
ITACs show a morpho logical spectrum
similar to that of adenoc arcinom as of
the intestines {1 39,1 238,206 3). They
are often exophytic with a papillary and
tubular growth (in approximately 75%
of cases) or may be mucinou s or com­
posed predomi nantly of signet ring cells.
The degree of differentiation varies from
extremely well differentiated to poorly
differentiat ed. Papillae and tubules are
lined by a single layer of columnar epi­
thelial cells that show differentiation and
cytological features similar to those seen
in intestinal adenocarcinomas. Most cells
appear columnar with eosinophilic, mu­
cinous cytoplasm. Paneth cells, goblet
cells, and endocrine cells are typically
also present in variable proportions. Al­
though atypia may be difficult to appreci­
ate, nuclear changes that appear at least
adenomatous are the rule. Thus, nuclei
are cigar-shaped, hyperchromatic, and
enlarged, and lose basement membrane
localization. Mitotic figures are frequent.
Necrosis is usually present, typically
within the tubular and folded spaces,
similar to what is seen in intestinal adeno­
carcinomas. As these tumours become
more poorly differentiated, tubular and
papillary structures are replaced by nest­
ed, cribriform, and solid growth patterns.
A minority of cases show abundant mu­
cus production {1 39,1 238). These cases
are similar to some primary intestinal
adenocarcinomas and consist of small
to medium-sized cystic spaces (alveoli)
partially lined by (and containing strips of)
attenuated neoplastic epithelium rich in
goblet cells. The strips often float like rib­
bons within mucus lakes and sometimes
form small cribriform structures. The indi­
vidual neoplastic cells have atypical and
hyperchromatic nuclei and abundant mu­
cinous cytoplasm. Less commonly, the
neoplastic ceJls are mostly single, with
a large amount of intracytoplasmic mu­
cus that compresses the nucleus (signet
ring cells). Finally, some tumours have a
mixed pattern of growth, appearing pap­
illary and tubular in some areas ar:id more
mucinous in others.
ITACs are invasive (often extensively in­
filtrating the submucosa) and may show
perineural and osseous invasion (139).
24 Tumours of the nasal cavity, paranasal sinuses and skull base
free at 5 years.
Stromal tissues are loose and fibrovas­ atients bei ng dise �se-
pap illar y tum o urs have
cular, often contain ing abunda nt chroni c � ade 2 and 3
rate s of 54% and 36%,
inflammatory cells. Histolo gical simila rity /year sur viv al .
res Pec tive ly. Muc ino us tum ours with al --
to p rimary gastrointestinal tract tumo u �s .
d or trans,·t·tonal
necessitates exclusion of a metastat ic veo lar growth and m1xe .
hav e pro gno ses s1m ·1 1 ar to th at
tumour. tum ours
our s, whereas
Proposed grading schemas are rather of gra de 2 pap illar y tu �
ring mo rp hology
complicated, given the rarity of these tu­ t mo urs sho win g sign et
ress ivel y. Loc ally
mours {139,1 238}. Tumours that are pre­ iehave the most agg
inva d � into the
dominately papillary can be graded as adv anc ed tum ours that
orbi t, skin , sph eno id or fron tal sinu se s, or
well, moderately, or poorly differentiated
brain have a sign ifica ntly wors e prog no­
(papillary tubular cylinder cell I, 1 1 , and
sis. Local dise ase is the most commo n
1 1 1; or papillary, colonic, and solid). Mu­ of
caus e of morta lity. Abou t 8% patients
cinous tumours are either moderately dif­
ferentiated (alveolar) or poorly differenti­ have lymp h node meta stase s and 13%
ated (signet ring cell). Mixed tumours are have distant meta stas es { 139} .
typically well to moderately differentiat­
ed. Overall survival rates at 3 years have
been shown to vary depending on grade. Non-Intestinal-type
Histochemical staining shows intracyto­ adenocarcinoma
plasmic, intraluminal, and/or extracellu­
lar material that is mucicarmine-positive Stelow E.B.
and gives a diastase-resistant positive Brandwe in-Gens ler M .
periodic acid-Schiff (PAS) reaction Franchi A .
{139). Neoplastic cells express pancy­ Nicolai P.
tokeratins, are variably reactive with CK? Wenig B . M .
and carcinoembryonic antigen, and are
mostly CK20-positive (1213,1573}. Most
tumours also express the markers CDX2, Definition
MUC2, and villin (358,121 3}. There may Sinonasal non-intestinal-type adeno­
be variable expression of neuroendo­ carcinoma (non-lTAC) is an adenocar­
crine markers (1 573,1 928}. cinoma of the sinonasal tract that does
not show the features of a salivary gland
Genetic profile neoplasia and does not have an intesti­
KRAS mutations occur in 6-40% of cas­ nal phenotype. Although these tumours
es, whereas BRAF mutations occur in are morphologically heterogeneous, this
< 1 0% (755,1 926,2037,2327). Tumours category may include some specific enti­
are microsatellite-stable and do not lose ties that are morphologically unique (e.g.
expression of mismatch repair proteins renal cell-like carcinoma).
(1 546,1 854}. EGFR mutations are infre­
quent and amplifications are uncommon ICD-0 code 8140/3
(755,1 926}. Expression of p53 is aber­
rant in more than half of all cases, and Synonyms
41 % have been shown to have TP53 Terminal tubulus adenoca rcinoma; tubu­
mutations {757). CDKN2A (also called lopapillar y low-grad e adenoca rcinoma;
P16) is frequently altered, due either to low-grade adenoca rcinoma; seromuci­
promoter methylation or to loss of hete­ nous adenoca rcinoma; renal cell-like
rozygosity at 9p21 {1 857}. Variable beta­ carcinoma
catenin expression has been reported,
with some studies showing > 30% of Epidemiology
cases with aberrant nuclear expression Sinonas al low-gra de non-int estinal-type
{757, 1 854). adenoc arcinom as (LG non-lTACs) are
very uncomm on. There is no sex predi­
Prognosis and predictive factors lection {967,1 1 39,1 721 }. Patients have
The grading systems described above range d in age from 9 to 89 years, with
predict survival and recurrence , although a mean age at present ation in the sixth
results have not been universal {1 39,754, decade of life. High-gra de non-intestinal­
760,1 238}. Low-grade papillary tumours type adenoc arcinom as (HG non-lTACs)
have the best outcomes , with > 80% of are rare, affect mer:i more frequently,
patients surviving 3 years and > 60% of and occur over a wide age range,. with a.
m ean patie nt age at pres en tatio n in th e
sixth decade of life ( 967, 2 266} .

Etiology
There is no known etiology for LG non­
lTACs or H G non-lTAC s. Rare HG non­
.
lTACs have been associ ated with h h­
risk HPV or si nonasal papil lomas 122��} .

Localization
Most LG non - l TACs (64% ) arise in the
nc sal cavit ies (freq uent ly the midd le tur­ Fig. 1 . 1 3 Sinonasal low-grade non-intestinal-type adenocarcinoma. Endoscopic view of the right nasal fossa (A} and
coronal turbo spin echo T2-weighted MRI (8). The tumour (T) is centred on the superior meatus and laterally displaces
Jinate), and 20% arise in the ethm oid si­
the �thmoidal complex (asterisks}; the point of origin was on the upper part of the septum. LW, lateral wall; MT, middle
nuses ( 967, 1 1 39). The rema ining tumou rs turbinate; NS, nasal septum.
inv� lve the other sinuse s or multip le lo­
cations throug hout the si nonas al tract .
Approximate ly half of all HG non-lTAC
cases are local ly advanc ed at presenta­
tion and i nvolve both the si nuses and the
nasal ca� ity (967, 2266) . Approxim ately
_
one third involve the nasal cavity only.

Cli nical features

Most patients with LG non- lTACs present
with obstruction { 1 72 1 , 2 1 93). Other symp­
toms include epistaxis and pai n . Patients
with HG non- l TACs present with obstruc­

�·.
tion , ep istaxis, pai n, deformity, and prop­
tosi s (967) . On imag i n g , LG non-lTACs
present as solid masses, filling the nasal
',I �·�&a!.�•-
' :.....:� \
cavity or sinuses . HG non - l TACs show Fig. 1 . 14 Sinonasal low-grade non-intestinal-type adenocarcinoma. Tubules grow back-to-back as they infiltrate the
more destructive g rowth, with osseous underlying stroma.
involvement and i nvasion i nto su rrou nd­
ing structures (e.g. the orbit).

Macroscopy
Low-grade non- lTACs may appear red
and polypoid or raspberry-l ike and firm
( 1 237 ) .

H istopathology
Low-grade non - l TACs have predomi­
nately papil lary and/or tubu lar (glandular)
features with complex g rowth , including
back-to-back glands (cribriform) with l it­
tle intervening stroma ( 967, 1 1 39, 1 237). A
single layer of un iform mucinous cuboi­
dal to col umnar epithelial cells li nes the
structures. These cells have eosinoph ilic
cytoplasm and uniform, basally located
nuclei . Mitotic figures are rare and necro­
sis is not seen. Invas ive g rowth , includ­
ing within the submucosa as well as into
bone, may be present. Calci spherules
are rarely seen (967) . Occasional tu­
mours have more di lated glands { 1 237,
1 72 1 } .
HG non-lTACs show much more diver­
sity in their histology (967, 2266 ) . Many
have a predom i nately solid g rowth with
columnar epithelium. 8 Renal cell-like carcinoma.
occasional microcysts.
occasional g landular structures and/
or individual mucocytes. Some have a
nested growth and are infi ltrative . Numer­
ous mitotic figures are seen with necrosis
(individual-cell and confluent), as well as
infiltrative growth with tissue destruction
and osseous invasion .
Occasional cases are com posed pre­
domi nately of clear cel ls, reminiscent of
metastatic renal cell carcinoma {2287 ).
These tumours have been referred to
as sinonasal renal cell-like carcino­
mas. The tumours are com posed of
monomorphous cuboidal to columnar
glycogen-rich clear cells that lack mucin
production. The cel lular cytoplasm may
be crystal clear or slightly eosinop hilic.
Perineural invasion , lymphovascular in­
vasion , necrosis, and severe pleomor­
phism are absent, and the overall histo­
logical impression is that of a low-grade
neoplasm.
I n most LG non-lTACs and H G non­
lTACs, intraluminal mucin or material
that gives a diastase-resistant positive
reaction with periodic acid-Schiff (PAS)

Carcinomas 25

. . ...-..aiu.aa..,11111111!, -..::� ;-.ii--..._.ao.,a._-.,__.., --.........- .
Fig. 1 .1 6 Smonasal high-grade non-intestinal-type adenocarcinoma. A Distinct glandular d1fferential1on 1s present , WI'th --;,e·cr�sis and
mostly solid, with focal tubular formation.
can be identified. I n HG non- lTAC , cells
with i ntracytoplasmic mucin or diastase­
resistant PAS positivity may be pres­
ent. The tumours express cytokeratins
(typically C K7 and infrequently l imited
CK20) { 2266). Sq uamous antigens, such
as p63, are typically not expressed or are
expressed only focally {2 1 93}. Markers of
i ntesti nal differentiation, such as CDX2
and M UC2, are also not expressed or
are expressed only focally {358, 2266) .
Some authors have reported expres­
sion of DOG 1 , SOX 1 0 , and S 1 00 { 1 9331.
HG non - l TACs can focally express
Teratocarcinosarcoma
Definition
Sinonasal teratocarcinosarcoma is a
malig nant si nonasal neoplasm with com­
bined histological features of teratoma
and carcinosarcoma, lacking malignant
germ cell components.
ICD-0 code
Synonyms
Malig nant teratoma; blastoma ; teratocar­
cinoma; teratoid carcinosarcoma
Epidemiology
Teratocarcinosarcoma is a rare tumour
affecting adults (median pati ent age: 60
years), with a strong male predilection.
Localization
The tumour most commonly involves the
26 Tumours of the nasal cavity, paranasal si nuses and skull base
,......,__r_,� -.-"--U l
••
•� . .
neuroendocrine antigens 122661. Renal
cell-like carci nomas express CAIX and
C D 1 0 , but do not express PAX8 or renal
cell carcinoma marker {2 1 561. Beta-cat­
enin and mismatch repair protein expres­
sion is wil dtype 12679). Overexpression
of p53 may occur as well 12 1 93).
Genetic profile
Only rare LG non-lTACs have been stu d­
ied for molecular abnormal ities. RAS mu­
tations are not seen 1 7551. Rare BRAF
mutations have been found 1 755).
nasal cavity, followed by the ethmoid si­
nus and the maxillary sinus 1 1 628}. l ntrac­
ranial extension occurs in approximately
20% of cases 1 1 628).
Clinical features
The most common presenting symptoms
908 1 /3 are nasal obstruction and epistaxis. Im­
aging studies show a nasal cavity mass
with opacification of paranasal sin uses
and frequent bone destruction.
Macroscopy
Tumour tissue is fi rm to friable , with a
variegated reddish-purple to brow n appear­
ance. When present, the surface mucosa
is often ulcerated, and areas of necrosis
and haemorrhage are evident at the cut
surface.
• . u:.,.:;
��-.;,..
increased mitotic activity.
Prog nosi s and pre dict ive factors
Appro ximat e ly 25% of LG non-l TACs
recu r, and only 6% of patien ts die from
their tumou rs, u sually as a result of loss
of local control 196 7 , 1 1 39, 1 72 1 ) . Patients
with HG non-lTA C fare much worse 196 7 };
most die from the diseas e within 5 years
of d iagnosis . Occasio nal H G non-lTACs
metasta size locally and distally. The re­
ported cases of renal cell-like carcinoma
have neither recurred nor metastasized
{ 2 1 56}.
Franchi A.
Wenig B . M .
Histopathology
Teratocarcinosarcoma is composed of
an ad mixture of epithelial, mesenchy­
mal , and neuroepithelial elements. The
epithelial components include kerati­
nizing and non-ke ratin izing squamous
e pithelium, pseudostratified columnar
ciliated epithelium, and glandular/duct­
al structures . An important d iagnostic
feature is the presence of nests of
immat ure squamous epithelium with clear
so-calle d fetal-app earing cells 1966}.
The most-represented mesenchymal ele­
ment s are spindle cells with features of
fibroblast s or myofibrob lasts , but are as
with rhabdom yoblastic , cartilagi n ous, os­
teoblasti c, smooth-m uscle, o r adip ocytic
diffe rentiati on can be seen, with appear­
ances ranging from benign to frankly ma­
lignant. The n eu roepithe lial compon ent
con sists of a prol iferation of immatu re
round to oval cells either in solid nests
or within a neurofi brillary backg round,
sometimes with rosette formation.
The immunohistochemical profil e matches
that of the tumour components , including
epithelial , mesenchymal, and neuroepi­
thelial components. PLAP, alpha-fetopro­
tei n, hCG , and CD30 are negative.
Cell of origin
The favoured hypothesis is ong1n from
somatic pluripotent stem cells of the
neuroepithelium related to the olfactory
membrane ( 1 801 , 2054 ).
Genetic profile
There are limited reports in the literature
on the cytogenetic abnormalities. These
abnormalities include extra copies of
chromosome 1 2p in a subpopulation of
neoplastic cel ls in a hybrid case that also
exhi bited foci of yolk sac elements 12380)
in addition to teratocarci nosarcoma fea­
tures, thus not comp letely meeting the
defi nition that excl udes malignant germ
cell components, and the presence of tri­
somy 12 with a subclone of cells showing
loss of 1p in one case (251 61. In another
study, no amplification of 1 2p was found
in any of 3 cases {2054).
Prognosis and predictive factors
Teratocarcinosarcoma is an aggressive
tumour, with frequent lymph node and
distant metastasis. Reported survival
rates range from 50% to 70% in different
series, with an average follow-up of 40
months ( 1 628}.
Teratocarcinosarcoma 27
S i no nasal pa pi l l omas
Sinonasa/ papilloma,
inverted type
Hu nt J . L.
Bell D.
Sarioglu S .
Definition
Si nonasal inverted papilloma is a surface
mu cosal lesion of the si nonasal tract that
usually shows inverted growth and has
multilayered epithelium with mucocytes
and transm igrati ng neutrophils.
IC D-0 code 8 1 2 1 /1
Synonyms
I nverting papilloma; inverted Schneide­
rian papilloma; Schneiderian pap i l loma,
inverted type
Epidemiology
Inverted papillomas are the most fre­
q uent papi llomas of the sinonasal reg ion,
arising from the sinonasal epitheljal lin­
ing. An esti mated 0.74-2. 3 new cases
may be expected per 1 00 000 popu lation
annually (294, 1 750) . The tumour is most
freq uent in the fifth and sixth dec1?des of
life ( patient age range: 6-84 years) and is
2. 5-3 times as common in males as in fe­
males ( 1 41 , 1 224 , 251 1 ). Recurrences are
frequent and malig nant transformation
28 Tu mours of the nasal cavity, paranasal sin uses and skull base
has been reported in 1 .9-27% of cases
in different series; most malig nancies
were sync hronous tumours ( 1 750) .
Etiology
Exposure to organic solvents seems to be
a risk factor for inverted papil loma devel­
opment / 505), whereas no such associa­
tion for smoki ng or alcohol consum ption
has been shown. Varying rates of H PV
detection have been reported. In a meta­
analysis including 760 inverted pap il loma
cases, 38.5% of the cases were H PV­
positive by either in situ hyb ridization or
PCR { 2323). Low- risk HPV ( H PV 6 and
1 1 ) is 2 . 8 times as frequent as high-risk
H PV ( H PV 16 and 1 8) in inverted papi l ­
loma. However, high-risk H PV i s more
frequent in cases with high-grade dys­
plasia and carcinoma { 1 352) . E6 and E7
mR NAs, associated with transcriptionally
active high-risk H PV infection, were de­
tected in all cases in a series of 19 in­
verted papillomas; however, this expres­
sion was seen in only 1 % of the tumour
cells in 58% of the cases, and H PV DNA
was positive in only 2 cases. Expression
of p1 6 , which is an accepted surrog ate
biomarker for high- risk H PV infection in
oropharyngeal carci noma , is controver­
sial in i nverted papilloma; in some series,
no correlation between p1 6 and H PV was
seen (420 , 2283).
Loc aliz atio n
The nasal cavity a n d the maxil lary sinus
are the most comm on locati ons of invert­
ed papillo ma, with the media l wall being
the most comm on site of origin i n the
maxillary sinus. Other location s as site
of pri mary origin are more rare , includ­
ing the ethmoid s i n u s , frontal sinus, and
nasal septum . About 30% of cases origi­
nate from m u ltiple sites. I nverted papil­
loma may rarely be bilateral and may
originate from m u ltiple extrasi nonasal
sites, i n c l u d i n g the nasopharynx, phar­
ynx, lacrimal sac, m i d d l e ear, temporal
bone, and neck (75,1 224 , 2 1 47 ) .
Clinical features
Patients may p resent with non-specific
symptoms such as n asal obstruction,
polyps , epistaxis, rhinorrhoea, hyposmia,
and headache of long d u ration . Rarely,
sensorineural and aud itory symptoms
are descri bed . Both CT and M R I are val­
uable; CT may p rovide i nformation about
the site of ori g i n of the tumour, and MRI
shows the extent of the d i sease. O n M R I ,
the lesion characteristically has a septate
striated ap pearance (75}. Several staging
systems have been proposed for invert­
ed papilloma (75,1 224}. O n e commonly
used stag i n g system ( 1 28 3 ) depends
on the extent of d i sease, considering
both rad iological and endoscopic find­
i n g s . The American J o i nt Committee on
Cancer (AJ CC ) sta gin g sys tem
is also
commonly used.
Macroscopy
l nverte � pap illom a is cov ere d with
a grey,
undulat ing surf ace rese mbl ing a mul
ber­
ry. Because of thei r cell ular den sity,
_ the
lesio ns do not trans illum inate .
Histopathology
Mul � iple i nver sion s of the surfa ce epi­
. among the most important features of
thelium i nto the u nder lying strom a, com­
posed of squa mous and/o r respir atory
cells and l i ned by a distinc t and i ntact
contin uous basem ent memb rane, is th�
typica l morph ology of i nverted papillo ma.
Non- keratini zing squam ous or transitio n­
al epitheliu m, 5-30 cells thick, frequent ly
predomin ates , and is covered by a layer
of ciliated columnar cells. Infiltration of
the epithelium by neutrophils (so-called
transmigratin g neutrophils) is frequently
seen . Mitoses are sparse and confined
to the basal layers { 1 41 ,2002, 2075).
There is usually a loss of underlying se­
romucinous glands {2075). The stroma
may be either loose or dense, and may
be inflamed . Cells showing squamous
and columnar differentiation are positive
for cytokeratins (e. g . C K1 0, C K1 0/1 3 , and
CK1/2/1 0/1 1 ) { 2 1 06).
Premalignant and malignant features,
dysplasia, carcinoma i n situ, and inva­
sive carcinoma can be seen arising in
inverted papilloma. Sampling should be
thorough, and evidence of malignant
transformation should be sought during
histopathological evaluation. There is no
consensus about the g rading of dyspla­
sia in i nverted papilloma, and the diag­
nosis of malignant transformation may be
challenging. Keratinizing squamous cell
carcinoma, non-keratinizing squamous
cell carcinoma, mucoepidermoid car­
cinoma, sinonasal undifferentiated car­
cinoma, and verrucous squamous cell
carcinoma can all be seen in malignant
transformation. Lymphovascular i nva­
sion, atypical mitoses , desmoplasia,
bone invasion, decreased transmigrating
neutrophils, paradoxical maturation, dys­
keratosis, increased Ki-67 expression,
and p53 expression in > 25% of cells are
malignancy / 1 750).
Genetic profile
I nverted papil lomas are neoplastic and
monoclonal proliferations, as shown by
X chromosome analysis. However, the
chromosomal LOHs at arms 3p, 9p2 1 ,
1 1 q 1 3 , 1 3q1 1 , and 1 7p1 3 that occur fre­
quently during neoplastic transformation
of the upper respiratory tract have not
been detected /315). In one small series
of 7 cases, at least one epigenetic event
of aberrant DNA hypermethylation was
observed , suggesting a role of epigenet­
ics in inverted papilloma development
{2276). Furthermore, from a small num­
ber of cases studied, it appears that acti­
vati ng mutations in the EGFR gene have
a high prevalence in inverted papillomas
and in concurrent squamous cell carci­
nomas arising from inverted papilloma
{2442A).
Prognosis and predictive factors
In one large series, cases originating from
the nasal cavity had a significantly lower
recurrence rate / 1 224). The ratio of low­
risk H PV (HPV 6 and 1 1 ) to high-risk HPV
(HPV 16 and 1 8) was 1 .1 : 1 in inverted pap­
illoma with high-grade dysplasia, versus
4.8:1 in the rest of the cases, suggesting
an association between high-risk HPV and
malignant transformation / 1 352). However,
no correlation was found between E6/E7
transcriptional activity and progression,
recurrence, or malignant transformation
{2283). In one series, malignant transfor­
mation in inverted papilloma was identified
more frequently in smokers (in 24.6% of
cases) than in non-smokers (in_ 2.8%), and
the odds ratio of malignancy for smoking
was 12.7 / 1 020). Type of surgery is also an
important prognostic factor for recurrence
{962).
Sinonasal papilloma,
oncocytic type
Hunt J . L .
Chiosea S.
Sarioglu S.
Definition
Sinonasal oncocytic papilloma is a papil­
loma derived from the sinonasal epithe­
lium composed of both exophytic fronds
and endophytic invaginations lined by
multiple layers of columnar cells with
oncocytic features. lntraepithelial micro­
cysts containing mucin and neutrophils
are characteristic.
ICD-0 code 8 1 2 1 /1
Synonyms
Oncocytic Schneiderian papilloma; cylin­
drical cell papilloma; columnar cell papil­
loma
Epidemiology
Oncocytic papilloma is equally distribut­
ed between the sexes, and most patients
are aged > 50 years { 25 1 1 ) .
Sinonasal papillomas 29
Etiology
U n like in exophy tic and inverte d papillo ­
mas, H PV has not been identifi ed in on­
cocytic papillom as 1 79 2 ) .
Localization
Oncocyti c papilloma al most always oc­
curs unilaterally on th e lateral nasal wall
or in th e paranasal sinuses (usually the
maxil lary or ethmoid ) . I t may remain lo­
cal ized , i nvolve both areas , or (if neglect­
ed) extend into contig uou s areas.
Clinical features
Patients present with nasal obstruction
and/or i ntermittent epistaxis.
Macroscopy
Oncocytic papilloma is a fleshy, pink,
tan, or red dish-brown polypoid g rowth .
Histopathology
Oncocytic papilloma exhibits both exo­
p hyti c and endophytic growth. The epi­
thelium i s multilayered, 2-8 cells thick,
and composed of columnar cells with
swol len, finely g ranular cytoplasm . The
high content of cytochrome c oxidase
and ultrastructu ral presence of numerous
mitochondria establi sh the papi l loma's
oncocytic natu re I 1 45) . The nuclei are
either small, dark, and un iform or slightly
vesicular with barely di scern ible nucleol i .
Cilia in various stages o f reg ression may
be observed in the outermost cells. The
epithelium usually contains small cysts
fil led with mucin or neutrophil s (microab­
scesses) . These cysts are not p resent in
the stroma, which helps distinguish this
lesion from rhinospori diosis. The stroma
varies from oedematous to fibrous, and
may contain modest numbers of lym pho­
cytes, plasma cell s, and neutrophil s, but
few eosinophil s. Seromucinous glands
are sparse to absent. Oncocytic pap­
illoma may rarely undergo malignant
transformation. It i s al so occasional ly
confused with low-grade papil lary ade­
nocarcinoma I 1 403). 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-fil led
cysts and microabscesses and the strati­
fied oncocytic epithelium of a papilloma
are rarely seen in low-grade adenocarci­
noma.
Prognosis and predictive factors
The clinical behaviour parallels that of
30 Tumours of the nasal cavity, paranasal sinuses and skull base
inverted papilloma. If inadequately � x­
cised , especially using mucosa! strip ­
ping , at least 2 5-35% of cases recu r,
usually within 5 years 196 2 ). Smaller tu ­
mours can b e resected endos copically.
About 4- 1 7% of all oncocytic papi llomas
harbour a carcinoma ( 1 20 1 , 1 44 1 , 25 1 1 ) .
Most of these are squamous, but mu ­
coepidermoid, small cel l, a n d sinonasal
und ifferentiated carcinomas have also
been described 1 2 370, 2 51 1 ) . Prog nosis
depends on the histological type, the
degree of invasion, and the extent of tu ­
mour. I n some instances, the carcinoma
i s in situ and of little consequence to the
patient, whereas other cases are locally
aggressive and may metastasize.
Sinonasal papilloma,
exophytic type
Hunt J . L .
Lewis J . S .
Richardson M .
Sariog lu S .
Syrjanen S .
Definition
Si nonasal exophytic papi lloma is a papil ­
loma derived from the sinonasal mucosa,
composed of papillary fronds with deli­
cate fi brovascular cores covered by mul ­
tilayered epithelium .
ICD-0 code
Synonyms
Schneiderian papi lloma, exophytic type;
fungiform papilloma; everted papilloma;
transitional cell papilloma; septa! papil ­
loma; Ri ngertz tumour
.:a.v.2-N....... � ;;;,., .
Fig. 1 .20 Sinonasal exophytic papilloma . Exophyt]c growth
Epid emi ology .
Exophy tic pap illoma s are 2 -1 0 tim es as
e n , and typ i­
co m mon in me n as i n wom
cally occ ur i n i n d ividu als age d 2 0- 50
yea rs (re porte d ran g e: 2-87 years) ( 44 1 ) .
Etiology
There is incre asi n g ev idenc e to sugg est
that exophy ti c papillo mas may be etio­
logica lly rel ate d to H PV. I n a l arge meta­
analy sis , exophy ti c papillom as were as­
sociated with H PV in 6 3 . 5 % of cases,
predo minantly w ith th e low-risk types 6
and 1 1 , and rarely w ith types 1 6 and 57b
123 2 3).
Localization
Exophytic papillomas usually arise on
the lower anterior n asal septum . As they
enlarge, they may secondarily i nvolve the
lateral n asal wal l , b ut only infrequently
originate from th is location. I nvolvement
of the paranasal si n uses i s practically
non-exi ste nt . B i l ate ra l lesions are ex­
ceptional . Benign keratinizing cutaneous
tu mours of nasal vestibule origin do not
constitute sinonasal exophytic papilloma.
C l i nical features
The typical p rese nti n g sym ptoms are
epistaxis , u n i l ateral n asal obstruction,
and the p rese n c e of a n asym ptomatic
mass .
M acros copy
The lesions p rese nt as papillary or
8 1 2 1 /0 war ty; g rey, pink, or tan; non-tran s lucent
g row ths attach ed to th e n asal septum by
a relat ively b road base .
H isto path olog y
Exophyti c papill omas are ty pically as
large as about 2 .0 cm . Microscopi cal ly,
'
pattem wi. th thick
.
ene d epithelium and focal mucocytes.
they are com pose d of papi lla ry frond s
wit h fibrovascu lar core s cove re d by
a m ultilayered epithe lium that is 5-20
cells thick. The epith elium varie s from
sq ua mous to cilia ted pse udo strati­
fie d columnar (respira tory) , or may be
tra nsitional between the two. Scat­
te red muco cytes are comm on. Surfa ce
keratini zatio n is abse nt or scant , unles s
the lesion has been irritat ed by traum a
or exposu re to the d rying effect s of air.
Mitoses are rare and are not usually
aty pical. U n less infecte d or irritate d, the
stroma contain s few inflamm ato ry cells.
Respi ratory epithelial lesions
Respiratory epithelial
adenomatoid hamartoma
Wenig B . M .
Franchi A .
Ro J.Y.
Definition
Sinonasal respiratory epithelial adenom­
atoid hamartoma (REAH) is a benign ac­
quired overgrowth of ind igenous glands
of the sinonasal tract arising from the sur­
face epithelium.
Synonym
Glandular hamartoma
Epidemiology
The lesions predominantly occur in adult
patients, with a distinct male predomi­
nance ( 1 367,2588). Patients range in
Malignant change in exophytic papillo­
ma is extremely rare 1 1 57,44 1 ) . Exophytic
papillomas must be distinguished from
keratinizing cutaneous squamous cell
papillomas, which are much more com­
mon in the nasal vestibu le. The absence
of extensive surface keratinization, pres­
ence of mucocytes, and presence of cili­
ated and/or transitional epithelium help
to confirm the diagnosis of exophytic
papilloma. The presence of seromuci­
nous glands and septa! cartilage further
ind icate that the lesion is of mucosa!
rather than cutaneous origin.
age from the third to ninth decades of
life, with a median patient age in the sixth
decade ( 1 367 ,2588) .
Localization
The majority occur in the nasal cavity,
in particular the posterior nasal septum
(2588) . Involvement of other intranasal
sites occurs less often, and may be iden­
tified along the lateral nasal wal l, middle
meatus, and inferior turbi nate. Uncom­
monly, the lesions may occur in the na­
sopharynx, ethmoid sinus, and frontal si­
nus. Most lesions are unilateral but some
are bilateral (2588 ) .
Clinical features
Patients present with nasal obstruction,
stuffiness, epistaxis, and chron ic (recur­
rent) rhinosinusitis occurring over the
course of months to years (2588).
Prognosis and predictive factors
Complete surgical excision is the treat­
ment of choice. Inadequate excision
(rather than multiplicity of lesions) proba­
bly accounts for the local recurrence rate
of 22-50% 1441 ). Exceptionally, carcino­
mas have been seen arising in exophytic
papillomas, with reported cases including
squamous cell carcinoma; mucoepider­
moid carcinoma ( 1 750); and low-g rade
non-intestinal, non-salivary gland ad­
enocarcinoma (220). H PV status has not
been clearly shown to correlate with re­
currence risk or carcinoma development.
Macroscopy
R EAHs are polypoid or exophytic lesions
with a rubbery consistency. They are tan­
white to reddish-brown and measure as
much as 6 cm in greatest dimension.
Histopathology
Histopathology shows a glandular pro­
liferation composed of widely spaced,
small to medi um-sized glands separated
by stromal tissue. The glands arise in
direct continuity with the surface epithe­
lium, which invaginates downwards into
the submucosa ( 1 852,2588) . The glands
are rou nd to oval and composed of multi­
layered ciliated respiratory epithelium, of­
ten with admixed mucin-secreting (gob­
let) cells; glandular dilatation distended
with mucus can be seen . A characteristic
finding is the presence of envelopment of
the glands by a th ickened, eosinophilic
basement membrane ( 2588) . Atrophic
Respiratory epithelial lesions 31
glandular alterations may be present,
l i ned by a single l ayer of flattened to
cuboidal-appearing epithel ium. Small re­
active-appearing seromucinous gl ands
are present among the g l andu lar prol if­
eration. Additional coexisti ng findings
may include si nonasal inflammatory pol­
yps, surface epithelial hyperplasia and/
or squamous metaplasia, and osseous
and/or chondroid metaplasia. Rarely, the
lesions may be associated with sinona­
sal inverted papill oma or sol itary fib rous
tumour { 2588 ) . The occasional pres­
ence of both REAH and seromuci nous
hamartoma sug gests a spectrum from
pure REAH to seromucinous hamartoma
{ 1 2 1 8).
The glands are immunoreactive for cy­
tokeratins such as AE 1 /AE3, CAM5.2,
and CK? but negative for CK20 and
CDX2. Myoepithelial/basal cell markers
(including p63) are typically present but
may be absent; the absence of markers
for myoepithelial/basal cells does not
confer a diagnosis of adenocarcinoma
{ 1 794 ) .
Genetic profile
The reported increased fractional allelic
loss of 3 1 % i s unusually high for a non­
neoplastic entity, raising the possibil ity
that REAH may in fact be a ben ign neo­
plasm rather than a hamartoma { 1 796) .
Prog nosis and predictive factors
Complete surg ical excision is curative .
32 Tu mours of the nasal cavity, paranasal sin uses and skull base
Seromucinous hamartoma
Ro J .Y.
Franchi A.
Defin ition
Sinon asal serom uci nous hama rtoma
(SH) is a benig n overg rowth of i nd ige­
nous serom uci nous gland s of the nasal
cavity and paranasa l sinuses.
Synonyms
Epithelial hamartoma; glandular hamarto­
ma; microglandular adenosis of nose {445)
Epidemiology
SHs are extrem ely rare { 1 2 1 8 ). They oc­
cur p redominantly in ad ults, with a male­
to-female ratio 3:2. The patient age range
is 1 4-85 years (mean: 56 years).
Etiology
SH has no association with any specific
etiological agent, but it often arises in the
setting of inflammatory polyps.
Localization
SH usually occurs at the posterior nasal
septum or nasopharynx , and is rarely de­
scri bed on the lateral nasal wall or in the
paranasal sin uses {2567 ) .
Clinical features
The typical sympto ms are nasal obstruc ­
tion and epistax is. The lesions are often
found incide ntally, and are somet imes
assoc iated with other medic al condi ­
tions, such as rheum atoid arthriti s , Par­
kinso n disea se, and chron ic sinus itis.
Physic a l exami nation reveal s a polypo id
. years), all patients are al ive and well after
mass witho ut other agg ressiv e featu res .
Macroscopy
SH � are typ icall y poly poid or exop hytic ,
typi c ally with a rubb ery con siste ncy a n d
H istop ath o logy
S H is a polypoi d mass covered by res pira­
tory epitheli u m , and contains small to larg e
glan ds and d ucts lined by a single layer of
cuboida l or f lattene d epithel ial cells with
bland, oval to round n uclei and ampho ­
philic to eosinophilic cytoplasm . Mitoses
are absent. The surroundin g fibrous stro­
ma often contains a lymphoplasmacytic
infi ltrate { 1 25 , 1 044}. Eosi nophilic secretion
can be seen in the lumen, and goblet or
clear cells may be observed . The tubular
g lands may be encircled by thick base­
ment membrane material. The prol iferat­
ing tubules intermingle with the pre-ex­
isting seromucinous acini or invagi nated
respi ratory epithelium forming glands or
cysts , similar to features of respiratory epi­
thelial adenomatoid hamartoma, support­
ing the possibi lity that SH and respiratory
epithelial adenomatoid hamartoma con­
stitute a spectrum of lesions , often seen
together (2565 , 2567}.
lm munoh istochem istry shows positiv­
ity for C K1 7, C K1 9 , E M A , lysozyme, and
S 1 00 , with an absence of myoepithe­
lial (basal) cells aro u n d the seromuci­
nous g la n d s ( 73 1 } . T h e stroma around
tubu les is positive for calponin , SMA.
and desmi n , i n d icati n g myofib roblastic /
smooth muscle d ifferentia tion ( 1 564} .
Progn osis and p redictive factors
Conse rvative but complete surgic al ex­
cisio n is c u rative . With follow-up avail­
able from 4 months to 1 O years (me an: 6
surg ical remova l , with no docum ented
cases of m etastasis and only one rep ort
of rec u rren ce { 73 1 ) .
Sa l iv ary g la n d tu m o u rs Bell D.
Bu llerdiek J.
Gnepp D. R .
Hunt J . L.

Pfeomorphic adenoma
D fm ition
P'e morphic adenoma ( PA) i s a benign
u our with vari able cytomorphological
and architectu ral man ifestations. The
iden ification of e pithelial and myoepithe­
lial/stromal components is essential for
he diagnosis of PA .
See also the Pleomorphic adenoma
section (p. 1 85) i n Chapte r 7 ( Tumours of
salivary glands).

ICD-0 code 8940/0

Synonym
Benign mixed tumour

Epidemiology
Most intranasal PAs present in the third to
sixth decades of l ife, with a slight female
preponderance {8 ,477, 2 1 09, 2257).

Local ization
The tumour gene rally (in about 80% of
cases) arises in the nasal septal m ucosa ,
despite the fact that the seromuci nous
glands are mainly located in the lateral
wall and turbi nates ( 8 , 1 286 , 2 1 09).

..
Cli nical features

.
The most common presenti ng symptom
-
is unilateral nasal obstruction. Epistaxis ; ... ' "' .,,
\.

and sinu sitis can occu r secondary to . \ " ... .

extension into the maxil lary sinus ( 2 1 09).
Affected patients present within 1 year of
the onset of symptoms ( 2 1 09).
Macroscopy
The range of tumour size is 0. 5-7 cm,
and the tumours are described as exo­
phytic or polypoid (with a broad base),
oval, dome-shaped , firm, and grey
( 8 , 2 1 09). No destruction of surrounding
tissue is see n .
Fig. 1 .23 Pleomorphic adenoma. A These mixed tumours have greater cellularity and a more dominant epithelial
component (vs chondroid, myxoid, and collagenous stromal components) than are seen in pleomorphic adenomas of
the major salivary glands. B Higher magnification showing myoepithelial and ductal elements.
H istopathology Prog nosis and predictive factors
In the nasal cavity, these neoplasms Complete surgical excision is the treat­
display a more domi nant epithelial com­ ment of choice. The recurrence rate is
ponent (vs stromal compone nts) than is lower than that of parotid PA . Malignant
seen in PAs of the major salivary glands transformation of PA of the nasal cavity
( 8 , 2 1 09 ). has been reported i n 2.4-1 0% of cases
{8,451 , 2 1 09).

Salivary gland tumours 33

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 Fig. 23.—Skeleton of the Perch.

Fig. 24.—Skeleton of a Perch’s Skull.

Fig. 25.—Hyoid arch, branchial apparatus, and scapulary arch of the Perch.
Fig. 26.—Lower view of Skull of Perch.
 Fig. 27.—Hyoid bone of the Perch.
The formation of the posterior part of the side of the skull is completed by the
mastoid and parietal bones. The former (12) projects outwards and backwards
farther than the paroccipital, forming the outer strong process of the side of the
cranium. This process lodges on its upper surface one of the main ducts of the
muciferous system, and affords the base of articulation to a part of the
hyomandibular. Its extremity gives attachment to the strong tendon of the dorso-
lateral muscles of the trunk. The parietals (7) are flat bones, of comparatively
much smaller extent than in higher Vertebrates, and separated from each other
by the anterior prolongation of the supraoccipital.
The anterior wall of the brain-capsule (or the posterior of the orbit) is formed
by the orbitosphenoids (14), between which, superiorly, the olfactory nerves, and
inferiorly, the optic, pass out of the cranium. In addition to this paired bone, the
Perch and many other fishes possess another single bone (15),—the os
sphenoideum anterius of Cuvier, ethmoid of Owen, and basisphenoid of Huxley; it
is Y-shaped, each lateral branch being connected with an orbito-sphenoid, whilst
the lower branch rests upon the long basal bone.
A cartilage, the substance of which is thickest above the vomer, and which
extends as a narrow stripe along the interorbital septum, represents the ethmoid
of higher Vertebrata; the olfactory nerves run along, and finally perforate it.
There remain, finally, the bones distinguishable on the upper surface of the
skull; the largest, extending from the nasal cavities to the occipital, are the frontal
bones (1), which also form the upper margin of the orbit. The postfrontals (4) are
small bones placed on the supero-posterior angle of the orbit, and serving as the
point from which the infraorbital ring is suspended. The pre-frontals (2), also
small, occupy the anterior margin of the orbit. A pair of small tubiform bones (20),
the turbinals, occupy the foremost part of the snout, in front of the frontals, and
are separated from each other by intervening cartilage.
After removal of the gill-cover and mandibulary suspensorium, the hyoid arch,
which encloses the branchial apparatus, and farther behind, the humeral arch are
laid open to view (Fig. 25). These parts can be readily separated from the
cranium proper.
The hyoid arch is suspended by a slender styliform bone, the stylohyal (29),
from the hyomandibulars; it consists of three segments, the epihyal (37),
ceratohyal (38), which is the longest and strongest piece, and the basihyal, which
is formed by two juxtaposed pieces (39, 40). Between the latter there is a median
styliform ossicle (41), extending forwards into the substance of the tongue, called
glossohyal or os linguale; and below the junction of the two hyoid branches there
is a vertical single bone (42), expanded along its lower edge, which, connected
by ligament with the anterior extremity of the humeral arch, forms the isthmus
separating the two gill-openings. This bone is called the urohyal. Articulated or
attached by ligaments to the epihyal and ceratohyal are a number of sword-
shaped bones or rays (43), the branchiostegals, between which the
branchiostegal membrane is extended.
The branchial arches (Figs. 25 and 27) are enclosed within the hyoid arch,
with which they are closely connected at the base. They are five in number, of
which four bear gills, whilst the fifth (56) remains dwarfed, is beset with teeth, and
called the lower pharyngeal bone. The arches adhere by their lower extremities to
a chain of ossicles (53, 54, 55), basibranchials, and, curving as they ascend,
nearly meet at the base of the cranium, to which they are attached by a layer of
ligamentous and cellular tissue. Each of the first three branchial arches consists
of four pieces movably connected with one another. The lowest is the
hypobranchial (57), the next much longer one (58) the cerato-branchial, and,
above this, a slender and a short irregularly-shaped epibranchial (61). In the
fourth arch the hypobranchial is absent. The uppermost of these segments (62),
especially of the fourth arch, are dilated, and more or less confluent; they are
beset with fine teeth, and generally distinguished as the upper pharyngeal bones.
Only the cerato-branchial is represented in the fifth arch or lower pharyngeal. On
their outer convex side the branchial segments are grooved for the reception of
large blood-vessels and nerves; on the inner side they support horny processes
(63), called the gill-rakers, which do not form part of the skeleton.
The scapular or humeral arch is suspended from the skull by the
(suprascapula) post-temporal (46), which, in the Perch, is attached by a triple
prong to the occipital and mastoid bones. Then follows the (scapula)
supraclavicula (47), and the arch is completed below by the union of the large
(coracoid) clavicula (48) with its fellow. Two flat bones (51, 52), each with a
vacuity, attached to the clavicle have been determined as the (radius and ulna)
coracoid and scapula of higher vertebrates, and the two series of small bones
(53) intervening between the forearm and the fin as carpals and metacarpals. A
two-jointed appendage the (epicoracoid) postclavicula, is attached to the clavicle:
its upper piece (49) is broad and lamelliform, its lower (50) styliform and pointed.
The ventral fins are articulated to a pair of flat triangular bones, the pubic
bones (80).
The bones of the skull of the fish have received so many different
interpretations that no two accounts agree in their nomenclature, so that their
study is a matter of considerable difficulty to the beginner. The following
synonymic table will tend to overcome difficulties arising from this cause; it
contains the terms used by Cuvier, those introduced by Owen, and finally the
nomenclature of Stannius, Huxley, and Parker. Those adopted in the present
work are printed in italics. The numbers refer to the figures in the accompanying
woodcuts (Figs. 23–27).
Cuvier. Owen. Stannius. Huxley, Parker, etc.
1. Frontal principal Frontal Os frontale
2. Frontal Prefrontal Os frontale Lateral ethmoid
antérieur anterius (Parker)
3. Ethmoid Nasal Os ethmoideum
4. Frontal Postfrontal Os frontale Sphenotic (Parker)
postérieur posterius
5. Basilaire Basioccipital Os basilare
6. Sphénoide Basisphenoid Os sphenoideum Sometimes referred
basilare to as “Basal”
7. Pariétal Parietal Os parietale
8. Interpariétal or Supraoccipital Os occipitale
occipital superius
supérieure
9. Occipital Paroccipital Os occipitale Epioticum (Huxley)
externe externum
10. Occipital lateral Exoccipital Os occipitale
laterale
11. Grande aile du Alisphenoid Ala temporalis Prooticum (Huxley)
sphénoide
12. Mastoidien Mastoid Os mastoideum + Opisthoticum[5]
 os +Squamosal
extrascapulare (Huxley)
13. Rocher Petrosal and Oberflächliche
Otosteal Knochen-
lamelle
14. Aile orbitaire Orbitosphenoid Ala orbitalis Alisphenoid (Huxley)
15. Sphenoide Ethmoid and Os sphenoideum Basisphenoid
antérieur Ethmoturbinal anterius (Huxley)
16. Vomer Vomer Vomer
17. Intermaxillaire Inter- or Pre- Os intermaxillare
maxillary
18. Maxillaire Maxillary Os maxillare
supérieur
19. Sousorbitaires Infraorbital ring Ossa infraorbitalia
20. Nasal Turbinal Os terminale
22. Palatine Palatin Os palatinum
23. Temporal Epitympanic Os temporale Hyomandibular
(Huxley)
24. Transverse Pterygoid Os transversum s.
pterygoideum
externum
25. Ptérygoidien Entopterygoid Os pterygoideum Mesopterygoid
interne (Parker)
26. Jugal Hypotympanic Os quadratojugale Quadrate (Huxley)
27. Tympanal Pretympanic Os tympanicum Metapterygoid
(Huxley)
28. Operculaire Operculum Operculum
29. Styloide Stylohyal Os styloideum
30. Préopercule Præoperculum Præoperculum
31. Symplectique Mesotympanic Os symplecticum
32. Sousopercule Suboperculum Suboperculum
33. Interopercule Interoperculum Interoperculum
34. Dentaire Dentary Os dentale
35. Articulaire Articulary Os articulare
36. Angulaire Angular Os angulare
37. Grandes pièces Epihyal Segmente der
latérales Zungenbein-
Schenkel
38. Ceratohyal
39. Petites pièces Basihyal
laterales
40.
41. Os lingual Glossohyal Os linguale s.
entoglossum
42. Queue de l’os Urohyal Basibranchiostegal
hyoide (Parker)
43. Rayon Branchiostegal Radii
branchiostège branchiostegi
46. Surscapulaire Suprascapula Omolita Post-temporal
(Parker)
 47. Scapulaire Scapula Scapula Supraclavicula
(Parker)
48. Humeral Coracoid Clavicula Clavicula (Parker)
49.
Postclavicula
Coracoid Epicoracoid
50. (Parker)
51. Cubital Radius Coracoid (Parker)
Ossa carpi
52. Radial Ulna Scapula (Parker)
Basalia (Huxley),
53. Os du carpe Carpals Ossa metacarpi
Brachials (Parker)
53 bis.
Chaine
55. Basibranchials Copula
intermédiaire
54.
56. Pharyngiens Lower Ossa pharyngea
inférieurs Pharyngeals inferiora
57. Pièce interne de Hypobranchial
partie
inférieure de
l’arceau
branchiale
58. Pièce externe „ Ceratobranchial
Segmente der
59. Stylet de Upper
Kiemenbogen-
prémière epibranchial of
Schenkel
arceau first branchial
branchiale arch
61. Partie Epibranchials
supérieure de
l’arceau
branchiale
62. Os pharyngian Pharyngobranchial Os pharyngeum Upper pharyngeals
supérieur superius
63. Gill-rakers
65. Rayons de la Pectoral rays Brustflossen-
pectorale Strablen
67, 68. Vertèbres Abdominal Bauchwirbel
abdominales vertebræ
69. Vertèbres Caudal vertebræ Schwanzwirbel
caudales
70. Plaque [Aggregated Verticale Platte Hypural (Huxley)
triangulaire et interhæmals]
verticale
71. Caudal rays Schwanzflossen
Strahlen
72. Côte Rib Rippen
73. Appendices or Epipleural spines Muskel-Gräthen
stylets
74. Interépineux Interneural spines Ossa interspinalia
s. obere
Flossentræger
75. Épines et Dorsal rays and Rückenflossen-
rayons spines Strablen u.
dorsales Stacheln
76. First interneural
78. Rudimentary
caudal rays
79. Apophyses Interhæmal spines Untere
épineuses Flossentræger
inférieures
80. Pubic Becken
81. Ventral spine Bauchflossen-
Stachel
 CHAPTER IV.

MODIFICATIONS OF THE SKELETON.

The lowermost sub-class of fishes, which comprises one form

only, the Lancelet (Branchiostoma [s. Amphioxus] lanceolatum),
possesses the skeleton of the most primitive type.

Fig. 28.—Branchiostoma lanceolatum. a, Mouth; b, Vent; c, abdominal porus.

Fig. 29.—Anterior end of body of Branchiostoma (magn.) d, Chorda dorsalis; e,

Spinal chord; f, Cartilaginous rods; g, Eye; h, Branchial rods; i, Labial
cartilage; k, Oral cirrhi.
The vertebral column is represented by a simple chorda dorsalis
or notochord only, which extends from one extremity of the fish to the
other, and, so far from being expanded into a cranial cavity, it is
pointed at its anterior end as well as at its posterior. It is enveloped in
a simple membrane like the spinal chord and the abdominal organs,
and there is no trace of vertebral segments or ribs; however, a series
of short cartilaginous rods above the spine evidently represent
apophyses. A maxillary or hyoid apparatus, or elements representing
limbs, are entirely absent.
[J. Müller, Ueber den Bau und die Lebenserscheinungen des
Branchiostoma lubricum, in Abhandl. Ak. Wiss. Berlin, 1844.]
The skeleton of the Cyclostomata (or Marsipobranchii) (Lampreys
and Sea-hags) shows a considerable advance of development. It
consists of a notochord, the anterior pointed end of which is wedged
into the base of a cranial capsule, partly membranous partly
cartilaginous. This skull, therefore, is not movable upon the spinal
column. No vertebral segmentation can be observed in the
notochord, but neural arches are represented by a series of
cartilages on each side of the spinal chord. In Petromyzon (Fig. 30)
the basis cranii emits two prolongations on each side: an inferior,
extending for some distance along the lower side of the spinal
column, and a lateral, which is ramified into a skeleton supporting
the branchial apparatus. A stylohyal process and a subocular arch
with a palato-pterygoid portion may be distinguished. The roof of the
cranial capsule is membranous in Myxine and in the larvæ of
Petromyzon, but more or less cartilaginous in the adult Petromyzon
and in Bdellostoma. A cartilaginous capsule on each side of the
hinder part of the skull contains the auditory organ, whilst the
olfactory capsule occupies the anterior upper part of the roof. A
broad cartilaginous lamina, starting from the cranium and overlying
part of the snout, has been determined as representing the ethmo-
vomerine elements, whilst the oral organs are supported by large,
very peculiar cartilages (labials), greatly differing in general
configuration and arrangement in the various Cyclostomes. There
are three in the Sea-lamprey, of which the middle one is joined to the
palate by an intermediate smaller one; the foremost is ring-like,
tooth-bearing, emitting on each side a styliform process. The lingual
cartilage is large in all Cyclostomes.
There is no trace of ribs or limbs.
 [J. Müller, Vergleichende Anatomie der Myxinoiden. Erster Theil.
Osteologie und Myologie, in Abhandl. Ak. Wiss. Berlin, 1835.]

Fig. 30.—Upper (A) and side (B) views, and vertical section (C) of the skull
of Petromyzon marinus.
a, Notochord; b, Basis cranii; c, Inferior, and d, Lateral process of basis; e,
Auditory capsule; f, Subocular arch; g, Stylohyal process; h, Olfactory
capsule; i, Ethmo-vomerine plate; k, Palato-pterygoid portion of subocular
arch; l-n, Accessory labial or rostral cartilages; with o, appendage; p,
lingual cartilage; q, neural arches; r, Branchial skeleton; s, Blind
termination of the nasal duct between the notochord and œsophagus.
 Fig. 31.—Heterocercal Tail of Centrina salviani.
a, Vertebræ; b, Neurapophyses; c, Hæmapophyses.
The Chondropterygians exhibit a most extraordinary diversity in
the development of their vertebral column; almost every degree of
ossification, from a notochord without a trace of annular structure to
a series of completely ossified vertebræ being found in this order.
Sharks, in which the notochord is persistent, are the Holocephali (if
they be reckoned to this order, and the genera Notidanus and
Echinorhinus). Among the first, Chimæra monstrosa begins to show
traces of segmentation; but they are limited to the outer sheath of the
notochord, in which slender subossified rings appear. In Notidanus
membranous septa, with a central vacuity, cross the substance of
the gelatinous notochord. In the other Sharks the segmentation is
complete, each vertebra having a deep conical excavation in front
and behind, with a central canal through which the notochord is
continued; but the degree in which the primitive cartilage is replaced
by concentric or radiating lamellæ of bone varies greatly in the
various genera, and according to the age of the individuals. In the
Rays all the vertebræ are completely ossified, and the anterior ones
confluent into one continuous mass.
In the majority of Chondropterygians the extremity of the
vertebral column shows a decidedly heterocercal condition (Fig. 31),
and only a few, like Squatina and some Rays, possess a diphycercal
tail
The advance in the development of the skeleton of the
Chondropterygians beyond the primitive condition of the previous
sub-classes, manifests itself further by the presence of neural and
hæmal elements, which extend to the foremost part of the axial
column, but of which the hæmal form a closed arch in the caudal
region only, whilst on the trunk they appear merely as a lateral
longitudinal ridge.

Fig. 32.—Lateral view.

Fig. 33.—Longitudinal section.
 Fig. 34.—Transverse section of Caudal
vertebra of Basking Shark (Selache
maxima). (After Hasse.) a, Centrum; b,
Neurapophysis; c, Intercrural cartilage; d,
Hæmapophysis; e, Spinal canal; f,
Intervertebral cavity; g, Central canal for
persistent portion of notochord; h, Hæmal
canals for blood-vessels.
The neural and hæmal apophyses are either merely attached to
the axis, as in Chondropterygians with persistent notochord, the
Rays and some Sharks; or their basal portions penetrate like wedges
into the substance of the centrum, so that, in a transverse section, in
consequence of the difference in their texture, they appear in the
form of an X.[6] The interspaces between the neurapophyses of the
vertebræ are not filled by fibrous membrane, as in other fishes, but
by separate cartilages, laminæ or cartilagines intercrurales, to which
frequently a series of terminal pieces is superadded, which must be
regarded as the first appearance of the interneural spines of the
Teleostei and many Ganoids. Similar terminal pieces are sometimes
observed on the hæmal arches. Ribs are either absent or but
imperfectly represented (Carcharias).
The substance of the skull of the Chondropterygians is cartilage,
interrupted especially on its upper surface by more or less extensive
fibro-membranous fontanelles. Superficially it is covered by a more
or less thick chagreen-like osseous deposit. The articulation with the
vertebral column is effected by a pair of lateral condyles. In the
Sharks, besides, a central conical excavation corresponds to that of
the centrum of the foremost vertebral segment, whilst in the Rays
this central excavation of the skull receives a condyle of the axis of
the spinous column.
The cranium itself is a continuous undivided cartilage, in which
the limits of the orbit are well marked by an anterior and posterior
protuberance. The ethmoidal region sends horizontal plates over the
nasal sacs, the apertures of which retain their embryonic situation
upon the under surface of the skull. In the majority of
Chondropterygians these plates are conically produced, forming the
base of the soft projecting snout; and in some forms, especially in
the long-snouted Rays and the Saw-fishes (Pristis) this prolongation
appears in the form of three or more tubiform rods.
As separate cartilages there are appended to the skull a
suspensorium, a palatine, mandible, hyoid, and rudimentary
maxillary elements.
The suspensorium is movably attached to the side of the skull. It
generally consists of one piece only, but in some Rays of two. In the
Rays it is articulated with the mandible only, their hyoid possessing a
distinct point of attachment to the skull. In the Sharks the hyoid is
suspended from the lower end of the suspensorium together with the
mandible.
What is generally called the upper jaw of a Shark is, as Cuvier
has already stated, not the maxillary, but palatine. It consists of two
simple lateral halves, each of which articulates with the
corresponding half of the lower jaw, which is formed by the simple
representative of Meckel’s cartilage.
 Some cartilages of various sizes are generally developed on
each side of the palatine, and one on each side of the mandible.
They are called labial cartilages, and seem to represent maxillary
elements.
The hyoid consists generally of a pair of long and strong lateral
pieces, and a single mesial piece. From the former cartilaginous
filaments (representing branchiostegals) pass directly outwards.
Branchial arches, varying in number, and similar to the hyoid,
succeed it. They are suspended from the side of the foremost part of
the spinous column, and, like the hyoid, bear a number of filaments.
The vertical fins are supported by interneural and interhæmal
cartilages, each of which consists of two and more pieces, and to
which the fin-rays are attached without articulation.
The scapular arch of the Sharks is formed by a single coracoid
cartilage bent from the dorsal region downwards and forwards. In
some genera (Scyllium, Squatina) a small separate scapular
cartilage is attached to the dorsal extremities of the coracoid; but in
none of the Elasmobranchs is the scapular arch suspended from the
skull or vertebral column; it is merely sunk, and fixed in the
substance of the muscles. Behind, at the point of its greatest
curvature, three carpal cartilages are joined to the coracoid, which
Gegenbaur has distinguished as propterygium, mesopterygium, and
metapterygium, the former occupying the front, the latter the hind
margin of the fin. Several more or less regular transverse series of
styliform cartilages follow. They represent the phalanges, to which
the horny filaments which are imbedded in the skin of the fin are
attached.
In the Rays, with the exception of Torpedo, the scapular arch is
intimately connected with the confluent anterior portion of the
vertebral column. The anterior and posterior carpal cartilages are
followed by a series of similar pieces, which extend like an arch
forwards to the rostral portion of the skull, and backwards to the
pubic region. Extremely numerous phalangeal elements, longest in
the middle, are supported by the carpals, and form the skeleton of
the lateral expansion of the so-called disk of the Ray’s body, which
thus, in fact, is nothing but the enormously enlarged pectoral fin.
The pubic is represented by a single median transverse cartilage,
with which a tarsal cartilage articulates. The latter supports the fin-
rays. To the end of this cartilage is also attached, in the male
Chondropterygians, a peculiar accessory generative organ or
clasper.
The Holocephali differ from the other Chondropterygians in
several important points of the structure of their skeleton, and
approach unmistakably certain Ganoids. That their spinal column is
persistently notochordal has been mentioned already. Their palatal
apparatus, with the suspensorium, coalesces with the skull, the
mandible articulating with a short apophysis of the cranial cartilage.
The mandible is simple, without anterior symphysis. The spine with
which the dorsal fin is armed articulates with a neural apophysis, and
is not immovably attached to it, as in the Sharks. The pubic consists
of two lateral halves, with a short, rounded, tarsal cartilage.
The skeleton of the Ganoid Fishes offers extreme variations with
regard to the degree in which ossifications replace the primordial
cartilage. Whilst some exhibit scarcely any advance beyond the
Plagiostomes with persistent cartilage, others approach, as regards
the development and specialisation of the several parts of their
osseous framework, the Teleosteans so closely that their Ganoid
nature can be demonstrated by, or inferred from, other
considerations only. All Ganoids possess a separate gill-cover.[7]
The diversity in the development of the Ganoid skeleton is well
exemplified by the few representatives of the order in the existing
Fish-fauna. Lowest in the scale (in this respect) are those with a
persistent notochord, and an autostylic skull, that is, a skull without
separate suspensorium—the fishes constituting the suborder Dipnoi,
of which the existing representatives are Lepidosiren, Protopterus,
and Ceratodus, and the extinct (as far as demonstrated at present)
Dipterus, Chirodus (and Phaneropleuron?). In these fishes the
notochord is persistent, passing uninterruptedly into the cartilaginous
base of the skull. Only now and then a distinct vertical segmentation