Tumors of neuroectodermal origin


Reactive lesions

Traumatic Neuroma

Definition

  • A reactive/reparative process characterized by proliferation of axons, Schwann cells, and perineurial fibroblasts in a disorganized pattern in the background of collagenous stroma (scar) at the proximal end of an injured/severed peripheral, cranial, or autonomic nerve

  • Causally related to trauma to a nerve as a result of diverse etiologies, most commonly surgical procedure

  • Peripheral sensory nerve(s) most commonly affected, followed by motor sensory nerves and autonomic nerves

Clinical features

Epidemiology

  • No gender predilection

  • No age predominance

  • Frequency varies according to the underlying causative event

    • Less than 3% of patients after radical neck dissection

    • As high as 26% of patients after bilateral limb amputation

  • Associated conditions, in addition to previous surgery, include burns, trauma, minor trauma (not readily apparent), human bite, arteriovenous aneurysm, nuchal- and extranuchal-type fibroma

Presentation

  • Solitary firm nodule or a raised, occasionally erythematous area within a preexistent scar

  • Not fixed to the underlying tissue

  • Generally measures less than 1 cm in greatest diameter

  • Usually painful, but asymptomatic examples not uncommon

  • Other sensory abnormalities include paresthesia, anesthesia, tenderness, and hypersensitivity

  • Multiple lesions infrequent

    • Genital locations

    • May be associated with previous burns

  • Site of origin generally related to the site of previous trauma and most commonly includes extremities and the head and neck area

  • Mucosal surfaces (e.g., oral cavity) can also be affected

  • Uncommon sites include intraosseous occurrence, subungual area, and penis

Prognosis and treatment

  • Treatment options include nonsurgical methods (injections of steroids, sympathetic ganglion block, therapy by ultrasound) with variable success, as well as surgical excision

  • Complete surgical excision usually curative, but recurrences not uncommon, and multiple procedures may be needed

Pathology

Histology

  • Disorganized/haphazard proliferation of all the elements of the nerve fascicle, including axons, Schwann cells, and perineural fibroblasts, in the dermis and/or subcutis

  • Variably cellular collagenous and hyalinized stroma in the background (scarring)

  • Cleft-like spaces between components of the lesion and stroma

  • Additional features

    • Intraepithelial proliferation of axons overlying the lesion has been described at mucosal sites

    • Granular cytoplasm of Schwann cells with centrally placed uniform nucleoli exceptionally reported in lesions developing in the breast

    • Mature ganglion cells, occasionally in clusters, with accompanying satellite cells

    • Dystrophic calcification

    • Mast cells in variable proportions

    • Chronic inflammation

    • Mucinous change in the stroma

  • Perineural and intraneural infiltration of nerve bundles by neoplastic cells reported in an exceptional case of squamous cell carcinoma and microcystic adnexal carcinoma

Main differential diagnoses

  • Accessory digit

  • Mucosal neuroma

  • Schwannoma

  • Neurofibroma

  • Ganglioneuroma

Fig. 1, Traumatic neuroma.

Fig. 2, Traumatic neuroma.

Fig. 3, Traumatic neuroma

Digital Pacinian Neuroma

Definition

  • A variant of neuroma characterized by aggregates of hyperplastic Pacinian corpuscles surrounded by increased numbers of small nerve fibers and mild pericorpuscular, perineural, and endoneural fibrosis

  • Probably not a true neoplasia, but likely rather represents a distinctive form of a hyperplastic tissue response

Clinical features

Epidemiology

  • No gender predilection

  • Middle-aged adults

  • Congenital occurrence in a single patient

  • About 50% of lesions associated with previous trauma

  • One lesion associated with Morton neuroma

Presentation

  • Progressive, sometimes excruciating pain in the affected digit, radiating to the arm

  • Local tenderness

  • Localized swelling or small, palpable nodule

  • Solitary lesions predominate, but multifocal occurrence possible

  • Site of occurrence includes fingers and toes

Prognosis and treatment

  • Complete excision associated with immediate relief of symptoms

  • No recurrences reported

Pathology

Histology

  • Main components of the lesion include Pacinian corpuscles, nerve fibers, and fibrosis

  • Pacinian corpuscles increased in numbers (hyperplasia) and size (hypertrophy)

    • Composed of central axon surrounded by a discontinued single Schwann cell layer and lamellae of perineurial cells

    • Pericorpuscular fibrosis generally present, but usually mild

  • Small nerve fibers increased in numbers

    • In between Pacinian corpuscles

    • Endoneural and perineural fibrosis

  • Additional histological features

    • Foreign body granuloma

    • Traumatic neuroma

    • Mild inflammation

    • Erosive changes of the proximal phalanx reported in a single case

Main differential diagnoses

  • Neurotized melanocytic nevus

  • Traumatic neuroma

  • Pacinian schwannoma

  • Pacinian neurofibroma

Fig. 1, Digital Pacinian neuroma.

Fig. 2, Digital Pacinian neuroma.

Fig. 3, Digital Pacinian neuroma.

Fig. 4, Digital Pacinian neuroma.

Morton Neuroma

Definition

  • An entrapment-related degenerative neuropathy, not a true neuroma, with a strong predilection for the third common digital nerve of the foot

  • Recognized morphologically by edema and hypertrophy of the affected nerve with associated degenerative changes, including degeneration/demyelinization of axons, intraneural and perineural fibrosis/sclerosis, and proliferation/hyalinization of intraneural vessels

Clinical features

Epidemiology

  • Striking female predominance (F:M = 5–10 : 1)

  • Different age groups can be affected, but most common between 40 and 60 years of age

Presentation

  • Fullness with enlargement of the interdigitating space with subsequent thickening

  • Well-defined mass or nodule generally not seen

  • Forefoot pain, irritating and debilitating at the bottom of the foot, usually on walking

  • Tenderness and paresthesia

  • Size of the lesion from 0.7 to 2.0 cm (mean size 1.1 cm)

  • Predilection for third to fourth web interspace of the foot, followed by second to third web interspace, but distal sites to the metatarsal heads not uncommonly affected

  • Associated conditions can include rheumatoid nodules at the same site(s) in the setting of rheumatoid arthritis

  • Multiple lesions rare

Prognosis and treatment

  • Gradual onset, but slowly progressive if left untreated

  • Nonsurgical treatment options include activity modification, use of appropriate footwear, nonsteroidal anti-inflammatory drugs, sonography-guided alcohol injections, injection of local anesthetics, and corticosteroids

  • Radiofrequency ablation and surgical neurectomy

Pathology

Histology

  • Thickening of the affected nerve

  • Degeneration and demyelinization of nerve fibers

  • Fibrosis/sclerosis of the epineurium, perineurium, and endoneurium

  • Proliferation, hyalinization, and sclerosis of endoneurial vessels

Main differential diagnoses

  • The diagnosis is generally made on clinical grounds

Fig. 1, Morton neuroma.

Fig. 2, Morton neuroma.

Fig. 3, Morton neuroma.

Fig. 4, Morton neuroma.

Hamartomas

Mucosal Neuroma

Definition

  • A benign lesion, most likely a hamartoma, characterized by proliferation of hyperplastic peripheral nerves in disorganized pattern, surrounded by frequently incomplete capsule containing perineurial cells

  • Multiple mucosal neuromas

    • Associated with the multiple endocrine neoplasia type 2B (MEN 2B) syndrome in the great majority of cases

    • Regarded due to their presence at birth or development shortly thereafter as an early marker of an underlying genetic disease

  • MEN 2B syndrome

    • Designated also as mucosal neuroma syndrome, Wagenmann–Froboese syndrome, or Gorlin syndrome

    • An autosomal-dominant inherited hamartoneoplastic syndrome

    • About 50% of patients present with sporadic mutations

    • Over 95% of cases due to a specific germline single-point mutation at codon 918 in exon 16 of the RET gene on chromosome 10 resulting in the replacement of methionine by threonine

    • Defining features of the syndrome include multiple mucosal neuromas, medullary thyroid carcinoma (in virtually all patients), Marfanoid body habitus with typical dysmorphic facies (features present in about 75% of the patients: widely set eyes, thickening and eversion of upper eyelid margins, visible tarsal plates, large and prominent eyebrows, flat nasal bridge, enlarged and nodular lips, elongated face), pheochromocytoma (in about 50% of patients, half of them multiple and frequently bilateral), and gastrointestinal (ganglio)neuromatosis (present in about 30% of patients, most commonly in the large and small bowel)

  • Patients presenting with typical physical features of MEN 2B but lacking identifiable germline mutation(s) and endocrinopathy likely represent a subgroup of the syndrome, designated as pure mucosal neuroma syndrome

  • Very rare association with dermal hyperneury even in clinically normal skin

Clinical features

Epidemiology

  • Equal gender distribution

  • Usually present at birth or develops shortly thereafter

  • Solitary mucosal or cutaneous lesions, not associated with MEN 2B, appear to develop in older patients

Presentation

  • Dome-shaped papules or small nodules covered by normal mucosa

  • Size about 5 mm in largest diameter

  • Sites of predilection include oral mucosa (lips, buccal area, gingivae, palate, tongue), but also eyelids, conjunctiva, and sclera

  • Cutaneous involvement in MEN 2B much more infrequent

    • Present as small papules or nodules, skin colored

    • Diverse sites of origin, including perinasal area, pinna, and face, less often on trunk

    • Widespread cutaneous neuromas (over 70) in association with macular amyloidosis on the back reported in a single patient

  • Dermal hyperneury consists of the presence of increased normal nerve bundles within the dermis

  • Solitary lesions not associated with MEN 2B also reported in the larynx, hard palate, and bronchial mucosa

  • Multiple intraosseous neural hyperplasia(s) in maxillary bone also reported and is thought to be highly suggestive for MEN 2B

Prognosis and treatment

  • No treatment generally required

  • Surgical treatment usually related to the location-induced functional impairment

  • Occurrence at particular location(s) (e.g., vocal cords) can be life threatening

Pathology

Histology

  • Poorly circumscribed nodular or multinodular (plexiform) arrangement(s) of hyperplastic peripheral nerves in the subepithelial stroma or dermis

  • Haphazardly arranged, disorganized, interlacing fascicles of Schwann cells and axons

  • Nuclear palisading of Schwann cells can occasionally be seen and usually represents a focal phenomenon

  • Mitoses and nuclear pleomorphism absent

  • Hyperplastic nerves surrounded at the periphery of fascicles by a discontinuous layer of perineurial cells

Immunohistochemistry/special stains

  • Schwann cells strongly positive for S100 protein

  • Perineurial cells highlighted by EMA

Main differential diagnoses

  • Traumatic neuroma

  • Solitary circumscribed neuroma

Fig. 1, Mucosal neuroma.

Fig. 2, Mucosal neuroma.

Fig. 3, Mucosal neuroma.

Fig. 4, Mucosal neuroma.

Primary Cutaneous Ganglioneuroma

Definition

  • A hamartomatous dermal proliferation composed of mature ganglion cells and fascicles of hyperplastic nerve fibers with Schwann cells and axons

Clinical features

Epidemiology

  • No gender predilection

  • Wide age distribution (0–92 years), most common in the fourth decade of life

Presentation

  • Asymptomatic, flesh-colored, dome-shaped, sometimes verrucous papule or groups of papules with occasional linear arrangement(s)

  • Solitary lesions predominate, multifocal occurrence exceptional

  • Size about 1 cm in greatest diameter in cases of a solitary papule

  • Predilection for the trunk, followed by extremities, head and neck, and acral locations

Prognosis and treatment

  • Diagnosis generally not suspected on clinical grounds

  • Excision usually performed due to other suspected pathology

  • Complete excision curative

Pathology

Histology

  • Well-circumscribed, nonencapsulated proliferation

  • Composed of mature ganglion cells and fascicles of hyperplastic nerves with Schwann cells and axons

    • Proportion of the component varies among the lesions

    • Components usually intermingled, but can be separated

  • Ganglion cells characterized by

    • Abundant eosinophilic to basophilic cytoplasm

    • Vesicular, eccentrically placed nuclei

    • Prominent nucleoli

    • Oval to stellate-shaped morphology

    • Retraction artifact between ganglion cells and surrounding stroma

  • Hyperplastic nerves characterized by proliferation of

    • Spindle-shaped Schwann cells with elongated and slightly wavy nuclei forming bundles and fascicles

    • Axons arranged in interweaving fascicles

  • Epidermal changes include acanthosis, papillomatosis, hypergranulosis, and hyperkeratosis

    • Features indistinguishable from seborrheic keratosis can also be seen

  • Additional changes include

    • Stromal desmoplasia

    • Focal myxoid change

    • Fatty metaplasia

    • Chronic inflammatory cell infiltrate composed of lymphocytes and macrophages

Immunohistochemistry/special stains

  • Ganglion cells strongly positive for synaptophysin, c-kit (CD117), and CD56; nearly always positive for neuron-specific enolase (NSE) and neurofilament; and positive for S100 protein

  • Schwann cells positive for S100 protein

Main differential diagnoses

  • Ganglion cell choristoma

  • Entrapment of ganglion cells by neurofibroma

  • Skin metastasis of a well-differentiated neuroblastoma (maturation into ganglioneuroma)

  • Benign and malignant melanocytic proliferations

  • Reticulohistiocytoma

  • Epithelioid fibrous histiocytoma

Fig. 1, Primary cutaneous ganglioneuroma.

Fig. 2, Primary cutaneous ganglioneuroma.

Fig. 3, Primary cutaneous ganglioneuroma.

Fig. 4, Primary cutaneous ganglioneuroma.

Fig. 5, Primary cutaneous ganglioneuroma.

Congenital Neurovascular Hamartoma

Definition

  • A hamartomatous proliferation of capillaries in the background of bland spindle cells showing neural differentiation

  • May represent a cutaneous marker for subsequent development of a malignant rhabdoid tumor

Clinical features

Epidemiology

  • Infancy and early childhood

Presentation

  • Not distinctive

Prognosis and treatment

  • Benign

  • No treatment generally required

Pathology

Histology

  • Dermal proliferation

  • Small capillaries

  • Background proliferation of bland, spindle-shaped cells

Immunohistochemistry/special stains

  • Spindle cells neuron specific enolase positive

Main differential diagnoses

  • Various nerve sheath tumors

Fig. 1, Congenital neurovascular hamartoma.

Fig. 2, Congenital neurovascular hamartoma.

Fig. 3, Congenital neurovascular hamartoma.

Benign neoplasms

Solitary Circumscribed Neuroma

Definition

  • A benign proliferation composed of fascicles, nests, and whorls of Schwann cells, admixed with a variable number of axons, usually surrounded by an incomplete capsule containing perineurial cells

  • Likely represents a reactive proliferation, a distinctive form of neuroma generally not associated with previous trauma within a small nerve

  • Originally reported as palisaded encapsulated neuroma

Clinical features

Epidemiology

  • Equal gender distribution

  • Most common in age groups between 30 and 60 years

  • Generally not associated with particular neurocutaneous syndrome(s), like neurofibromatosis, multiple endocrine neoplasia (MEN), Cowden syndrome, Bannayan–Riley–Ruvalcaba syndrome, or Gorlin syndrome

Presentation

  • Solitary pink or flesh-colored papule or small nodule

    • Slowly growing, dome shaped, and firm

    • Asymptomatic or slightly painful

    • Size between 0.2 and 0.6 cm

  • Multiple lesions an exception

    • Synchronous occurrence of multiple lesions in a linear distribution on both hands (palms and fingers) reported recently

  • Loss of hair follicles and hairs in areas of skin overlying the lesion usually noted

  • Predilection for the face, especially areas close to the interface between skin and mucosal sites

  • Less frequent sites include neck, trunk, shoulders, proximal extremities, and acral sites

  • Mucosal surfaces can also be affected, including oral and nasal mucosa and glans penis

Prognosis and treatment

  • Complete excision curative

  • Recurrences after incomplete/marginal excision unlikely

Pathology

Histology

  • Nodular and less commonly multinodular (plexiform) proliferation in the dermis with exceptional extension into the subcutaneous fatty tissue

  • Main components include Schwann cells, axons, and perineurial cells

  • Schwann cells forming broad intersecting elongated fascicles, nests, or whorls of bland spindle cells

    • Nuclei pointed at ends, but also plump, fusiform, and wavy

    • Palisading of nuclei with formation of Verocay bodies an exception; if present, generally a focal phenomenon

    • Mitoses absent or exceptional

    • Nuclear pleomorphism absent or mild and limited

    • Cytoplasm poorly delineated, pale, and eosinophilic

    • Fascicles separated by artifactual clefts, also present at the peripheral aspects of the proliferation

  • Axons

    • Arranged in parallel to the orientation of the fascicles

    • Usually evenly distributed and numerous

    • Axon(s) to Schwann cells ratio usually does not exceed 1 : 2 (A:SC ≤1 : 2)

    • In rare cases, their distribution can be focal and scarce

  • Perineurial cells

    • Within the discontinuous capsule at the periphery of the lesion

    • Not present in between Schwann cells within the lesion

  • Preexistent peripheral nerve can be identified in about 50% of the lesions

    • Serial sections may be necessary to demonstrate this phenomenon

  • Histological variants include epithelioid, multinodular (plexiform), and vascular

    • Epithelioid variant, as the name implies, features more epithelioid cells with round to oval nuclei and more prominent eosinophilic cytoplasm

    • Multinodular (plexiform) variant essentially corresponds to multiple interconnecting nodules representing a single lesion sectioned at multiple planes throughout the dermis

    • Vascular variant is characterized by an increase in cavernous-type blood vessels with possible thromboses and perivascular hyalinization (“ancient-like” changes)

  • Additional histological features

    • Overlying epithelium normal, atrophic, or hyperplastic

    • Myxoid change and stromal mucin, rarely extensive

    • Limited inflammatory cell infiltrate composed of lymphocytes and, rarely, eosinophils

    • Limited collagenized connective tissue stroma

Immunohistochemistry/special stains

  • Schwann cells positive for S100 protein and collagen type IV

  • Axons can be delineated by neurofilament stain

  • Perineurial cell population EMA, GLUT-1, and/or claudin-1 positive

  • GFAP staining consistently negative

Main differential diagnoses

  • (Multiple) mucosal neuroma(s)

  • Traumatic neuroma

  • Neurofibroma

  • Schwannoma

Fig. 1, Solitary circumscribed neuroma.

Fig. 2, Solitary circumscribed neuroma.

Fig. 3, Solitary circumscribed neuroma.

Fig. 4, Solitary circumscribed neuroma.

Fig. 5, Solitary circumscribed neuroma.

Fig. 6, Solitary circumscribed neuroma.

Epithelial Sheath Neuroma

Definition

  • A distinctive benign proliferation composed of numerous thickened and enlarged nerves surrounded by a perineural epithelial sheath, restricted to the superficial dermis

Clinical features

Epidemiology

  • Fewer than 10 cases reported

  • Slight female predominance (F:M = 4 : 3)

  • Adult patients (from 43 to 86 years, mean age 63 years)

Presentation

  • Solitary erythematous plaque, papule, or nodule

  • Size from 0.5 to 2 cm in greatest diameter

  • Asymptomatic, pruritic, or painful

  • Exclusively reported on the skin of the back so far

Prognosis and treatment

  • Simple excision curative

  • No recurrences reported

Pathology

Histology

  • Proliferation restricted to the papillary and superficial reticular dermis

  • Numerous thickened peripheral nerves surrounded by perineural epithelial sheath

  • Peripheral nerves

    • Disorganized proliferation

    • Occasionally display parallel orientation to the surface epidermis

    • May not be associated with perineural epithelial sheath, especially at the periphery of the lesion

  • Perineural epithelial sheath

    • Composed of regular squamous epithelium, likely of infundibular derivation

    • Cornification generally preserved with formation of dyskeratotic keratinocytes, presence of granular cell layer, and orthokeratotic basket-weave keratin

    • Epithelial elements only can occasionally be seen, not associated with peripheral nerves, especially in the central parts of the lesion

    • Epithelial sheath can be absent, especially at the peripheral aspects of the lesion, composed of thickened nerves only

  • Additional features

    • Perineural inflammatory cell infiltrate composed of lymphocytes and plasma cells, variably prominent

    • Minimal and delicate perineural fibroplasia

    • Myxoid/mucinous perineural stromal degeneration

  • Overlying epidermis usually normal

  • No connection to the epidermis or adnexal structures

Immunohistochemistry/special stains

  • Nerve bundles

    • Consistent positivity for S100 protein, neurofilament, CD57, and nerve growth factor receptor

  • Perineural epithelial sheath(s)

    • Strong positivity for CK-MNF116 and less intense positivity for CK-AE1/AE3

    • Negative for CAM5.2, EMA, and CEA

Main differential diagnoses

  • Traumatic neuroma

  • Idiopathic neuroma

  • Reactive neuroepithelial aggregates

  • Cutaneous hamartomas containing nerve fibers

    • Neurofollicular hamartoma

    • Congenital neural hamartoma

    • Striated muscle hamartoma/rhabdomyomatous mesenchymal hamartoma

  • Reexcision perineural invasion by nonneoplastic squamous epithelium

  • Perineural infiltration by epithelial tumors (e.g., squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma) or keratoacanthoma

  • Dermal hyperneury

Fig. 1, Epithelial sheath neuroma.

Fig. 2, Epithelial sheath neuroma.

Fig. 3, Epithelial sheath neuroma.

Conventional Schwannoma

Definition

  • A benign peripheral nerve sheath tumor composed of Schwann cells

Clinical features

Epidemiology

  • Equal gender distribution

  • Most common in the fourth and fifth decade of life

Presentation

  • Slowly growing, painless swelling or nodule

  • Pain on percussion over the nerve (Tinel sign) present in over 90%

  • Multiple lesions can be associated with neurofibromatosis type 2

  • Multiple nonintradermal schwannomas in the absence of vestibular schwannomas can represent part of a schwannomatosis, an autosomal-dominant multiple neoplasia syndrome associated with a mutation in the SMARCB1 tumor suppressor gene located on chromosome 22q11

Prognosis and treatment

  • Benign tumor with very low malignant potential

  • Complete excision generally curative

Pathology

Histology

  • Biphasic morphological pattern, designated as Antoni A and Antoni B areas, intermixed and in variable proportions

  • Antoni A areas

    • Cellular component

    • Closely packed spindle cells with wavy, elongated, and tapering nuclei

    • Cytoplasm ill defined, eosinophilic

    • Verocay bodies: two rows of nuclear palisading separated by Schwann cell processes

    • Mitoses rare

    • Degenerative nuclear pleomorphism

    • Stroma frequently hyalinized or collagenized with focal dystrophic calcifications

    • Small blood vessels with frequently hyalinized vessel walls

  • Antoni B areas

    • Hypocellular component

    • Irregularly distributed spindle and stellate cells

    • Abundant myxoid stroma

    • Scattered chronic inflammatory cell infiltrate

    • Small blood vessels with frequently hyalinized vessel walls

    • Degenerative changes not uncommon, including deposition of hemosiderin and microcystic change

  • Very rarely schwannoma can show Pacinian differentiation

    • Such lesions were previously considered neurofibromas with Pacinian features

    • These are not associated with neurofibromatosis, but have been associated in a few cases with vascular malformations

Immunohistochemistry/special stains

  • Strong nuclear and cytoplasmic S100 protein positivity

  • Capsule contains EMA-positive perineurial cells

Genetic profile

  • Aberrations on chromosome 22 frequent (loss of 22q or monosomy of chromosome 22)

Main differential diagnoses

  • Solitary circumscribed neuroma

  • Neurofibroma

  • Leiomyoma

Fig. 1, Conventional schwannoma.

Fig. 2, Conventional schwannoma.

Fig. 3, Conventional schwannoma.

Fig. 4, Conventional schwannoma.

Fig. 5, Conventional schwannoma.

Fig. 6, Conventional schwannoma.

Fig. 7, Conventional schwannoma.

Plexiform Schwannoma

Definition

  • A variant of schwannoma characterized by multinodular (plexiform) proliferation of Schwann cells

  • The majority of the tumors occur in the superficial nerves; origin from major peripheral nerves much more uncommon

Clinical features

Epidemiology

  • Represents about 5% of schwannomas

  • No sex predilection

  • Wide age distribution, but most common in young adults (fourth decade of life)

  • Congenital/childhood occurrence signifies possible association with neurofibromatosis type 2 or schwannomatosis, especially when lesions are multiple

Presentation

  • Slowly growing, generally nonpainful nodule

  • Single lesions predominate

  • Size usually less than 2 cm, but giant variants also reported

  • Multiple lesions can develop within the single anatomical area, or are widely distributed

  • Most common at superficial locations (dermis/subcutis) (90%), with predilection for the head and neck, upper extremities, and trunk

  • Mucosal sites (e.g., oral cavity), deep soft tissues (about 50% develop in extremities, followed by pelvis), or visceral locations (gastrointestinal tract) affected less frequently (in about 10%)

  • Association with neurofibromatosis type 2 (NF2) (with multiple lesions in the dermis and subcutis) and, less often, with schwannomatosis, whereas occurrence in the setting of neurofibromatosis type 1 (NF1) much more uncommon

  • Plexiform schwannoma in the setting of NF1 and NF2 exceptionally associated with macrodactyly

Prognosis and treatment

  • Benign tumors with no malignant potential, but may cause severe nerve dysfunction

  • Recurrences rare, usually after incomplete excision

  • Complete excision curative

  • Tumors developing within plexiform schwannoma in exceptional cases

    • Epithelioid angiosarcoma

    • Intratumoral metastases, mainly from the breast

Pathology

Histology

  • Antoni A elements (cellular) predominant/exclusive component of the lesions

  • Antoni B elements present focally or lacking altogether

  • Generally encapsulated by thin layer of perineurial cells, which may be discontinuous/lacking immediately beneath the surface, especially at the mucosal sites

  • Increased cellularity, mitotic activity, nuclear pleomorphism, and focal areas of necrosis (12% of deep-seated variants of plexiform schwannoma) do not have any biological significance

Immunohistochemistry/special stains

  • S100 protein positive

Genetic profile

  • Chromosomal abnormalities appear to be different than in conventional schwannoma, with trisomy of chromosome 17 and 18, not associated with chromosome 22 aberrations

Main differential diagnoses

  • Plexiform neurofibroma

  • Malignant peripheral nerve sheath tumor

Fig. 1, Plexiform schwannoma.

Fig. 2, Plexiform schwannoma.

Fig. 3, Plexiform schwannoma.

Fig. 4, Plexiform schwannoma.

Ancient Schwannoma

Definition

  • A subtype of schwannoma characterized by extensive degenerative changes thought to result from vascular insufficiency, usually in a long-standing lesion

Clinical features

Epidemiology

  • Elderly patients

  • Occurrence in pediatric population most unusual

  • Represents about 0.8% of soft tissue tumors

Presentation

  • Generally a long-standing lesion

  • Predilection for deeper locations, particularly soft tissues of the head and neck, thorax, retroperitoneum, pelvis, and extremities

  • An exceptional case occurring within the lymph node has also been reported

Prognosis and treatment

  • Lesions generally follow a benign clinical course

  • Malignant transformation of ancient schwannoma an exceedingly rare phenomenon with fewer than 10 such cases reported (see malignant peripheral nerve sheath tumor)

  • Complete excision curative

Pathology

Histology

  • Degenerative nuclear atypia characterized by nuclear hyperchromasia, pleomorphism, intranuclear cytoplasmic pseudoinclusions, and often multilobated nuclei

  • Mitotic activity absent or very low

  • Relative loss of cellular Antoni A areas with increase in the proportions of hypocellular areas

  • Recent/old hemorrhage with extravasation of erythrocytes or hemosiderin deposition

  • Pseudocystic areas

  • Calcification and osseous metaplasia

  • Xanthomatous change and/or formation of cholesterol clefts

  • Vascular thrombosis in different stages of organization

  • Perivascular hyalinization

  • Stromal edema, hyalinization, and fibrosis

  • Background changes of conventional schwannoma

Immunohistochemistry/special stains

  • See conventional schwannoma

Main differential diagnoses

  • See conventional schwannoma

Fig. 1, Ancient schwannoma.

Fig. 2, Ancient schwannoma.

Fig. 3, Ancient schwannoma.

Fig. 4, Ancient schwannoma.

Fig. 5, Ancient schwannoma.

Cellular Schwannoma

Definition

  • A histological variant of schwannoma characterized by high cellularity, fascicular growth pattern, and mild cytological atypia, but associated with a benign biological behavior

Clinical features

Epidemiology

  • Middle-aged adults

  • Plexiform variant of cellular schwannoma can be congenital and shows predilection for childhood

  • Represents about 5% of schwannomas

  • Association with neurofibromatosis rare

Presentation

  • Slowly growing nodular proliferation

  • Predilection for paravertebral areas of the mediastinum and retroperitoneum

  • Neurological disturbances related to the site of origin; erosion of the bone occasionally present

  • Plexiform variant of cellular schwannoma

    • Multinodular occurrence, occasionally associated with a rapid growth

    • Predilection for extremities

    • Generally lacks association with neurofibromatosis

  • An unusual collision of cellular schwannoma and plexiform neurofibroma in the absence of neurofibromatosis reported recently

Prognosis and treatment

  • Benign clinical course with lack of malignant alteration

  • Recurrences after incomplete excision common, with increased mitotic activity demonstrated to be predictive of possible recurrence

  • Complete excision curative, but might be difficult to achieve due to the site of origin

Pathology

Histology

  • Predominance of highly cellular Antoni A areas with spindle cells growing in interlacing fascicles, but additional storiform or whorled pattern not uncommon

  • Mitotic activity

    • Typically present and may be as high as 10 mitoses per 10 high-power fields

    • Atypical mitoses absent

  • Isolated microfoci of necrosis not uncommon, but larger areas of necrosis or multifocal necrosis an exception

  • Mild to moderate nuclear pleomorphism associated with nuclear hyperchromasia

  • Absence of Verocay bodies, but vague nuclear palisading can be present at least focally

  • Additional features

    • Foamy macrophages, may be particularly prominent

    • Inflammatory cell infiltrate, usually composed of lymphocytes

Immunohistochemistry/special stains

  • Diffuse and strong S100 protein positivity

Main differential diagnoses

  • Malignant peripheral nerve sheath tumor

  • Leiomyosarcoma

Fig. 1, Cellular schwannoma.

Fig. 2, Cellular schwannoma.

Fig. 3, Cellular schwannoma.

Fig. 4, Cellular schwannoma.

Epithelioid Schwannoma

Definition

  • A variant of schwannoma characterized by the predominance of epithelioid Schwann cells growing in cords and nests

Clinical features

Epidemiology

  • Female predominance

  • Adult patients, most common in the fifth decade of life

Presentation

  • Slowly growing, asymptomatic nodule

  • Lesions can also be painful

  • Generally less than 2 cm in greatest diameter

  • Predilection for the head and neck area, followed by the back

  • Rare sites include intracranial nerves and neck of the bladder

Prognosis and treatment

  • Benign lesion with no malignant potential

  • Recurrences rare, even after incomplete excision

  • Conservative excision generally curative

Pathology

Histology

  • Highly cellular, multinodular proliferation surrounded by a thin capsule (may be absent in rare instances)

  • Lesional cells grow in small nests, trabeculae, cords, or strands (can be separated by artifactual clefts)

  • Epithelioid cells with round to oval nuclei containing small nucleoli and well-defined, abundant eosinophilic cytoplasm

  • Mitoses rare (usually up to 1 per 10 high-power fields), atypical mitoses absent

  • Necrosis absent

  • Focal symplastic change with nuclear pleomorphism and intranuclear cytoplasmic pseudoinclusions frequently present

  • Transitions to classic schwannoma can be seen focally in a proportion of cases

  • Medium-sized blood vessels with hyalinized walls

  • Myxoid matrix

  • Plexiform variant characterized by

    • Multiple nodules composed of epithelioid Schwann cells in the dermis and subcutis

    • Each nodule surrounded by a thin layer of perineurial cells

    • Up to 5 mitoses per 10 high-power fields

Immunohistochemistry/special stains

  • Diffuse and strong nuclear and cytoplasmic S100 protein positivity

  • EMA, melan A, CD34, various cytokeratins negative

  • Proliferative activity (Ki-67) generally low

Main differential diagnoses

  • Epithelioid neurofibroma

  • Myoepithelial tumors

  • Epithelioid malignant peripheral nerve sheath tumor

Fig. 1, Epithelioid schwannoma.

Fig. 2, Epithelioid schwannoma.

Fig. 3, Epithelioid schwannoma.

Fig. 4, Epithelioid schwannoma.

Fig. 5, Epithelioid schwannoma.

Fig. 6, Epithelioid schwannoma.

Fig. 7, Epithelioid schwannoma.

Fig. 8, Epithelioid schwannoma.

Fig. 9, Epithelioid schwannoma.

Neuroblastoma-Like Schwannoma

Definition

  • A variant of schwannoma characterized by proliferating Schwann cells forming a rosette-like growth pattern

Clinical features

Epidemiology

  • Female predominance (F:M = 6 : 1)

  • Wide age distribution, most common in fourth decade of life

  • Not associated with neurofibromatosis

Presentation

  • Solitary asymptomatic nodule, occasionally painful

  • Predilection for neck, followed by trunk and extremities

  • Unusual locations include vulva and orbit

Prognosis and treatment

  • Benign lesion

  • Complete excision curative

Pathology

Histology

  • Well-circumscribed and encapsulated

  • Dermis and/or subcutis

  • Lesional cells small with round to oval nuclei, indistinct nucleoli, and scant cytoplasm

  • Epithelioid morphology not uncommon, either focally or more extensive

  • Formation of rosette-like structures around blood vessels or collagenous cores

  • Mild nuclear atypia occasionally present

  • Mitoses generally absent

  • Necrosis absent

  • Multinodular/plexiform growth pattern in a single case

  • Typical features of conventional schwannoma present at least focally in the majority of cases

Immunohistochemistry/special stains

  • Diffuse and strong S100 protein positivity

  • Occasional focal positivity for synaptophysin, GFAP, and neuron specific enolase

  • EMA delineates perineurial cells within the capsule

Main differential diagnoses

  • Neuroblastoma

  • Dendritic cell neurofibroma with pseudorosettes

Fig. 1, Neuroblastoma-like schwannoma.

Fig. 2, Neuroblastoma-like schwannoma.

Fig. 3, Neuroblastoma-like schwannoma.

Fig. 4, Neuroblastoma-like schwannoma.

Fig. 5, Neuroblastoma-like schwannoma.

Microcystic/Reticular Schwannoma

Definition

  • A distinctive variant of schwannoma characterized by anastomozing and intersecting cords/strands of spindled Schwann cells with the formation of a delicate microcystic or reticular growth pattern

Clinical features

Epidemiology

  • Wide age distribution (11–93 years, median 63 years)

  • No gender predominance

Presentation

  • Slowly growing solitary nodule

  • Multinodular growth reported in a single case, presented with facial swelling

  • Size from 0.4 to 23 cm (median size 4.3 cm)

  • Predilection for visceral sites, especially gastrointestinal tract (isolated cases reported also in adrenal gland, respiratory tract, pancreas, cervical spine)

  • Rare sites include subcutis and deep soft tissue

Prognosis and treatment

  • Benign clinical course

  • No recurrences after complete excision

Pathology

Histology

  • Lesions at visceral sites generally well circumscribed but not encapsulated

  • Cutaneous tumors encapsulated

  • Spindle cells growing in anastomozing and interconnecting strands with formation of a microcystic/reticular and, less often, cribriform growth pattern

  • Nuclei round, oval, or tapered with inconspicuous small nucleoli

  • Nuclear atypia generally absent

  • Mitoses rare (usually fewer than 3 per 50 high-power fields)

  • Cytoplasm ill defined, eosinophilic

  • Myxoid material or fibrillary collagen occasionally present within microcystic/reticular structures

  • Intervening stroma myxoid, fibrillary, or sclerotic/collagenized

  • Areas resembling conventional schwannoma, foci with epithelioid morphology, and fascicular growth pattern occasionally present

  • Scattered inflammatory cell infiltrates composed of lymphocytes (aggregates or formation of germinal centers rare)

Immunohistochemistry/special stains

  • Strong and diffuse nuclear and cytoplasmic S100 protein positivity

  • Variable positivity for GFAP and CD117 (c-kit)

  • Negative for various cytokeratins, smooth muscle actin, desmin

Main differential diagnoses

  • Extraskeletal myxoid chondrosarcoma

  • Perineurioma

  • Myoepithelial tumors

Fig. 1, Microcystic/reticular schwannoma.

Fig. 2, Microcystic/reticular schwannoma.

Fig. 3, Microcystic/reticular schwannoma.

Fig. 4, Microcystic/reticular schwannoma.

Hybrid Schwannoma/Perineurioma

Definition

  • A benign, peripheral, nerve sheath tumor composed of an intimate admixture of Schwann cells and perineurial cells in variable proportions

Clinical features

Epidemiology

  • Equal gender distribution

  • Most common in the fourth decade of life, although age distribution is quite broad (about 70% develop from second to fifth decade)

  • Association with neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis appears to be more frequent than initially estimated, especially for multiple lesions

Presentation

  • Solitary, slowly growing nodule

  • Generally asymptomatic, occasionally painful

  • Mean size about 3 cm

  • Predilection for limbs, head and neck, and trunk

  • Lesions can also develop at diverse sites, including visceral locations (gastrointestinal tract), mucosal sites (oral mucosa), lymph nodes, and external genital area

  • Two lesions reported recently, developed after previous irradiation, but the causative relationship uncertain

Prognosis and treatment

  • Benign proliferation

  • Local recurrence rare

  • Malignant alteration an exception (demonstrated in a single case)

Pathology

Histology

  • Well-circumscribed (infiltrative growth rare) and unencapsulated proliferation in the dermis and/or subcutis

  • Growth patterns include storiform, whorled, fascicular, with nuclear palisading, plexiform, and lamellar

  • Two cell populations intimately admixed (may be difficult to separate on sections stained with hematoxylin and eosin [H&E])

    • Schwann cells: nuclei more plump or tapering, eosinophilic cytoplasm with indistinct cell borders

    • Perineurial cells: slender nuclei with bipolar cytoplasmic processes

  • Mitoses usually absent

  • Degenerative nuclear atypia present in about 25% of the lesions

  • Myxoid and/or hyalinized stroma

  • An exceptional example with triple hybrid components, including schwannomatous, neurofibromatous, and perineuriomatous differentiation, has recently been reported in the nasal cavity

Immunohistochemistry/special stains

  • S100 protein–positive Schwann cells usually comprise about 50% to 60% of the population

  • EMA-positive and frequently also claudin-1–positive perineurial cells represent about 30% to 40% of the tumor cell population

  • No tumor cells coexpressing S100 protein and EMA

  • CD34 usually diffusely positive

  • Variable positivity for GFAP

  • Neurofilament demonstrates entrapped axons in about one-third of the lesions

Main differential diagnoses

  • Congenital melanocytic nevus with areas of neurotization

  • Schwannoma

  • Low-grade malignant peripheral nerve sheath tumor

Fig. 1, Hybrid schwannoma/perineurioma.

Fig. 2, Hybrid schwannoma/perineurioma.

Fig. 3, Hybrid schwannoma/perineurioma.

Fig. 4, Hybrid schwannoma/perineurioma.

Fig. 5, Hybrid schwannoma/perineurioma.

Cutaneous Perineurioma

Definition

  • A benign, peripheral nerve sheath tumor composed almost exclusively of perineurial cells occurring in the dermis or dermis/subcutis

  • Perineuriomas are traditionally separated into tumors developing either within (intraneural) or outside (extraneural) peripheral nerves

  • Perineuriomas can represent distinctive component of hybrid tumors, like schwannoma-perineurioma, cellular neurothekeoma–perineurioma, neurofibroma-perineurioma, and perineurioma–granular cell tumor (see hybrid tumors )

Clinical features

Epidemiology

  • Female predominance

  • Wide age distribution, but most common in the fifth decade of life

Presentation

  • Solitary, slowly growing papule or a superficial nodule

  • Cutaneous lesions generally smaller than soft tissue counterparts, with a median size of less than 1 cm

  • Most common on lower limbs and trunk, with the exception of sclerosing variant showing special predilection for fingers and palm

Prognosis and treatment

  • Complete excision curative

  • Recurrences distinctly uncommon

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