neural tumors

TUMORS OF PERIPHERAL NERVES

Presented byAnjum Baker

III MDS PostgraduateDept of Oral Pathology & Microbiology

VIDS & RC

CONTENTS■ Introduction

■ Classification

■ Traumatic Neuroma

■ Palisaded encapsulated neuroma

■ Mucosal neuroma

■ Neurofibroma/ Neurofibromatosis

■ Schwannoma

■ Granular cell tumor

■ Nerve Sheath Myxoma

■ Pigmented Neuroectodermal Tumor of Infancy

■ Malignant peripheral nerve sheath tumor

■ Olfactory Neuroblastoma

■ Peripheral neuroectodermal tumour

■ References

Introduction ■ Peripheral nerve tumors are a heterogeneous and complex group of

lesions and reflects the intricate structure of peripheral nerves

■ The range of structure and cell types from which the nerve sheath

tumors may either arise, or differentiate toward, is quite broad.

■ Majority of tumors of PNS are derived from Schwann cells and

their peripheral nerve elements.

■ In the oral region, neural tumors occur both in the soft tissues

and in jaw bones.

■ They occur as painless, smooth surface swelling in the soft

tissues, with tongue being the most common site.

■ Within the jaw bones they exhibit a slow rate of growth and

mild expansion of the cortical plates.

■ Majority are benign and the malignant neoplasms generally have

a propensity for local invasion rather than regional or distant

metastasis.

Benign Tumours: 1. Traumatic Neuroma2. Palisaded encapsulated neuroma3. Hamartomas – i. Mucosal neuroma ii.Neuromuscular hamartoma 4. Neurofibroma/ Neurofibromatosis5. Schwannoma6. Granular cell tumor7. Nerve Sheath Myxoma 8. Pigmented Neuroectodermal Tumor of Infancy

Malignant Tumours: 4. Malignant peripheral nerve sheath tumor5. Olfactory Neuroblastoma 6. Malignant granular cell tumor7. Peripheral neuroectodermal tumour

WHO CLASSIFICATION OF SOFT TISSUE TUMORS;2013

Traumatic Neuroma

■ Occurs in response to injury(lacerating/penetrating)

■ Benign non neoplastic overgrowth of nerve fibres & schwann cells.

■ Traumatic injury swelling,fragmentation,disintegration of nerves at

distal endsdebris cleared by macrophages,shrinkage of neural

sheathsproliferation of axis cylinders, schwann cells,endoneurium

from proximal endneural reinnervation

■ If proliferating proximal end meets scar tissue/malaligned

bonecontinuous proliferationNeuroma

C/F

■ small, firm, slow growing often painful nodules

■ Oral lesions-near mental foramen, alveolar ridge, lips, tongue

■ May occur centrally in association with nerve trunk

■ Pain on digital pressure/reflex neuralgia

■ Pathologic Features.

■ Haphazard arrangement of small nerve fascicles, containing axons, Schwann cells, and perineural cells, with surrounding fibrosis

■ No distinctive myelin sheath

■ Reactive changes, such as capillary and myofibroblastic proliferation.

IHC- CD68+

Differential Diagnosis.

■ Neurofibroma

(does not grow in distinct nerve twigs and consists of wavy spindled cells dispersed among randomly arranged collagen bundles)

■ Mucosal neuromas

( submucosal nodular lesions without surrounding fibrosis occurring in patients with MEN 2B)

Treatment

■ Complete excision

Solitary Circumscribed/ Palisaded Encapsulated Neuroma

■ Benign neoplasm/primary hyperplasia of nerve fibres, axons &

Schwann cells

■ 90% are facial lesions.

C/F

■ 5th-7th decade

■ Limited to areas bordering mucocutaneous junctions of face

■ Intra oral – hard palate

■ Solitary sessile well circumscribed papule on the nose, cheek, and

perioral skin less than 1cm diameter

■ Rubbery feel on palpation

Pathologic Features.

■ Lacks a distinct capsule

■ Overlying epithelium- acanthosis/ pseudoepitheliomatous hyperplasia

■ composed of bland eosinophilic spindle cells with poorly defined cell margins and small wavy hyperchromatic nuclei

■ Cells arranged in fascicles set in collagenous stroma and often separated by artefactual clefts

IHC- strongly S-100 +,EMA+


Schwannomas ( hyalinized, thick-walled vessels or myxoid change,

presence of central axons)

Treatment

No treatment required

Surgical excision for esthetic correction

MUCOSAL NEUROMASMultiple Endocrine Neoplasia Syndrome (MEN IIB/III)■ Also called multiple mucosal neuroma syndrome

■ Features-

• Adrenal pheochromocytoma

• C cell hyperplasia of thyroid

• Medullary thyroid carcinoma

• Diffuse ganglioneuromatosis of alimentary tract

• Submucosal neuromas of upper aerodigestive tract

■ AD disorder

■ Mutation of RET proto oncogene

C/F

■ Tall lanky marfanoid build with narrow face, muscle wasting

■ Oral mucosal neuromas- 1st decade of life

■ Also on mucosal surfaces of eyelids, GIT

■ Multiple mucosal nodules-2-7mm yellowish white sessile painless nodules on lips, anterior tongue,commisures

■ 2-8 neuromas usually- Bumpy lip appearance

■ Thyroid Ca, pheochromocytoma- manifest after puberty

■ Increased calcitonin levels, altered epinephrine: norepinephrine ratio


■ Partially encapsulated aggregate of nerves with thickened perineurium, intertwined in plexiform pattern seen in loose endoneurium like fibrous stroma

■ Individual nerves flow in fascicles of two to three fibers and are histologically normal except for occasional hyperplasias and bulbous expansions.

■ Myxoid change may be prominent

■ IHC- S-100+,collagen IV+,vimentin+,NSE+,neurofilament+,

■ Special stains- Early lesions- Alcian blue +

■ Luxol fast blue- myelinated nerve fibres


■ Traumatic neuromas

(single lesions, history of trauma)

Rx

■ Excision for esthetic reasons

■ Self limiting/asymptomatic

Neurofibroma/Neurofibromatosis

■ May be solitary or associated with NF

■ Benign tumor derived from endoneural fibroblasts

■ Multiple lesions- Neurofibromatosis/Von Recklinghausen’s disease

■ Autosomal Dominant/spontaneous mutations

■ 2 subtypes

■ NF1- mutation of genes coding for neurofibromin on chromosome 17 (1 in 2500-3300 live births)

■ NF2- mutation of genes coding for Schwannomin on chromosome 22 ( 1 in 33,000-40,000 live births)

■ Syndrome associated neurofibromas- malignant transformation rate – 15%, NF2>NF1

Diagnostic Criteria for NF1 (3 or more)

(1) six or more café au lait macules,

(2) two or more neurofibromas of any type,

(3) One plexiform neurofibroma,

(4) axillary or inguinal freckling,

(5) optic glioma,

(6) two or more iris hamartomas (Lisch nodules),

(7) sphenoid dysplasia or thinning of long bone cortex, or

(8) a first-degree relative with known NF1.

Diagnostic criteria for NF2 (any 1)

1. Bilateral acoustic neuroma/family history of NF2+ unilateral

acoustic neuroma/any 2 of meningioma, neurofibroma,

schwannoma,corneal opacities

2. Unilateral acoustic neuroma+any 2 of meningioma, neurofibroma,

schwannoma,corneal opacities

3. 2 or more meningiomas + unilateral acoustic neuroma/any 2 of

glioma,schwannoma or cataract

4. 1st degree relative with NF2 and any 1 of the above criteria

■ Clinical Features.

■ Neurofibroma- Present in young adults as a relatively small, soft, dermal or subcutaneous nodule.

■ Discrete non ulcerated nodules with normal overlying skin

■ Oral lesions in 7-20% patients, site- buccal mucosa, alv. ridge, palate

■ Multiple conventional neurofibromas, prompt consideration of possible NF1

■ Diffuse neurofibromas, associated with NF1 in approximately 10% of cases, are usually deeply situated.

■ Pain/paresthesia may present

Gross description

■ Not encapsulated, softer (more gelatinous) than schwannoma

■ Superficial tumors are small, pedunculated nodules

■ Deeper tumors are larger, may cause tortuous enlargement of peripheral nerves- ‘tuber root’ app

■ Plexiform neurofibromas, grossly visible, large masses, with a characteristic “bag of worms” appearance.


■ Well circumscribed, unencapsulated

■ Elongated spindle cells with poorly defined pale eosinophilic

cytoplasm and tapering wavy or buckled nuclei admixed with

intermediate short spindle cells, numerous small nerve fibres and mast

cells.

■ often show zonation with a more cellular central region containing residual

nerve twigs and more myxoid areas at the periphery.

■ Sometimes spindle cells b/w bundles of collagen arrayed in a characteristic

“shredded carrot” pattern

Subtypes

■ Plexiform neurofibroma: irregularly expanded nerve bundles with nodular appearance, prominent myxoid matrix; associated with NF1

■ Diffuse cutaneous: traps adnexa, infiltrates into fat

■ Intraneural

■ Epitheloid

■ Granular cell

■ Pigmented

■ Dendritic cell

Positive stains

■ S100, CD34+ (focal), Factor 13a (focal)

■ axons (highlight with silver or acetylcholinesterase stain, NSE, neurofilament)

■ EMA- in plexiform neurofibromas

Differential diagnosis

■ Palisaded encapsulated neuroma (parallel fascicles)

■ MPNST ( mitoses,pleomorphism)

Rx

■ Asymptomatic/self limiting

■ Periodic monitoring in case of NF1/2 Patients

■ Genetic counselling

Schwannoma■ Also known as neurilemoma/ perineural fibroblastoma/neurinoma.

■ Benign tumor of Schwann sheath

■ Defined as - Encapsulated biphasic nerve sheath tumor derived from

Schwann cells with highly ordered cellular component (Antoni A)

that palisades (Verocay bodies) and a myxoid component (Antoni B)

■ Small tumors may be all Antoni A

■ Schwannomatosis – familial, inactivating mutations of Schwannomin-

multiple peripheral + vestibular schwannomas

■ Schwannomatosis – predisposition for malignant change

■ Clinical features

■ Ages 20-50; M=F

■ Head, neck, flexor upper and lower extremities, retroperitoneum,

■ Intra oral region- slowly enlarging, painless submucosal nodule that is

somewhat movable beneath the surface and rarely becomes larger than 2 cm

in greatest diameter

■ Pain or rapid enlargement of preexisting lesion are suggestive of malignant

change

■ may wax and wane in size

■ Gross description

■ Usually solitary, large tumors may be cystic

■ Gelatinous appearance, periphery may show fibrosis

■ Nerve of origin present in periphery - does not penetrate substance of tumor

■ Pathologic Features

■ Encapsulated Biphasic tumor with compact hypercellular Antoni A areas and myxoid hypocellular Antoni B areas

■ Antoni A type tissue-

■ Fascicles of monomorphic spindle-shaped Schwann cells with poorly defined eosinophilic cytoplasm and pointed basophilic nuclei in variably collagenous stroma

■ These cells show nuclear palisading, and parallel arrays of such palisades with intervening eosinophilic cytoplasm (cell processes) are known as Verocay bodies- ‘Soldiers across battle lines’ appearance

■ Antoni B type tissue-

■ Antoni B areas are also composed of Schwann cells, but their cytoplasm is inconspicuous, and the nuclei appear suspended in a copious myxoid, often microcystic, matrix. These areas are probably degenerative in nature.

■ A common feature, most prominent in Antoni B areas, is the presence of blood vessels with thick hyaline walls and gaping tortuous lumina with occasional thrombi

■ Normal mitotic figures are a common finding in benign

schwannoma, especially in Antoni A areas, but it is exceptional for

these to exceed 5 per 10 high-power fields (hpf) in number.

■ May have foamy macrophages

■ Often displays degenerative nuclear atypia (ancient change)

■ collagenous spherules: large nodular masses of collagen with

radiating edges

■ Variants

Ancient schwannoma

■ Degenerative change to tumors, usually large and of long duration, commonly deep within retroperitoneum

■ Cyst formation, calcification, hemorrhage (stromal hemosiderin), hyalinization, histiocytic infiltration, severe nuclear atypia (nuclear hyperchromasia, irregular nuclear shapes)

■ No mitotic figures

Cellular schwannoma

■ Primarily Antoni A areas without Verocay bodies

■ May have nuclear atypia and focal necrosis

■ 0-3 mitotic figures/10HPF

■ 5% recur, no metastases

Pigmented schwannoma■ Pigmented tumor cells have widely scattered, coarse pigment, reactive

with Fontana Masson stain ,nonreactive with Prussian blue■ Laminated psammoma bodies also seen■ Some are clinically aggressive, metastasizing■ Positive stains-S100 (strong), vimentin, ■ Negative stain-Pussian blue, tyrosinase, HMB45

Plexiform schwannoma•5% of schwannomas

•Pattern not associated with neurofibromatosis 1 or 2

•Plexiform architecture with nuclear palisading

•Biphasic pattern may not be prominent

•Often cellular with hyperchromatic nuclei and mitotic activity

•No necrosis, no myxoid change

Positive stain- S100 (strong staining of nodules but not intervening

stroma)

Differential diagnosis•MPNST

•Plexiform neurofibroma

Epitheloid Schwannoma

■ Nests or trabeculae of epitheloid cells in a myxoidstroma

■ Closely resemble myoepithelioma

■ S-100 positive

■ EMA, Keratin – negative

Hybrid Schwannoma/Perineurioma

■ predominantly Antoni A areas; markedly whorled growth pattern

■ Mixed positivity S-100 & EMA

Glandular Schwannoma

■ Glandular differentiation rare

■ Usually entrapped glandular structures

Microcystic-reticular variant Not associated with neurofibromatosis types 1 or 2

Microcystic and reticular growth pattern with anastomosing and

intersecting spindle cells, distributed around islands of myxoid or

collagenous/hyalinized stroma

Positive stains- S100, variable GFAP

Negative stains-Muscle markers, keratin, p63

Angiosarcoma in schwannoma

■ Benign schwannoma with transition to angiosarcoma (irregular

vasoformative structures lined by multilayered cells with nuclear atypia or

atypical endothelial cells with a solid growth pattern,)

■ Cytoplasmic staining for CD31, CD34 or vWF

Epithelioid malignant change

■ Large epithelioid cells with abundant eosinophilic cytoplasm, vesicular

chromatin, prominent nucleoli, resembles epithelioid MPNST

■ May recur locally, may be a precursor lesion to MPNST since they present

at younger age than MPNST

■ Strongly S100+

IHC

Positive stains

■ EMA (capsule), S100 (Schwann cells),calcinurin, laminin, type 4 collagen, vimentin, CD68, GFAP

Negative stains

■ Keratin, neurofilament, desmin

■ Malignant transformation

■ Transforms to MPNST, angiosarcoma or epithelioid malignant change (EMC),common in tumors with epitheloid cells.

■ Most common sites are limb, limb girdles, head/neck

■ Schwannoma with MPNST: benign schwannoma with no other primary tumor, histologically malignant cells resembling epithelioid MPNST; 5 year survival < 20%

Nerve sheath Myxoma/ NeurothekeomaClinical Features

■ Solitary painless swelling

■ Upper limb/ HN areas

■ adolescents, young adults

■ Female prediliction

■ <3cm size

Pathological Features

■ Multinodular growth pattern and copious myxoid matrix

■ Tumor cells-predominantly spindle shaped, maybe epitheloid OR multinucleate

■ fascicular or plexiform arrangement in myxoid stroma

■ Rare foci of cartilaginous metaplasia

■ IHC -S100+ (sporadic)

Differential diagnosis- Myxoid neurofibroma: S100+ (strong)

Granular Cell Tumor■ Usually benign, Neuroectodermal origin

■ C/F

■ Classic location is tongue.

■ Rare congenital tumors occur in gingiva.

■ Female predilection

■ Slow growing, rarely tender.

■ Usually <3cm diameter

Pathological Features

■ Maybe well defined or poorly defined with infiltrative margins

■ Nests or trabeculae of tumor cells seen which are large, rounded, or polygonal and have copious, finely granular, eosinophilic cytoplasm.

■ Larger eosinophilic droplets or granules maybe seen.

■ Tumor cell nuclei are small, centrally situated, and usually pyknotic/hyperchromatic/vesicular.

■ scattered mitoses or mild nuclear atypia, which often appears degenerative.

■ Nests of tumor cells are commonly found around, or adjacent to, small nerves, often being located within the epineurium.

■ Superficial tumors- acanthosis or pseudoepitheliomatous hyperplasia of ep

■ Positive stains-NSE, S100 (nuclear and cytoplasmic), inhibin and calretinin, acid phosphatase, luxol fast blue, PAS

RxSurgical excision is curativeRecurrence is mostly due to incomplete excision

Malignant Granular Cell Tumor■ Accounts for no more than 2% to 3% of all granular cell tumors

■ Among the reported cases, more than 50% have pursued a metastasizing or fatal clinical course.

■ Criteria for its recognition are very hard to define because some cases have appeared histologically to be remarkably bland and monomorphic.

■ Any unusually large or deep-seated lesion with infiltrative margins or necrosis and in which cytologic pleomorphism or nucleoli are prominent and mitoses are quite frequent should be regarded with suspicion

Pigmented neuroectodermal tumor of infancy Also called melanotic neuroectoderrmal tumor of infancy

Historically called melanotic progonoma /retinal anlage tumor

Uncommon, rapidly growing mesenchymal tumor of jaw or skull in

infants, neural crest origin, with biphasic histology of melanin

containing cells and neuroblast-like cells.

C/F 90% occur in HN region

Presents in 1st year of life

Male predilection

Rapidly growing jaw tumors

Usually benign but may be locally aggressive or undergo malignant

change

■ Pathological Features■ two principal cellular components:

■ small basophilic neuroblast-like cells, set in a fibrillary matrix, and larger epithelioid, eosinophilic cells with vesicular nuclei and containing variable amounts of melanin pigment (melanocyte-like cells)

■ The melanin-producing cells are often arranged in alveolar or pseudoglandular structures set in a dense fibroblastic stroma

Minimal mitotic activity, no atypia

IHC Epitheloid cells: keratin and HMB45, Melan A, Fontana stain for

melanin pigment, rarely vimentin, Ki-67

Neuroblast like cells: CD57/Leu7 and NSE


Neuroblastoma/other small round blue cell tumors or melanoma

Treatment

Excision with negative margins. Recur in 37%, metastasis in 7%, no

prognostic factors have been identified

MPNST■ Formerly known as malignant schwannoma/neurofibrosarcoma

C/F

■ Sporadic or NF1 associated (in 30%-40% cases)

■ Sporadic cases associated with previous benign tumors (Schwannoma, ganglioneuroma) or history of irradiation

■ Peak incidence- 5th decade of life

■ Earlier incidence if NF1 associated.

■ Male preponderance

■ Bulky deep-seated tumor usually arising from major nerves in

limbs, retroperitoneum & HN regions.

■ High clinical suspicion for MPNST in NF1 patient or tumor arising

within anatomic component of a major nerve or contiguous with

neurofibroma

■ most MPNSTs are greater than 10 cm in maximum diameter by the time of presentation. (unless associated with neurological symptoms- rare)


■ Large infiltrative mass producing fusiform enlargement of major nerve

■ those arising in a preexisting benign tumor may show a zoned appearance

■ It was formerly believed that to make a diagnosis of MPNST one must demonstrate:

■ (1) origin from a nerve or preexisting benign nerve sheath tumor,

■ (2) ultrastructural evidence of Schwann cell differentiation, or

■ (3) development of a spindle cell sarcoma in a patient with NF1

■ Pathological Features

■ Spindle celled fascicular appearance

■ Distinctive features that may suggest neural differentiation are the abrupt alternation between cellular and more myxoid areas and the apparent perivascular accentuation or whorling of tumor cells

■ Up to 10% of cases have a copious myxoid stroma throughout.

■ Diagnostic clues at the cellular level are the presence of pale, poorly defined cytoplasm and nuclei with a narrow, tapering outline, often with a wavy or buckled configuration in some areas (not as common as in neurofibromas)

■ Hyperchromatic nuclei ,focally pleomorphic with inconspicuous nucleoli.

■ Nuclear palisading is infrequent

■ Frequent mitotic figures, May have bizarre cells

■ Geographic necrosis with tumor palisading at edges

■ 15% cases have metaplastic cartilage, bone, muscle

■ May have glandular differentiation (positive for keratin, EMA, CEA, chromogranin)

■ May have melanin in tumor cells (overlaps with primary melanoma of nerves)

Variants

■ Epitheloid MPNST

■ Glandular MPNST

■ Pigmented MPNST

■ IHC -CD99/O13 (86%), S100 (62%), CD57 (55%), collagen IV, , GFAP

Leu7/CD57 in neurofibroma-like areas

P53, topoisomerase II- prognostic markers

■ Differential diagnosis

■ Pleomorphic liposarcoma

■ Amelanotic melanoma

■ Synovial sarcoma: usually CK7+, CK19+

■ Malignant triton tumor (MTT)

■ MPNST with well developed skeletal muscle component

■ Diagnostic criteria of Woodruff (Cancer 1973;32:426):– Tumor arises along a peripheral nerve, in a ganglioneuroma, in

NF1 patient, or is a metastasis from such a tumor– Tumor has characteristics of Schwann cell tumor– Rhabdomyoblasts arise from body of tumor

■ Rx and Prognosis

■ Wide surgical excision

■ Tumors are chemotherapy and radiotherapy resistant

■ Recur locally, distant metastases frequent

■ Plexiform variant in children has better prognosis, otherwise cannot

predict prognosis

■ 5 yr survival rate -30-60%

OLFACTORY NEUROBLASTOMA

■ Also called esthesioneuroblastoma

■ Rare, malignant neuroectodermal tumor thought to arise from

olfactory membrane or olfactory placode which extends from roof

of nasal cavity in fetus to mid nasal septum and superior turbinate

■ Not related to neuroblastomas elsewhere in body

■ Clinical Features

■ Median age 50 years, range 3-79 years; no gender preference

■ Painful swelling in nasal fossa

■ 20% develop distant metastases, usually to cervical lymph nodes

and lung; late recurrence (after 10 years) is common

■ Usually upper nasal vault; rarely in nasopharynx, maxillary or

ethmoid sinus. Locally invasive into paranasal sinuses, nasopharynx,

palate, orbit, base of skull, brain

■ Staging(Kadish)

A. Confined to nasal cavity

B. Confined to nasal cavity and paranasal sinuses

C. Other

■ 40-50% cases are Stage B

■ 5 year survival by stage:

■ A: 75%, B: 68%, C: 41%


Red-gray, highly vascular, polypoid mass of soft tissue


■ Nests or sheets of uniform small cells with scant cytoplasm, round

nuclei with indistinct nuclear membrane and punctuate chromatin,

no/indistinct nucleoli

■ Mild to moderate nuclear pleomorphism

■ Prominent fibrillary or reticular background in 85% of cases

■ Variable mitotic figures

■ Variable Homer Wright rosettes (cells surrounding central zones of fibrils)

■ tumor cell melanin maybe present

■ Necrosis is poor prognostic factor

■ IHCKeratin, NSE (strong), synaptophysin (strong), chromogranin, neurofilament, catecholamines, S100 in cells at periphery of cell nests


■ Ewing/PNET

■ Lymphoma

■ Rhabdomyosarcoma

Rx

Surgery/Radiotherpay

PNET■ Rare soft tissue tumor, morphologically indistinguishable from Ewing

sarcoma of bone.

■ Definition : a cohesive family of tumors that show varying degrees of neuronal differentiation and almost invariable EWSR 1 gene rearrangement, most often as a consequence of a reciprocal t(11;22)(q24;q12) chromosomal translocation

■ C/F

■ Deep soft tissue of trunk/lower limb is common

■ Usually age 30 or less, usually male preponderance

■ Patients typically present with a rapidly enlarging, often painful mass,

■ Aggressive; common metastases to lung, bones

■ Gross Features

■ Large pale soft irregular masses with central necrosis


■ Predominantly lobular, or sometimes trabecular, growth pattern

■ Associated with a prominent ramifying capillary network.

■ little or no stroma is seen (although rare hyaline examples do occur)

■ confluent or “filigree” pattern of necrosis is commonly found.

■ Small round/oval cells with scanty cytoplasm containing glycogen

■ Poorly differentiated- ‘dusty chromatin pattern’/ pleomorphism

■ Usually more neuroepithelial features than similar bone tumors

■ Homer wright rosettes

IHC

■ Glycogen, vimentin, CD99 / O13 / mic2, S100, keratin (20%)


■ Lymphoma

■ Rhabdomyosarcoma

■ Rx & Prognosis

■ Wide surgical excisison

■ Chemotherapy/Radiotherapy resistant

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http://www.pathologyoutlines.com/

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