Malignant Melanotic Nerve Sheath Tumor

Not clinically relevant

Two genetic loci have been identified in Carney complex: PRKAR1A (CNC1) and CNC2, mapping to 17q22-q24 and 2p16, respectively. PRKAR1A inactivation is seen in roughly 50% of Carney complex kindreds. PRKAR1A encodes a tumor suppressor; PRKAR1A mutations and loss of PRKAR1A protein expression are seen in the overwhelming majority of studied MMNSTs, almost all of which have occurred in patients lacking other stigmata of Carney complex. SNP arrays typically show hypodiploidy, with monosomies of chromosomes 1, 2, and 17. Inactivation of both alleles of PRKAR1A through mutations and/or loss of heterozygosity of 17q has been reported. Gene expression analyses show MMNST to clearly segregate from conventional schwannomas and melanomas.

Most MMNSTs are solitary, although multiple and multicentric tumors may be seen in patients with Carney complex. Grossly, the tumors appear circumscribed or partially encapsulated, and they are frequently heavily pigmented, with the appearance of dried tar.

The neoplastic cells grow in short fascicles or sheets, vary in shape from polygonal to spindled, and often have a syncytial appearance. Vague palisading or formation of whorled structures may be present. Cellular detail is often difficult to discern, owing to the heavy pigment deposits. The melanin pigment may be coarsely clumped or finely granular and varies from area to area. It stains positively with the Fontana stain and negatively for iron and PAS. In less pigmented areas, the tumor cells have eosinophilic to amphophilic cytoplasm, round to ovoid nuclei (often with nuclear grooves and pseudoinclusions), and usually small nucleoli. Occasional tumors show marked nuclear hyperchromatism with prominent macronucleoli. Mitoses and necrosis can be present, but they are not clearly associated with outcome. Psammoma bodies are present in roughly 50% of cases, although extensive sampling may be required to identify them. There are no clinical differences between psammomatous and non-psammomatous MMNSTs, with both showing a variable association with Carney complex, loss of PRKAR1A expression, and similar clinical behavior. Immunohistochemically, MMNSTs strongly express S100; SOX10; and various melanocytic markers, including HMB45, melan-A, and tyrosinase. PRKAR1A expression is typically lost. Ultrastructurally, the cells resemble Schwann cells with elaborate cytoplasmic processes that interdigitate or spiral in the manner of mesaxons; premelanosomes and melanosomes are routinely present.

Not clinically relevant

The behavior of MMNST is difficult to predict, and metastases can occur in the absence of morphologically malignant features. In the past, it was thought that most of these lesions had a benign, indolent course, with a < 15% metastatic risk. However, more-recent reports have shown frequently aggressive behavior, with a local recurrence rate and metastatic risk of 26–44%. Additionally, only 53% of patients followed for > 5 years have been reported to be disease-free, suggesting that long-term follow-up is required to fully judge metastatic risk. In general, histopathological features are not predictive of outcome, although there are limited data suggesting more-aggressive behavior in mitotically active tumors.

PRKAR1A expression is typically lost, corresponding to mutations of the gene.

Essential: frequent origin from paraspinal or visceral autonomic nerves; fascicular to sheet-like proliferation of heavily pigmented, relatively uniform plump spindled cells; coexpression of S100/SOX10 and melanocytic markers (e.g., HMB45, melan-A).

Desirable: loss of PRKAR1A expression.