—  SHORT COURSE #46  —

Cutaneous Mesenchymal Tumors and Non-Mesenchymal Mimics:
An Update and Approach to Diagnosis

Case 3 - Cellular Neurothekeoma

Steven D. Billings, M.D.
Andrew L. Folpe, M.D.


Clinical History
The 23-year-old woman presented with an asymptomatic flesh colored papule on her face. A subsequent punch biopsy was performed.

Morphology
The tumor was composed of a nested arrangement of epithelioid tumor cells with abundant eosinophilic cytoplasm. The nests of tumor cells were embedded in a slightly hylanized stroma. The individual tumor cells had round to oval nuclei with abundant, pale eosinophilic cytoplasm. Focal nuclear atypia and mitotic figures were present.

Diagnosis: Cellular neurothekeoma

Discussion

Historical Perspective
The true nature of the cellular neurothekeoma remains in question. When originally described, this tumor was so named cellular neurothekeoma (CNT) because of the resemblance to myxoid neurothekeoma (MNT). Both had a nested to fascicular growth pattern and presented as small tumors centered in the reticular dermis. MNT also shows, at least focally, some epithelioid cells similar to those seen in CNT and vice versa Therefore it was postulated that these entities represented ends of a spectrum within the same neoplasm. This view has been questioned, however. There is convincing immunohistochemical and ultrastructural evidence to support a nerve sheath origin for MNT, but this evidence is lacking in CNT. CNT does not express more conventional markers of nerve sheath tumors such as S100 protein or EMA. While they do express NKI-C3 and neuron specific enolase, these antigens are non-lineage specific. Although it has been suggested that CNT is an unusual variant of a pilar leiomyoma or dermatofibroma, the evidence in support of these hypotheses is far from compelling. Ultrastructural studies have also not yielded many clues to the origin of this unusual tumor, with no convincing evidence of nerve sheath, smooth muscle or fibroblastic differentiation.

Clinical and Histopathological Features:
CNT are typically tumors of children and young adults. They usually present as small, asymptomatic cutaneous nodules on the upper portion of the body, especially the head and neck area.

CNT is a dermal tumor with a distinctive nested to fascicular pattern of growth. Within the tumor nests, the cells may have a subtle, whorled arrangement or be more sheet-like. The tumor cells are predominantly epithelioid in appearance with well defined cytoplasmic membranes and abundant pale, eosinophilic cytoplasm. Spindled cells comprise a minority of the cellular constituents. The surrounding stroma ranges from hyalinized, to myxoid stroma. The nuclei are round to slightly oval and have a vesicular chromatin pattern, but nuclear hyperchromasia and moderate nuclear atypia are common focal features. Some mitotic figures are usually present, but the mitotic rate is usually less than 5/10HPF. Rare cases with atypical mitotic figures have been reported. Associated osteoclast-like giant cells are relatively common.

Rarely, CNT may show more worrisome features including large size (>5 cm), a sheet-like growth pattern, a more infiltrative growth pattern, vascular invasion, prominent nuclear atypia and a high mitotic rate (>10mf/10 HPF). These atypical features do not appear to be associated with a more aggressive clinical course.

CNT are consistently immunoreactive for NKI/C3 and vimentin. NKI/C3 is a relatively non-specific antibody that is often positive in nerve sheath and melanocytic tumors. Microphthalmia transcription factor (MiTF), a somewhat more specific marker of melanocytic tumors among others, is also expressed in a high percentage of CNT. Immunoreactivity for neuron specific enolase is seen in the majority of cases, and approximately one half of cases may show some immunoreactivity for smooth muscle actin. CNT is strongly positive for PGP 9.5, a sensitive but entirely non-specific neuron-related ubiquitin hydrolase. Expression of S-100A6 has also been suggested as a helpful adjunctive marker, although there is very limited data in this area. There is evidence, however, that S100A6 may be expressed by other tumors that enter the differential diagnosis of CNT, including Spitz nevus, melanoma and various fibrohistiocytic tumors. CNT is consistently negative for S-100 protein, HMB45, MelanA, cytokeratins, desmin, EMA and CD34.

Differential Diagnosis:
Owing to its nested architecture, CNT is most frequently confused with melanocytic tumors including Spitz nevus and melanoma. Spitz nevus, like CNT, is a tumor of young patients and is commonly seen in the head and neck area. Like CNT, Spitz nevus is composed of epithelioid to spindled tumor cells arranged in a nested growth pattern. Melanomas may also have a prominent epithelioid appearance. Both Spitz nevus and melanoma usually have an overlying intraepidermal component which is never seen in CNT. The presence of melanin pigment is also a clue to the diagnosis of melanocytic tumors. In contrast to CNT, melanocytic tumors are almost always S100 protein-positive and frequently HMB45/ Melan-A positive.

CNT may also be confused with myxoid neurothekeoma (MNT) (dermal nerve sheath myxoma). MNT has a similar nested to lobular growth pattern, but often with more prominent fibrous septae separating the tumor nodules. Although MNT may show foci with epithelioid cells similar to cellular neurothekeoma, it is predominantly a spindled cell tumor. Myxoid stroma is invariably abundant in this neurothekeoma variant, whereas myxoid stroma is more variable in CNT. MNT also shows strong and consistent immunoreactivity for S-100 protein.

Epithelioid schwannoma also enters the differential diagnosis of CNT. The Antoni-A and Antoni-B of epithelioid schwannoma can be confused with the nodular growth pattern of CNT, and some epithelioid schwannomas show a more sheet-like pattern of growth that is occasionally seen in CNT. The epithelioid tumor cells in this variant of schwannoma may bear a striking resemblance of the tumor cells of CNT. Histologic clues to the diagnosis of epithelioid schwannoma include areas resembling conventional schwannoma and the presence of a true fibrous capsule. The strong immunoreactivity for S-100 protein seen in epithelioid schwannoma is also useful.

CNT arising on the head can be confused with extracranial meningiomas. Meningiomas may also have a nodular growth pattern that may have a subtle whorling arrangement of tumor cells with relatively abundant cytoplasm. Extracranial cutaneous meningiomas typical occur along cranial closure lines. The presence of psammoma bodies may provide a clue to the diagnosis of cutaneous meningioma. Meningiomas are also positive for EMA.

The palisaded encapsulated neuroma (solitary neuroma) is occasionally considered in the differential diagnosis, largely due to the overlapping clinical presentation as a small dermal nodule in the head and neck region. The palisaded encapsulated neuroma is a circumscribed tumor with a thin capsule that is composed of spindled cells with slightly wavy nuclei and prominent intratumoral clefting. These histologic features readily allow the histologic distinction between CNT.

Malignant tumors in the differential diagnosis other than melanoma include epithelioid sarcoma and, less commonly, myxoid malignant fibrous histiocytoma. Epithelioid sarcoma is also a tumor of young adults, but typically presents on the distal extremities. Cases arising in the head and neck area do occur, but are distinctly uncommon. Epithelioid sarcoma may have a nodular growth pattern that could be confused with CNT, but the tumor nodules within the epithelioid sarcoma frequently show central tumor necrosis, a feature not seen in CNT. Epithelioid sarcoma also shows a higher mitotic rate and atypical mitotic figures are often seen. By immunohistochemistry, epithelioid sarcoma show strong immunoreactivity for cytokeratins, EMA and immunoreactivity for CD34 in roughly half of cases.

Myxoid malignant fibrous histiocytomas is more likely to be confused with the MNT variant, except for the rare cases of cellular neurothekeoma with more prominent myxoid stroma. Myxoid malignant fibrous histiocytoma is a tumor that arises in the subcutis rather than the dermis, has more nuclear atypia, atypical mitotic figures and a characteristic arborizing vasculature.

Prognosis and Treatment:
It is clear that cellular neurothekeoma is a benign cutaneous neoplasm. CNT may rarely recur, but no cases of metastasis have been documented. Exceptionally, they may show worrisome histological clinical features as outline above. However, there is no evidence to suggest that these "aggressive" histologic features alter the behavior of CNT. Simple excision remains the mainstay of treatment.

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