Traumatic neuromas are composed of an irregular arrangement of nerve fascicles embedded in fibrous scar tissue. There may be concentric condensations of fibrous tissue around individual fascicles, giving the appearance of multiple separate nerves (Fig. 37.1). Intraepithelial nerve fibers were present in one traumatic neuroma removed from the lower lip. ¹⁶ Perineurial cells, which contain epithelial membrane antigen, surround each fascicle, in contrast to solitary circumscribed neuromas, in which only the peripheral capsule contains these cells. ¹⁷ A Bodian stain will confirm the presence of numerous axons (Fig. 37.2). As in most neural tumors, mast cells are scattered throughout.

There are numerous bundles of nerve fibers embedded in connective tissue in the upper dermis, and in dermal papillae (Fig. 37.3). Many oval corpuscles, resembling small Meissner corpuscles, are also present. This latter feature, together with the indefinite outline and the position in the upper dermis, all differ from the usual traumatic neuroma.^{20. and 25.} This supports the view that the traditional explanation for these lesions is incorrect. ²³

Solitary circumscribed neuroma usually presents as a single nodule confined to the dermis (Fig. 37.4). A multinodular or plexiform growth pattern is uncommon. ³³ The neuroma is composed of well-developed fascicles separated by a loose matrix resembling the endoneurium of normal nerve (Fig. 37.5). Rarely, cells with an epithelioid appearance are present. ³⁴ A thin perineural connective tissue capsule often surrounds the tumor, but there is no fibrous tissue sheath around fascicles, as seen in a traumatic neuroma. ¹³ The perineurial cells in the capsule contain epithelial membrane antigen. ²⁶ The fascicles contain axons, and many are also myelinated; ³⁵ they stain for S100 protein.^{36. and 37.} Kossard and colleagues have presented evidence challenging the concept that these tumors always contain axons. ³⁸ They found that some tumors lacked a significant axonal content, thus merging with the features of a schwannoma. ³⁸

The superficial part of a solitary neuroma is sometimes more loosely arranged, with a myxomatoid stroma, resembling a neurofibroma. ¹¹ In one case, most of the lesion was myxoid raising the possibility that the lesion was a nerve sheath myxoma with neuroma-like features. ³⁹ Prominent stromal vascularity has been reported. ⁴⁰ Occasionally a nerve can be traced into the lesion from below.

The overlying epidermis is usually normal or attenuated, but there is one report of overlying pseudoepitheliomatous hyperplasia. ⁴¹

Two different patterns may be seen. ¹¹ The usual mucosal neuromas resemble solitary neuromas with haphazardly arranged bundles of Schwann cell fascicles. In the other pattern there are tortuous hyperplastic nerves with a thickened perineurium. ¹¹

Hypertrophy of small nerves in the dermis (‘dermal hyperneury’) has also been noted in the clinically normal skin of patients with this syndrome. ⁵⁴ Nerve hypertrophy has been reported in a patient with striated pigmentation and a marfanoid habitus, a possible forme fruste of this syndrome, but without the endocrine tumors. ⁵⁵ Rarely, it may follow chronic irritation or rubbing of the skin (Fig. 37.6). ⁵⁶

Ganglioneuromas consist of mature ganglion cells, which are usually intermixed with fascicles of spindle cells.59. ^{and 63.} In one reported case the ganglion cells were separate from the neuromatous elements. ⁶⁴ The term ‘ganglion cell choristoma’ has been used for rare cases with ganglion cells and no stromal component.^{65. and 66.} At the other end of the spectrum is a case with abundant collagenous stroma containing scattered spindle and ganglion cells – a desmoplastic ganglioneuroma. ⁶⁷ Overlying hyperkeratotic epidermal changes have been reported in two cases. ⁶⁸

The fusiform cells are strongly positive for S100 protein, but not the ganglion cells. ⁶⁹ In two recent reports both the spindle-cell component and the ganglion cells were positive for S100 protein and CD56.^{61. and 70.} In one of these reports they were also positive for neuron-specific enolase (NSE) and glial fibrillary acid protein (GFAP), ⁶¹ and in the other report for neurofilament protein. ⁷⁰

The tumor is characterized by a proliferation of enlarged nerve fibers in the upper dermis ensheathed by squamous epithelium. The nerve fibers are much larger than normal for the dermis, and the perineural squamous epithelium is mature with focal cornification. ⁷³ These structures are surrounded by delicate fibroplasia and a mild inflammatory cell infiltrate of lymphocytes with a few plasma cells. ⁷⁴ There is a superficial resemblance to perineural invasion by a squamous cell carcinoma.

As expected, the nerves stain for a variety of neural markers, including S100 protein, and the epithelial sheaths for cytokeratins. ⁷¹ This entity differs from perineural invasion by the increased number and size of nerve fibers and by the lack of cytological atypia of the ensheathing cells. ⁷⁵

The neoplasms are circumscribed non-encapsulated lesions composed of spindle cells with elongated, bipolar cytoplasmic processes.^{81. and 90.} On low power they usually resemble neurofibromas, with fascicles or individual cells oriented either parallel to each other or forming small concentric collections (Fig. 37.7). ⁶⁹ These concentric whorls (‘onion bulbs’) are an important clue to the diagnosis. ¹⁰⁴ They sometimes have pacinian-like features. ¹⁰² Variants with granular cells and others with a plexiform or reticular pattern have been reported.^{84.105. and 106.} The reticular (retiform) variant is composed of anastomosing cords of fusiform cells with bipolar cytoplasmic processes that wrap around islands of fibromyxoid stroma. ⁸⁴ The stroma of the conventional type is also fibromyxoid; rarely, it contains calcospherites. ⁹¹ Myxoid features were prominent in one subungual perineurioma. ¹⁰⁷ Uncommonly, there is a fibrous or sclerotic stroma. ¹⁰⁸Lipomatous perineurioma refers to the presence of mature adipocytes admixed with spindle cells. ⁸⁶

The cases described by Mentzel and colleagues were more cellular lesions with a mixed lamellar and whorled pattern, sometimes with a marked storiform pattern. Focal stromal hyalinization and small aggregates of foam cells were present in some of their cases. ⁹⁰ Such cases can be misdiagnosed as epithelioid histiocytomas. ¹⁰⁹

The epithelioid perineurioma is composed of a syncytial-like proliferation of epithelioid cells with moderate amounts of eosinophilic cytoplasm. The cells in the reported case were positive for epithelial membrane antigen (EMA) and claudin-1. ¹¹⁰

The atypical cellular perineurioma is a well-circumscribed lesion composed of spindle cells arranged in a storiform pattern. ⁸⁷ Focally, it may appear laminated. The cytoplasm of the cells is eosinophilic and well demarcated. The nuclei are elongated. Larger atypical cells are scattered through the tumor. A few cells have several nuclei. Mitoses are uncommon (1/20 high-power fields); atypical mitoses are not found. ⁸⁷

Most of the tumor cells stain for EMA and vimentin. ⁹⁷ Most cases show membranous positivity for claudin-1 protein, ⁸⁸ a recently described tight junction-associated protein. ¹¹¹ In recent reports, cells have also expressed GLUT-1, protein gene product 9.5 (PGP 9.5), CD57, ⁸³ vascular endothelial (VE)-cadherin, ¹¹² and CD99. ⁹⁹ Focal positivity for factor XIIIa is often present. ¹⁰⁹ The cells do not usually stain for S100 protein, CD34, chromogranin or NSE,^{90. and 91.} but Hornick and Fletcher reported a significant number of cases (64%) that expressed CD34. ⁸² In the variant with granular cells (see above), these cells expressed S100 protein but not EMA, supporting their Schwann cell origin. ¹⁰⁵

One of the reported granular perineuriomas expressed NK1/C3 but not S100 protein. ⁹²

The sclerosing perineurioma is composed of abundant dense collagen and variable numbers of small, epithelioid, and spindled cells exhibiting corded, trabecular, and whorled (onion skin) patterns. ⁹⁴ This tumor may be confused with the fibroma of tendon sheath, the sclerotic fibroma of Cowden’s disease (see p. 815), and the pacinian collagenoma (see p. 816). ¹¹³ A lipomatous variant of sclerosing perineurioma has been reported in the skin. ¹¹⁴ The cells stain for EMA and vimentin and often muscle-specific actin as well. ⁹⁴ They also express GLUT-1, claudin 1, and collagen type IV. ¹¹⁴ The fibrous perineurioma is probably a less dense, more cellular, and better vascularized variant of the sclerosing perineurioma. ¹⁰⁸

Intraneural perineuriomas cause fusiform expansion of a nerve, usually in the deep soft tissues. There are ‘pseudo-onion bulbs’ of concentrically arranged perineurial cells surrounding a central zone containing axons, Schwann cells, and fibrovascular stroma. ⁸⁸

Multiple hybrid granular cell tumors with admixed perineurioma elements were present in one patient. ¹¹⁵ Schwannoma–perineurioma hybrids also occur.^{116. and 117.}

Schwannomas are circumscribed encapsulated tumors, usually confined to the subcutis. The nerve of origin may sometimes be seen along one border (Fig. 37.8). The agminate tumors and some of those in schwannomatosis are often situated in the dermis. ¹²⁴ Multiple small tumor nodules may be present in these forms, as well as hypertrophied peripheral nerves.^{124. and 128.} The term ‘plexiform schwannoma’ has been applied to this type (Fig. 37.9).^{140.141.142.143. and 144.} It originates from nerve sheath (see below). ¹⁴⁵

Schwannomas are characteristically composed of two tissue types. ¹²² In the so-called ‘Antoni A’ areas there are spindle-shaped Schwann cells arranged in interlacing fascicles. The cells have indistinct cytoplasmic borders. The nuclei may be aligned in rows or palisades, between which the cell processes are fused into eosinophilic masses forming Verocay bodies. A variant in which the Verocay bodies form 75–100% of the tumor has been described. ¹⁴⁶ Conspicuous Verocay bodies were present in a schwannoma of the penis. ¹⁴⁷ Antoni B tissue consists of a loose meshwork of gelatinous and microcystic tissue with widely separated Schwann cells. Lipid-laden macrophages, dilated blood vessels with thick hyaline walls, old and recent hemorrhage, lipofuscin, and sometimes calcified hyaline areas may also be present in Antoni B areas.2.^{122. and 148.} ‘Collagenous spherulosis’ (radiating eosinophilic collagen fibers) has been reported in one case. ¹⁴⁹ Mast cells and non-specific cholinesterase may be demonstrated. ¹³ Merkel cells are increased in the epidermis overlying schwannomas. ¹⁵⁰

Immunoperoxidase methods demonstrate S100 protein, ¹²⁴ vimentin, ¹⁵¹ SOX 10, ¹⁵² and myelin basic protein¹⁵³ in the tumor cells. Glial fibrillary acidic protein (GFAP) is present in a small number of cases.^{151. and 154.} Epithelial membrane antigen is found in the perineurial cells in the capsule of schwannomas, as in that of solitary neuromas (see above).^{146. and 155.} The conventional view has been that schwannomas, unlike neurofibromas, do not possess intratumoral axons. However, a recent study using an antibody to neurofilament protein found axons in 30–70% of schwannomas, the incidence varying with the histological subtype. ¹⁵⁶ All types of Schwann-cell-derived tumors express the DNA-binding transcription factor, activating protein 2 (AP-2), mainly in their nucleus. ¹⁵⁷

A cellular variant (cellular schwannoma), mostly found in the deeper tissues, has been described.^{158. and 159.} There are compact spindle-shaped cells with mitoses and some storiform areas, and a near absence of Verocay bodies and Antoni B tissue. ¹⁵⁸ Rare variants with multiple glandular elements, ¹⁶⁰ with pseudoglandular structures, ¹⁶¹ and with sweat duct differentiation¹⁶² have been reported.

The plexiform schwannoma (see above) has a superficial resemblance to the plexiform neurofibroma with multiple interlacing and interconnecting fascicles and nodules, composed predominantly of Antoni A-type tissue. ¹⁴⁵ Most tumors occur in the dermis and subcutis. A deep-seated variant has also been described. ¹⁶³ In comparison with the superficial variety, the deep variant has a predilection for females, can occur in a congenital setting, and can show necrosis and myxoid change. ¹⁶³ A further subset of plexiform schwannomas occurs in a congenital or childhood setting. It was previously considered a form of malignant peripheral nerve sheath tumor (MPNST). ¹⁶⁴ Despite their cellular pleomorphism they are now known to have a benign behavior.

A neuroblastoma-like variant, with large rosette-like structures and fibrillary collagenous centers, has been described.^{165. and 166.} The presence of intervening Antoni B areas and an absence of necrosis or mitoses assist in making a diagnosis. One case presented with anetoderma-like features. ¹⁶⁷ The cells express S100 protein, but not neuron-specific enolase, as occurs in the smaller rosettes of neuroblastoma. ¹⁶⁸ Only one of the several cases tested expressed GFAP. ¹⁶⁶

The epithelioid schwannoma is an extremely rare variant composed largely of epithelioid cells, in which there is a lack of mitotic activity.^{169.170.171. and 172.} In a study of 33 cases of benign epithelioid peripheral nerve sheath tumors (BEPNSTs), 18 were subclassified as epithelioid neurofibromas and 15 cases as epithelioid schwannoma, although in five of these cases the absence of nuclear palisading, the presence of uniform cellularity, and the presence of a significant CD34-positive spindle-cell population led to their classification as BEPNSTs of indeterminate histogenesis. ¹⁷² A collagen-rich variant of BEPNST has since been reported. ¹⁷³ Features of classic schwannoma are usually present in some areas of the tumor. ¹⁷⁰ There is a thin capsule containing EMA-positive cells although this was not present in a subsequent case. ¹⁷⁴ Type IV collagen encircles individual cells within the tumor. ¹⁶⁹ The cells stain for S100 protein but not HMB-45. An epithelioid schwannoma that was also plexiform has been reported. ¹⁷⁵

The pseudoglandular schwannoma is an extremely rare variant composed of gland-like spaces containing mucinous material and lined by Schwann cells that are strongly positive for S100 protein and GFAP.^{176. and 177.} In another case the glandular cells stained with CAM5.2 and EMA, but not for S100 protein. ¹⁷⁸ This may be a true glandular variant. This variant is more common in schwannomas of the central nervous system. ¹⁷⁷

Another type of schwannoma is the psammomatous melanotic schwannoma, which contains melanin and scattered psammoma bodies (see below).

The Wagner–Meissner schwannoma has a monomorphous morphology with sheets of corpuscles having a lamellar structure. ¹⁷⁹ The nuclei are predominantly located at the periphery of the corpuscle. ¹⁷⁹ They are separated by thin fibrous strands. There are some similarities to a perineurioma in the published photomicrographs.

The term ‘congenital neural hamartoma (fascicular schwannoma)’ has been used for an unencapsulated dermal tumor composed of fascicles of Schwann cells with frequent Verocay body-like structures. ¹⁸⁰ Unlike cutaneous neuromas, there are no axons present.

This tumor is usually well circumscribed but only partly encapsulated. There is a mixture of polygonal and fusiform cells, many of which are heavily pigmented melanocytes. ⁶⁹ Psammoma bodies are present in varying numbers. Sometimes they coalesce to form larger, irregular masses. Adipocytes are often present.

The tumor cells stain positively for S100 protein, HMB-45, MART-1, synaptophysin, and vimentin. ¹⁸⁷

A malignant melanotic schwannoma has been reported. ¹⁸⁸ It did not occur in the setting of Carney’s complex, nor were there psammoma bodies. Epithelioid cells with melanin were seen in the primary lesion, whereas spindle cells dominated in the recurrence. ¹⁸⁸

Cutaneous neurofibromas are non-encapsulated, loosely textured tumors centered on the dermis.^{13. and 278.} There is often extension into the subcutis, sometimes in a diffuse infiltrative pattern. ²⁷⁸ An overlying grenz zone separates the lesion from the undersurface of the epidermis. The lesion is composed of delicate fascicles, usually only a single cell thick. ¹¹ The cells have an oval or spindle-shaped nucleus and scant, indefinite cytoplasm (Fig. 37.10). Vacuolated cells are found focally in a small number of tumors. ²⁷⁹ Floret-like multinucleated giant cells were present in a neurofibroma arising in a patient with NF-1. ²⁸⁰ There is sometimes nuclear pleomorphism, but mitoses are rare. Neurofibromas with high cellularity and atypia have been called dysplastic neurofibromas. Patients with such lesions require increased surveillance because of a potential risk for malignant transformation. ²⁸¹ The matrix is pale staining with delicate wavy collagen; rarely, the matrix is rich in mucin or is sclerosing or hyalinized.^{191.278. and 282.} Solitary neurofibromas are sometimes more compact than those in neurofibromatosis. ¹²² Blood vessels are increased in number in the stroma. ²⁸³ A Bodian stain will demonstrate some axonal material, but not in the 1 : 1 ratio with Schwann cells, as occurs in neuromas. ¹¹ Mast cells, ²⁸⁴ non-specific cholinesterase, ²⁶³ S100 protein, myelin basic protein, ¹⁵³ and factor XIIIa^{285. and 286.} can be demonstrated by the appropriate techniques. Podoplanin expression, using the D2-40 antibody, is found in a small number of neurofibromas. It is found more often in neurilemmomas. ²⁸⁷ The mast cells may not always be quiescent as evidenced by the report of abundant eosinophils in a solitary neurofibroma. ²⁸⁸

Various growth factors and their receptors are also present. ²⁸⁹ Neural cell adhesion molecule (NCAM – CD56) was present in one recent study in 100% of schwannomas and MPNSTs, in 86% of neurofibromas, 76% of neurotized nevi, but only 50% of desmoplastic/spindle-cell melanomas. ²⁹⁰ The staining was less intense in the melanomas than in the neural tumors. ²⁹⁰

Plexiform neurofibromas are a distinct variant in which there is irregular cylindrical or fusiform enlargement of a subcutaneous or deep nerve; ¹³ rarely, they arise in the dermis. ²⁹¹ Numerous large nerve fascicles are embedded in a cellular matrix containing abundant mucin as well as collagen, fibroblasts, and Schwann cells. ¹¹ Initially, this proliferation of nerve fibers is confined within the epineurium of the involved nerve. ¹¹ The massive soft tissue neurofibroma is highly specific for NF-1. It is worrisome because its size may mask the development of a malignant peripheral nerve sheath tumor. ²⁹²

The pigmented plexiform neurofibroma is a subset of plexiform neurofibromas with hyperpigmentation and hypertrichosis of the overlying skin. ²⁹³ There is melanocytic hyperplasia at the dermoepidermal junction and single pigmented melanocytes with occasional small nests in the papillary dermis, and scattered within the underlying neurofibromatous tissue. ²⁹³ Immunohistochemical staining with melan-A (MART-1) confirms the melanocytic differentiation of these scattered nests and individual cells, whereas GFAP and Leu-7 are detected only within plexiform areas and neuroid spindle cells. ²⁹³ The case reported as a cutaneous melanocytoneuroma had an intraneural proliferation of large epithelioid cells with eosinophilic cytoplasm with prominent cell borders, imparting a plant-like pattern. ²⁹⁴ Involvement of smaller nerve twigs gave the lesion a plexiform appearance. The cells expressed S100 protein, melan-A, HMB-45, microphthalmia-associated transcription factor (MITF), and PGP9.5. ²⁹⁴ The lesion was surrounded by an EMA-positive perineurial layer. ²⁹⁴

Other findings in neurofibromatosis are schwannomas (neurilemmomas), tumors with features of both neurofibroma and schwannoma (hybrid lesions),^{295. and 296.} and neurofibromas containing scattered, possibly entrapped, ganglion cells. Pilar dysplasia and folliculosebaceous proliferations have been reported overlying neurofibromas.^{297. and 298.} Vascular changes are rarely found. ²⁹⁹ They include smooth muscle islands in the intima of vessels. ²²⁹ Fibromuscular dysplasia of larger cutaneous vessels was so extensive in one case that it resulted in cutaneous ulceration. ³⁰⁰ If random biopsies are taken from apparently normal skin in patients with NF-1, microscopic (occult) neurofibromas are sometimes found. Abundant S100-positive cells may also be found within the perifollicular fibrous tissue.^{301. and 302.} In elephantiasis neuromatosa there is a diffuse proliferation of Schwann cells and axons in the subcutis. ¹²² Islands of cartilage are present, rarely, in this tissue. ¹²² Glandular epithelial structures (epithelioid neurofibroma) have been reported in the stroma.^{172.251. and 303.}

In a review of the histopathological variants of neurofibroma, Megahed listed 10 variants: ²⁷⁸ classic, cellular, myxoid, hyalinized, epithelioid, plexiform, diffuse, pigmented, granular cell, and pacinian. Some of these variants are regarded by others as discrete entities, whereas others represent morphological curiosities.

An additional variant is the recently described dendritic cell neurofibroma with pseudorosettes.^{304. and 305.} Its development within the confines of the perineurium in the skin in one case supports its origin as a peripheral nerve sheath tumor and not a melanocytic nevus as was thought for a brief period. ³⁰⁶ It does not appear to be associated with NF-1 or NF-2. ³⁰⁷ The dermis is filled with tumor nodules that are oval shaped and oriented more or less vertically. Two types of cells are present: type I cells are small, dark, lymphocyte-like cells with inconspicuous cytoplasm, and the type II cells are larger, with pale-staining vesicular nuclei and abundant pale eosinophilic cytoplasm. ³⁰⁶ Type I cells are arranged concentrically around type II cells, forming pseudorosettes. Both cell types express S100 protein and CD57, and varying proportions of both cell types express CD56 and PGP9.5. ³⁰⁶

The sclerotic neurofibroma is an extremely rare variant in which there are scant cells and thick collagen bundles arranged chiefly in an interweaving pattern with prominent clefts.^{308. and 309.} The tumor cells have uniform fusiform nuclei. There are some similarities to sclerotic fibroma. ³¹⁰

The rare pigmented neurofibroma, six cases of which were described by Bird and Willis in 1969, ³¹¹ had received scant attention until a report of 19 cases. ³¹² It is composed of whorled fibrillar ovoid structures resembling Wagner–Meissner bodies.^{312. and 313.} Melanin is present in macrophages and in some of the tumor cells, which stain for S100 protein, HMB-45, and melan-A. In the few cases tested, the cells also expressed CD34. ³¹² There is also co-expression of MET proto-oncogene and MITF. ³¹⁴

The cellular neurofibroma can be difficult to distinguish from a malignant peripheral nerve sheath tumor (MPNST), particularly if atypia and low-grade mitotic activity are present. It has been suggested that ancillary studies (p53 expression, Ki-67 immunostaining, and flow cytometry to assess DNA content) may be useful in confirming a benign diagnosis in these cases. ³¹⁵ Further studies are needed to confirm these findings. ³¹⁶

The lipomatous neurofibroma is a recently described variant of neurofibroma characterized by the presence of intratumoral fat.^{317.318. and 319.} In one study of 320 cases of neurofibroma, fat was observed in 22 (6.9%). ³²⁰ It was focal in 18 of these cases, while in the other four it was diffuse with mature adipocytes regularly interspersed with the spindle cells of the neurofibroma. ³²⁰

Giant pigment granules (macromelanosomes) are often present in melanocytes and basal keratinocytes in the café-au-lait spots of neurofibromatosis. ³²¹ The granules can just be seen with the light microscope. They are probably increased in older individuals. ³²² Macromelanosomes are not present in all cases of neurofibromatosis; their presence is not pathognomonic, as they can also be found in several other conditions.^{321. and 323.}

The nerve sheath myxoma is multilobulated and non-encapsulated (Fig. 37.12). It is centered on the reticular dermis but often extends into the superficial subcutis. ³⁴⁵ The lobules are composed of spindle-shaped, stellate, and sometimes epithelioid cells arranged in a swirling, lamellar, and often concentric pattern. Syncytial-like aggregates are also present. Vacuolated cells are often seen. The cellular elements are embedded in a myxoid stroma, which is usually abundant in those tumors in which stellate and bipolar cells predominate. Chondroitin-4 or chondroitin-6 sulfate is the principal heteroglycan present.^{334. and 344.} There is a peripheral fibrous border. There is variable nuclear hyperchromatism and sometimes nuclear atypia. Mitoses are uncommon. In one case, melanin was present in some tumor cells. ³⁴²

The cells are immunoreactive for S100 protein, GFAP, NSE, and CD57.^{340.346.347. and 348.} They are bordered by collagen IV. Perineurial cells expressing EMA are present in small numbers, primarily in the fibrous tissue directly adjacent to the myxoid nodules. ³⁴⁰ Both nerve sheath myxoma and neurothekeoma express S100A6. ³⁴⁹

Although neurothekeoma is usually a dermal tumor, subcutaneous extension and/or skeletal muscle involvement may occur.^{350. and 361.} It is composed of nests and fascicles, giving a multilobular appearance (Fig. 37.13). The intervening stroma may be hyalinized; often there are myxoid foci. ³⁶² The nests of spindle cells sometimes have a concentric or whorling arrangement. A plexiform pattern may sometimes be present. ³⁶³ There may be a poorly differentiated interface between the fascicles and the dermal collagen. ³⁶⁴ Some of the cells may have large hyperchromatic nuclei and some mitoses are common (Fig. 37.14). ³⁶⁵ Dermal melanocytosis, in which the cells expressed NKI/C3 but not S100 protein, has been reported in the stroma of neurothekeomas. ³⁶⁶ Extensive dystrophic calcification³⁶⁷ and ossification have been reported. ³⁶⁸ Osteoclast-like giant cells are present in nearly 40% of cases. ³⁵¹ Several cases of a tumor with extensive ossification and features similar to ossifying neurothekeoma have been called ossifying plexiform tumor, as the authors believed it was probably a lesion sui generis. ³⁶⁹ A variant of neurothekeoma, with epithelioid as well as spindle-shaped cells and a cellular morphology, has been reported as a ‘cellular neurothekeoma’, a term often used now to include all neurothekeomas.^{350.370. and 371.} The authors speculated that it was an epithelioid variant of pilar leiomyoma, although only three were positive for smooth muscle actin. ³⁷⁰

In 1998, Busam and colleagues described an atypical cellular neurothekeoma, ³⁵⁶ characterized by at least one of the following features: large size, deep extension of the lesion, infiltrating borders, high mitotic activity (>3 mitoses/10 high-power fields), marked cytological pleomorphism, and signs of vascular invasion. ³⁵⁶ Based on a limited number of cases, it appears that surgical excision may be curative. ³⁷²

The immunohistochemical findings are different from those found in nerve sheath myxomas. Neurothekeomas do not express S100 protein, but all express NKI/C3.^{346.350. and 353.} This latter marker is frequently positive in histiocytic tumors, limiting its usefulness. ³⁷³ The marker PGP9.5 (protein gene product 9.5) is often expressed but some experts do not use it because of its profound lack of specificity. ³⁵⁰ Interestingly, anti-PGP9.5 targets ubiquitin carboxyl terminal esterase L1, an enzyme said to be found exclusively in neurons. ⁴ In one study, 89% of cases expressed NSE, and half showed at least focal positivity for smooth muscle actin. ³⁵⁰ S100A6 is frequently positive. ³⁴⁹ Focal positivity for factor XIIIa has also been noted.^{374. and 375.} One case expressed PG-M1, a reliable histiocytic marker. ³⁶⁰

The tumors are non-encapsulated and composed of irregularly arranged sheets of large polyhedral cells with a small central hyperchromatic nucleus and abundant fine to coarsely granular eosinophilic cytoplasm (Fig. 37.15). Large cytoplasmic granules, surrounded by a clear halo (pustulo-ovoid bodies of Milian) are present in varying numbers in all tumors. ⁴²⁷ Dermal tumors often extend into the upper subcutis. Cells infiltrate between collagen bundles and may displace them. They surround appendages, but may extend into the arrector pili muscle. Rarely, a plexiform or dermatofibroma-like pattern is present.^{428.429.430. and 431.} Cytoplasmic borders are not always distinct. The clear cell variant is also very rare, but focal clear cell change is not uncommon in conventional cases. ⁴³² Prominent lymphoid nodules were present at the periphery in the clear cell variant. ⁴³² The cytoplasmic granules are PAS positive and diastase resistant. They are also well seen with Movat’s pentachrome technique. ⁴²⁶ The nuclei contain one or two nucleoli. Elastosis is common in the stroma of granular cell tumors. ⁴³³

The overlying epithelium often shows prominent pseudoepitheliomatous hyperplasia, which may be misdiagnosed as squamous cell carcinoma if only a superficial biopsy is available for examination. ³⁷⁹ Attempts have been made to quantify the morphometric differences between these two processes. ⁴³⁴ This epithelial response is usually not present in congenital gingival tumors, ⁴⁰⁶ and is absent in some cutaneous tumors, especially if multiple. ³⁹³ The rare granular cell tumors that extend into the epidermis are potential mimics of melanocytic neoplasia. An immunohistochemical panel will distinguish these two processes, if there is any doubt, on light microscopy. ⁴³⁵

Congenital gingival tumors have a more prominent vascular stroma, often with perivascular collections of lymphocytes and histiocytes. ⁴²² The amount of stromal collagen increases as the lesion ages. Small nerve fibers are sometimes found in and around acquired granular cell tumors. ³⁹³

The polypoid granular cell tumors of the skin are mostly in the upper dermis and associated with an epithelial collarette. ⁴²⁵ Some tumors are situated more deeply in the reticular dermis with limited extension into the subcutis. They are composed of spindled to ovoid cells with abundant granular, eosinophilic cytoplasm and vesicular nuclei with small prominent nucleoli (Fig. 37.16). ⁴²⁵ Cytological atypia and scattered mitoses are often features of this tumor. ⁴²⁴ A majority of polypoid granular cell tumors express NKI/C3, vimentin, PGP9.5, and CD68, and some also express NSE. They are negative for S100 protein, as well as for epithelial and myoid markers.^{425. and 436.}

Immunohistological studies of granular cell tumors have given conflicting results. Granular cell tumors usually express S100 protein,^{416.437.438. and 439.} CD68, ⁴⁴⁰ low-affinity nerve growth factor receptor (NGFR-5), ³⁸⁶ microphthalmia transcription factor (MITF), ⁴⁴¹ inhibin-α, ⁴⁴⁰ NSE, ⁴²⁰ PGP9.5, ⁴⁴² and the melanoma-associated antigen NKI/C3. ⁴²⁰ Myelin basic protein (MBP) and calretinin have been present in some cases;^{386. and 443.} MBP was absent in all 25 cases in one series. ⁴²⁰ The cells are negative for myoglobin,^{439. and 444.} HMB-45, ⁴⁴¹ and GFAP. ¹⁵⁴ Melan-A is focally positive in rare cases only. ⁴⁴¹ Some reports have suggested the presence of carcinoembryonic antigen (CEA), ⁴⁴⁴ but this appears to be a false positive result, due to a related antigen in the tumor cells.^{445. and 446.} The cells are also positive for esterase and acid phosphatase. ⁴²⁶

There are no well-defined criteria for malignancy. Tumor size greater than 5 cm, vascular invasion, necrosis, and rapid growth are important indicators of malignant behavior.^{400. and 414.} Mitoses, apoptotic cells, and pleomorphic nuclei may also be present, but not necessarily so; they are invariably absent in benign variants. ⁴¹⁵ Cell spindling and angiogenesis have been reported in malignant lesions. So-called atypical variants have one or two of the following features: spindling of the tumor cells, necrosis, diffuse pleomorphism, prominent nucleoli, a high nuclear–cytoplasmic ratio, and a mitotic rate >2 per 10 high-power fields. ⁴¹⁷ Three or more of these findings are present in malignant tumors. ⁴¹⁷ The number of cells positive for Ki-67 and phosphohistone-H3 (PHH3) is higher in atypical forms.^{417. and 440.}

The exact nosological position of the congenital lesion reported as CD34-positive granular cell dendrocytosis is currently unknown. ⁴⁴⁷ The patient had numerous papules and plaques on the face and extremities. The lesions were composed of S100-negative, CD34-positive dermal dendrocytes, with a granular morphology due to an abundance of phagolysosomes and an appearance resembling a granular cell tumor. ⁴⁴⁷ A similar case with CD34-positive cells has been reported as a congenital granular cell tumor. ³⁸⁸

There is usually a spindle-cell growth pattern with cells arranged in tight wavy or interlacing bundles (Fig. 37.17). ⁴⁷¹ There are sometimes densely cellular areas alternating with more loosely textured areas. ⁴⁷² A rare plexiform variant has been reported. ⁴⁷³ The cellularity and number of mitoses determine the grading of the tumor.

Purely epithelioid variants have been reported (malignant epithelioid schwannoma).^{474.475.476.477.478. and 479.} There appears to be a tendency for MPNSTs arising in a benign schwannoma to show epithelioid morphology. ⁴⁸⁰ Cartilaginous differentiation was present in one case. ⁴⁸¹ Metastatic melanoma needs consideration in the diagnosis. ⁴⁸²

Focal divergent differentiation, with the formation of foci of osteogenic sarcoma, chondrosarcoma, angiosarcoma, ⁴⁸³ rhabdomyosarcoma, or an epithelial element, is present in about 15% of tumors.^{484. and 485.} The epithelial element is usually glandular in type. ³⁰³ The presence of rhabdomyosarcomatous elements can be confirmed by immunoperoxidase stains for myoglobin, ⁴⁸⁶ desmin, muscle-specific actin, and myogenin. ⁴⁸⁷ This variant is known as a ‘triton tumor’.^{479.486.487. and 488.} More than half of the patients have NF-1. ⁴⁸⁷ It has a worse prognosis than the classic MPNST. This may be due to its expression of c-myc. ⁴⁸⁷ A breakpoint involving 11p15 (the region of the myogenic differentiation 1 gene) has been identified in one case. ⁴⁸⁹ It should not be confused with the rare neuromuscular hamartoma of infancy composed of nerve fibers admixed with well-differentiated skeletal muscle. ⁴⁹⁰

In the past, the diagnosis of a malignant nerve sheath tumor was difficult, particularly in the absence of a clinical history of neurofibromatosis, and in those tumors in which no anatomical relationship to a nerve trunk could be demonstrated. The development of immunoperoxidase techniques has assisted considerably in making a specific diagnosis. ⁴⁹¹ These tumors contain S100 protein, neuron-specific enolase, neurofilament protein, and myelin basic protein, although sometimes this staining is weak.^{5.451. and 454.} Some cases do not express S100 protein. ⁴⁵⁷ Tumor cells do not express melan-A. ⁴⁹² Vimentin, AE1/AE3, SOX 10, and EMA may also be present.^{152.154. and 493.} Expression of CD117 is extremely uncommon.^{494. and 495.} Whereas the majority of monophasic synovial sarcomas stain for one or both of cytokeratins 7 and 19, most MPNSTs do not express these cytokeratin subsets. ⁴⁹³ A high Ki-67 labeling index (>25%) is associated with a reduced survival rate. ⁴⁹⁶

The perineurial variant is composed of spindle cells with long processes disposed in whorls or storiform patterns. Necrosis is sometimes present. Their characteristic immunohistochemical profile is EMA positive, S100 negative.^{462. and 463.}

In nasal gliomas there are islands of neural and fibrovascular tissue in the subcutis. The neural tissue is composed of astrocytes enmeshed in a neurofibrillary stroma (Fig. 37.18). Multinucleate astrocytes are not uncommon, but neurons are usually inconspicuous and few in number. They were the predominant element in one case. ⁵¹⁸ The nodules are interlaced with vascular fibrous septa. A markedly sclerosed stroma may be seen in older lesions. ⁵¹⁹ Calcification and sweat duct hyperplasia are two other rare associations. ⁵²⁰

Heterotopic neural islands occurring on the scalp may be surrounded by a capsule that structurally resembles the leptomeninges.^{504. and 521.} Clusters of ependymal cells with central vascular channels and myxoid stroma (myxopapillary ependymal rests) are found rarely in the sacrococcygeal region. ⁵²²

Immunoperoxidase staining demonstrates glial fibrillary acid protein (GFAP) and S100 protein in the glial tissue. ⁵¹⁹

Whereas type I lesions are usually confined to the subcutis, type II and III tumors may also involve the dermis. Some type I lesions consist merely of irregular strands of meningothelial cells set in a collagenous stroma, ⁵⁴³ whereas others resemble type II and III tumors in being circumscribed and more cellular, akin to intracranial meningiomas and including spindle-cell areas and meningothelial whorls. Psammoma bodies are variable in number. Inflammatory cells may be present in type II and III lesions.

When meningoceles and related malformations are studied, a range of tissue types can be identified, including dura-like tissue, blood vessels, lipoma formation, hypertrophy of the arrector pili muscle, nerve fibers, meningothelial cells, and neural tissue. ⁵⁰⁹ The infant who presented with several nodules on the face composed of meningeal tissue, smooth muscle, and connective tissue was regarded as a hamartoma of ‘cephalic neural-crest derived tissues’. ⁵⁴⁴

Immunoperoxidase studies for S100, vimentin, and epithelial membrane antigen have been positive.^{523.524. and 545.} A recent case was S100 negative but positive for epithelial membrane antigen and vimentin. ⁵³⁷ Ultrastructural studies have shown a similar appearance to intracranial meningiomas.^{525. and 526.}

Barr and colleagues have described three cases of an unusual cutaneous tumor with a superficial resemblance to a meningioma or the canine hemangiopericytoma. ⁵⁴⁶ The tumors had a whorled configuration of spindle cells, some concentrically arranged around blood vessels. Only vimentin positivity was present.

Paragangliomas are characterized by nests of large polygonal cells with central oval nuclei and abundant eosinophilic and granular cytoplasm. ⁵⁴⁸ The nests are separated by thin fibrous septa, giving a ‘zellballen’ (cell-ball) appearance.

The cells express vimentin, neuron-specific enolase, chromogranin, and synaptophysin. ⁵⁴⁸

The tumor is composed of small, round to oval cells of uniform size with a vesicular nucleus and multiple small nucleoli (Fig. 37.19). Mitoses and apoptotic bodies are usually numerous. ⁶⁴⁷ The cytoplasm is scanty and amphophilic and the cell borders are vaguely defined. Tumor cells may be larger in recurrences after radiotherapy. ⁶⁴⁸ An initial large cell variant also occurs. ⁶⁴⁹ A few tumors have scattered areas with spindle-shaped nuclei. The cells are present as sheets and solid nests, infiltrating the entire dermis and sometimes extending into the subcutis (Fig. 37.20). Some authors have attempted to define three distinct patterns of histological differentiation: trabecular, small cell, and intermediate. Overlap features are common and the trabecular pattern may be limited to the peripheral areas of the tumor. ⁶⁵⁰ Pseudorosettes are quite uncommon. ⁶⁵¹ There is a dissociation of tumor cells in poorly fixed areas. Other features include focal necrosis, particularly in large tumors, frequent involvement of dermal lymphatics, ⁶⁵⁰ and a scattered infiltrate of lymphocytes and sometimes plasma cells. Vascular proliferation is present in approximately 20% of cases. ⁶⁵² Increased vascular density is associated with a worse prognosis. ⁶⁵³ Strongly hematoxyphilic blood vessels, due to nuclear DNA deposition from tumor necrosis (the Azzopardi phenomenon), are most uncommon. ⁶⁵⁴ Stromal desmoplasia is a rare finding. ⁶⁵⁵ Amyloid has been demonstrated in a few tumors.^{656. and 657.} Focal argyrophilia is sometimes present, and this is enhanced by fixation in Bouin’s solution. ⁶⁴⁷

The overlying epidermis is ulcerated in about 20% of cases. Sometimes there is epidermal hyperplasia. Epidermotropism of tumor cells is uncommon.^{552.583.658.659. and 660.} Epidermal involvement was present in 11 of 132 cases in one series. ⁶⁶¹ Several cases have been reported in which the tumor cells were confined exclusively to the epidermis.^{662. and 663.} Cases with prominent epidermal involvement have been used as evidence of a Merkel cell origin of these tumors. ⁶⁵⁹ Overlying and contiguous Bowen’s disease has also been reported,^{559.664. and 665.} as has the admixture of a Merkel and squamous cell carcinoma.^{666.667. and 668.} No transition was seen between the two cell types. ⁶⁶⁷ Bowen’s disease and concurrent intraepidermal Merkel cell carcinoma have been reported. There was no dermal component of either tumor. ⁶⁶⁹ Another rarity is the finding of a tumor composed of Merkel, squamous, and basal cell carcinoma. ⁶⁷⁰ Areas that resemble basal cell carcinoma are not uncommon. ⁶⁷¹ This can lead to misdiagnosis on small biopsy specimens, and on frozen sections.^{671. and 672.} Patients with Merkel cell carcinoma have often had numerous skin cancers in the past. ⁶⁶⁷ Small swirls of squamoid differentiation, ⁶⁷³ and even sweat duct differentiation,^{661.664.674. and 675.} are occasionally seen within the tumor itself. Merkel cell carcinoma with squamous and sarcomatous differentiation is another rare finding. ⁶⁷⁶ Tripartite differentiation (squamous, glandular, and melanocytic) has been recorded. ⁶⁷⁷ This has led to the suggestion that the tumor arises from a primitive cell that can differentiate in either a neuroendocrine or a sudoriferous direction. ⁶⁶⁴ Prominent microcystic features mimicking eccrine carcinoma have been reported. ⁶⁷⁸ Other exceedingly rare patterns of differentiation include skeletal muscle, leiomyosarcomatous, fibrosarcomatous, lymphoepithelioma-like, and atypical fibroxanthoma-like.679.^{680.681.682.683.684. and 685.} Well-differentiated follicular structures were present in one of these cases. ⁶⁸¹ They have since been reported in the more usual type of Merkel cell carcinoma. ⁶⁸⁶ Cases of Merkel cell carcinoma arising in an epidermal cyst,^{687. and 688.} and others associated with a trichilemmal cyst have been reported.^{689. and 690.} In-situ Merkel cell carcinoma was present in a trichilemmal cyst in one case. ⁶⁹¹

Examination of the sites of a regressed lesion shows perivascular lymphocytes, some lymphoid nodules, variable numbers of foamy histiocytes, and some fibrosis. No tumor cells remain. ⁶⁰⁹ In partial regression, there is usually a heavy lymphocytic infiltrate with prominent apoptosis of tumor cells and some fibrosis. ⁶⁹²

Histological features associated with a worse survival include lymphovascular invasion, high tumor mast cell numbers, ⁶⁹³ increased vascular density, ⁶⁵³ small cell size, and a high mitotic rate. ⁶¹¹ The expression of bcl-2, bax, and p53 did not correlate with survival in one study, ⁶⁹⁴ although in another small series, the presence of p53 did correlate with increased recurrence/death. ⁶⁹⁵ This tumor expresses Cox-2 in low levels and its expression is not a prognostic factor. ⁶⁹⁶ The expression of p63, survivin, and Ki-67 are associated with a worse prognosis.^{697.698.699. and 700.} High expression of certain matrix metalloproteinases (MMP-1 and MMP-3) may influence the invasive and metastatic potential of this tumor. ⁷⁰¹

Merkel cell carcinomas need to be differentiated histologically from anaplastic primary and secondary tumors; therefore there have been numerous immunoperoxidase studies assessing the specificity of various markers.^{702. and 703.} The variability in the reported results for the same marker probably reflects the different sensitivity of the techniques used and the level of specificity of the monoclonal antibodies. Most tumors are positive for neuron-specific enolase^{673. and 704.} and epithelial membrane antigen. ⁷⁰² Cytokeratin is usually present as paranuclear globules (Fig. 37.21),^{705.706.707. and 708.} which are present in mitotic as well as interphase cells. ⁷⁰⁹ Both the CAM5.2 and CK20 stains will show this paranuclear dot-like immunoreactivity.^{710. and 711.} Cytokeratin 20 (CK20) was initially regarded as a sensitive and specific marker for Merkel cell carcinoma, which allowed distinction from other small cell carcinomas.^{712.713.714. and 715.} However, one study has shown that one-third of small cell carcinomas of the lung are positive for CK20. ⁷¹⁶ In this same study, 28 of 33 of the lung tumors stained for thyroid transcription factor-1 but none of the 21 Merkel cell carcinomas stained. ⁷¹⁶ Other studies have confirmed the value of a negative TTF-1 in distinguishing Merkel cell carcinoma from other small cell carcinomas.^{717. and 718.} Positive staining for CK20 and neurofilaments (NF), performed in association with negative TTF-1, completes this distinction between the two tumors. ⁷¹⁸ MOC-31, an antibody that recognizes epithelial cell adhesion molecule (Ep-CAM), can be positive in both tumors. ⁷¹⁹ A series of seven cases of CK20⁻/CK7⁺ Merkel cell carcinomas has been described. ⁷²⁰ All tumors expressed synaptophysin. ⁷²⁰ CK20 can also be used for the detection of micrometastases in lymph nodes. ⁷²¹ It improves the detection of these deposits.^{722. and 723.} Tumor cells may also stain with Ber-EP4, an antibody directed against an epithelium-specific membrane antigen. ⁶⁶¹ CD117 is expressed in 55–95% of cases, as granular cytoplasmic staining.^{710.724.725.726. and 727.} Nuclear HUR is expressed in Merkel cell carcinoma and normal skin, while cytoplasmic staining is found only in a subset of tumors, but not normal skin. ⁷²⁸ Neurofilaments, ⁷²⁹ chromogranin,^{730.731. and 732.} synaptophysin, guanine nucleotide-binding proteins, ⁷³³ CD171, ⁷³⁴ CD24, ⁷³⁴ CD56, ⁷³⁵ and polypeptides such as calcitonin, ⁷³⁶ gastrin, ⁷³⁷ somatostatin, and corticotropin are sometimes present (Fig. 37.22). ⁵⁵³ Chromogranin was present in all 20 cases in one series. ⁷³⁸ CD99 was detected in 11 of these cases. ⁷³⁸ Expression of CD44 may indicate a metastatic potential. ⁷³⁹ Pax5, a marker of B-cell lineage, is expressed in Merkel cell carcinomas.^{740. and 741.} So too is terminal deoxynucleotidyl transferase (TdT), which is also expressed in some lymphomas/leukemias.^{742. and 743.} Acetylcholine receptors are also expressed. ⁷⁴⁴ The tumor cells are negative for S100 protein, laminin, CD45 (leukocyte common antigen), ⁷⁰² and metenkephalin,^{616. and 706.} the latter being a marker for normal Merkel cells. Tumor cells often contain high levels of bcl-2 protein.^{745. and 746.} The cells of secondary ‘oat-cell’ carcinomas and carcinoids, some of which are spindle shaped, usually have more cytoplasm; they may be immunoperoxidase positive for bombesin, leucine, enkephalin, and β-endorphin, markers which are absent in Merkel cell carcinomas. ⁷⁰³

In one case, the nodal metastasis of a Merkel cell carcinoma of the skin showed rhabdomyosarcomatous differentiation. ⁷⁴⁷

Malignant primitive neuroectodermal tumors are composed of sheets of hyperchromatic cells with small amounts of cytoplasm. Homer–Wright rosettes are frequently present, and central neurofibrillary material may be seen in them. ⁷⁶⁶ Glycogen may be present, a feature once thought to be restricted to Ewing’s sarcoma (see below). ⁷⁷¹ The tumor cells contain neurosecretory granules and are usually positive for neuron-specific enolase, CD99, and PGP9.5. ⁷⁷¹ They show restricted expression of S100 protein and the various neuropeptides.

Extraskeletal Ewing’s sarcoma has cells that often contain glycogen, but there are no neurosecretory granules or well-developed desmosomes. ⁷⁷² Several histological variants have been reported in skeletal tumors. ⁷⁷³ The cells express CD99 in a characteristic membranous pattern,^{762. and 774.} but are negative for S100 protein and desmin. ⁷⁷⁵ CD117 and FLI-1 are sometimes expressed.^{495. and 767.} The presence of p16^INK4a alteration is associated with a poorer prognosis. ⁷⁷⁶ Merkel cell carcinomas are frequently positive for epithelial membrane antigen and cytokeratin 20 (CK20), features not seen usually in MPNETs. Neuroblastomas are usually negative for CD99. ⁷⁷⁷

A final diagnosis can usually be made only after the fluorescent in-situ hybridization studies and immunohistochemistry results have been correlated. ⁷⁷³ Electron microscopy is now used infrequently.