Neural tumors

Tumors of peripheral nerves

1. Tumors of peripheral nerves Presented by Anjum Baker III MDS Postgraduate Dept of Oral Pathology & Microbiology VIDS & RC

2. 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

3. 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.

4. M ajority 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.

5. Benign Tumours : Traumatic Neuroma Palisaded encapsulated neuroma Hamartomas – i. Mucosal neuroma ii.Neuromuscular hamartoma 4 . Neurofibroma / Neurofibromatosis 5. Schwannoma 6. Granular cell tumor 7. Nerve Sheath Myxoma 8. Pigmented Neuroectodermal Tumor of Infancy Malignant Tumours : Malignant peripheral nerve sheath tumor Olfactory Neuroblastoma Malignant granular cell tumor Peripheral neuroectodermal tumour WHO CLASSIFICATION OF SOFT TISSUE TUMORS;2013

6. 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 endsdebris cleared by macrophages,shrinkage of neural sheathsproliferation of axis cylinders, schwann cells,endoneurium from proximal end neural reinnervation If proliferating proximal end meets scar tissue/ malaligned bonecontinuous proliferationNeuroma

7. 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

8. 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 .

9. IHC- CD68 + Differential Diagnosis. Neurofibroma (does not grow in distinct nerve twigs and consists of wavy spindled cells dispersed among randomly arranged collagen bundles) M ucosal neuromas ( submucosal nodular lesions without surrounding fibrosis occurring in patients with MEN 2B ) Treatment Complete excision

10. Solitary Circumscribed/ Palisaded Encapsulated Neuroma Benign neoplasm/primary hyperplasia of nerve fibres , axons & Schwann cells 90% are facial lesions. C/F 5 th -7 th 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

11. 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

12. IHC- strongly S-100 +,EMA+ Differential Diagnosis. Schwannomas ( hyalinized , thick-walled vessels or myxoid change, presence of central axons ) Treatment No treatment required Surgical excision for esthetic correction

13. MUCOSAL NEUROMAS Multiple 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

14. C/F Tall lanky marfanoid build with n arrow face, muscle wasting Oral mucosal n euromas- 1 st 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

15. Pathologic Features. 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

16. IHC- S-100+,collagen IV+,vimentin+,NSE+, neurofilament +, Special stains- Early lesions- Alcian blue + Luxol fast blue- myelinated nerve fibres Differential Diagnosis. Traumatic neuromas (single lesions, history of trauma ) Rx Excision for esthetic reasons Self limiting/asymptomatic

17. 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

18. 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.

19. Diagnostic criteria for NF2 (any 1) Bilateral acoustic neuroma/family history of NF2+ unilateral acoustic neuroma/any 2 of meningioma, neurofibroma , schwannoma,corneal opacities Unilateral acoustic neuroma+any 2 of meningioma, neurofibroma , schwannoma,corneal opacities 2 or more meningiomas + unilateral acoustic neuroma/any 2 of glioma,schwannoma or cataract 1 st degree relative with NF2 and any 1 of the above criteria

20. 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 M ultiple 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

21. 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 .

22. Pathologic Features. 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 .

23. 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

24. 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 )

25. Rx Asymptomatic/self limiting Periodic monitoring in case of NF1/2 Patients Genetic counselling

26. 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

27. 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

28. 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

29. Pathologic Features Encapsulated Biphasic tumor with compact hypercellular Antoni A areas and myxoid hypocellular Antoni B areas

30. 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

31. 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

32. 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

33. 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

34. 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

35. 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

36. 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

37. 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

38. 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+

39. 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%

40. Nerve sheath Myxoma / Neurothekeoma Clinical 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 )

41. 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

42. 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

43. Rx Surgical excision is curative Recurrence is mostly due to incomplete excision

44. Malignant Granular Cell Tumor A ccounts 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

45. 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 1 st year of life Male predilection Rapidly growing jaw tumors Usually benign but may be locally aggressive or undergo malignant change  

46. 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

47. IHC Epitheloid cells:  keratin and HMB45, Melan A, Fontana stain for melanin pigment, rarely vimentin, Ki-67 Neuroblast like cells:  CD57/Leu7 and NSE Differential diagnosis 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

48. 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- 5 th decade of life Earlier incidence if NF1 associated. Male preponderance

49. 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)

50. Gross description Large infiltrative mass producing fusiform enlargement of major nerve those arising in a preexisting benign tumor may show a zoned appearance

51. 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

52. Pathological Features Spindle celled fascicular appearance D istinctive 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

53. Up to 10% of cases have a copious myxoid stroma throughout. D iagnostic 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

54. 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 )

55. 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+

56. 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

57. 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%

58. 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

59. 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 %

60. Gross description Red-gray, highly vascular, polypoid mass of soft tissue Pathological Features Nests or sheets of uniform small cells with scant cytoplasm, round nuclei with indistinct nuclear membrane and punctuate chromatin, no/indistinct nucleoli

61. 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

62. IHC Keratin , NSE (strong), synaptophysin (strong), chromogranin, neurofilament , catecholamines , S100 in cells at periphery of cell nests Differential diagnosis Ewing/PNET Lymphoma Rhabdomyosarcoma Rx Surgery/ Radiotherpay

63. 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

64. Gross Features Large pale soft irregular masses with central necrosis Pathological Features Predominantly lobular , or sometimes trabecular, growth pattern A ssociated with a prominent ramifying capillary network.

65. 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

66. IHC Glycogen , vimentin, CD99 / O13 / mic2, S100, keratin (20 %) Differential diagnosis Lymphoma Rhabdomyosarcoma Rx & Prognosis Wide surgical excisison Chemotherapy/Radiotherapy resistant

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