Case 1 History
The patient is a 54-year-old male with a circumscribed, skin-colored papule on his chest.
Microscopic Findings
Sections show a dermal proliferation of small, wavy, spindled cells arranged in thin fascicles separated by clefts or stroma that contain mucin and mast cells. There are associated thin bands of collagen ( Fig. 16.1 ).
Diagnosis
Neurofibroma
Clinical Presentation
Neurofibromas are indolent, painless, soft, skin-colored papules. Diffuse neurofibromas present as larger nodules or deeply situated plaques. Plexiform neurofibromas present as irregular, snakelike, multinodular tumors. Diffuse and plexiform neurofibromas more commonly present in younger patients (children or young adults) compared with sporadic neurofibromas. Neurofibromas are related to inactivating mutations in NF1 .
Histopathology
Neurofibromas present as nonencapsulated papules or nodules and include an admixture of spindled cells, collagen fibers, lymphocytes, and mast cells. The myxoid subtype is rich in stromal mucin, the “sclerotic” (or desmoplastic) subtype is associated with dense collagen, and the “lipomatous” subtype conspicuously incorporates adipocytes. Diffuse neurofibromas infiltrate the subcutis and usually show entrapped adnexal epithelium. Plexiform neurofibroma exhibits a tortuous architecture because peripheral nerves are expanded by a proliferation of axons, Schwann cells, and fibroblasts. Neurofibromas show invariable positivity for SOX-10 and S100, and CD34 shows a characteristic fingerprint pattern of CD34+ perineurial fibroblasts. ,
Differential Diagnosis
The differential diagnosis includes other spindle cell tumors, including neurotized melanocytic nevus, dermatofibroma, perineurioma, palisaded encapsulated neuroma (PEN), and early desmoplastic melanoma ( Table 16.1 ).
| Neurofibroma | Dermatofibroma | Perineurioma | Neurotized Nevus | Palisaded Encapsulated Neuroma | |
|---|---|---|---|---|---|
| Composition | Small, wavy, spindled cells in myxoid and/or collagenous stroma with mast cells | Spindled cells with coarse collagen | Small spindled cells in myxoid and collagenous stroma | Melanocytes and deep neuroid cells | Fascicles of nerve sheath cells with incorporated axons |
| Epidermal changes | None | Acanthosis with basilar pigmentation and flat rete ridges | None | None | None |
| Immunohistochemistry | SOX-10, S100, CD34+ | Factor XIIIa+ in the epithelioid subtype | EMA, Glut-1, CD34+ | SOX-10, S100, MART1+ | SOX-10, S100, neurofilament+ |
Neurotized Melanocytic Nevus
Clinical Presentation
Melanocytic nevi are benign melanocytic proliferations and can present anywhere as either skin-colored or pigmented nodules or macules. Neurotization is an epiphenomenon of senescence whereby the melanocytes exhibit neurofibroma-like or perineurioma-like differentiation.
Histopathology
Neurotized nevi typically show conventional melanocytic differentiation superficially ( Fig. 16.2 ). With descent in the dermis, melanocytes transition to neural areas composed of spindled cells in a fibrillar matrix.
Dermatofibroma
Clinical Presentation
Dermatofibroma presents as a small, brown to skin-colored, firm papule or nodule on the trunk or extremity.
Histopathology
Dermatofibroma consists of a proliferation of spindled and stellate cells arranged interstitially or as short fascicles in the mid to upper dermis. There are associated wiry or keloidal collagen bundles present. The density of the spindled cells is often highest centrally, whereas at the periphery, isolated spindled cells are seen interposed between thickened collagen bundles (colloquially, collagen trapping or collagen balls). The epidermis above the spindled cell proliferation is often acanthotic and hyperpigmented with flat-based rete ridges. A number of variants of dermatofibroma, including cellular, hemosiderotic, lipidized, and epithelioid, have been described. The epithelioid subtype of dermatofibroma is typically induced by rearrangement in ALK1 .
Perineurioma
Clinical Presentation
Classically, perineuriomas have been grouped according to their location within a nerve (intraneural) or within soft tissue. The latter situation is far more common in the practice of dermatopathology. Perineuriomas can also present in neurofibroma-like fashion in the dermis. A solitary slow-growing skin-colored tumor on an extremity represents a common presentation.
Histopathology
Intraneural perineuriomas display expansion of axons by onion bulbs morphology, and these structures are composed of layers of perineurial cells that surround axons and Schwann cells. Soft tissue perineuriomas are nonencapsulated, partially circumscribed proliferations of spindled perineurial cells with thin elongate cytoplasmic processes. Cutaneous perineuriomas involve the dermis and exhibit a neurofibroma-like configuration with internal whorls of small cells, which are often perivascular in distribution ( Fig. 16.3 ). The perineurial cells may express epithelial membrane antigen (EMA) or Glut-1.
Palisaded Encapsulated Neuroma (Solitary Circumscribed Neuroma)
Clinical Presentation
PEN typically affects the face as a small skin-colored papule. Extrafacial presentations can also occur.
Histopathology
PEN consists of a circumscribed, lobulated cellular proliferation of wavy spindled cells arranged as intertwined fascicles , ( Fig. 16.4 ). Although encapsulated is included as part of the tumor name, often there is a lack of a well-formed capsule. There may be associated myxoid change. PEN may present in plexiform fashion. The key defining element of any neuroma, including PEN, is the presence of axonal differentiation, which can be identified using neurofilament.
Case 2 History
The patient is a 28-year-old male with a painful nodule on the lower leg.
Microscopic Findings
Sections show circumscribed, pseudoencapsulated spindle cell proliferation in the deep dermis. Internally, there are areas of high cellularity alternating with myxoid areas of low cellularity. There is an increase in vascularity ( Fig. 16.5 ).
Diagnosis
Schwannoma (Neurilemmoma)
Clinical Presentation
Schwannomas may present in the dermis or subcutis. They may be symptomatic and are often included in the differential diagnosis of painful tumors. The clinical morphology is not distinct.
Histopathology
Sections show a pseudoencapsulated tumor with areas of high cellularity (Antoni A) alternating with myxoid areas of low cellularity (Antoni B). The pseudocapsule often includes perineurial cells and may express EMA. The spindled Schwann cells are variably packed together but tend to be uniform. Nuclei are generally nonatypical, although scattered nucleomegaly can be seen as a degenerative change. There is often fibrous to myxoid stroma. Occasionally, the spindled cells are arranged in parallel rows in apposition to one another (so-called Verocay bodies). The vessels in a long-standing schwannoma are often variably dilated and may show hyalinization in their walls.
Differential Diagnosis
The differential diagnosis includes other spindle cell tumors, including dermatofibroma, perineurioma (see earlier) and neurotized melanocytic nevus (see earlier). Schwannoma is distinctive in that it is prone to be encapsulated and characteristically exhibits biphasic morphology.
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Neurofibroma
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Nonencapsulated admixture of spindled cells, collagen fibers, lymphocytes, and mast cells
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Perineurioma
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Whorls of EMA+ perineurial cells that often are centered on vessels
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Schwannoma
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Pseudoencapsulated nodular array of S100+ Schwann cells with both Antoni A and Antoni B areas
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Case 3 History
An 82-year-old male presents with a rapidly enlarging violaceous nodule on the forehead.
Microscopic Findings
Sections show nodules and sheets of compact malignant cells ( Fig. 16.6 ). The atypical cells have scant cytoplasm and enlarged irregular nuclei with finely granular chromatin. There are numerous mitotic figures and apoptotic bodies evident. Immunohistochemistry for CK20 highlights the tumor cells and shows perinuclear dot positivity.
Diagnosis
Merkel Cell Carcinoma
Clinical Presentation
Merkel cell carcinoma (MCC) commonly presents as a rapidly growing violaceous nodule. MCC is most common in elderly adults and shows a slight male predominance. Risk factors include age, chronic ultraviolet light exposure, and immunosuppression. Approximately 70% of cases in North America are related to infection by Merkel cell carcinoma polyomavirus (MCPV). By contrast, MCPV-negative tumors harbor a high somatic mutation burden (including mutations affecting TP53, RB1, and Notch family) as well as a high frequency of genomic instability. MCPV+ tumors are believed to hold a better prognosis in comparison to MCPV-negative tumors, although conflicting data exist.
Histopathology
MCC exhibits varied microscopic morphology. The constant feature is a proliferation of malignant cells with neuroendocrine features, including large nuclei with finely granular chromatin, scant cytoplasm, nuclear molding, and an elevated mitotic index. Immunostaining is typically required to establish the diagnosis. MCC expresses CK20 and neurofilament (both in dot fashion) as well as other neuroendocrine markers, including as insulinoma-associated protein 1, synaptophysin, and chromogranin. MCPV large T antigen also highlights tumors triggered by MCPV.
Differential Diagnosis
The differential diagnosis includes metastatic neuroendocrine carcinoma ( Fig. 16.7 ) and other types of basaloid primary carcinoma ( Table 16.2 ).
