Primary Melanocytic Neoplasms of the Central Nervous System and Melanotic Schwannoma

Clinical Findings.

The tumors of the melanocytoma group may be encountered in children but come to attention most frequently in middle-aged and older adults, having a peak incidence in the fifth decade of life. A majority arise along the spinal neuraxis (cervicothoracic segments being favored) or in the foramen magnum region, an observation that may reflect the particular concentration in these locations of melanocytes normally colonizing the leptomeninges. Less frequently involved are the posterior fossa rostral to the foramen magnum and Meckel cave, with only a small fraction of melanocytomas originating in the supratentorial compartment. Although most of these neoplasms present as leptomeningeal or dura-based growths, intramedullary cases are well recognized and melanocytomas have been encountered within the ventricular compartment, in the sellar region, and as growths situated along spinal nerves and involving neural foramina in schwannoma-like fashion. On record, although most exceptional, are patients presenting with arguably multicentric melanocytomas ; one report described the association of a cerebellopontine angle melanocytoma with an extracranial, intermediate-grade melanocytic neoplasm in the occipital subcutaneous tissues. Rarely, meningeal melanocytomas are associated with blue nevi or nevi of Ota. Clinical manifestations are attributable mainly to compression of adjoining neuroparenchyma and include myeloradiculopathy, cranial nerve deficits, cerebellar dysfunction, symptoms of hydrocephalus, and seizures. On preoperative neuroradiologic assessment, melanocytomas are typically solid, circumscribed, and contrast enhancing ( Fig. 25.1A ). The paramagnetic properties of melanin often result in such lesions being T1 hyperintense and T2 hypointense on magnetic resonance imaging (MRI), a profile that can suggest the diagnosis of a melanocytic neoplasm (see Fig. 25.1B ).

Gross, Histopathologic, and Ultrastructural Findings.

The high melanin content that characterizes a majority of melanocytomas results in most being grossly pigmented and composed of friable, red-brown to coal-black tissue on examination by the unaided eye ( Fig. 25.2 ).

On microscopic evaluation, melanocytomas are populated by compactly arranged neoplastic elements that may assume both spindled and epithelioid profiles ( Fig. 25.3 ). Melanization of tumor cell cytoplasm is usually obvious, entirely amelanotic melanocytomas being the exception, and interstitial aggregates of melanophages are often apparent. Spindle cell components tend to be a vague or more tightly regimented whorling that accounts for the once-prevalent view of such tumors as melanotic meningiomas. Spindled elements may also be disposed in fascicles or storiform arrays and can exhibit perivascular pinwheeling. Epithelioid variants are characterized by nested or sheetlike architecture. Cytologic monomorphism and a lack of conspicuous atypia are the rule, with tumor cell nuclei containing distinct but small nucleoli and in some cases evidencing longitudinal grooves similar to those seen in spindled melanocytic neoplasms of the uvea ( Fig. 25.4 ). Mitotic activity typically is less than 1 mitosis per 10 high-power microscopic fields. Necrosis and invasion of neighboring neural tissues are not seen. A neoplasm apparently representing a melanocytoma with oncocytic components has been depicted.

Designation as melanocytic neoplasms of intermediate grade has been suggested for tumors retaining the cytologic features expected of melanocytomas while exhibiting increased, although not dramatically elevated, mitotic activity (this usually in the range of 1 to 3 mitoses per 10 high-power microscopic fields) and/or neuroparenchymal invasion. The neural tissues infiltrated by such lesions often exhibit striking astrogliosis associated with Rosenthal fiber formation, evidence of a chronically evolving (as opposed to a rapid and destructive) process. Intermediate-grade melanocytic neoplasms of this kind are classed under the rubric of meningeal melanocytoma in the current WHO classification, which does not list these as a distinct entity or endorse specific mitotic (or other) criteria for segregating these tumors from the melanocytomas and from frank CNS melanomas. It is the author's experience that amelanotic melanocytomas nearly always fall in this ill-defined category, as do most melanocytomas of predominantly or exclusively epithelioid character.

On ultrastructural examination, the tumor cells constituting melanocytomas contain premelanosomes and melanosomes at differing stages of maturation ( Fig. 25.5 ). Not seen are the complex interdigitations of cytoplasmic processes or the desmosome formation characteristic of meningiomas. Basal lamina material may surround aggregates of tumor cells but typically does not invest individual neoplastic elements in schwannian fashion.

Histochemical and Immunohistochemical Findings.

The presence of intratumoral melanin can be confirmed by its black coloration in Fontana preparations ( Fig. 25.6A ) and failure to react as iron, although extracellular deposits of hemosiderin and siderophages may be revealed by iron methods. Tumor cells typically do not express epithelial membrane antigen (EMA), cytokeratins, glial fibrillary acidic protein, or synaptophysin on immunohistochemical assessment; instead they label for a panoply of melanocyte/melanoma-associated antigens that can include S100 protein, HMB-45 (see Fig. 25.6B ), Melan A (A103) (see Fig. 25.6C ), Sox10, microphthalmia transcription factor (MITF), and tyrosinase. Immunoreactivity for c-KIT and p-ERK has been reported. Nuclear expression of BRCA-associated protein 1 (BAP1) is usually retained, reflecting the observation that BAP1 mutation appears to be quite uncommon in this setting, but loss of expression associated with mutation has been documented in select cases. Reticulin staining, as well as type IV collagen and laminin labeling, about groups of tumor cells may be apparent ( Fig. 25.7A and B ), reflecting the deposition of basement membrane materials in some cases, but labeling around individual cells is rarely encountered (see Fig. 25.7C and D ). The latter phenomenon is generally restricted to cellular elements situated peripherally and neighboring the meninges or fibrous stromal tissues. Ki-67 labeling indices generally do not exceed 1% to 2% but may be higher in lesions of intermediate grade.

Genetic Findings.

Activating mutations of the G protein–encoding GNAQ and GNA11 genes constitute the most prevalent and earliest oncogenic events documented to date in tumors of the meningeal melanocytoma group ; these mainly involve codon Q209, which is mutually exclusive and identical to the GNAQ and GNA11 mutations associated with blue nevi, nevi of Ota, uveal melanomas, and ophthalmic melanocytomas ( Fig. 25.8 ). One meta-analysis found GNAQ mutations to have been detected in approximately 40%, and GNA11 mutations in approximately 15%, of melanocytomas and intermediate-grade melanocytic neoplasms investigated, whereas approximately 70% of cases examined in a series proved to be GNAQ mutant. Tumors of the latter type are overrepresented among those harboring GNA11 alterations. Subsets of GNAQ/GNA11 -mutant meningeal melanocytomas further resemble uveal melanomas in acquiring mutations of SF3B1 or EIFAX1 . BAP1 mutation, associated with metastatic behavior on the part of uveal melanomas, has been documented in the meningeal setting but, as stated previously, appears to be uncommon. Only exceptionally have tumors interpreted as belonging to the meningeal melanocytoma class been found to harbor BRAF ^V600E , KRAS, or NRAS mutations, and the histologic diagnosis in at least some of these cases is open to question. In a similar vein, KIT and TERT promoter mutations have proven foreign to CNS melanocytomas. Furthermore, meningeal melanocytomas have methylation profiles distinct from those of metastatic melanomas and other melanotic neoplasms involving the nervous system. The most common copy number changes in this setting are chromosome 6p gains and loss of 3 or 3q.

Differential Diagnosis.

The differential diagnosis of meningeal melanocytomas is considered later, following discussion of localized meningeal melanomas.

Treatment and Prognosis.

Gross total resection is the treatment of choice for tumors of the meningeal melanocytoma group and can effect control of these circumscribed and slow-growing neoplasms. The best prognosis would appear to attach to completely resectable examples confined to the meninges (i.e., without neuroparenchymal invasion) and manifesting the very low mitotic and Ki-67 labeling indices characteristic of well-differentiated melanocytomas. However, even tumors meeting these criteria may recur in the face of ostensibly complete excision, and the risk of regrowth following subtotal removal is substantial. Meningeal lesions qualifying as intermediate-grade melanocytic neoplasms by virtue of secondary spinal cord or brain infiltration are especially prone to recur, as are melanocytomas situated primarily in the substance of the spinal cord. In addition to locally relapsing, tumors of the meningeal melanocytoma group may seed the cerebrospinal fluid ( Fig. 25.9 ), giving rise to subarachnoid metastases, and rarely spread to extraneural sites. In our experience, intermediate-grade lesions have been overrepresented among cases complicated by leptomeningeal dissemination. SF3B1 and BAP1 mutations may prove to be markers of aggressive biologic potential in this setting. Radiation therapy can benefit patients with residual or recurrent disease, but only isolated reports describe tumor responsiveness to conventional chemotherapeutic agents. Whether the targeting of mutant GNAQ/GNA11- or GNAQ/GNA11 -driven pathways emerges as a treatment option for patients with refractory tumors remains to be seen. The “malignant transformation” of melanocytomas to frank melanomas is a recognized but uncommon phenomenon.