Reactive lesions
Traumatic Neuroma
Definition
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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
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Causally related to trauma to a nerve as a result of diverse etiologies, most commonly surgical procedure
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Peripheral sensory nerve(s) most commonly affected, followed by motor sensory nerves and autonomic nerves
Clinical features
Epidemiology
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No gender predilection
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No age predominance
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Frequency varies according to the underlying causative event
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Less than 3% of patients after radical neck dissection
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As high as 26% of patients after bilateral limb amputation
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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
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Solitary firm nodule or a raised, occasionally erythematous area within a preexistent scar
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Not fixed to the underlying tissue
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Generally measures less than 1 cm in greatest diameter
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Usually painful, but asymptomatic examples not uncommon
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Other sensory abnormalities include paresthesia, anesthesia, tenderness, and hypersensitivity
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Multiple lesions infrequent
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Genital locations
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May be associated with previous burns
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Site of origin generally related to the site of previous trauma and most commonly includes extremities and the head and neck area
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Mucosal surfaces (e.g., oral cavity) can also be affected
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Uncommon sites include intraosseous occurrence, subungual area, and penis
Prognosis and treatment
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Treatment options include nonsurgical methods (injections of steroids, sympathetic ganglion block, therapy by ultrasound) with variable success, as well as surgical excision
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Complete surgical excision usually curative, but recurrences not uncommon, and multiple procedures may be needed
Pathology
Histology
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Disorganized/haphazard proliferation of all the elements of the nerve fascicle, including axons, Schwann cells, and perineural fibroblasts, in the dermis and/or subcutis
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Variably cellular collagenous and hyalinized stroma in the background (scarring)
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Cleft-like spaces between components of the lesion and stroma
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Additional features
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Intraepithelial proliferation of axons overlying the lesion has been described at mucosal sites
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Granular cytoplasm of Schwann cells with centrally placed uniform nucleoli exceptionally reported in lesions developing in the breast
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Mature ganglion cells, occasionally in clusters, with accompanying satellite cells
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Dystrophic calcification
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Mast cells in variable proportions
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Chronic inflammation
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Mucinous change in the stroma
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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
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Accessory digit
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Mucosal neuroma
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Schwannoma
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Neurofibroma
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Ganglioneuroma
Digital Pacinian Neuroma
Definition
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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
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Probably not a true neoplasia, but likely rather represents a distinctive form of a hyperplastic tissue response
Clinical features
Epidemiology
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No gender predilection
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Middle-aged adults
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Congenital occurrence in a single patient
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About 50% of lesions associated with previous trauma
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One lesion associated with Morton neuroma
Presentation
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Progressive, sometimes excruciating pain in the affected digit, radiating to the arm
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Local tenderness
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Localized swelling or small, palpable nodule
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Solitary lesions predominate, but multifocal occurrence possible
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Site of occurrence includes fingers and toes
Prognosis and treatment
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Complete excision associated with immediate relief of symptoms
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No recurrences reported
Pathology
Histology
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Main components of the lesion include Pacinian corpuscles, nerve fibers, and fibrosis
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Pacinian corpuscles increased in numbers (hyperplasia) and size (hypertrophy)
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Composed of central axon surrounded by a discontinued single Schwann cell layer and lamellae of perineurial cells
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Pericorpuscular fibrosis generally present, but usually mild
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Small nerve fibers increased in numbers
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In between Pacinian corpuscles
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Endoneural and perineural fibrosis
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Additional histological features
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Foreign body granuloma
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Traumatic neuroma
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Mild inflammation
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Erosive changes of the proximal phalanx reported in a single case
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Main differential diagnoses
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Neurotized melanocytic nevus
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Traumatic neuroma
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Pacinian schwannoma
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Pacinian neurofibroma
Morton Neuroma
Definition
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An entrapment-related degenerative neuropathy, not a true neuroma, with a strong predilection for the third common digital nerve of the foot
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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
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Striking female predominance (F:M = 5–10 : 1)
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Different age groups can be affected, but most common between 40 and 60 years of age
Presentation
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Fullness with enlargement of the interdigitating space with subsequent thickening
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Well-defined mass or nodule generally not seen
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Forefoot pain, irritating and debilitating at the bottom of the foot, usually on walking
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Tenderness and paresthesia
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Size of the lesion from 0.7 to 2.0 cm (mean size 1.1 cm)
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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
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Associated conditions can include rheumatoid nodules at the same site(s) in the setting of rheumatoid arthritis
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Multiple lesions rare
Prognosis and treatment
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Gradual onset, but slowly progressive if left untreated
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Nonsurgical treatment options include activity modification, use of appropriate footwear, nonsteroidal anti-inflammatory drugs, sonography-guided alcohol injections, injection of local anesthetics, and corticosteroids
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Radiofrequency ablation and surgical neurectomy
Pathology
Histology
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Thickening of the affected nerve
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Degeneration and demyelinization of nerve fibers
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Fibrosis/sclerosis of the epineurium, perineurium, and endoneurium
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Proliferation, hyalinization, and sclerosis of endoneurial vessels
Main differential diagnoses
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The diagnosis is generally made on clinical grounds
Hamartomas
Mucosal Neuroma
Definition
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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
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Multiple mucosal neuromas
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Associated with the multiple endocrine neoplasia type 2B (MEN 2B) syndrome in the great majority of cases
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Regarded due to their presence at birth or development shortly thereafter as an early marker of an underlying genetic disease
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MEN 2B syndrome
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Designated also as mucosal neuroma syndrome, Wagenmann–Froboese syndrome, or Gorlin syndrome
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An autosomal-dominant inherited hamartoneoplastic syndrome
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About 50% of patients present with sporadic mutations
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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
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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)
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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
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Very rare association with dermal hyperneury even in clinically normal skin
Clinical features
Epidemiology
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Equal gender distribution
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Usually present at birth or develops shortly thereafter
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Solitary mucosal or cutaneous lesions, not associated with MEN 2B, appear to develop in older patients
Presentation
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Dome-shaped papules or small nodules covered by normal mucosa
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Size about 5 mm in largest diameter
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Sites of predilection include oral mucosa (lips, buccal area, gingivae, palate, tongue), but also eyelids, conjunctiva, and sclera
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Cutaneous involvement in MEN 2B much more infrequent
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Present as small papules or nodules, skin colored
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Diverse sites of origin, including perinasal area, pinna, and face, less often on trunk
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Widespread cutaneous neuromas (over 70) in association with macular amyloidosis on the back reported in a single patient
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Dermal hyperneury consists of the presence of increased normal nerve bundles within the dermis
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Solitary lesions not associated with MEN 2B also reported in the larynx, hard palate, and bronchial mucosa
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Multiple intraosseous neural hyperplasia(s) in maxillary bone also reported and is thought to be highly suggestive for MEN 2B
Prognosis and treatment
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No treatment generally required
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Surgical treatment usually related to the location-induced functional impairment
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Occurrence at particular location(s) (e.g., vocal cords) can be life threatening
Pathology
Histology
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Poorly circumscribed nodular or multinodular (plexiform) arrangement(s) of hyperplastic peripheral nerves in the subepithelial stroma or dermis
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Haphazardly arranged, disorganized, interlacing fascicles of Schwann cells and axons
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Nuclear palisading of Schwann cells can occasionally be seen and usually represents a focal phenomenon
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Mitoses and nuclear pleomorphism absent
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Hyperplastic nerves surrounded at the periphery of fascicles by a discontinuous layer of perineurial cells
Immunohistochemistry/special stains
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Schwann cells strongly positive for S100 protein
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Perineurial cells highlighted by EMA
Main differential diagnoses
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Traumatic neuroma
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Solitary circumscribed neuroma
Primary Cutaneous Ganglioneuroma
Definition
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A hamartomatous dermal proliferation composed of mature ganglion cells and fascicles of hyperplastic nerve fibers with Schwann cells and axons
Clinical features
Epidemiology
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No gender predilection
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Wide age distribution (0–92 years), most common in the fourth decade of life
Presentation
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Asymptomatic, flesh-colored, dome-shaped, sometimes verrucous papule or groups of papules with occasional linear arrangement(s)
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Solitary lesions predominate, multifocal occurrence exceptional
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Size about 1 cm in greatest diameter in cases of a solitary papule
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Predilection for the trunk, followed by extremities, head and neck, and acral locations
Prognosis and treatment
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Diagnosis generally not suspected on clinical grounds
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Excision usually performed due to other suspected pathology
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Complete excision curative
Pathology
Histology
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Well-circumscribed, nonencapsulated proliferation
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Composed of mature ganglion cells and fascicles of hyperplastic nerves with Schwann cells and axons
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Proportion of the component varies among the lesions
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Components usually intermingled, but can be separated
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Ganglion cells characterized by
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Abundant eosinophilic to basophilic cytoplasm
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Vesicular, eccentrically placed nuclei
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Prominent nucleoli
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Oval to stellate-shaped morphology
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Retraction artifact between ganglion cells and surrounding stroma
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Hyperplastic nerves characterized by proliferation of
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Spindle-shaped Schwann cells with elongated and slightly wavy nuclei forming bundles and fascicles
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Axons arranged in interweaving fascicles
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Epidermal changes include acanthosis, papillomatosis, hypergranulosis, and hyperkeratosis
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Features indistinguishable from seborrheic keratosis can also be seen
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Additional changes include
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Stromal desmoplasia
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Focal myxoid change
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Fatty metaplasia
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Chronic inflammatory cell infiltrate composed of lymphocytes and macrophages
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Immunohistochemistry/special stains
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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
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Schwann cells positive for S100 protein
Main differential diagnoses
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Ganglion cell choristoma
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Entrapment of ganglion cells by neurofibroma
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Skin metastasis of a well-differentiated neuroblastoma (maturation into ganglioneuroma)
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Benign and malignant melanocytic proliferations
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Reticulohistiocytoma
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Epithelioid fibrous histiocytoma
Congenital Neurovascular Hamartoma
Definition
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A hamartomatous proliferation of capillaries in the background of bland spindle cells showing neural differentiation
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May represent a cutaneous marker for subsequent development of a malignant rhabdoid tumor
Clinical features
Epidemiology
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Infancy and early childhood
Presentation
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Not distinctive
Prognosis and treatment
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Benign
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No treatment generally required
Pathology
Histology
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Dermal proliferation
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Small capillaries
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Background proliferation of bland, spindle-shaped cells
Immunohistochemistry/special stains
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Spindle cells neuron specific enolase positive
Main differential diagnoses
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Various nerve sheath tumors
Benign neoplasms
Solitary Circumscribed Neuroma
Definition
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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
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Likely represents a reactive proliferation, a distinctive form of neuroma generally not associated with previous trauma within a small nerve
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Originally reported as palisaded encapsulated neuroma
Clinical features
Epidemiology
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Equal gender distribution
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Most common in age groups between 30 and 60 years
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Generally not associated with particular neurocutaneous syndrome(s), like neurofibromatosis, multiple endocrine neoplasia (MEN), Cowden syndrome, Bannayan–Riley–Ruvalcaba syndrome, or Gorlin syndrome
Presentation
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Solitary pink or flesh-colored papule or small nodule
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Slowly growing, dome shaped, and firm
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Asymptomatic or slightly painful
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Size between 0.2 and 0.6 cm
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Multiple lesions an exception
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Synchronous occurrence of multiple lesions in a linear distribution on both hands (palms and fingers) reported recently
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Loss of hair follicles and hairs in areas of skin overlying the lesion usually noted
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Predilection for the face, especially areas close to the interface between skin and mucosal sites
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Less frequent sites include neck, trunk, shoulders, proximal extremities, and acral sites
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Mucosal surfaces can also be affected, including oral and nasal mucosa and glans penis
Prognosis and treatment
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Complete excision curative
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Recurrences after incomplete/marginal excision unlikely
Pathology
Histology
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Nodular and less commonly multinodular (plexiform) proliferation in the dermis with exceptional extension into the subcutaneous fatty tissue
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Main components include Schwann cells, axons, and perineurial cells
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Schwann cells forming broad intersecting elongated fascicles, nests, or whorls of bland spindle cells
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Nuclei pointed at ends, but also plump, fusiform, and wavy
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Palisading of nuclei with formation of Verocay bodies an exception; if present, generally a focal phenomenon
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Mitoses absent or exceptional
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Nuclear pleomorphism absent or mild and limited
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Cytoplasm poorly delineated, pale, and eosinophilic
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Fascicles separated by artifactual clefts, also present at the peripheral aspects of the proliferation
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Axons
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Arranged in parallel to the orientation of the fascicles
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Usually evenly distributed and numerous
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Axon(s) to Schwann cells ratio usually does not exceed 1 : 2 (A:SC ≤1 : 2)
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In rare cases, their distribution can be focal and scarce
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Perineurial cells
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Within the discontinuous capsule at the periphery of the lesion
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Not present in between Schwann cells within the lesion
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Preexistent peripheral nerve can be identified in about 50% of the lesions
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Serial sections may be necessary to demonstrate this phenomenon
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Histological variants include epithelioid, multinodular (plexiform), and vascular
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Epithelioid variant, as the name implies, features more epithelioid cells with round to oval nuclei and more prominent eosinophilic cytoplasm
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Multinodular (plexiform) variant essentially corresponds to multiple interconnecting nodules representing a single lesion sectioned at multiple planes throughout the dermis
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Vascular variant is characterized by an increase in cavernous-type blood vessels with possible thromboses and perivascular hyalinization (“ancient-like” changes)
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Additional histological features
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Overlying epithelium normal, atrophic, or hyperplastic
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Myxoid change and stromal mucin, rarely extensive
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Limited inflammatory cell infiltrate composed of lymphocytes and, rarely, eosinophils
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Limited collagenized connective tissue stroma
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Immunohistochemistry/special stains
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Schwann cells positive for S100 protein and collagen type IV
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Axons can be delineated by neurofilament stain
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Perineurial cell population EMA, GLUT-1, and/or claudin-1 positive
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GFAP staining consistently negative
Main differential diagnoses
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(Multiple) mucosal neuroma(s)
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Traumatic neuroma
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Neurofibroma
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Schwannoma
Epithelial Sheath Neuroma
Definition
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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
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Fewer than 10 cases reported
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Slight female predominance (F:M = 4 : 3)
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Adult patients (from 43 to 86 years, mean age 63 years)
Presentation
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Solitary erythematous plaque, papule, or nodule
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Size from 0.5 to 2 cm in greatest diameter
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Asymptomatic, pruritic, or painful
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Exclusively reported on the skin of the back so far
Prognosis and treatment
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Simple excision curative
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No recurrences reported
Pathology
Histology
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Proliferation restricted to the papillary and superficial reticular dermis
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Numerous thickened peripheral nerves surrounded by perineural epithelial sheath
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Peripheral nerves
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Disorganized proliferation
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Occasionally display parallel orientation to the surface epidermis
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May not be associated with perineural epithelial sheath, especially at the periphery of the lesion
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Perineural epithelial sheath
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Composed of regular squamous epithelium, likely of infundibular derivation
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Cornification generally preserved with formation of dyskeratotic keratinocytes, presence of granular cell layer, and orthokeratotic basket-weave keratin
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Epithelial elements only can occasionally be seen, not associated with peripheral nerves, especially in the central parts of the lesion
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Epithelial sheath can be absent, especially at the peripheral aspects of the lesion, composed of thickened nerves only
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Additional features
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Perineural inflammatory cell infiltrate composed of lymphocytes and plasma cells, variably prominent
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Minimal and delicate perineural fibroplasia
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Myxoid/mucinous perineural stromal degeneration
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Overlying epidermis usually normal
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No connection to the epidermis or adnexal structures
Immunohistochemistry/special stains
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Nerve bundles
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Consistent positivity for S100 protein, neurofilament, CD57, and nerve growth factor receptor
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Perineural epithelial sheath(s)
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Strong positivity for CK-MNF116 and less intense positivity for CK-AE1/AE3
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Negative for CAM5.2, EMA, and CEA
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Main differential diagnoses
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Traumatic neuroma
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Idiopathic neuroma
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Reactive neuroepithelial aggregates
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Cutaneous hamartomas containing nerve fibers
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Neurofollicular hamartoma
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Congenital neural hamartoma
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Striated muscle hamartoma/rhabdomyomatous mesenchymal hamartoma
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Reexcision perineural invasion by nonneoplastic squamous epithelium
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Perineural infiltration by epithelial tumors (e.g., squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma) or keratoacanthoma
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Dermal hyperneury
Conventional Schwannoma
Definition
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A benign peripheral nerve sheath tumor composed of Schwann cells
Clinical features
Epidemiology
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Equal gender distribution
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Most common in the fourth and fifth decade of life
Presentation
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Slowly growing, painless swelling or nodule
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Pain on percussion over the nerve (Tinel sign) present in over 90%
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Multiple lesions can be associated with neurofibromatosis type 2
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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
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Benign tumor with very low malignant potential
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Complete excision generally curative
Pathology
Histology
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Biphasic morphological pattern, designated as Antoni A and Antoni B areas, intermixed and in variable proportions
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Antoni A areas
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Cellular component
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Closely packed spindle cells with wavy, elongated, and tapering nuclei
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Cytoplasm ill defined, eosinophilic
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Verocay bodies: two rows of nuclear palisading separated by Schwann cell processes
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Mitoses rare
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Degenerative nuclear pleomorphism
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Stroma frequently hyalinized or collagenized with focal dystrophic calcifications
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Small blood vessels with frequently hyalinized vessel walls
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Antoni B areas
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Hypocellular component
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Irregularly distributed spindle and stellate cells
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Abundant myxoid stroma
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Scattered chronic inflammatory cell infiltrate
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Small blood vessels with frequently hyalinized vessel walls
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Degenerative changes not uncommon, including deposition of hemosiderin and microcystic change
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Very rarely schwannoma can show Pacinian differentiation
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Such lesions were previously considered neurofibromas with Pacinian features
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These are not associated with neurofibromatosis, but have been associated in a few cases with vascular malformations
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Immunohistochemistry/special stains
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Strong nuclear and cytoplasmic S100 protein positivity
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Capsule contains EMA-positive perineurial cells
Genetic profile
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Aberrations on chromosome 22 frequent (loss of 22q or monosomy of chromosome 22)
Main differential diagnoses
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Solitary circumscribed neuroma
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Neurofibroma
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Leiomyoma
Plexiform Schwannoma
Definition
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A variant of schwannoma characterized by multinodular (plexiform) proliferation of Schwann cells
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The majority of the tumors occur in the superficial nerves; origin from major peripheral nerves much more uncommon
Clinical features
Epidemiology
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Represents about 5% of schwannomas
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No sex predilection
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Wide age distribution, but most common in young adults (fourth decade of life)
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Congenital/childhood occurrence signifies possible association with neurofibromatosis type 2 or schwannomatosis, especially when lesions are multiple
Presentation
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Slowly growing, generally nonpainful nodule
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Single lesions predominate
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Size usually less than 2 cm, but giant variants also reported
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Multiple lesions can develop within the single anatomical area, or are widely distributed
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Most common at superficial locations (dermis/subcutis) (90%), with predilection for the head and neck, upper extremities, and trunk
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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%)
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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
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Plexiform schwannoma in the setting of NF1 and NF2 exceptionally associated with macrodactyly
Prognosis and treatment
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Benign tumors with no malignant potential, but may cause severe nerve dysfunction
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Recurrences rare, usually after incomplete excision
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Complete excision curative
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Tumors developing within plexiform schwannoma in exceptional cases
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Epithelioid angiosarcoma
- •
Intratumoral metastases, mainly from the breast
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Pathology
Histology
- •
Antoni A elements (cellular) predominant/exclusive component of the lesions
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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
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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
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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
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Plexiform neurofibroma
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Malignant peripheral nerve sheath tumor
Ancient Schwannoma
Definition
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A subtype of schwannoma characterized by extensive degenerative changes thought to result from vascular insufficiency, usually in a long-standing lesion
Clinical features
Epidemiology
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Elderly patients
- •
Occurrence in pediatric population most unusual
- •
Represents about 0.8% of soft tissue tumors
Presentation
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Generally a long-standing lesion
- •
Predilection for deeper locations, particularly soft tissues of the head and neck, thorax, retroperitoneum, pelvis, and extremities
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An exceptional case occurring within the lymph node has also been reported
Prognosis and treatment
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Lesions generally follow a benign clinical course
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Malignant transformation of ancient schwannoma an exceedingly rare phenomenon with fewer than 10 such cases reported (see malignant peripheral nerve sheath tumor)
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Complete excision curative
Pathology
Histology
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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
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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
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See conventional schwannoma
Cellular Schwannoma
Definition
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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
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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
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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
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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
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
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
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
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
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
Pathology
Histology
- •
Nonencapsulated, well-demarcated, and often dumbbell-shaped proliferation within the dermis with possible extension into subcutis
- •
Lesional cells arranged in various growth patterns, including whorled, storiform, fascicular, and lamellar
- •
Cellularity can vary greatly within and among the lesions, from paucicellular to densely cellular areas
- •
Lesional cells typically display spindled morphology with long and delicate cytoplasmic processes
- •
Stroma is usually fibrotic or sclerotic, but there are areas of myxoid degeneration
- •
Additional histological features include
- •
Metaplastic bone formation
- •
Mononuclear inflammatory cell infiltrate, especially at the periphery of the lesion
- •
Immunohistochemistry/special stains
- •
Positive for EMA, variable positivity for claudin-1 and GLUT-1
- •
Negative for S100 protein, neuron specific enolase, chromogranin, neurofilament, desmin, CD34, and smooth muscle actin
Main differential diagnoses
- •
Neurofibroma
- •
Epithelioid fibrous histiocytoma
- •
Melanocytic lesions
- •
Cellular neurothekeoma
Soft Tissue Perineurioma
Definition
- •
A benign, peripheral nerve sheath tumor composed of perineurial cells occurring in deep soft tissues
Clinical features
Epidemiology
- •
Equal gender distribution
- •
Middle-aged adults (fifth decade of life)
- •
Development in the setting of neurofibromatosis type 1 and 2 reported in isolated cases
Presentation
- •
Painless mass
- •
Generally larger than cutaneous variants, with a mean size of about 4 cm
- •
Wide site distribution, but most common on the limbs, followed by the trunk and head and neck area
- •
Rare sites include retroperitoneum, paratesticular region, uterine cervix, intestine, lacrimal gland, tongue, kidney, oral mucosa
Prognosis and treatment
- •
Complete excisions curative
- •
Recurrences after marginal excision rare
- •
Malignant alteration with development of malignant peripheral nerve sheath tumor (MPNST) rare (may be difficult to recognize preexistent perineurioma on histological grounds alone)
Pathology
Histology
- •
Well-circumscribed but nonencapsulated, infiltrative growth in about 15%
- •
Morphology similar to the cutaneous variants (see corresponding chapter)
- •
About 50% are hypocellular and 20% are markedly hypercellular
- •
Low mitotic activity (mean number 1 per 30 high-power fields)
- •
Stroma usually collagenous, about 40% display focal myxoid changes, whereas about 20% show predominantly myxoid areas
- •
Atypical histological features (not associated with biological behavior)
- •
Scattered pleomorphic cells
- •
Increased mitotic rate
- •
Abrupt transition to highly cellular areas with fascicular growth pattern
- •
Infiltrative margins
- •
- •
Reticular/retiform variant
- •
Formation of lacelike, reticular, or pseudocystic arrangement of tumor cells
- •
Pseudocystic spaces can contain amorphous mucoid material
- •
Degenerative nuclear atypia of lesional cells not uncommon
- •
Mitoses generally absent
- •
Transition to more cellular areas usually present
- •
The majority occur in soft tissue
- •
- •
Epithelioid variant
- •
Tumor cells with round to oval nuclei
- •
Abundant amphophilic or eosinophilic cytoplasm
- •
May represent the predominant morphological pattern in the lesion
- •
- •
Plexiform variant
- •
Plexiform distribution of nodules composed of plump spindle cells
- •
Collagenous matrix with numerous small blood vessels
- •
- •
Additional rare histological variants include Pacinian-like, lipomatous, granular cell, and ossifying perineurioma
Immunohistochemistry/special stains
- •
EMA, collagen IV, and laminin positive; variable positivity for CD34 and claudin-1
- •
Coexpression of S100 protein detected in about 5%, staining generally focal
- •
Negative for desmin, GFAP, and neurofilament
Genetic profile
- •
Abnormalities of chromosome 22, generally involving neurofibromatosis 2 gene, particularly deletions of a part or of a whole chromosome
Main differential diagnoses
- •
Solitary fibrous tumor
- •
Dermatofibrosarcoma protuberans
- •
Malignant peripheral nerve sheath tumor
- •
Low-grade fibromyxoid sarcoma
Intraneural Perineurioma
Definition
- •
A benign, peripheral nerve sheath tumor characterized by intraneural proliferation of perineurial cells growing in whorls with a characteristic onion ring appearance, surrounding centrally located Schwann cells and axon(s)
- •
Initially reported as interstitial hypertrophic neuritis, alternatively designated as localized hypertrophic neuropathy
Clinical features
Epidemiology
- •
Adolescents and young adults
- •
Equal gender distribution
Presentation
- •
Slow-growing, painless swelling with fusiform expansion of the nerve, with subsequent progressive loss of motor and sensory function of the nerve
- •
Predilection for sciatic nerve and its branches; other nerves include brachial and lumbosacral nerve plexus, as well as radial, ulnar, median, femoral, and trigeminal nerves
- •
A single case of cutaneous intraneural perineurioma reported recently on the finger
Prognosis and treatment
- •
Benign clinical course, yet progressive motor and sensory abnormalities as the lesion increases in size
- •
Complete resection desirable with possible nerve grafting, might be difficult to achieve without loss of function
Pathology
Histology
- •
Intraneural proliferation of slender perineurial cells in a concentric pattern around centrally located Schwann cells and axon(s), producing a characteristic onion ring appearance
- •
Progressive increase in the collagenous matrix within the nerve
- •
Reticular variant rare (see earlier)
- •
A hybrid perineurioma–granular cell tumor recently reported within peripheral nerve fascicles in the subcutis of the elbow
Immunohistochemistry/special stains
- •
Usually positive for EMA, GLUT-1, claudin-1
- •
Negative for S100 protein
- •
Endoneurial fibroblasts CD34 positive
Genetic profile
- •
Cytogenetic abnormalities consistently detected on the long arm of chromosome 22
Main differential diagnoses
- •
Traumatic neuroma
- •
Solitary circumscribed neuroma
- •
Plexiform pattern in various neural tumors, including schwannoma and perineurioma
- •
Plexiform fibrohistiocytic tumor
Sclerosing Perineurioma
Definition
- •
A histological variant of perineurioma characterized by proliferation of epithelioid and spindle-shaped perineurial cells embedded in abundant collagenized/sclerotic stroma
Clinical features
Epidemiology
- •
More common in males
- •
Adolescents and young adults, most common in the third decade of life
Presentation
- •
Slowly growing, painless mass, frequently of hard consistency
- •
Nonencapsulated but well demarcated
- •
Size from 0.7 to 3.3 cm (mean size 1.5 cm)
- •
Predilection for acral locations, particularly hands and fingers
- •
An exceptional case with bilateral lesions involving both hands reported recently
- •
Nonacral sites, including mucosal sites, can also be affected, albeit more rarely
Prognosis and treatment
- •
Benign clinical course
- •
Complete excision curative
Pathology
Histology
- •
Hyalinized, dense, collagenous stroma with thick collagen bundles containing variable numbers of small, plump, epithelioid or spindle cells, growing in cords, trabeculae, and onion ring–like (whorled) growth pattern in the dermis or dermis/subcutis
- •
Lesional cells with hyperchromatic nuclei, pale cytoplasm with indistinct cell borders
- •
Mitoses absent or rare (generally about 1 per 10 high-power fields)
- •
Cellularity may vary within the lesion (paucicellular vs. cellular)
- •
Swirling of lesional cells around blood vessels and/or nerve branches occasionally seen
- •
Additional features
- •
Mild mononuclear inflammatory cell infiltrate
- •
Scattered mast cells
- •
Mature adipocytes with the lesion (lipomatous variant)
- •
Proliferation of small blood vessels
- •
Immunohistochemistry/special stains
- •
EMA, GLUT-1 positive
- •
Cytokeratin positivity in up to 30%, generally focal
- •
S100 protein, GFAP, and CD57 negative
Main differential diagnoses
- •
Fibroma of tendon sheath
- •
Epithelioid schwannoma
- •
Epithelioid perineurioma
- •
Epithelioid hemangioendothelioma
Neurofibroma
Definition
- •
A benign, peripheral nerve sheath tumor composed of an admixture of Schwann cells, perineurial cells, endoneurial fibroblasts, cells with intermediate differentiation between these cells, axons, and intralesional nerve bundles/twigs
- •
Sporadic occurrence or associated with neurofibromatosis, most commonly type 1 (NF1)
- •
Numerous histological variants reported: myxoid, plexiform, diffuse, pigmented (melanotic), epithelioid, dendritic cell, cellular with atypia (atypical), lipomatous, and hybrid lesions (see corresponding chapters)
- •
Pacinian neurofibroma is better regarded as a variant of schwannoma (see Pacinian schwannoma)
Clinical features
Epidemiology
- •
Most common type of peripheral nerve sheath tumor
- •
Majority of cases solitary and not associated with neurofibromatosis
- •
Equal distribution between genders
- •
Adults
Presentation
- •
Dome-shaped, polypoid, pedunculated, or nodular proliferation, usually soft on palpation
- •
Well circumscribed, nonencapsulated
- •
Predilection for trunk, followed by extremities and head and neck area
- •
Lesions associated with neurofibromatosis can be numerous and large, located in the skin (superficial), as well as at deeper locations (deep soft tissues, visceral sites) (see Plexiform neurofibroma )
Prognosis and treatment
- •
Benign lesion
- •
Complete excision curative, local recurrence exceptional
- •
Deep lesions in the background of NF1 associated with about 15% lifelong risk for malignant transformation, whereas such an event is exceptional in typical cutaneous neurofibroma, regardless of NF status
Pathology
Histology
- •
Tumor-free grenz zone between the epidermis and the lesion common
- •
Spindle cells with oval, elongated, wavy, or comma-shaped uniform nuclei, generally lacking true atypia
- •
Degenerative nuclear atypia and hyperchromatism rare
- •
Multinucleated, floretlike giant cells occasionally present and may be numerous (not a clue for neurofibromatosis)
- •
Mitoses generally absent
- •
Isolated mitosis in otherwise typical sporadic neurofibroma not associated with malignancy
- •
The presence of mitoses in neurofibromas associated with NF1 is suggestive of malignancy
- •
- •
Cytoplasm scant, eosinophilic with indistinct borders
- •
Numerous small nerves within the lesion
- •
Wirelike collagen fibers
- •
Stroma fibrillar, collagenous, or myxoid, but can also be sclerotic
- •
Scattered inflammatory cell infiltrate, particularly mast cells
- •
Very rare variants include granular cell, clear cell, balloon cell, collagenous, and sclerotic neurofibroma
Immunohistochemistry/special stains
- •
S100 protein positivity in 50% to 60% of lesional (Schwann) cells
- •
Variable positivity for EMA (perineurial cells) and CD34 (lesional fibroblasts)
- •
Neurofilament delineates intralesional axons and nerve twigs
Genetic profile
- •
Chromosomal aberrations, particularly involving chromosomes 17 and 22
- •
Loss of function mutation in NF1 (17q11.2)
Main differential diagnoses
- •
Neurotized melanocytic nevus
- •
Plaque-stage dermatofibrosarcoma protuberans
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