Ebook Surgical pathology of the head and neck (Vol 2 - 2/E): Part 1

(BQ) Part 1 book Surgical pathology of the head and neck - Vol 2 has contents: Tumors of the nervous system, tumors and tumor like lesions of the soft tissues.

Surgical Pathology

of the

Head and Neck

Surgical Pathology

Head and Neck

Second Edition, Revised and Expanded

Leon Barnes

University of Pittsburgh School of Medicine

University of Pittsburgh School of Dental Medicine

Pittsburgh, Pennsylvania

M A R C E L

This book is printed on acid-free paper

Headquarters

Marcel Dekker, Inc

270 Madison Avenue New York, NY 10016

Copyright 0 2001 by Marcel Dekker, Inc All Rights Reserved

Neither this book nor any part may be reproduced or transmitted In any form or by any means electronic or mechanical, including photocopying microfilming, and rccording, or by any information storage and retrieval system without permission in writing from the publisher

Current printing (last digit):

1 0 0 8 7 6 5 4 3 2 1

This book is dedicated to:

My parents, Mt: r m l Mrs E l l i s L Bnrlws, whose sacrifices provided the foundation for achieving many of my personal goals

The memory of my grandmother, Mrs Mcrty Barnes, who was a good friend and constant source of inspiration

My wife C m ) / who, during the preparation o f this book, gave her unwavering support and tolerated a prolonged unorthodox schedule

My children, Christy Leigh t r r d Lori Beth, for providing many pleasant diversions from the seemingly endless tasks of writing and editing

DL Rohcrt S Totten, now deceased, and Dt: R o h r t H Femell, J t : who taught me the principles of pathology

Preface

Head and neck pathology, defined here as including a l l structures contained in the area from the level of the clavicles to the sella turcica, has finally come of age and can rightfully take its place among other well-recognized subspecialties, such as hematopathology, neuropathology and dermatopathology Considering all the tissues contained in this small area-skin, mucosal surfaces, bone, soft tissue, lymph nodes, salivary glands, odontogenic structures, thyroid, parathyroids, eyes, and peripheral and central nervous system-one may rightfully argue that head and neck pathology is “nothing more” than the practice of general pathology above the clavicles Therein lies the problem To write a textbook on head and neck pathology is to write yet another book on general pathology

The tirst edition of this book was published 15 years ago and took almost S years to produce Naively, I thought the second edition would take less time, certainly not the seven years i t ultimately did To this end, I am most appreciative

secretary, Mrs Donna Bowen, who over the years typed and retyped an endless array of papers: and to the staff of Marcel Dekker, Inc., for patiently guiding me through this venture

The second edition contains five new chapters on nwlecular biology, fine-needle aspiration, vesiculobullous diseases, neck dissections, and radiation The book has also been completely updated and reformated for easier access to specific information The index has been expanded and is included in each volume

As in the first edition, our goal has been to condense into one source the vast literature on head and neck pathology that is so widely scattered in numerous specialty books and journals Although we have tried to be thorough, we do not profess to have been complete Only feedback from our readers will determine whether we have come close to our intent

Leon Barnes

Richard L Carter, M.D., DSc., F.R.C.P Department of Histopathology Royal Marsden Hospital Sutton, Surrey

England

Silloo B Kapadia, M.D Professor of Pathology and Surgery, Department of Pathology, The Pennsylvania State University College of Medicine, and Director o f Surgical Pathology, Department of Anatomic Pathology, The Milton S

Hershey Medical Center Hershey, Pennsylvania

Marsha C Kinney, M.D Associate Professor Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee

Mario A Luna, M.D Professor Department of Pathology, The University of Texas M D Anderson Cancer Center, Houston Texas

Robert L Peel, M.D Associate Professor o f Pathology and Otolaryngology, Department of Pathology, University of

Pittsburgh School of Medicine, and Department of Pathology Presbyterian-University Hospital, Pittsburgh Pennsylvania

Steven H Swerdlow, M.D Director, Division of Hematopathology and Professor Department of Pathology University

of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Robert S Verbin, D.M.D., Ph.D.* Professor and Chairman, Department of Oral Medicine and Pathology, University

of Pittsburgh School of Dental Medicine Pittsburgh, Pennsylvania

*Retired

vii

17 Diseases o f the Bones and Joints

Lcou Btrrrles, Rohert S K>rl>illv Rohert L P d m d Billy N Appd

18 Hematopoietic and Lymphoid Disorders

MarsIItr C Kirlrwy w d Stevm H Swertllow

19 The Pathology of Neck Dissections

1405

l42 I

ix

I- I

1 Uses, Abuses, and Pitfalls of Frozen-Section Diagnoses of Diseases of the Head and Neck

4 Molecular Pathology of Head and Neck Cancer

Regina Candour-Edwards rrnd Pcul H Gumerlock

5 Diseases of the Larynx, Hypopharynx, and Esophagus

Leon Barnes

6 Benign Neoplastic and Nonneoplastic Lesions of the Oral Cavity and Oropharynx

Robert S Verbin, James Guggenheitner, Leon Bames, and Billy N Appel

7 Noninfectious Vesiculoerosive and Ulcerative Lesions of the Oral Mucosa

Susan Muller

8 Premalignant Lesions of the Oral Cavity

Susat1 Muller and Charles A Waldron

9 Cancer of the Oral Cavity and Oropharynx

IO Diseases of the Nasal Cavity, Paranasal Sinuses, and Nasopharynx

Leotl Barnes, Margaret Brandwein, and Peter M Son1

11 Diseases of the External Auditory Canal, Middle Ear, and Temporal Bone

Leon Barnes crnd Robert L Peel

12 Diseases of the Trachea

Cysts and Cyst-like Lesions of the Oral Cavity, Jaws, and Neck

Rohert S Verhin und Leon Burnes

Odontogenic Tumors

Rohert S Verhin nnci Billy N A p p d

Developmental Lesions of the Head and Neck

Alfo Ferlito and Alessanclru Rinaldo

Pathology of the Thyroid Gland

Virginia A LiVOlsi

The Parathyroid Glands

Rol,?:n L Ape1 uncl Sylvicr L Asu

Pathology of Selected Skin Lesions of the Head and Neck

Ste\wl M Ruhoy, Kevin J Flynn, Alun R Silvrrnlan, M u n J ~ a n Dd3uzmczn, unrl Michael L Nielunrl

Diseases of the Eye and Ocular Adnexa

Brucr L Johnson

Infectious Diseases o f the Head and Neck

Mcrrgaret Brc~nclcraitr

Radiation Injury

Luis Fdipe Fujurclo

Miscellaneous Disorders of the Head and Neck

Tumors of the Nervous System

I Organ of Chievitz

11 Nasal Glioma

111 Nasal Encephalocele

IV Traumatic (Amputation) Neuroma

V Peripheral Nerve Sheath Tumors

A Neurilemonla (Benign Schwannoma)

B Neurofibroma

C Plexiform Neurofibroma

D Diffuse Neurofibroma

E Neurotibromato~is 1

F Neurofibronlatosix 2 (NF-2; Bilateral Acoustlc Neuroma)

G Acoustic Neuroma (Unilateral)

E Other Sites (Orhltal Thyroid, Nasal)

X Malignant Peripheral Nerve Sheath Tumor (Malignant Schwannoma, Neurotibrosarcoma)

XI Olfactory Neuroblastoma

XII Melanotic Neuroectodermal l’umor of Infancy

XIII Ewing’s Sarcoma and Primitive Neuroectodermal Tumor (Peripheral Neuroepithelioma)

References

7xx 7x8

792

793

795

795 79x

800 X03 X03

806 X08

809

X 1 0 x12 x13 X17 X22 X26 x27

830 X30 x3 I

x3 I

832 X32

I ORGAN OF CHIEVITZ

Introduction The juxtaoral organ of Chievitz (JOC)

is a normal microscopic anatomical structure that was first

described in 1885 by the Danish histologist Chievitz (1)

This nonneoplastic epithelial structure has been the subject

of a detailed monograph (2) The function of the JOC is

as of yet unknown The suggestion has been made, but

not universally accepted, that it might have neuroreceptor

functions

Clinical Features The JOC is located at the angle

of the mandible, bilaterally, near the buccotemporalis

fascia and is intimately associated with branches of the

buccal nerve (3-10) Lutman found these structures in the

soft tissue on the anterior medial surfaces of 9 of 14

hemimandibulectomy specimens at a point where the

ascending ramus joins the body (4) These structures were

located near the medial surface of the pterygomandibular

ligament deep to the minor salivary glands Tschen and

Fechner noted their presence in 14 of 25 consecutive

autopsies, in 3 of which they could demonstrate bilateral-

ity (5) Danforth and Baughman found these epithelial

nests associated with sensory nerve fibers in 11 of 25

autopsy specimens evaluated (3) JOC have been noted in

all age groups, including newborns, stillborns, and adults

(3) There is no gender bias

Pathology JOC is not usually visualized on gross

examination, although it may measure up to 0.8 cm in

maximum dimension It is important to recognize the JOC

on histological examination because it has a potential for

being misdiagnosed as perineural spread of carcinomas

arising from this area (2-10) Histologically, JOC is char-

acterized by an ovoid zone of condensed connective tissue

containing clusters of small well-defined nests of squa-

mous epithelial cells exhibiting intercellular bridges and

Figure 1 Juxtaoral organ of Chievitz: A normal anatomical

structure composed of small well-defined clusters of epithe-

lial cells intimately associated with nerves (arrow) It must

not be confused with penneural invasion by a carcinoma

(hematoxylin and eosin stain [H&E] X400.)

bordered by cells of the basal type, some with palisading nuclei, in close proximity to small myelinated nerves (Fig

1) (3) The cell nests have been observed between or

adjacent to axons of small nerves and not actually in the perineural space (4) The cells have an eosinophilic or clear cytoplasm and varying-sized cytologically bland nuclei, with uniform chromatin distribution and inconspic- uous nucleoli Although intercellular bridges are observed

in the cell nests, there is no evidence of keratin formation

or keratohyalin granules Occasionally, duct-like lumina have been described Mitoses are absent JOC are mucic- armine-negative, whereas periodic acid-Schiff (PAS) stain

shows a prominent basement membrane around the cell nests (3) Dense core granules resembling neurosecretory granules have been noted on ultrastructural examination

Differential Diagnosis Because the nests of squa-

mous epithelial cells in JOC are in close proximity to nerves, they may be confused for perineural invasion in oral carcinoma (2-4,7-9,ll) Difficulty in diagnosis may arise on permanent sections or during intraoperative fro- zen-section diagnosis giving rise to erroneous stage or unnecessary surgical intervention (4) The differential di- agnosis includes perineural spread of squamous cell carci- noma, adenoid cystic carcinoma, or mucoepidermoid car- cinoma The characteristic anatomical location and normal nuclear features lacking cellular atypia distinguish JOC from carcinomas In addition, there is no stromal des- moplastic response to the JOC, whereas invasive squa- mous cell carcinoma is often associated with this feature

II NASAL GLIOMA Introduction Heterotopic mature glial tissue pre- senting outside the craniospinal axis most frequently oc- curs in and around the nose and is referred to as "nasal

Tumors of the Nervous System 789

glioma” (NG) (1-3) Used in this context, the term nasal

“glioma” is a misnomer as it implies a true neoplasm

capable of autonomous growth NG is not a true neoplasm

but instead is a congenital malformation in which there is

anterior displacement of mature cerebral tissue that has

lost its connection with the intracranial contents, perhaps

as a consequence of sequestration of an anterior or naso-

frontal encephalocele (3) Although the term “heterotopic

nasal glial tissue” is more appropriate than nasal glioma

for this lesion the latter is entrenched in the literature and

is familiar t o the head and neck surgeons Therefore, its

continued usage is probably justified, provided its true

nature is explained in the surgical pathology report

Clinical Features The clinical finding of a congeni-

tal nasofrontal mass presenting in infancy or childhood is

usually duc to either a nasal glioma, nasal encephalocele,

or nasal dermoid (1-10) Although most NG present at

birth, some may remain asymptomatic and present later

in life (3) There is no sexual prevalence In the study by

Yeoh et a l , all but I of 22 lesions were known to be

congenital; 1 child who had no symptoms at birth pre-

sented with an intranasal mass present for several years

(3) I n the same study, I 1 of 22 cases were operated on

in the first 6 months of life and 20 (90%) by the age of

2 years (3) There is no familial occurrence or associated

congenital abnormality in patients with NG; however,

glial heterotopias arising i n the pharynx may be associated

with cleft palate or choana1 stenosis i n about one-third of

the cases The heterotopic glial mass is situated externally

o n or near the bridgc of the nose i n 60% of cases, within

the nasal cavity i n 30% of cases, and in 1 0 % both

intranasal and extranasal components are present (3-24)

Less frequently, glial heterotopia may present in other

extracranial sites of the head and neck (“facial glioma”),

such as the nasopharynx palate, tongue paranasal sinuses,

tonsil, orbit, mandible or face (25-28) A recent report

describes the occurrence of glial heterotopia in the midline

occipital or parietal scalp gluteal region, and even away

from the midline in the temporal region of scalp and chest

wall (29)

Presenting manifestations of NG include a mass caus-

ing nasal obstruction or external nasal deformity (Fig

2A) (3-24) It presents a s a solid noncompressible, non-

pulsatile, gray or purple mass (1-3 cm) filling one side

of the nose and causing airway obstruction NGs are

usually solitary, but may rarely present as multiple masses

wall in the region of the middle turbinate Extranasal

lesions usually present as a smooth noncompressible sub-

cutaneous mass on either side of the dorsum of the nose,

near the inner canthus or between the frontal, nasal

ethmoid, and lacrimal bones The overlying skin may be

normal or have a blue or red discoloration When com- bined, the intra- and extranasal components communicate through a defect in the nasal bone NG lacks a connection with the cerebrospinal fluid (CSF) pathway and does not

contain a fluid-filled space connected with either the ventricles or the subarachnoid spaces of the brain The Furstenberg test (in which expansion or pulsation of the mass occurs on application of pressure to the ipsilateral jugular vein) is, therefore, negative in NG

Radiography Radiographs, computed tomographic

(CT) scans, and magnetic resonance imaging (MRI) reveal the presence of a soft-tissue mass in or around the nose, with no associated intracranial component or any bony defect in the floor o f the anterior cranial fossa (8,18) If such communication is found then the lesion qualifies as

an encephalocele, rather than a NG

Pathology On gross examination, a NG appears as

a polypoid, smooth, soft, gray tan, nontranslucent mass

with encephaloid features Histologically, NGs are com- posed of an unencapsulated disorganized mixture of neu- roglial tissue and fibrovascular tissue The large clumps

or small islands neuroglial tissue display evenly spaced astrocytes within an abundant fibrillar matrix (Fig 2B) The neuroglial tissue is often traversed by interlacing bands of vascularized fibroconnective tissue that merge with the collagen of the mucosal lamina propria or dermis

tissue vary Recurrent NG or lesions presenting i n children older than I8 months of age tend to contain a considerable amount of fibrosis and may be misdiagnosed as a fibrosed nasal polyp or fibroma (Fig 2C) ( 3 ) Neurons are usually rare or absent although in rare instances a prominent neuronal component has been reported in NG (3,24); Yeoh

et a l identified rare neurons i n 6 of 22 NG studied (3)

The cause for the paucity of neurons in NG, whether owing to ischemic changes or lack of differentiation of

the isolated primitive neuroectoderm, is unclear Mitoses are absent The astrocyte nuclei may appear enlarged or multinucleated These “gemistocytic” astrocytic changes are reactive and they should not be confused with malig- nancy The presence of choroid plexus, ependyma-lined clefts, or pigmented retinal epithelium is observed in some glial heterotopias, especially those found i n the palate and nasopharynx However, tissue elements from other embryonic germ layers are absent

Phosphotungstic acid-hematoxylin staining may help identify glial fibers, but when suspected, the presence of ectopic glial tissue can be easily confirmed by demonstra- ting positivity for glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), and S-l00 protein (3,30-

ectopic glial tissue in NG and herniated brain tissue of

Figure 2 (A) Nasal deformity sec-

ondary to heterotopic neuroglial tis-

sue (nasal glioma) (B) Heterotopic

neuroglial tissue in the nasopharynx

presenting with airway obstruction

in a 14-day-old baby boy (C) Disor-

ganized neuroglial cells with evenly

spaced nuclei are seen within a

prominent fibrous stroma in this na-

sal glioma from a 1 l-year-old boy

H&E, X 115; (A: Courtesy of EN

Myers, Eye and Ear Hospital, Pitts-

burgh, PA B: Courtesy of E Yunis

and J Hubard, Children's Hospital,

Pittsburgh, PA.)

an encephalocele Electron microscopic examination of such as nasal encephalocele (NE), nasal dermoid, and heterotopic glial tissue reveals features of astrocytes, such more remotely, a teratoma (1-3,7) Occasionally, NG may

as the presence of elongated interdigitating cell processes also be mistaken for an inflammatory nasal polyp Nasal

associated with a continuous basement membrane encephaloceles (NE) also present at birth and may be

Differential Diagnosis The clinical differential diag- NG, in which the mass of glial tissue is isolated from the nosis of NG includes other nasofrontal congenital lesions, intracranial contents, the NE represents a herniation of

'hmors of the Nervous System 791

brain tissue through a bony defect in the skull (1-10) This

communication with the intracranial ventricular system or

subarachnoid space leads to a positive Furstenberg test in

some, but not all, encephaloceles (see discussion in Sec

111, Encephalocele) A definitive diagnosis, however,

should await radiographic imaging (8) CT and MW allow

visualization of the soft-tissue mass, with an intracranial

connection in an encephalocele (8) Histologically, al-

though neurons are generally easily found in an encephalo-

cele and are sparse or absent in NG, there is an overlap

and the distinction between these lesions is not always

possible (1,3) Furthermore, the ectopic cerebral tissue in

both lesions shows reactivity for glial fibrillary acidic

protein (GFAP), S-100 protein, and neuron-specific eno-

lase (NSE)

Nasal dermoid cysts or dermal sinuses represent devel-

opmental abnormalities that contain only ectodermal ele-

ments, without tissue elements from the other embryonal

germ layers (1,4-10) Failure of the fonticulus nasofron-

talis or foramen cecum to close allows dermal elements

to invaginate through the frontonasal suture line area or

between the developing nasal bones and cartilage (2)

Nasal dermoids present on the dorsum of the nose with

an intra- or extranasal cyst that can be clinically mistaken

for either NG or NE The association of a sinus tract

located at any point from the glabella to the base of the

columella is characteristic In some nasal dermoids an

intracranial connection may be seen on CT or MRI

Histologically, nasal dermoids are easily distinguished

because they are lined by epidermis replete with dermal

appendages and lack glial tissue (1,2,7)

Occasionally, recurrent or long-standing heterotopic glial tissue is mistaken for fibrosed sinonasal polyp or

fibroma, when there is increased fibrosis relative to the glial tissue (3,32) It should be remembered, however, that sinonasal polyps are highly unlikely occurrences in the newborn infant or even in children younger than 5

years of age Furthermore, sinonasal polyps are bilateral, often multiple, and present as glistening, translucent masses that fill the nasal cavity or sinuses Histologically, sinonasal polyps typically demonstrate stromal edema, thickening of the mucosal basement membrane, and a chronic inflammatory cell infiltrate, including eosinophils The history of a congenital mass should suggest the

possibility of heterotopic glial tissue, rather than a sinona-

sal polyp, and the diagnosis can be confirmed by demon- strating immunoreactivity for GFAP or S-IO0 protein (1)

Finally, the mere presence of respiratory epithelium (sinonasal) or ependymal-lined clefts in NGs should not

be mistaken for teratoma Because of their malignant potential, teratomas containing neuroglial tissue should be distinguished from pure NGs that have no malignant potential Teratomas are neoplasms that arise from germ cells and are composed of tissue elements formed from all three germ layers (ectoderm, mesoderm, and endoderm); (1,33-35) Extracranial teratomas are rare and account for less than 5% of teratomas in childhood They have been reported in the neck; nasopharynx, oropharynx, or hypo- pharynx; face; and orbit (1) Pharyngeal teratomas are often disfiguring, with extreme malformation and associ- ated respiratory distress or cleft lippalate (1) Teratomas

may be solid and/or cystic and are histologically classified

as mature or immature, the latter containing tissue of

neuroectodermal origin Less than S% of head and neck

teratomas in children have a malignant component ( I )

Treatment and Prognosis The treatment of NG is

surgical excision With no evidence of an intracranial

connection, adequate initial excision offers a cure in most

cases (9,10,21) The importance of radiographic imaging

(CT and MRI) performed before surgery in any congenital

nasofrontal mass, to exclude the possibility of an intra-

cranial connection, cannot be overemphasized At opera-

tion no bony defect is found in NG, but in 10-15% of

cases a fibrous connection may be seen to persist with the

cribriform plate NGs may recur or persist in 15-30% of

patients, usually following incomplete excision, but there

is no evidence of local aggressive behavior nor of any

malignant potential

Introduction Meningoceles and encephaloceles are

herniations of meninges alone or meningeal-lined brain

substance that communicate with the intracranial ventricu-

lar system and subarachnoid space through a bony defect

in the skull (1-8)

Clinical Features Most encephaloceles present at

birth, although some may be diagnosed later in life About

80% of all encephaloceles occur in the area of the cranial

vault, 15% in the frontal-ethmoidal (sincipital) region and

less than 5% basally (9-28) Nasal encephaloceles (NE)

may be asymptomatic, or they may present with a nasal

mass or deformity, nasal obstruction, recurrent meningitis,

or cerebrospinal fluid (CSF) leak About one-third of NEs

are associated with other midline facial anomalies, such

as cleft palate or choana1 stenosis Patients with encepha-

loceles usually, but not invariably, have a positive Furs-

tenberg test, which constitutes pulsation-expansion of the

mass seen on compression of the ipsilateral jugular vein

To avoid the increased risk of meningitis or life-threaten-

ing CSF leak resulting from the spread of infection along

the intracranial communication, a congenital nasofrontal

mass should be considered to be an encephalocele until

proved otherwise by radiographic imaging before surgery

Although encephaloceles that involve the cranial vault

or the fronto-ethmoidal area generally present as external

masses, basal encephaloceles herniate internally and,

therefore, are clinically difficult to diagnose (9-32) How-

ever, CT and MRI scans have greatly facilitated the

diagnosis (2 1,23,32-35) Basal encephaloceles are classi-

fied based on anatomical location of the skull defect and

pattern of extracranial extension of the encephalocele

cavity, as follows: (a) transethmoid, through the cribriform

plate into the anterior nasal cavity; (h) sphenoethmoid,

through the sphenoethmoid junction into the posterior nasal cavity; (c) spheno-orbital, through the superior or- bital fissure or osseous defect into the orbit; (d) transphe- noidal, through the body of the sphenoid into the naso- pharynx or sphenoid sinus; and (e) sphenomaxillary through the junction of the body and wing of the sphenoid into the pterygopalatine fossa

Only about SO cases of lateral basal sphenoidal enceph- aloceles have been reported to date (23-32) Lateral sphe- nomaxillary basal encephaloceles in which the cystic mal- formation protrudes into the pterygopalatine fossa with widening of the superior and inferior orbital fissures are extremely rare (32) They may present with unilateral decreased vision or with nonlocalizing symptoms, and on radiographic imaging, they protrude through defects in the greater wing of the sphenoid and rarely, into the infratemporal fossa A recent report described a spheno- maxillary encephalocele located in the pterygopalatine and infratemporal fossae causing widening of the inferior orbital fissure and communicating with the middle cranial fossa through an enlarged foramen rotundum (32) Tempo- ral lobe epilepsy may be associated with basal encephalo- celes that herniate through the base of the greater sphenoid wing in the region of the foramen rotundum and the pterygoid process

Radiography A skull defect, seen on radiographic

imaging, including CT and MRI, shows a smoothly mar- ginated lesion which, depending on its content, may have the same image characteristics as brain or CSF (32-35) The use of CT and MRI together allows better visualiza- tion of the soft-tissue mass in NE with its connection to

the brain through a bony defect in the skull

Pathology The excised lesion in a meningocele

shows a cystic mass composed of loose areolar connective tissue in the dermis, whereas that of an encephalocele shows fully formed cerebral tissue with easily found neurons or disorganized islands of neuroglial tissue sur- rounded by collagenous septa (1-2,36) Ependyma and choroid plexus may be present The presence of glial tissue may be confirmed by demonstrating immunoreactivity for GFAP, S-100 protein, and NSE NE of long-standing from children older than 18 months of age may result in

excessive fibrous tissue relative to the amount of glial cells and may be associated with an absence of neurons

Differential Diagnosis The clinical differential diag-

nosis includes mainly NG and nasal dermoid and, less often, a sinonasal polyp ( 1 , I 1,36) The Furstenberg test is

generally positive in NE because of its connection to the subarachnoid space This test is negative in NG, most nasal dermoid cysts and sinonasal polyps As mentioned under the discussion for nasal glioma (see Sec 11) the (I-2,36)

Tumors of the Nervous System 793

distinction between NE and NG cannot be made with

certainly on histological examination, and it is important

to perform radiographic imaging (CT and MRI scans)

to demonstrate the communication with the intracranial

contents through a bony defect in NE When NE of long-

standing results in excessive fibrous tissue relative to the

amount of glial cells and is associated with an absence of

neurons, the histological distinction between NG and NE

may be impossible (l-2,36) Nasal dermoid cysts may

also show an intracranial connection, and are often associ-

ated with a sinus tract Histologically the dermoid cyst

lacks glial tissue and is lined by epidermis containing

dermal appendages

Treatment Following radiographic imaging, exci-

sion through a combined intra- and extracranial approach

with closure of the dural defect is safer than the transnasal

approach (15-17,22)

Pathogenesis Theories of formation of NE include

arrested closure of bone of the frontal floor, and early

outgrowth of neural tube preventing closure of cranial

coverings (37) The transsphenoidal type may occur as

part of the median facial cleft syndrome, which includes

median craniofacial dysraphism (38) Patients with orbito-

temporal neurofibromatosis often have partial or complete

absence of the greater wing of the sphenoid, resulting in

a defect in the posterolateral wall of the orbit (39)

Although the pathogenesis of sphenoidal encephalo-

celes is unknown, it is possible that lateral basal encepha-

loceles may result when ossification centers of the greater

wing of the sphenoid fail to fuse with those of the body

of the sphenoid (32) Occasionally, an acquired mass of

herniated brain tissue may be found in the nose related to

prior trauma (posttraumatic encephalocele) or sinonasal

surgery (40)

IV TRAUMATIC (AMPUTATION)

NEUROMA

Introduction Although discussed with neurogenic

tumors, the traumatic or amputation neuroma is a reactive

nonneoplastic process, rather than a true neoplasm (1-9)

It is a pseudotumor that results when the proximal segment

of a disrupted peripheral nerve undergoes a proliferative-

reparative response, while the distal segment undergoes

wallerian degeneration (1-4) Etiologic factors include

previous trauma or surgical procedures, including amputa-

tions Failure to recognize neural injury after trauma or

inadequate surgical repair with scar formation may be

important factors in the development of traumatic neu-

roma (2)

Clinical Features Traumatic neuroma may occur at

any age In one series, 50% of cases occurred in the third

and fourth decades, with two-thirds following trauma and one-third following amputation (2) The mass may occur

at any site and, depending on the nerve involved, may be asymptomatic or may manifest with pain or tenderness, paresthesia, loss of sensation, muscle weakness, or paraly- sis (1-4) Cieslak and Stout reviewed 63 such neuromas following trauma (2) The most common symptom in this series was pain (41 cases), anesthesia (24 cases), and paralysis ( 17 cases), and the duration of symptoms ranged from 2 months to 20 years (2) On physical examination the mass varies in size although most are less than 2.0

cm in diameter

The principal features of traumatic neuromas in the head and neck are no different from those at other sites (3-7) The mental foramen, lower lip, and tongue are common oral sites of traumatic neuroma, which may follow dental extraction, soft-tissue trauma or elective surgery (3-5) Daneshvar reviewed 14 cases of traumatic neuroma detected in laryngoscopic biopsy specimens (6) Hoarseness, dysphagia, choking spells, intermittent apho- nia, and cough were the most frequent symptoms of lesions of the pharynx The mean age of the 8 females and 6 male patients in this series was 59 years (6) The site was the vallecula (6 cases), aryepiglottic fold (3 cases), pyriform sinus (2 cases), pharyngoepiglottic fold (2 cases), and arytenoid (1 case) At laryngoscopy, traumatic neuroma appears as a small, solitary submucosal nodule

Pathology On gross examination, traumatic neuroma

usually appears as a gray-white firm, circumscribed, bulbous nodule, without a true capsule (Fig 3A) Normal healing follows trauma or surgery if the distance between the severed nerve ends is narrow However, if the gap is large or filled with fibrosis, blood clot, or infected tissue, the proximal and distal segments may not be able to establish contact with each other The distal end of the proximal nerve segment then proliferates in a bulbous, tumor-like, haphazard fashion, with regenerated axons and Schwann cells in interlacing bundles passing through the scar tissue (Fig 3) (2) This disorganized bulbous proliferation of all elements of the nerve fascicles (axons, Schwann cells, and fibroblasts) supported by scar or gran- ulation tissue is referred to as a “traumatic neuroma” (Fig

3B) (1-4)

Differential Diagnosis Traumatic neuromas are

composed of a nonencapsulated haphazard proliferation

of all elements of the nerve fascicles embedded in scar tissue They may be confused histologically with cutane- ous leiomyoma, plexiform neurofibroma, or mucosal neu- roma, associated with multiple endocrine adenomatosis type 11 syndrome (MEN 11: see later discussion in this section) The presence of myofibrils on trichrome stain

or, more specifically, immunoreactivity of the spindle

Figure 3 Traumatic neuroma: (A)

Gross specimen shows a bulbous

mass arising from the stump of a

severed nerve (B) The residual nor-

mal nerve is expanded by a bulbous

tumor-like mass of disorganized

nerve bundles and scar tissue

(H&E, X 40)

cells for desmin or muscle-specific actin distinguishes a

leiomyoma Some traumatic neuromas may contain gan-

glion cells This finding may suggest the possibility of a

ganglioneuroma, which is a true neoplasm, rather than a

reparative pseudotumor (6) Ganglioneuromas are encap-

sulated and found most frequently along the sympathetic

ganglion chain Binucleate or multinucleate ganglion cells

are common in ganglioneuroma, but are quite rare in

nonneoplastic lesions such as traumatic neuroma If muco-

sal neuroma is considered in the differential diagnosis,

the possibility of multiple endocrine neoplasia (MEN)

syndromes (type Ilb) can be clinically excluded by ob-

taining a serum calcium level and looking for the presence

of hypertension or a palpable thyroid mass, features not

associated with a traumatic neuroma Furthermore, pa- tients with traumatic neuromas have a history of prior trauma or surgery to the involved area, and the sur-

rounding tissue is fibrotic, a finding not present in mucosal neuroma

Treatment and Prognosis When symptomatic, exci- sion of the traumatic neuroma with repair (neurorrhaphy) and approximation of the distal and proximal segments of the nerve is the recommended treatment The lesion may need to be excised to distinguish it from recurrent malig- nancy in individuals previously operated on for can- cer (9) With adequate excision and repair, there may

be recovery or improvement of sensation and motion Traumatic neuromas may recur Reapposing the cut ends

Tumors of the Nervous System 795

of nerves after surgery or trauma prevents their develop-

ment

V PERIPHERAL NERVE SHEATH TUMORS

Introduction Peripheral nerve sheath tumors may

be benign or malignant The benign types include the

closely related tumors neurilemoma (benign schwannoma)

and neurofibroma Neurofibromas may be of the solitary

diffuse or plexiform types Malignant schwannoma or

malignant peripheral nerve sheath tumors (MPNST) may

occur de novo, or arise i n a neurofibroma, or in ;I plexi-

form neurofibroma (PNF) in patients with von Reckling-

hausen’s disease (neurofibromatosis I ; NF- I ) Malignant

transformation is extremely rare i n neurilemoma

A Neurilemoma (Benign Schwannoma)

Introduction Neurilemoma (benign schwannoma

neurilemmoma neurinoma) is a common histologically

distinctive, benign, usually encapsulated, peripheral nerve

tumor of Schwann cell origin (1-7) I t can arise from any

nerve in the body associated with Schwann cells including

the cranial nerves (with the exception of the olfactory and

optic nerves), as well as autonomic nerves and peripheral

nerves

Clinical Features Although any age group may be

affected, most patients are between the ages of 20 and S0

years, with an equal sex incidence ( I ) Most neurilemomas

are solitary and arise in soft tissues In rare instances,

they may be multiple or associated with NF- 1 ( I , 3 ) The

head and neck, flexor aspects of the extremities, posterior

mediastinum, and retroperitoneum are common locations,

although any site may be involved (1) About 2 5 4 5 % of

neurilemomas present in the head and neck, with the

lateral neck being the most frequent site (8-9) The spinal

roots and the cervical sympathetic, and vagus nerves are

commonly involved (I) Less frequent sites include the

oral cavity, wherc the tongue is the preferred site, parana-

sal sinuses (mainly the maxillary antrum and ethmoids),

nasal cavity, nasopharynx, orbit, parapharyngeal space,

larynx, oral cavity and other unusual sites (9-30) Neu-

rilemomas of the larynx are uncommon and most often

present i n the supraglottic region, including the false

cords, aryepiglottic folds and arytenoids Bilateral acoustic

neuroma (neurilemoma of the eighth cranial nerves) is

diagnostic of neurofibromatosis 2 (discussed in Sec V.F)

Neurilemomas are often asymptomatic and moveable,

typically attached to or arising from the nerve Depending

on their site in the head and neck, the tumors may interfere

with swallowing, phonation, or cause airway obstruction

Facial nerve tumors may cause hearing loss, vertigo, otitis

media postauricular pain, or facial nerve palsy

Radiography Cohen et al found areas of mixed

attenuation on CT, usually considered an indication of malignancy, i n histologically proved neurilemomas, corre- lating with confluent areas of hypocellularity adjacent to densely cellular or collagenous regions, cystic degenera- tion or xanthomatous change (31) Varama et al found a

target pattern on MRI scans in half of neurofibromas and neurilemomas, the peripheral hyperintense rim and central low intensity, corresponding histologically to peripheral myxomatous and central fibrocollagenous tissue (32) This study also found that inhomogeneity on MRI can represent benign or malignant disease (32)

Pathology On gross examination, neurilemomas ap-

pear as eccentric discrete, globular, expansile masses Most are 1 4 cm in size although some may be larger The nerve of origin can at times be seen stretched over the surface of the encapsulated neurilemoma and the cross surface of the tumor is gray-tan, myxoid, and solid to

cystic, with recent or old hemorrhage being common (Fig 4A) The histological appearance is distinctive in that the tumor is usually encapsulated and displays two classic growth patterns in highly variable proportions, referred to

as Antoni A and Antoni B types (Fig 4B) (4,lM) The Antoni type A pattern is characterized by a compact arrangement of elongated spindle cells with wavy nuclei and poorly defined borders i n loosely arranged fascicles having a palisading arrangement of nuclei, the Verocay body, and stromal hyalinization (Fig 4C) (7) The Antoni type B pattern is characterized by a less orderly arrange- ment of fewer spindled tumor cells i n a loose myxoid stroma In the sinonasal tract and nasopharynx the tumors tend to be unencapsulated and, when combined with hypercellularity, often raise the suspicion of malignancy (13) Unlike neurofibroma, neurilemomas do not contain axons and are typically separated from the nerve fibers

by a capsule Vessels with thick hyalinized walls and microcystic changes may be prominent Mitoses are rare

or absent, but some cells may display enlarged hyperchro- matic nuclei, which should not be mistaken for a malig- nant criterion

Many histological variants of neurilemoma have been described, including, degenerated or ancient cellular (33-

(multinodular; 42-50), multiple schwannomas (“schwan- nomatosis”) and melanotic schwannomas (S 1-6 I ) These variants may cause diagnostic difficulty and be mistaken for sarcoma; however, they have no prognostic signifi- cance

Cellular schwannomas are often located in the paraver- tebral sites in the pelvis, retroperitoneum, and mediasti-

n u m , and are circumscribed or encapsulated tumors that are composed predominantly or exclusively of Antoni A

Figure 4 (A) Cross section of a

parapharyngeal neurilemoma with

attached nerve: Note the hemor-

rhagic and cystic degeneration of the

mass (B) Neurilemoma displays a

well-developed fibrous capsule and

an Antoni A pattern (H&E stain,

X40); (C) Higher magnification of

Anton1 A pattern consisting of a

compact arrangement of elongated

spindle cells in loosely arranged fas-

cicles having a palisading arrange-

ment of nuclei (Verocay bodies)

Antoni B pattern (top left) has a

less orderly arrangement of fewer

spindled tumor cells in a loose myx-

oid stroma (H&E, X 230)

areas, without formed Verocay bodies (1.33-36) They

display intersecting fascicles, whorls of Schwann cells,

and long fascicles of Schwann cells arranged in a her-

ringbone pattern (1) Mitotic activity may be seen, but is

low (fewer than four per ten high-power fields; HPF) and

foci of necrosis may be present in 10% of cases These

necrotic foci are surrounded by differentiated Schwann

cells (1)

Goldblum et al further expanded the histological spec-

trum of neurilemomas by describing three cases of neuro-

blastoma-like neurilemoma, which on occasion may histo-

logically mimic a neuroblastoma (62) The involved sites

were the superficial soft tissues of the neck, palm, and flank This variant has a fibrous capsule suggesting a

perineurium, with areas of typical neurilemoma- and neu- roblastoma-like zones (62) The latter are composed of sheets or groups of small rounded or spindled Schwann

cells with scant cytoplasm and central dark nuclei lacking significant atypia The cells often form perivascular ro-

settes, pseudorosettes, and rosettes around central cores

of radiating spokes of collagen Mitoses are rare Necrosis and hemorrhage are absent

-mors of the Nervous System 797

a

5

Ultrastructurally, neurilemomas are composed of cells

showing features of differentiated Schwann cells (63-65)

Interdigitating slender cytoplasmic processes covered by

a prominent, often reduplicated, continuous layer of basal

lamina constitute the single most important ultrastructural

characteristic of the tumor cells They are devoid of

pinocytotic vesicles The nuclei and cytoplasm of neu-

rilemomas and its variants are diffusely and strongly

immunopositive for S-100 protein, and a smaller propor-

tion of cells may be epithelial membrane antigen- and

glial fibrillary acidic protein-positive (66-69) Tumor cells

are negative for synaptophysin, neurofilament, and PGP

9.5 According to Weiss et al., CD34 is expressed by a

distinctive cell population in peripheral nerve, benign

nerve sheath tumors, and related lesions, cytologically

and immunophenotypically different from a fibroblast and

conventional Schwann cell (70) Nerve growth factor

receptor immunoreactivity has been shown in human be-

nign peripheral nerve sheath tumor (71)

Differential Diagnosis Neurilemomas should be dis-

tinguished from neurofibromas, and other spindle cell

tumors, such as leiomyoma, meningioma, fibrous histiocy-

toma, and monomorphic synovial sarcoma The character-

istic features of neurilemoma, including the presence of

encapsulation, the two types of Antoni areas (i.e., cellular

Antoni A areas with Verocay bodies, and loose myxoid

Antoni B areas), and uniformly intense immunostaining

for S-100 protein distinguish neurilemoma from neurofi-

broma (1,66) In addition, frequent degenerative changes

and hyaline thickening of vascular walls are typically seen

in neurilemoma and are usually absent in neurofibromas

(discussed later) With the S-l00 protein immunostain, neurofibromas show variable staining of tumor cells In contrast with neurilemomas, which are associated with NF-l in 18% of cases (3) and rarely undergo malignant change, neurofibromas are often associated with N F - 1

and have a definite risk of malignant transformation Therefore, it is important to distinguish between these two closely associated tumors

Cellular neurilemoma, with its herringbone pattern, may be mistaken for malignant schwannoma, fibrosar- coma, or leiomyosarcoma However, the increased cellu- larity in this variant is disproportionately high compared with the level of mitoses and atypia, and features such as circumscription or encapsulation, perivascular hyaliniza- tion, and strong, diffuse immunoreactivity for S-l00 pro- tein should suggest a benign diagnosis Differentiated

Schwann cells surround the necrotic foci, rather than the hyperchromatic anaplastic cells seen around necrotic foci

in malignant schwannoma (1) Fewer than 5% of cellular neurilemomas recur and none undergo metastasis (1)

Cellular schwannomas should be distinguished from ma- lignant peripheral nerve sheath tumors by the relative lack

of mitoses and necrosis (33-36)

The neuroblastoma-like variant of neurilemoma is dis- tinguished from neuroblastoma or primitive neuroepithe- lial tumor by the presence of microscopic areas of conven- tional neurilemoma with strong diffuse S-IO0 positivity, absence of immunoreactivity for PGP 9.5, and ultrastruc- tural features of Schwann cells (62) Melanotic schwanno- mas may be difficult to separate from melanoma How- ever, over half the patients are associated with Carney's

syndrome, and the tumors are usually circumscribed or

encapsulated with psammoma bodies present in most

cases and focal areas reminiscent of neurilemoma ( I ,72)

Similar to melanoma, this variant of neurilemoma is

positive for S-100 protein and HMB45, and shows mela-

nosomes and premelanosomes on electron microscopy

Except for the presence o f melanosomes, the cells resem-

ble Schwann cells, with cytoplasmic processes that inter-

digitate ( 1 )

Neurilemomas are histologically distinguished from

leiomyomas, fibrous histiocytomas, and monomorphic sy-

novial sarcomas by identification of the characteristic

Antoni A and Antoni B patterns of proliferation and dif-

fuse immunoreactivity for S-100 protein, together with ab-

sence of reactivity for muscle markers (desmin and actin)

and cytokeratins Meningiomas typically have a dual im-

munoreactivity for vimentin and epithelial membrane an-

tigen (EMA) However, in rare instances, it may not be

possible to inlt~lunohistochemically distinguish between

neurilemomas and meningiomas, because both tumors

may be positive for vimentin, EMA, and S-100 protein

In these cases, the ultrastructural demonstration of tumor

cells surrounded by basal lamina may be helpful in con-

firming Schwann cell features in neurilemoma (63-65)

Treatment and Prognosis Simple excision with

preservation of the nerve of origin, if possible, is consid-

ered adequate therapy In contrast to neurofibroma in

which the nerve is an integral part of the neoplasm and

must be sacrificed to excise the tumor, neurilemomas are

separated from the nerve fibers by a fibrous capsule,

making i t possible i n most instances to excise or enucleate

the tumor without damage to the nerve Total excision is

usually curative Neurilemomas are slow-growing tumors,

which may not cause a problem even when incomplete

excision of the lesion is performed to prevent damage to

the adjacent nerve Radiation therapy is not effective in

these tumors Malignant transformation of neurilemoma

is exceedingly rare, and from a practical point of view,

this can be discounted (I ,73-75)

B Neurofibroma

Introduction Neurofibroma is a benign, usually

well-defined, but nonencapsulated, tumor of Schwann cell

origin ( 1 ) “Solitary” neurofibroma is a localized neurofi-

broma that, by definition occurs outside the setting of

neurofibromatosis 1 (NF- I o r von Recklinghausen’s dis-

ease) ( 1 ) Solitary neurofibroma is far more common than

its inherited counterpart associated with NF- 1 However,

the diagnosis of solitary neurofibroma is always condi-

tional, especially in young individuals, because the pres-

ence of one may herald the onset of others ( I )

Clinical Features Patients with solitary neurofi- broma are generally young between the ages of 20 and

30 years ( I ) There is no sex predisposition Solitary neurofibromas are slow-growing, painless, superficial tu- mors of the dermis or subcutaneous tissue, evenly distrib- uted over the body ( l ) When associated with NF-I, neurofibromas are multiple or segmental in distribution, superficially o r deeply located and more likely to undergo malignant transformation ( 1 )

The head and neck region is a common location for neurofibromas, which often present in the skin and subcu- taneous tissue as small, soft, sessile or pedunculated tu- mors (2-5) However, other sites, such a s those involved

by neurilemoma, may less frequently be involved, includ- ing the nasal cavity (6,7) paranasal sinuses (6,8,9), naso- pharynx ( 6 ) , orbit (10-14), conjunctiva (IS), paraphar- yngeal space (16), larynx (l7-33), maxilla (34-36), oral cavity (37-39), and mandible (40) Neurofibromas of the larynx are rare and may be solitary or an uncommon component of NF-I (17-33) They should be included

in the differential diagnosis of a submucosal smooth supraglottic mass, although the tumor may also arise from the vocal cord or subglottis (17-33) Hoarseness and a sensation of a lump in the throat on swallowing may be the initial manifestation Most orbital nerve sheath tumors affect the first division of the trigeminal nerve and present with an orbital mass, with pain or sensory loss being unusual ( 1 2) In one study, 25% of patients with orbital, isolated neurofibromas, but none with neurilemomas, had associated NF- 1 (12)

Radiography In a study of CT scans in paraphar- yngeal neurofibromas (16), the tumors appeared a s well- circumscribed, moderately enhancing masses in 10 of the

IS patients In a review of 32 extracranial nerve sheath tumors (23 benign and 9 malignant), Varma et al found

a target pattern on MRI scans in 5/10 neurofibromas and 7/13 neurilemomas, the peripheral hyperintense rim and central low-intensity corresponding histologically to pe- ripheral myxomatous and central fibrocollagenous tissue (41) Moreover, they found that MRI cannot distinguish between neurofibromas and neurilemomas, and that be- nign nerve sheath tumors may mimic their malignant counterparts when necrosis and cystic or hemorrhagic degeneration is present (41)

Pathology On gross examination, neurofibromas are white-gray and lack degenerative changes Most often these tumors arise from small nerves and extend into soft tissue, resulting in a well-circumscribed, but nonencapsu- lated mass ( l ) However less frequently, the tumor may arise in and expand a large nerve to form a fusiform mass, when, if confined by the epineurium a true capsule may

be present ( l ) With the exception of “plexiform” neurofi-

Tumors of the Nervous System 799

Figure 5 Neurofibroma of floor of

mouth: (A) In contrast to neurilemomas

(see Figure 4B), neurofibromas are not

encapsulated (H&E, X50); (B) micro- scoplcally, they are composed of undu-

lating Schwann cells and axons (H&E,

X 140)

broma (to be discussed later), solitary neurofibromas have

the same histological features as those neurofibromas

associated with NF- 1

Histologically, in contrast with neurilemomas, which

are encapsulated and contain a more homogeneous

population of cells, neurofibromas are not encapsulated

and are composed of a mixture of varying proportions

of Schwann cells, fibroblasts, axonal processes of

neurons, and perineurial cells (Fig 5A and B) Widely

separated irregular spindled or stellate cells with long,

thin cytoplasmic processes and wavy dark-staining nuclei

are loosely arranged in a fibrous or myxoid matrix rich

in mucopolysaccharide (1,43) The amount of cells and

fibromyxoid stroma varies The stroma contains mast

cells, lymphocytes and, rarely, xanthoma cells (1,42,43)

Less frequently, neurofibromas may be cellular and com-

posed of fascicles of Schwann cells in a uniform collagen

matrix devoid of myxoid substance (1) Focal atypia

or rare mitoses are not uncommon in neurofibroma

or the plexiform variant However, when seen to a

marked degree, malignant transformation should be con-

sidered

The nerve sheath origin of neurofibromas can be con-

firmed immunohistochemically or ultrastructurally Neuro-

fibromas demonstrate S-100 protein positivity, but the

positivity is variable in a given lesion and not as striking

in intensity or uniformity as in neurilemoma (1,s) Ultra-

structurally, spindle-shaped cells, with long and thin bipo-

lar cytoplasmic processes, bearing discontinuous external

laminas and numerous pinocytotic vesicles, are seen

widely scattered in a stroma of fibrillogranular material

and bundles of collagen fibrils (1,8,43,44) The predomi-

nant cells have ultrastructural features more consistent with perineurial cells than Schwann cells (43)

Differential Diagnosis In contrast with neurilemo- mas, which are predominantly composed of Schwann cells, neurofibromas contain a variety of cells that are associated with peripheral nerves: namely, perineurial cells, fibroblasts, entrapped axons, and Schwann cells

(1,4344) Furthermore, they lack a capsule, Verocay bod-

ies, hyaline thickening of vascular walls, Antoni A and B growth patterns, and degenerative change (1) At times,

however, it may be difficult to distinguish between cellular neurofibroma and neurilemoma because of the presence

of common features of benign nerve sheath tumors In such cases, histochemical stains to determine the presence

of acid mucopolysaccharide-rich myxoid matrix in neuro- fibromas, which is absent in neurilemoma, may be of diagnostic help (1) The nerve sheath origin of these tumors is confirmed by the demonstration of immunoposi- tivity for S 1 0 0 protein, which is less striking in neurofi-

broma than in neurilemoma (1) If special stains are not useful, then the noncommittal term “benign nerve sheath tumor” is appropriate

Treatment and Prognosis Whenever possible, sim-

ple excision is the treatment of choice (1,3,18) Aggressive

debilitating surgery should be avoided In the study by Rose and Wright of 54 orbital peripheral nerve sheath

tumors, despite incomplete resection of some tumors, with follow-up up to 23 years, no recurrences requiring further

surgery were found (12) Although solitary neurofibromas

do not have the same incidence of malignant transforma- tion as neurofibromas associated with NF-l, the exact risk

is unknown, but is probably quite small (1)

C Plexiform Neurofibroma

Introduction Plexiform neurofibroma (PNF) is a be-

nign peripheral nerve tumor of Schwann cell origin almost

exclusively seen in patients with neurofibromatosis 1 (NF-

important criteria for diagnosis (Table 1) ( 1 4 ) The vast

majority of patients with PNF meet the strict criteria for

NF-I and its presence strongly correlates with the diagno-

sis of NF-I However, its mere presence may not be

pathognomonic of NF-I, as patients with neurofibro-

matosis 2 (NF-2; bilateral acoustic neurofibromatosis) can

also rarely develop this tumor

Clinical Features PNFs generally develop early in

childhood, although they may present at any age (1,4)

PNF may occur at any location, however, the head and

neck, back, and inguinal areas are most often involved

tations in NF-I varies between 14 and 37% (9) Of ten

patients with PNF of the head and neck, Krueger et al

found a mean age at diagnosis of 10 years 6 months (range

8 months to 3 years), with a slight male predominance of

3:2; in seven of these patients, there was a family history

of NF-I (S) In the head and neck region the neck and

scalp ( 1 0-1 3), tongue (14,15), major nerves ( 16-22), orbit

(23-26) larynx (27-35), paranasal sinuses (36-39), and

salivary glands (40,41) may be the site of tumor PNF of

the tongue usually produces unilateral macroglossia with

impairment of function, and almost always occurs in

children younger than 3 years of age (Fig 6A) (4.15)

Otolaryngological manifestations include cosmetic de-

formities, often an enlarging facial mass, and functional

impairments, the most common being hearing loss, airway obstruction, facial paresis, and impaired mastication (9) PNF presents as a nodular or fusiform, poorly circum- scribed mass forming tortuous cords along segments and branches of a nerve The tumor itself usually remains within the confines of the perineurium; hence, the tortu-

resembles a “bag of worms” or “string of beads” (1)

When extensive, it may be associated with local soft- tissue and skin overgrowth, referred to as “elephantiasis neuromatosa” (1 )

Radiography In the study by Chui, on CT scans,

benign neurofibromas and PNF appeared as well-defined, oval, spherical, or fusiform masses, centered at the ana- tomical location of a cranial, spinal, autonomic, or periph- eral nerve, with displacement of adjacent muscle and blood vessels (42) On IV-enhanced CT, none of the neurilemomas but close to half of neurofibromas and PNF were homogeneously hypodense (42) The most reliable, although not infallible, criterion of malignant nerve sheath tumors was poor definition of their margins (42) According to Truhan and Filipek, MRI with gadolin- ium enhancement appears to be more sensitive than CT

in the detection of neurofibromatosis type I , including PNF, and may be the imaging method of choice for following certain patients or screening family members (43)

Pathology On gross examination, the enlarged, tortu-

ous nerve is confined by its perineurium; therefore, i t has

a nodular or fusiform appearance, with a resemblance to

a bag of worms or string of beads (Fig 6B) Histologically, PNF consist of tortuous masses of expanded nerve

Table l Criteria for Diagnosis of Neurofibromatoses

Neurc!Jihromatosis I ( N F - I )

NF-I may be diagnosed when two or more of the following are present:

Six o r more cafe a u lait rnacules the greatest diameter of which is more than 5 n m in prepubertal patients and more than IS mm

Two or more neurofibromas of any type or one plexiform neurofibroma

Freckling In the axillary or inguinal region

Optic glioma

Two or more Lwh nodules (iris hamartomas)

A distinctive osseous lesion, such as sphenoid dysplasia or thinning of long-bone cortex, with or without pseudoarthrosis

A parent, sibling, or child with NF-I according to the foregoing criteria

Nerlrofihrorllrrtosis 2

NF-2 may be diagnosed when one of the following is present:

Bilateral eighth nerve masses seen with appropriate Imaging techniques (CT scans or MRI)

A parent sibling or child wlth NF-2 and either unilateral eighth nerve mass or any two of the following: neurofibroma,

In postpubertal patients

meningioma, glioma schwannoma, or juvenile posterior subcapsular lenticular opacity

S o u r w : Sec V.F, Ref 2

'Thmors of the Nervous System 801

branches, with a prominent increase in endoneuria1 myxo-

matous matrix that separates myelinated or nonmyelinated

axons; a disorderly proliferation of fusiform Schwann

cells, fibroblasts, and axons; as well as perineurial fibrous

thickening (Fig 6C) As in other benign nerve sheath

tumors, hypercellularity and nuclear pleomorphism may

be seen in PNF, but it is the presence of increased mitotic

activity that is indicative of malignant change (1,4) PNF

shows variable immunoreactivity with S-100 protein and

the myelin-associated glycoprotein Leu-7, and ultrastruc-

turally, several cell types are seen with predominant

Schwann cells surrounded by basal lamina (1,44)

Differential Diagnosis In the tongue, PNF should be

distinguished clinically from other causes of macroglossia,

such as hemangioma, lymphangioma, amyloid, myx-

Figure 6 Plexiform neurofibroma:

(A) Unilateral macroglossia of the right side of the tongue in a 6-year- old girl; (B) cross section of portion

of tongue with plexiform neurofi-

broma displaying enlarged tortuous masses of nerve; (C) hlstological section shows enlarged and tortuous nerves as a result of increased num- bers of Schwann cells and endoneu- rial matrix (H&E, X30)

edema, and muscular hypertrophy Macroglossia caused

by PNF differs from these conditions in that it is unilateral,

firm, noncompressible, and covered by normal mucous membrane, without a tendency to bleed at surgery In contrast, macroglossia caused by hemangioma is usually bilateral, compressible, imparts a red color to the mucosa, and bleeds profusely at surgery

Histologically, PNF should be distinguished from neu- rilemoma (see prior discussion), plexiform neurilemoma, and mucosal neuroma (45,46) Plexiform neurilemoma is

a rare nodular variant of schwannoma not associated with

NF-1 and without a propensity for malignant transforma- tion (45) It involves the dermis or subcutis and, except

for its multinodular or plexiform architecture, has the

same histological features as the usual nerilemoma, but

Figure 6 Continued (C)

with marked cellularity dominated by Antoni type A pat-

tern (45) In contrast to plexiform schwannoma, PNF is

usually hypocellular, has a prominent myxoid matrix, and

contains a disorderly array of Schwann cells, fibroblasts,

and axons, with wiry cytoplasmic processes within and

often outside the perineurium (1,44) It is important to

distinguish mucosal neuromas, a component of multiple

endocrine neoplasia (MEN) type IIb with a risk of devel-

oping medullary thyroid carcinoma (see discussion in Sec

V.H on mucosal neuroma) from PNF associated with NF-

tortuous nerve fibers surrounded by a thickened perineu-

rium that expresses the cellular phenotype EMA( +), S-

100 protein (-), whereas a PNF consists of enlarged

nerve fascicles with a loose myxoid stroma that is

EMA( - ) (46)

Malignant transformation occurs in 1 6 1 5 % of patients

with PNF associated with N F - I (1,2,4) Such malignant

transformation occurs most often in deep-seated, large,

centrally located PNF, with a peak incidence in the third

decade of life (1,2,4) Recently, McCarron et al found

only 1 of 39 PNF (2.5%) demonstrated accumulation of

p53 protein in about 5% of the nuclei (4) In contrast, 12

of 15 PNF with associated malignant peripheral nerve sheath tumor (MPNST) stained for p53 (80%), with the

extent of staining ranging from 1 to 25% of the tumor cells in MPNST areas (4) The detection of intranuclear p53 protein is uncommon in the PNF regions of these tumors, but may be common in MPNST (4,47) However, the rarity of p53 staining in the PNF regions precluded its use in predicting those PNF that were likely to progress

Tumors of the Nervous System 803

in those PNF that progress to MPNST and may be

impossible because of the extent of tumor

Kluwe et al examined 14 PNF from ten patients

with NF- I for allele loss of the NF-I gene Loss of

heterozygosity was found in 8 tumors from five patients,

suggesting that loss of the second allele, and thus inactiva-

development of PNF This study found no p53 mutation in

any of the tumors (49)

D Diffuse Neurofibroma

Introduction Diffuse neurofibroma (DNF) is an un-

common, histologically distinctive variant of neurofi-

broma (NF) that is characterized by an infiltrative growth

pattern and the presence of laminated bodies resembling

Wagner-Meissner tactile corpusclcs (l,2) Unlike plexi-

form neurofibroma (PNF), which is associated with neuro-

fibromatosis I (NF-I) in the vast majority o f cases, only

10% of (DNF from all anatomical sites are found to have

this association ( I ) However, the true incidence of this

association may be higher, as an unequivocal diagnosis of

NF-I cannot often be established in these young patients

Unlike PNF, the incidence of malignant change in D-NF

must be extremely infrequent ( l )

Clinical Features DNF involves the subcutaneous

tissue and presents in children and young adults usually

in the region of the head and neck as a solitary, plaque-

like elevation of the skin ( I ) On rare occasion, it has been

reported in other sites, including the orbit, gastrointestinal

tract and genitourinary tract (Fig 7A) (1-1 l) Kap a d' la et

al recently reported the case of an 8-year-old girl with a

6.0-cm orbital DNF and NF-I who presented with a

congenital enlarging, pulsatile, mass that protruded from

the orbital rim (6) CT scans showed a defect in the lesser

and greater sphenoidal wing a s well as a large temporal

meningoencephalocele that protruded into the orbit from

the middle cranial fossa The patient underwent a right

frontotemporal craniotomy with orbital exenteration, re-

pair of meningoencephalocele sac, and titanium plate

reconstruction There was no tumor recurrence a t 2 years

after surgery

Pathology Diffuse neurofibromas are poorly defined

masses, ranging in size from 0.5 t o 6.5 cm (1J.6) A

glistening, gelatinous, pink-gray, homogeneous, nodular

forming soft, raised, plaque-like lesions of the skin Or-

bital diffuse neurofibroma may form a fleshy mass that

surrounds, but does not invade the optic nerve (Fig 7B)

Schwann cells having short fusiform o r rounded nuclei

and inapparent cytoplasm, and sheets of S- 100-positive

laminated bodies resembling Wagner-Meissner tactile cor- puscles that are suspended in a fine fibrillary collagenous matrix (Fig 7C) (1-12) In other areas the cells have a

wavy twisted appearance with elongated nuclei

Differential Diagnosis DNF lacks the characteristic

cordlike structure confined by perineurium seen in PNF, and is distinguished by its highly infiltrative pattern, the presence of rounded or slightly fusiform cells that are uniformly distributed within ;I delicate collagenous back- ground, and sheets of laminated bodies resembling Wagner-Meissner tactile corpuscles (1-12) The tumor typically insinuates itself throughout the soft tissue and envelopes, rather than invades nerves or cutaneous ad- nexal structures These histological features and S- 100

positivity of tumor cells distinguish DNF from other spindle cell lesions that have a similar infiltrative pattern; namely, spindle cell lipoma and dermatofibrosarcoma pro- tuberans ( I ,6)

Treatment and Prognosis Surgical excision is the

treatment of choice These lesions may be difficult to

excise and may recur if not totally removed However unlike the PNF, the incidence of malignant change in DNF must be extremely infrequent ( l )

E Neurofibromatosis 1 Introduction The neurofibromatoses are genetic dis-

orders of neural crest-derived cells that primarily affect growth of neural tissues (14) The 1986 meeting of the Neurofibromatosis Task Force led to the acknowledgment

of a t least three categories of NF: (a) von Recklingh- ausen's neurofibromatosis or NF- I , (h) bilateral acoustic

NF (BANF or NF-2) and (c) all other neurofibromatoses

(NF-3 to NF-4 and NF-NOS) (5,6) The last category encompasses alternative or atypical forms of the disease NF- I is more common and comprises 90% of all cases of neurofibromatosis (4)

NF-I and NF-2 are clinically and genetically distinct disorders, the genes for which are located on chromo- somes 17 and 22, respectively (7) NF-I is one of the more common autosomal dominant disorders affecting

1 :4000 persons (4) Progress in mapping of the NF- 1 gene with linkage analysis has been rapid (8-13) The gene is

on the proximal long arm of chromosome 17 (8) The spontaneous mutation rate is high, with 50% of patients representing new mutations Biological studies suggest that hormonal or growth factors play a role in tumorigen- esis

Clinical Features The clinical expression of NF-I

is strikingly diverse (4) About 40% of patients experience the onset of their disease before I year of age and only 8% after the age of 25 years The full-blown disease may

Figure 7 (A) Cross sectlon of dif-

fuse neurofibroma shows a plaque-

like cutaneous mass of temporal

scalp; (B) cross section of a fleshy

orbital diffuse neurofibroma sur-

rounding the uninvolved optic

nerve; (C) Diffuse neurofibroma ex-

tending into adipose tissue Note the

Wagner-Meissner corpuscles in the

lower, central portion (H&E stain,

X 40)

not become manifest until adult life There is an equal

sex distribution, and all races may be affected The protean

manifestations of NF-l affect the peripheral nerves and

skin as well as other tissues, such as the CNS and the

skeleton ( 1 4 ) NF-1 is diagnosed when two or more of

the criteria listed in Table 1 are present Multiple mela-

notic skin macules (“cafe au lait” spots), intertriginous

freckling, multiple Lisch nodules (iris melanocytic hamar-

tomas) (14,15), and multiple cutaneous neurofibromas are

highly characteristic Cafe au lait spots are often found

on the trunk, pelvis, and axilla They increase with age

and are seen in more than 90% of patients W-1 is characterized by a high incidence of neurofibromas, which may be found in any location and first appear in childhood Optic gliomas, spinal or peripheral neurofibromas, neuro-

logical impairment, scoliosis, and other bone abnormali- ties may be present (16,17) Although Schwann cell tu-

mors may develop on any nerve in NF-1 patients, bilateral acoustic neuromas are not seen

Head and neck manifestations of NF-1 are frequent and have been reported in 1 6 3 7 % of patients with NF-I

(18-20) Nerve sheath tumors can occur anywhere, but

'hmors of the Nervous System 805

are most often found in the midlateral neck, eyelids, and

orbits They are most common in the skin and soft tissues

However, these tumors may present in less common sites,

such as the orbitotemporal region (21-27), otolaryngic

tract (28-35), jaws and skull (36), and oral cavity (37)

Neurofibromas, plexiform neurofibromas, optic pathway

gliomas, and bone lesions may involve the orbit with

skull and facial deformities in 5-20% of patients (21-27)

In severe NF-I, vision may be markedly reduced owing

to the presence of ocular NF-I or functional ambylopia

(25) Bony malformations, such as hypoplasia and perfo-

rating defects are typical in those with craniofacial NF-I

Orbital plexiform neurofibromas are frequently associated

with hypoplasia or dysplasia of the greater wing of the

ipsilateral sphenoid bone, which may result in herniation

of the dura into the orbit and manifest as a pulsating

exophthalmos The increased volume of the orbital con-

tents due to tumor and the herniated temporal lobe may

result in inferior displacement of the globe Laryngeal or

nasopharyngeal involvement is rare in N F - I and includes

plexiform or localized neurofibroma of the aryepiglottic

fold or supraglottis manifesting as hoarseness, dysphagia,

or stridor (20,32-35) The oral cavity is affected in 5%

of cases, the major findings being soft-tissue or intra-

osseous neurofibromas and macroglossia (37) At this

site, neurofibromas may involve the lips, gingiva, buccal

mucosa, tongue, floor of mouth, and mucous membranes

Radiography Skeletal abnormalities occur in 40%

of patients with N F - 1 (4,38) Plain radiographs, CT or MRI scans of the craniofacial and spine and paraspinal regions may be important to assess the presence of neuro- fibromas or other tumors that may compromise neurologi- cal function (3940) CT and MRI scans of the orbit and brain may be necessary to confirm the diagnosis of NF-1

or to determine the nature of the tumors, such as optic glioma and orbital neurofibromas, and cranial vault dys- plasias Using MRI, in 90% of children a high frequency

of hyperintense signals appears on T2-weighted images and should not be overinterpreted to indicate brain tumors (4,40) This finding is less common in adults with NF-l For visualizing bony anatomy of craniofacial structures

or sphenoid wing, CT scans may be preferred However, MRI with gadolinium enhancement has been extremely valuable and has replaced CT as the primary neuroimaging modality, especially when serial studies of eyes and brain are needed or when estimating tumor volume (4,40) MRI

offers superior soft-tissue contrast, and provides more detailed imaging than CT of the characteristic CNS lesions

(40)

Pathology Neurofibromas are the most common tu- mors in NF-l and are the hallmark of the disease (41) These may be of the localized, plexiform or diffuse types, based on their gross and histological appearance (see discussions in Secs V.B-V.D; on neurofibroma, plexiform

neurofibroma, and diffuse neurofibroma) (41) The plexi-

form type of neurofibroma is nlmost exclusively seen in

NF-1 and is the most specific whereas diffuse ncurofi-

broma is associated with NF-I i n approximately 10% o f

cases (41 ) Although localized neurofibromas arc the most

common type seen i n NF-I, histologically they are the

least characteristic, a s they are identical with the solitary

neurotibromas seen outside the setting of NF Localized

neurofibromas tend to be larger than solitary neurotibro-

mas They characteristically occur in the dermis and sub-

cutis but may be seen i n deep soft tissue (41)

Treatment and Prognosis There is n o treatment that

alters the course of NF- I In most patients with NF-I,

there is an inevitable progression of the skin tumors The

neurofibromas cause significant morbidity and their large

number makes surgical treatment impractical (42) How-

ever, surgery may be indicated for tumors associated with

disabilities for cosmetic deformities, and for large or

painful tumors, or for those located in critical areas im-

pairing organ function Recurrences may occur because

of the poorly defined nature of some of these tumors (43)

A more dangerous complication is malignant transfor-

mation (see discussion on malignant schwannoma) (44)

Malignant peripheral nerve sheath tumors (MPNST) de-

velop in about 2 4 % of patients with NF-I either de novo

or i n a preexistent neurofibroma (43,44) Such transforma-

tion occurs most frequently in deep-seated large central

lesions The risk of developing malignant transformation

in NF- I increases in individuals who have had the disease

for several years (75%' o f patients who develop MPNST

have had NF- 1 for 10 years or more) and only rarely does

than S years The treatment of MPNST in this setting is

radical surgery but the prognosis is poor in these high-

grade neoplasms with a 5-year survival of less than 20%

(44) Brain tumors, benign or malignant, and kyphoscolio-

sis, with its concomitant restrictive effects on cardiopul-

monary function may a l s o prove life-threatening in NF-

1 patients

The treatment and prognosis o f head and neck manifes-

tations depend on the extent of the disease and site of

occurrence For example the treatment of orbitotemporal

NF-I depends on the severity of the orbital involvement

and the functional state of the eye (25)

F Neurofibromatosis 2 (NF-2; Bilateral

Acoustic Neuroma)

Introduction Neurofibromatosis 2 (NF-2; bilatcral

;kcoustic neurofibroma) is a genetic disorder inherited a s

an autosotnal dominant trait distinct from NF-I (or von

Recklinghausen's neurofibromatosis) occurring i n about

I :50,000 individuals with penetrance of over 95% (1-6)

Offspring of a patient with NF-2 have a 50% risk that

they will develop the disease The gene for NF-2 was mapped to chromosome 22 i n 1986 (7), and isolated i n

1993 confirming the presence of the NF-2 locus on the

long arm o f chromosome 22 in band 22q 1 I 2 (8) Loss of heterozygosity was identitied for 22q markers in both sporadic and NF-2-associated acoustic neuromas and mc- ningiomas a s well a s NF-2-associated neurofibromas (3.9) NF-2 should be differentiated from NF-I because the genetic basis spectrum of features, and overall natural history are different (3) NF-2 should also be distinguished from sporadic, nonfamilial acoustic neuromas which de- velop later in life, are not inherited, and present fewer problems in management ( 2 ) (sec later discussion)

Clinical Features The criteria for the diagnosis o f

NF-2 are listed in Table I The hallmark of NF-2 is bilateral acoustic neuromas (vestibular schwannomas), ac-

counting for 5% of all acoustic neuromas Because both acoustic neuromas do not always arise at the same time any individual with an acoustic neuroma or a meningioma who is younger than 30 years of age should raise suspicion

of NF-2 Presenile lens opacities o r subcapsular cataracts

are present i n 50% of patients and may precede the onset

of symptoms thus allowing for early identitication of family members with the gene (2.10) NF-2 affects young patients with a mean age at presentation of 27.5 years with no gender effect except for preponderance of menin- giomas i n females ( I I ) The disease may caltse serious problems in hearing, facial expression, and brain stem function (see discussion of acoustic neurofibroma: see Sec V.G) Symptoms usually begin in the teens or early 20s (2) Multiple meningiomas occur i n most NF-2 pa- tients These occur earlier in life than sporadic meningio- mas Close examination of NF-2 patients may reveal skin neurofibromas cafe au lait spots, and rarely even plexiform neurofibroma (PNF) but less commonly than

in NF-I

Occasionally, unilateral acoustic neuromas may be seen

in families in the absence of other criteria necessary for the diagnosis o f NF-2 ( 12) I n one study, polytnerase chain reaction-single-stralld chain polymorphism was used to screen germline NF-2 mutations i n six such families and direct sequencing of DNA from blood was done in af- fected subjects from three families, but n o germline muta- tions were identitied ( 12) Because NF-2 mutations are detected i n only 33% of patients with NF-2 hereditary transmission of mutations cmnot entirely be excluded However in the absence of germline mutations, familial occLII-rcnce of unilateral acoustic neuromas may represent either ;I chance somatic NF-2 gene mutation or origination from a separate genetic focus ( 12)

Tumors of the Nervous System 807

I n addition to bilateral acoustic neuromas seen i n Inore

than 90% of persons with the NF-2 gene other head and

neck manifestations include meningiomas of the posterior

fossa and cranial nerves i n young patients ( I3), ectopic

meningioma ( 13) otological nerve sheath tumors and

deafness ( 14) ocular nbnormalities (cataracts, retinal ha-

martomas and motor deticits) (10) and neurofibroma or

neurilemoma of the tongue (IS) In contrast to NF-I

cutaneous neurofibromas and cafe au lait spots are fewer

and less colnlnon i n NF-2 ( 13)

Radiography MRI is the neuroimaging procedure

of choice in patients with hearing impairments or abnor-

mal brain stem auditory-evoked response (6.16,17) Gndo-

linium-enhanced high-resolution MRI has replaced the use

of brain stem audiometry to evaluate patients suspected of

having acoustic tumors in some centers and in others by

a new MRI technique that uses fast spin-echo without

gadolinium The latter modality gives a clear delineation

of the lateral portion of the internal auditory canal, re-

quires less time i n the scanner, has a reported scnsitivity

comparable with that of conventional gadolinium-en-

hanced MRI, and has a lower inlaging cost because

contrast is not needed (18) MRI is more sensitive than

CT i n detecting and defining tumors of the posterior fossa

spinal nerve roots, and within the spinal cord

Pathology Acoustic neuromas (vestibular schwanno-

mas) are neurilemomas They have a thin capsule and

similar to neurilemomas at other sites display two classic

growth patterns (Antoni type A and B ) in highly variable

proportions (19.20) Thc Antoni type A pattern shows a

compact arrangement of elongated spindle cells, with

wavy nuclei, poorly defined borders, and loosely arranged

fascicles having a palisading arrangement o f nuclei, the

Verocay body The Antoni type B pattern is composed of

a less orderly arrangement o f fewer spindled tumor cells

from the nerve fibers by a thin capsule Vessels with thick

hyalinizcd walls and microcystic changes may be seen

Mitoses are rare Enlarged hyperchromatic nuclei may be

seen In these benign tumors According to Sobel and

Wang, acoustic neuronns in NF-2 are more likely to have

a lobular pattern, to be highly cellular and contain Verocay

bodies whereas sporadic tumors are more likcly to contain

hyalinizcd vessels recent thrombosis, and hemosiderin

deposition (20)

Differential Diagnosis Advances i n neuroradiology

have increased the clinical accuracy of distinguishing

acoustic neurolnas fro111 other cerebellopontine angle le-

sions that present i n a similar fashion These include

meningioma, cholesteatoma, and neuromas of other c m

nial nerves Histologically acoustic neuromas should be

distinguished from other tumors, such as leiomyoma

neurofibroma, paraganglioma, and meningioma I n addi- tion to characteristic morphological features that distin- guish neurilemomas, such a s the presence of Antoni A pattern with Verocay bodies, neurilemomas are 111ore strongly and diffusely positive for S-100 protein than are neurofibromas Leiomyomas are distinguished by their positivity for desmin and actin Paragangliomas have a

characteristic :c/lha//er~ pattern and arc positive for neuro- endocrine markers (synaptophysin and chromogranin): only the supporting or sustentacular cells not the tumor cells, are positive for S - 1 0 0 protein Meningiomas typi- cally have a dual immunoreactivity for virnentin and epithelial membrane antigen (EMA) However in some cases, it may not be possible on small biopsies to immuno- histochemically distinguish between acoustic neuroma and meningioma, because both may be positive for vimentin, EMA, and S-l00 protein I n such cases, the ultrastructural demonstration o f basal lamina around tumor cells may help confirm the Schwann cell origin of acoustic neuroma

Treatment and Prognosis Acoustic neuromas have

an unpredictable natural history and a highly variable growth rate There is an increased risk in developing other intracranial and intraspinal tumors, neurilemomas (schwannomas) of other cranial nerves and spinal roots being the most common, but also meningeal and glial tumors Although growth may be slow or only minimal

in some ncoustic neuromas others may progress relent- lessly and cause significant disability, and even death by local growth into brain structures However there is

no malignant potential Serial MRI is useful to follow the growth of tumors accurately Acoustic neurwnas seen

in NF-2 are typically more aggressive than sporadic t u -

The treatment depends on patient's age, turnor size, prescncc or absence of hearing and facial nerve function and tumor growth rate (21.32) Treatment should be di- rected toward preserving hearing (21.22).) For most tu- mors requiring intervention, surgery is the treatment of

choice with the optimal goal being rcnloval o f the tumor while maintaining preoperative hearing and facial func-

MRI with gadolinium enhancement, making complete surgical excision possible (2.4,22) I n other situations however, watchful waiting may often be the best manage- ment for acoustic neuromas in NF-2 (2.4) The indication and timing of turnor resections in NF-2 are dependent on the tumor extension necessity for brain stem decompres- sion, and on auditory function (21 ) As stated by Saami

functional eighth nerve preservation, and a suggested acceptable compromise involves subtotal microsurgical resection with functional cochlear nerve prcservatinn i n

mors

the last hearing ear (21) In many cases hearing in the

affected ear cannot be preserved

G Acoustic Neuroma (Unilateral)

Introduction Acoustic neuroma (vestibular schwan-

noma) is a benign tumor of the eighth nerve at the base

of the brain (l-S) It accounts for 8% of intracranial

tumors and has an incidence of 1 : 100,000 per year (4) It

may be sporadic and unilateral or familial and bilateral,

the latter as part of neurofibromatosis 2 (NF-2) Acoustic

neuroma is the most common tumor of the cerebellopon-

tine angle (84%) Molecular genetic studies show that the

NF-2 gene is inactivated in the familial and sporadic

acoustic neuromas (2.3) The known tumor suppressor

genes investigated, such as von Hippel-Lindau (VHL),

familial adenomatous polyposis coli (APC), Wilms’ tumor

(WT2) pS3, and NF- I , do not appear to be important in

the pathogenesis of acoustic neuroma (23)

Clinical Features Sporadic tumors are unilateral and

occur later in life than bilateral acoustic neuroma (NF-2)

Typically, unilateral acoustic neuromas become symptom-

atic after 30 years of age, and early symptoms include

unilateral decrease in hearing or speech discrimination,

tinnitus, dizziness, and dysequilibrium (6-9) Later symp-

toms include headache facial pain, numbness or tingling,

facial weakness or twitching, double vision, and symp-

toms of brain stem compression, such a s weakness of

extremities, difficulty swallowing or talking Brain stem

audiometry (ABR) has been used as a screening test and,

when hearing levels are sufficient to obtain a response, it

provides a rapid, noninvasive method to detect acoustic

tumors However, recent studies have reported sensitivity

rates of only 67-7696 for detection of intracanalicular

acoustic tumors (8-10) Therefore the use of ABR to

evaluate patients suspected of having acoustic tumors has

been replaced in some centers by gadolinium-enhanced

high-resolution MRI o r an MRI technique that uses fast-

spin-echo without gadolinium ( I 1-13)

Radiology After appropriate clinical evaluation and

hearing and balance testing, the definitive diagnostic test

is an MRI scan with gadolinium enhancement ( 1 1.13)

MRI demonstrates a smooth-bordered round, nodular,

extra-axial mass within the vestibular portion of the eighth

nerve, usually beginning at the internal auditory canal,

with extension to the cerebellopontine angle The MRI

characteristics of acoustic neuroma may correlate with the

histological features (13) In one study, all 21 tumors were

of low-signal intensity in the TI-weighted MRI In the

T2-weighted MRI, 9 cases were of homogeneous high-

signal intensity, and 12 cases were of heterogeneous high-

signal intensity (13) Tumors with T2-weighted homoge-

neous high-signal intensity were generally associated with capsular enhancement, and were usually cystic tumors with high vascularity and mainly Antoni A type tissue, whereas those of heterogeneous high-signal intensity were generally associated with homogeneous enhancement, and were mostly solid tumors with low vascularity and various tissue components ( I 3)

Pathology Acoustic neuromas have a round, smooth,

and well-demarcated surface, with a thin layer of connec- tive tissue that encapsulates the tumor, and display two classic growth patterns of neurilemoma in varying propor- tions: namely, Antoni A and Antoni B types (14-16)

Immunohistochemically, they are strongly and dif- fusely positive for S-100 protein (see foregoing discussion Sec V.F on bilateral acoustic neuroma)

Estrogen and progesterone receptors have been identi- tied in a small subset of acoustic neuromas (about IS%

of cases) in some, but not all studies, with the incidence

of estrogen receptor being lower than that of progesterone receptors ( 17-2 I ) It has been speculated that pregnancy stimulates the growth of acoustic neuroma However Beatty et al., using immunohistochelllical stains for steroid hormone receptors and proliferation cell nuclear antigen, and DNA flow cytometry, found no evidence to suggest that binding of estrogen to receptor sites results in growth

of tumor in either pregnant or nonpregnant subjects ( 1 8)

Differential Diagnosis Acoustic neuroma should be

distinguished histologically from other neoplasms, includ- ing meningioma, leiomyoma, neurofibroma and paragan- glioma, by identification of its characteristic patterns of proliferation (Antoni A and Antoni B) and diffuse, strong reactivity for S-100 protein, together with absence of

reactivity with desmin, cytokeratins neuroendocrine markers and, in most cases, epithelial membrane antigen (EMA: see discussion on bilateral acoustic neuroma: Sec

V F)

Treatment and Prognosis There is a striking vari- ability i n the natural history and growth rate of sporadic unilateral acoustic neuromas (22) Therapeutic options are based on age, symptoms, tumor size, hearing level, and rate of tumor growth (25-36) Serial MRI scanning has shown that most tumors (80%) are slow growing (<2n1m/ year) over decades or show no growth, whereas some ( 1 3- 20%) may progress rapidly (>Smm) (22-2533) Earlier diagnosis and complete or partial removal by microsurgi- cal removal or stereotactic radiosurgery has contributed

to decrease in morbidity, with preservation of hearing and facial movement and sensation to preoperative levels (26- 36) Little is known about long-term outcome after these modes of therapy (31) The incidence of postoperative neurological deficits increases with increasing tumor size and is 47% for both microsurgery and radiosurgery (30)

Tumors of the Nervous System 809

For patients who are unable t o undergo surgery, radiation

therapy or observation with yearly MRI scan may be

options (24) (also see Sec V.F discussion on bilateral

acoustic neuroma)

The explanation for the variation i n tumor growth

rate is unclear There is currently no preoperative o r

morphological mechanism that can identify rapidly pro-

gressive tumors from those that have a lower rate of

proliferation (24) Recent studies have used flow cytome-

try or immunohistochemical analysis using antibodies to

the proliferating cell nuclear antigen (PCNA) and MIB-I

(Ki-67) to determine whether the tumor proliferative frac-

tion is related to clinical course, operative findings, or

tumor volume ( 3 7 4 1 ) No correlation was found between

duration of symptoms, patient age, and tumor volume

with results of flow cytometry Almost all tumors were

DNA diploid and no relation was found between S-phase

value and historical data (37.38) By using quantitative

DNA measurements and a monoclonal antibody to the

proliferating cell nuclear antigen (PCNA), Welkosborsky

et al demonstrated a lack o f correlation between results

of quantitative DNA measurements PCNA score, history,

symptoms, or predominant histological classification (38)

Charabi et al found a relation between the proliferation

fraction and symptom duration, with a high Ki-67 prolifer-

ation fraction in tumors with a short preoperative symptom

duration and a low-proliferation fraction in those who had

a long symptom duration (40) Lesser et al found two

different growth rates, the higher rate being five times

that of the lower rate, suggesting that elevated levels of

Ki-67 may be associated with more aggressive tumor

(41 1

H Mucosal Neuroma

Introduction The multiple endocrine neoplasia

(MEN) syndromes, defined as the association of tumors

of two or more endocrine glands are usually inherited as

an autosomal dominant characteristic, although they tnay

a l s o occur in a sporadic fashion ( l ) The major syndromes

include three distinct disorders as follows: (a) MEN type

I (Wermer’s syndrome) consists of tumors or hyperplasia

involving the parathyroid glands pituitary, and pancreatic

islets ( I ) Its putative gene has been mapped to chromo-

some 1 lq13 (b) MEN type 2A (Sipple’s syndrome) con-

sists of the association of medullary thyroid carcinoma

adrenal pheochromocytotlla, and parathyroid disease ( I )

(c) The third type, MEN type 2B, or MEN 3 as i t is

referred to by some, is characterized by the presence of

medullary thyroid carcinoma pheochromocytoma, and

ocular and oral neuromas, as well as gastrointestinal

ganglioneurotnatosis often with a marfanoid habitus and

the absence of parathyroid disease (1-9) Khairi et al proposed the designation MEN type 3 to emphasize the mucosal neuromas and the marfanoid habitus (8) In the literature, the terms MEN 2B and MEN 3 are used inter- changeably However, i n the following discussion of mu- cosal neuromas, the designation MEN 2B will be used The gene for MEN 2A, 2B and the familial medullary thyroid carcinoma-only syndrome is present on chrorno-

some l O q l I .2 and has been recognized as the rc‘t proto- oncogene ( I , 10-17) A missense mutation in codon 9 I8

of the proto-RET has been identified in the germline of patients with MEN 2B and is due to the substitution of a threonine for a methionine in the tyrosine kinase domain

of the protein ( 13,16)

Clinical Features In a review of 41 patients with MEN 2B (or MEN 3) syndrome by Khairi et a l (g), there were 19 males and 22 females with a mean age of 22 years (range 4 t o S3 years) Mucosal neuromas especially oral or ocular, are noted at birth or during the tirst few years of life and are a constant component of this syn- drome ( 1-9,IX-2 I ) They are often multiple and are be- lieved to represent hamartomatous growths, rather than true neoplasms Clinically, mucosal neuromas appear as small sessile, nodular excrescencies on the vermilion of the lip on the anterior third of the dorsal or ventral tongue or buccal mucosa almost invariably by 8 years

of age (1-9) In these patients similar neuromas occur on

the eyelid margins causing thickened and everted eyelids,

as well a s on the palpebral and bulbar conjunctiva ( 1 8-2 1 ) The exact incidence o f the various ocular manifestations is unknown, because many of the patients with the MEN 2B syndrome have not had the benefit of ophthaltnological examination In those who have had such an examination, bilateral gray-white, prominent thickened corneal nerves are seen as a constant manifestation (20.21) In one study

of IS patients with the MEN 2B syndrome, prominent corneal nerves were observed i n 10O%, conjunctival neu- romas in 87%, and eyelid neuromas in 80% (19) The nasal, laryngeal, pharyngeal, and conjunctival mucosae tnay also be rarely involved

The MEN 2B syndrome frequently manifests with a neck mass or diarrhea, or it may be identified during screening of individuals with affected relatives The muco- sal neuromas and a marfanoid habitus manifest at an early age, whereas the medullary thyroid carcinoma and adrenal pheochromocytoma occur later in life (I-6,8) In a review

of S 1 patients reported with MEN 2B, Carney et al found 40 of the S 1 patients (78%) had medullary thyroid carcinoma (mean age of 20 years), and 16 (31%) had pheochromocytoma, which was bilateral in two-thirds of

cases ( 2 ) Of the 40 patients with medullary carcinoma, 22

( 5 5 % ) had metastatic or locally invasive tumor a t diagno-

sis and 9 ( 18%) died of metastatic tumor (2) Once the syn-

drome is suspected, medullary thyroid carcinoma can be

diagnosed by calcium-stimulated calcitonin assays earlier

than by physical examination or thyroid function tests

Radiology Cotnputed tomography (CT) is a rela-

tively quick and inexpensive method to identify adrenal

masses However, the ability of MRI scans to enhance

tissue contrast without intravenous injection of contrast

medium, and to obtain multiplanar images permitting it

to localize ectopic tumors without risk of precipitating

;I hypcrtensive crisis, make i t preferable in evaluating

suspected pheochromocytoma (22) The high-signal inten-

sity of adrenal medullary tissue on T2-weighted images

distinguishes pheochromocytoma from other adrenal

masscs and contributes to the successful diagnosis o f

ectopic pheochromocytoma i n MEN 2B (22)

Pathology Multiple nodules up to several millime-

ters i n diameter stud the lips a s well as the tip and

anterior third of the tongue, at times forming confluent or

sessile masscs mainly on the dorsal aspect, but * ‘l I ’ !A) on

the frenulum or ventral surface ( 1,223) Histologically

sections of mucosal neuromas show subepithelial en-

larged tortuous fascicles of myelinated peripheral nervcs

that contain loose, mucoid endoneural tissue and Schwann

cell cords with a disorderly arrangement of axons sur-

rounded by a thickened perineurium that expresses epithe-

lial membrane antigen (EMA), but is negative for S-l00

protein (223.24) Ganglion cells may be present (2)

Differential Diagnosis Mucosal neuromas should be

distinguished from the non-neoplastic traumatic neuroma

and from peripheral nerve sheath tumors, mainly plexi-

form neurofibroma (2,2324) Plexiform neuroma is almost

invariably a component ofncurotibrotnatosis- I (NF- I ) and

has a predisposition to develop malignant transformation

Unlike mucosal neuronus the plexiform neuroma and

traumatic neuroma are not a component of the MEN type

2B syndrome Patients with traumatic tleuroma often have

a clinical history of trauma or prior surgery Histologically

mucosal neuromas are composed of bundles o f disorga-

nized and tortuous nerve fibers surrounded by thickened

perineurium, which is EMA-positive and S- I O 0 protein-

ncgative while i n plexiform neurofibroma enlarged nerve

which is S I 0 0 protein-positive and EMA-negative (24)

Traumatic neuroma is composed of a noncncapsulated

haphazard proliferation of a11 elements of the nerve lasci-

cles, including axons Schwann cells and perincurial cells

i n a fibrous background Traumatic neuromas may be

positive for EMA and S- 1 0 0 protein

Treatment and Prognosis Mucosal neuromas are

often asymptomatic benign tumors with a self-limited

growth (2,X) They may be excised for cosmetic reason

F ‘ ,~sc~cles are seen with a loose myxoid or fibrous stroma

cance of the oral neuromas and refer the patient and family members for appropriate endocrine evaluation ( 2 )

The histological finding of mucosal neuromas should also initiate the search for other components of MEN 2B,

especially medullary thyroid carcinoma The importance

of early diagnosis and screening for medullary thyroid carcinoma is emphasized as i t often pursues an aggressive course and can metastasize or cause death unless total thyroidectomy is performed i n childhood (8) Affected individuals should be periodically screened for pheochro- mocytoma High calcitonin levels after total excision of

medullary carcinoma suggest the presence of residual tumor tissue or occult metastasis

I Neurothekeoma Introduction Neurothekeoma, also referred to as

dermal nervc sheath myxoma or perineurial myxoma, is

an uncommon, histologically distinctive, benign myxoid neoplasm of presumed nerve sheath origin (1-3) This lesion was first described in 1969 by Harkin and Reed under the name “nerve sheath myxoma” based on its histological features ( l ) I n 1980, Gallager and Helwig applied the term “nc~trothekeoma“ (from the Greek o d e ,

meaning sheath) based on their study of 53 casts t o

indicate a relation of these tumors to the Schwann sheath

of peripheral nerve ( 2 )

Clinical Features Neurothekeomas usually occur in

the first or second decade of life ( 2, 3) In their study of S3 cases Gallagher and Helwig found a mean age o f 2 1 .G

years (range 2-76 years) with 60% o f patients younger than 20 years of age, and a female predominance of 4.3: I (2) Clinically the tumor usually presents as a solitary slowly growing, flesh-colored or erythematous soft der- mal nodule, ranging i n size from 0.4 t o I 8 cm, usually involving the central area of the face arms or shoulders

known anatomical site i n their series, Gallager and Helwig noted 31 2% involved the face (usually the nasomalar- nasolabial or lower forehead region) 3 1.2% the arm,

addition to the face, shoulders, and extremities, these lesions may occur less frequently on the back, neck, axilla scalp, and chest (2-1 l ) I n rare instances the tumor may occur i n the oral cavity lip tongue, palate, or external auditory canal (2.12-1 6) Neurothekeomas are not known

to be associated with neurofibromatosis ( 1-4)

Pathology On gross examination, neurothekeomas

are flesh-colored soft dermal nodules Histologically the classic or myxoid type of neurothekeoma is composed of

a lobulated, well-circumscribed proliferation o f spindle and epithelioid cells in varying proportions separated by

"hmors of the Nervous System 811

scant collagen fibers and embedded in an abundant myx-

oid matrix composed of hyaluronic acid or sulfated acid

mucins (Fig 8) (1-3) The spindle-shaped cells have an

eosinophilic cytoplasm, with a variation in nuclear size

and shape, and may be arranged in nests and cords The

presence of a close histological relation between tumor

cells and small nerves is a characteristic feature of neuro-

thekeoma, and atypical hyperchromatic nuclei and a vari-

able number of mitotic figures (0-5/10 HPF) are not

infrequent in these benign tumors (2) Scattered mast cells

may be seen

A cellular variant of neurothekeomas has also been

described based on greater cellularity, striking fascicular

pattern, and absent or sparse myxoid stroma when com- pared with the myxoid type (17-22) Cellular neurothe- keomas also involve the head and neck of young adults Histologically, they are composed of well-defined cellular proliferations that involve the reticular dermis and consist

of fascicles of polygonal or spindled cells, with eosino- philic or pale-staining cytoplasm and neuroid characteris- tics (17) As in the myxoid variant, low-grade cytological atypia and mitotic activity are common and, although

worrisome, are not criteria for malignancy (20)

Ultrastructurally, the spindled tumor cells in neurothe- keoma have features supportive of Schwann cell origin, with folded, convoluted cytoplasmic membranes and base-

;$j ;,> myxoid type, displays a lobulated,

, I, U ' ' circumscribed proliferation of spin-

c; , '., dle cells embedded In an abundant

' myxoid matrix (H&E X40); (B)

I :' /',' tween tumor and small nerves

ment membrane-like material surrounding most cells

(2,3,5,6,8,11,19) The spindle cells contain variable

amounts of rough endoplasmic reticulum, rounded mito-

chondria, and variable numbers of large membrane-bound

vesicles, and lack myofilaments, melanosomes, and to-

nofilarnents (2)

Immunohistochemical study shows positivity of myx-

oid neurothekeomas for S-100 protein and vimentin, and

absence of staining for epithelial membrane antigen

(EMA) and Leu 7 (CD57) (3-6.9) Cellular neurothekeo-

mas differ from the myxoid variant in that they are u s ~ ~ a l l y

negative for S-100 protein (17-22) Calonje et al found

nine of their cellular neurothekeomas were strongly posi-

tive for NKI/C3, an antibody raised against a formalin-

resistant melanoma-associated antigen, but which stains

a wide range of neuroectodermal lesions, and negative for

S- 100 protein, EMA, desmin, and PGP9.5 a broad neural

marker (2 I ) However, a recent study by Wang et al

showed that immunoreactivity to protein gene product 9.5

(PGP9.5) was positive i n all neurothekeomas (myxoid and

cellular types) using the antigen retrieval method (23)

Because only 3 of their I2 cases of cellular neurothekeoma

were immunoreactive to S 1 0 0 protein, PGP9.5 may be

a useful marker for identifying cellular neurothekeorna

together with absence of staining with other neural mark-

ers including Leu-7, synaptophysin, glial fibrillary acidic

protein, EMA, and neuron-specific enolase (23)

Differential Diagnosis Neurilemoma, neurofibroma,

myxoma, leiomyoma fibrohistiocytic lesions, and neuro-

nevus with a myxoid stroma may be confused with neuro-

thekeoma (2,4) However, these lesions lack the tumor

cell nests and cords with distinct borders and the lobular

growth typical of neurothekeoma Furthermore neuro-

thekeomas lack the palisading characteristics and altcrnat-

ing Antoni A and B areas of neurilemomas, and the

eosinophilic neurofibrillary matrix and diffusely scattered

small nerve twigs typical of neurofibromas Myxoid neu-

rothekeornas are distinguished from leiornyomas by their

diffuse positivity for S-100 protein and absence ofdesmin

positivity The presence of S-100 protein positivity in

neurothekcorna also excludes myxoma and fibrohistiocytic

lesions Neurothekeotna may be occasionally mistaken for

neuronevus on the basis of the nesting pattern Junctional

activity and melanin pigment are lacking, however, in

all neurothekeomas (2) Ultrastructural examination of

neurothekeomas may be used to demonstrate features

supportive of Schwann cell origin in neurothekeomas:

namely basement membrane surrounding tumor cells and

the lack of structures such as myofilaments or melnno-

s o n m that would suggest a non-Schwann cell origin ( 2 )

Treatment and Prognosis Local excision is the rec-

ommended treatment Both variants of neuothekeomas-

myxoid and cellular-behave in a benign fashion with no aggressive growth or malignant potential (2,3) Occasion- ally, they may recur with inadequate excision I n one large study of patients with neurothekeoma, only 1 of 70 tumors recurred, and none metastasized (3)

J Perineurioma Introduction Perineurioma is an uncommon benign tumor of nerve sheath derivation that is composed purely

of cells resembling those of normal perineurium (1-16)

It has also been referred to i n the past by the terms

“storiform perineurial fibroma” and “hypertrophic mono- neuropathy” (7-10) Lazarus and Trombetta, in 1978 first

described the ultrastructural identification of a benign perineurial cell tumor composed of cells shown to have morphological characteristics similar to those of perineu- rial cells from small peripheral nerves of skin ( 1 ) Perineu- rial cells lack well-defined histological criteria on light microscopic examination; therefore either electron mi- croscopy or immunohistochemical confirmation of the diagnosis is often necessary ( 1-1 6)

The true nature of perineurioma, whether neoplastic or

reactive has long been debated However, Emory et al recently demonstrated the clonal nature of intraneural pcrineurioma and its association with abnormalities of chromosome 22, suggesting that it is neoplastic, rather than reactive, in nature (17) Giannini et al also recently described deletion of part or a l l of chromosonle 32 in soft tissue and intraneural perineurioma, further lending support t o the view that perineurioma are part of a spec- trum of perineurial neoplasia ( 1 8)

Clinical Features Most patients with perineurioma are middle-aged, with a mean age of 44 years, although the age range is wide (19-66 years), with a female pre- dominance (2: 1) Perineuriomas usually present as soli- tary, painless, discrete superficial nodules in soft tissue of the extremities and shoulder girdle (1.2,6-13,15,17,18) Only occasionally have they been reported i n the head and neck region (8,10.18-21) Of the tumors reported in the head and neck, Mentzel et al and Tsang et al reported one case each of perineurioma presenting in the soft tissue

of the neck (&IO) Giannini et al reported one case of perineurioma arising i n the maxillary sinus (18) Li et al and Daqing et al described one case each of intratemporal facial nerve perineuriotnas associated with a history of gradual facial palsy of 15 years duration, respectively ( I 9,20) High-resolution CT showed enlargement of the inferior mastoid segment of the right fallopian canal and stylomastoid foremen, and MRI revealed strong gadolin- ium enhancement of the distal mastoid segment o f the facial nerve, believed to be suggestive of neuroma (19)

Tumors of the Nervous System 813

Kusarna et al reported a case of perineurioma of the

mandible (21) There is no known association of perineuri-

oma with the neurofibromatoses

Emory et al described the clinicopathological charac-

teristics of eight intraneural perineuriomas, all of which

involved extremities (17) Neurological symptoms were

sensory or motor Fusiform segmental enlargement of the

nerve was evident clinically in two tumors and in five of

the eight tumors on MRI (17) Another rare variant, the

sclerosing perineurioma, was described by Fetsch et al

with a predisposition for the fingers and palms of young

adults ( I I )

Pathology Soft-tissue perineurioma is typically a

solid white to light tan, lobulated, well-circumscribed,

but not encapsulated, soft-tissue mass, ranging from I to

12 cm in size Histologically, the tumor is composed of

layers o f remarkably elongated, slender, spindled-shaped

cells arranged in variable patterns ranging from short

bundles, fascicles, or lamellae, to the formation of loose

whorls or a storiform pattern, supported by a collagenous

stroma (I-3.8,lS) The tumor cells have elongated, ta-

pered, wavy nuclei, with inconspicuous nucleoli and long

delicate bipolar cytoplasmic processes Mitoses nuclear

pleomorphism, and necrosis are absent

The diagnosis of perineurioma is confirmed on the

finding of a predominant population of cells that have the

classic ultrastructural or immunohistochemical features of

perineurial cells ( 1,3-6,8-18) Ultrastructurally, the tumor

cells possess thin polar cytoplasmic processes that show

frequent intercellular junctional complexes, numerous pi-

nocytotic vesicles, sparse profiles of rough endoplasmic

reticulum and intermediate tilaments, and either absent or

fragmented and variable basement membrane ( 1 ,5.6.10-

13, I X) Interdigitating cell processes are absent

Immunohistochemically the tumor cells typically ex-

press virnentin and epithelial tnembrane antigen (EMA),

and lack reactivity with antibodies to S-100 protein neu-

rofilament cytokeratins desmin, actin CD34 and Leu-7

(4.8.9.1 1-18) Tumor cells show a delicate membranous-

staining pattern with EMA, laminin, and collagen IV ( 1 l )

The intraneural variant o f perineurioma shows an archi-

tecturally complex, focal fusiform intraneural proliferation

of perineurial cells with pseudo-onion bulb formation

(EMA-positive) around nerve fibers (17) A wide range of

proliferative activity was found in these lesions, including

nuclear labeling with an antibody to the proliferating cell

nuclear antigen (PCNA; 0-17.5% mean 6%), and MIB-

1 (labeling index 4-17%, mean 7.4%), and the occasional

expression o f p53 ( i n two of six cases) Together with

clonal cytogenetic abnormalities, these findings suggest

that perineuriomas are benign neoplasms, rather than a

reactive process ( 17)

Differential Diagnosis Perineurioma is distin-

guished from other spindle cell tumors, such as neurofi- broma, fibrous extracranial meningioma, and dermato- fibrosarcoma protuberans (DFSP) not only by its immuno- phenotype, but by its characteristic ultrastructural features These include the presence of intercellular junctional com- plexes, pinocytotic vesicles, and fragmented variable base- ment membrane, and the lack of interdigitating cell pro- cesses (1,4,5,8,14) Unlike perineuriomas, neurofibromas are often cutaneous, may be associated with neurotibro- matosis I , have a more heterogeneous make-up, and are

100 protein and neurofilament staining in perineurioma excludes the presence of underlying nerves, especially axons or Schwann cells, both of which are common findings in neurofibroma (8) Fibrous menink' 'lomas are

oma by the presence of psammoma bodies, reactivity for S100 protein and CD34, and the absence of pinocytotic vesicles on ultrastructural examination Occasionally, when perineuriomas are cellular or exhibit a focal stori- form pattern, the differential diagnosis includes DFSP However their circumscription typical cellular features and immunophenotype (EMA-positive, CD34-negative) separate perincurioma from DFSP, which is typically hy- percellular, uniformly storiform, and positive for CD34,

from fibroma or giant cell tumor of tendon sheath by its expression of EMA Moreover, unlike perineuriorna, giant cell tumor o f tendon sheath typically contains xanthoma cells, siderophages, and osteoclast-like giant cells ( 1 l )

Treatment and Prognosis Surgical excision is the

treatment of choice Perineuriomas are slow-growing lo-

calized, self-limited lesions that have a benign course and are not known to develop malignant transformation

K Granular Cell Tumor Introduction Granular cell tumor (GCT) is a usually

benign lesion of nerve sheath origin with a predilection

for the skin, soft-tissue, or mucosal sites of the upper aerodigestive tract (1-7) Abrikossoff originally proposed

a primitive striated muscle origin; hence the term "granu- lar cell myoblastoma" ( I & I O ) However, electron micro- scopic, enzyme histochemical and itnmunohistochelnical studies have shown strong evidence in support of a

Schwann cell derivation of GCT ( I 1-26)

Clinical Features The tumor may occur at any age,

but is most common i n persons in the fourth to sixth

decades of life ( 2 ) The mean age of patients with GCT

is 38 years (range, 1 1 months to 68 years), with a female preponderance of 2: I except for laryngeal GCT, which

has a male/female ratio of about I : 1 Rarely, GCT may

occur i n childhood (27-29) There is a propensity for

GCT to occur i n the skin and subcutaneous tissue, mucous

membranes of the aerodigestive tract, and breast (2-5,27-

54) I n a review of the English literature for a 5-year

period between 1967 ;md 197 I ( 3 0 ) , the most common

sites of GCT were the subcutaneous tissue (32.6%) oral

cavity (28 I %), breast ( I S.9%), larynx (7.6%), gastrointes-

tinal tract (4.7%~) and bronchus 3.4% The remaining

involved the perineum (2.4%), hypophysis (2.4%) and

miscellaneous sites (2.9%) (30) Common cutaneous sites

in the head and neck include the forehead nose, neck

and eyelids; the scalp is rarely involved In the oral cavity

the tongue is the most common site, and less frequently

the lip, floor of mouth buccal mucosa and palate are

involved (30,33-36) Most GCT present as a solitary

smooth, tirm painless mass, ranging i n size from 1 .O to

times synchronous (33.54-57) Ulceration is uncommon

1 Gr-crrtrrltrr C d l fir~lror OJ'tlre L r r r : \ n s

Patients with laryngeal GCT are usually adults in the third

to fifth decades and hove a median age (35 years) similar

t o those occurring at other sites (3.4.27-32.3749) I n

contrast to GCT at other sites laryngeal tumors either

show no sex bias or there may be a slight prcdominance

of males ( 5 5 % ) (3,4) Laryngeal GCT is found most

commonly on the true vocal cords, especially the posterior

one-third The lesion is associated with slowly increasing

hoarseness over a period of 2-10 months (3) I n the series

described by Compagno et al., the vocal cord was the

most common site (20 cases), followed by the arytenoid

(4 cases), false cord ( 2 cases) anterior commissure ( 2

cases), subglottis ( 2 cases), and postcricoid area ( I case);

i n 5 cases the exact sitc was not specified (3) Clinically

laryngeal GCT may be mistaken for vocal cord nodule

papilloma, or squamous carcinoma The location on the

posterior true cord, coupled with the relatively young

age of patients with GCT ( 2 5 4 0 years), contrasts with

squamous cell carcinoma, which preferentially involves

the anterior half of the vocal cord and occurs in an older

population (55-60 years of age or more) There is no

known relation of GCT with smoking

On examination laryngeal GCT presents as a firm,

polypoid, smooth, granular papillary, or cystic lesion that

is often I .O cm or less i n size, although it may be a s large

a s 3.0 cm ( 3 ) Fixation of the vocal cord is absent

Microscopic characteristics of laryngeal GCT are similar

t o those described in the following discussion Compagno

et al found mild t o severe pscudoepitheliotllatous hyper-

plasia of the overlying epithelium in 64% of 36 laryngeal

GCT studied (3) Eight o f the tumors were initially sus-

pected of being squamous cell carcinomas (3) Since laryngeal biopsies tend t o be superticial, the potential for misinterpreting pseudoepitheliomatous hyperplasia as squamous cell carcinoma is high However, pscudoepithe- liotnatous hyperplasia lacks nuclear atypia and thc squa-

mous epithelium does n o t extend beyond the lower limits

of the GCT

2 Gr-mrrltrr Cell T l r r r r o r - c ? f ' t l l c T o l l g l r c J

About 23% of a l l GCT and 81% of a l l oral GCT occur

exhibit the same clinical and histological features a s those

at other sites (2,s 17.27.3 1-36) The most common loca-

lateral border and base and ventral surfaces of tongue (2.4.5.3 1-35)

Pathology On gross examination, the tumors range

in s i x from 0.5 to 2.0 cm i n diameter and the smooth, lirm feature of GCT contrasts with the usually ulcerative squamous cell carcinoma GCT from all sites arc similar

on histological examination The circumscribed or poorly defined tumor is unencapsulated and composed of polyhe- dral, round or spindle-shaped cells with acidophilic gran- ular cytoplasm, and poorly defined cytoplasmic borders imparting a syncytial growth pattern (Fig 9 A ) (2-7) They may be arranged in broad sheet well-demarcated groups

or rows The cytoplasmic granules arc periodic acid-Schiff (PAS) positive diastase-resistant, and range from being barely visible t o the size of ;I red blood cell The nuclei are small, centrally or eccentrically loca~ed and moderately hyperchromatic with little pleomorphism Nucleoli are generally not prominent Mitoses and necrosis are usually absent The granular cells, howcvcr, may appear to "in- vade" nerve, but i n GCT this is not a sign of malignancy

plasmic structures (angulatc bodies), which are more PASD-positive than the cytoplasmic granules, may be seen

on close inspection Pseudocpithelionlatous hyperplasia of the overlying squamous epithelium of varying degrees may be seen with downward proliferation of epithelial cells often with squamous pearl formation (Fig 9B) (3.4)

On electron microscopy the small cytoplasmic gran- ules consist of membrane-bound vesicles of Golgi origin whereas thc larger granules represent phagolysosomcs (Fig 9C) ( 1 I I2,14.18) The angulate bodies are oval membrane-enclosed structures formed by the deposition

of fibrillar material within the endoplasmic reticulum Histochemical analysis of the granules has shown the presence o f glycolipid, ;I sialomucin-protein complex

or ribonucleic acid Immunohistochemic~~l studies have