2021 NPA-04

This case was originally published in 2021. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.

The patient is a 46-year-old man who presented with low back pain and sciatica. MRI revealed an intradural extramedullary T12-L2 spinal mass, which was subsequently resected. The specimen was submitted to the pathology lab and consisted of multiple, irregular, dark brown-black fragments of soft tissue measuring 2.4 x 1.5 x 0.3 cm in aggregate.

Tissue Site
Spinal cord, T12-L2, intradural extramedullary tumor

The whole slide image provided is an H&E-stained slide from the intradural extramedullary tumor resection specimen.

The workup of pigmented lesions in the spinal or paraspinal region is often extremely challenging, and there is considerable histopathologic overlap among several entities, including primary meningeal melanocytic neoplasms (melanocytoma versus melanoma), metastatic melanoma, and malignant melanotic nerve sheath tumor (MMNST), which was previously referred to as “melanotic schwannoma” (see further discussion below). For this reason, it is often useful to know the precise localization from the neuroimaging studies and/or the surgeon’s intraoperative impression, since melanocytic tumors typically arise from the leptomeninges or dura of the spinal cord or brain (especially posterior fossa/base of brain where meningeal melanocytes are most prominent), whereas MMNST is usually associated with a paraspinal peripheral nerve or nerve root. The cytologic features in this particular case, including at least focally large epithelioid cells with vesicular chromatin and macronucleoli, along with the presence of necrosis, increased mitotic activity, and increased Ki-67 labeling index (Image A, Image B, Image C, Image D, and Image H) essentially exclude the diagnostic consideration of meningeal melanocytoma. MMNST is a tumor with both Schwannian and melanocytic features, two cell types with a common embryologic origin. Melanosomes and pre-melanosomes are seen ultrastructurally. As such, both MMNST and melanoma (either primary or metastatic) are immunoreactive for melanoma-associated markers, such as S100 protein (Image E), SOX10, HMB-45 (Image F), and Melan-A; therefore, these immunostains cannot distinguish these differential diagnostic considerations. Since Schwann cells produce abundant basement membrane and melanocytes do not, the increased intercellular collagen IV staining (Image G) favors MMNST over melanoma, although there are many exceptions to this rule. Instead, surrogate markers for known molecular alterations can be particularly helpful. Since roughly half of all cutaneous melanomas harbor the BRAF V600E mutation, immunoreactivity would be highly suggestive of metastatic melanoma. This particular case was negative (Image I) making this possibility less likely. Another rare consideration is a schwannoma with lipofuscin pigment deposition, but these tumors do not usually look brown-black grossly and are not immunopositive for melanocytic markers, such as HMB-45 or Melan-A. Schwannomas may also contain abundant hemosiderin.

Similar to uveal melanocytic tumors and cutaneous blue nevi, the majority of primary meningeal tumors harbor GNAQ or GNA11 mutations. Unfortunately, there are no surrogate IHC stains for those alterations. Nevertheless, the malignant variant (ie, primary meningeal melanoma) often inactivates the BAP1 gene, with loss of protein product detectable using IHC. Since this particular case had retained BAP1 expression (Image J), a primary meningeal melanoma is also less likely. It should also be noted that rare examples of diffuse meningeal melanocytosis or melanomatosis arise in patients with underlying neurocutaneous melanosis, a phakomatosis associated with large or multiple congenital nevi; these lesions are mostly associated with mutations of the NRAS gene. In contrast, the vast majority of both sporadic and syndromic MMNSTs inactivate the PRKAR1A gene, with germline pathogenic variants responsible for the most common form of Carney complex (CNC1). Therefore, the loss of PRKAR1A expression seen in this case (Image K) is diagnostic of MMNST, and since this is a major manifestation of Carney complex, the latter should be excluded clinically or via genetic testing. It is also particularly important to rule out Carney complex because another major manifestation is atrial myxoma, which can embolize and lead to stroke or even death. Other common findings in Carney complex include spotty skin and mucosal pigmentation, blue nevi, breast myxomas, ductal adenomas of the breast, Cushing syndrome due to primary pigmented nodular adrenocortical disease, thyroid follicular adenomas and carcinomas, acromegaly due to a somatotroph pituitary adenoma/neuroendocrine tumor, osteochondromyxomas, and large cell calcifying Sertoli cell tumor (LCCST) of the testis. Followup in the current case revealed the following: 1) next-generation sequencing of the tumor identified mutations of the PRKAR1A, NF1, and TP53 genes; 2) he was treated with localized radiation therapy, but was found to have widespread leptomeningeal disease three months later; 3) he died of disease five months after tumor resection. Of interest, his past medical history included a testicular germ cell tumor during childhood (potentially misdiagnosed LCCST?) and a “large, black birth mark” on the thigh removed at age 13. On physical exam, he was noted to have spotty skin pigmentation, but no perioral pigmentation. Since germline testing was not performed, it remained unclear if he had Carney complex, though these findings were at least suspicious for this possibility.

MMNST is a rare tumor that has been described in the literature since at least the first half of the 20th century under a variety of names, but most commonly “melanotic schwannoma” or “psammomatous melanotic schwannoma.” In 1990, Dr. Aiden Carney first described the syndromic association of the psammomatous counterparts within his eponymous “complex” (not to be confused with Carney triad, also described by this same author). Although the presence of psammoma bodies and, to a lesser extent, lipoma-like lipidization of tumor cells have been touted as signs of underlying Carney complex, these changes have now been recognized commonly in sporadic MMNSTs as well. Nevertheless, these two features are diagnostically helpful, since they’re rarely seen in purely melanocytic neoplasms. Otherwise, the syndromic cases typically present roughly a decade earlier (peak age in the 20’s) than the sporadic counterparts (peak age in the 30’s). The presence of multiple MMNSTs or other common manifestations obviously favor a syndromic association, with anywhere from 5% to 50% of all MMNSTs being associated with Carney complex in different series. Roughly half of Carney complex patients have germline pathogenic variants of PRKAR1A (CNC1) on chromosome 17q, whereas the CNC2 gene on chromosome 2p is implicated less often. The majority of both syndromic and sporadic MMNSTs show biallelic gene inactivation resulting in loss of PRKAR1A expression, making this immunostain particularly valuable as a diagnostic tool. Although initially favored to represent a schwannoma variant, both the genetic underpinnings and clinical behavior are highly distinct in MMNST, warranting this tumor’s current classification as a completely separate entity. In fact, a clinicopathologic series by Torres-Mora et al in 2014 found local recurrences and distant metastases in 35% and 44%, respectfully. Given these unusually aggressive features, they suggested the term “melanotic schwannian tumor,” which was modified slightly to MMNST in the 2020 soft tissue and bone World Health Organization scheme.

• Pigmented tumors of the spinal or paraspinal region are diagnostically challenging due to extensive histopathologic overlap. Nevertheless, the entities have distinct genetic underpinnings.
• Several surrogate IHC markers are now available to assist in the differential diagnosis of MMNST, primary meningeal melanoma, and metastatic melanoma, though they are not 100% sensitive. As such, molecular testing is needed in a subset.
• MMNST is much more aggressive than previously appreciated, thus warranting the malignant terminology.
• A subset of MMNSTs are associated with Carney complex, and therefore this syndromic association should be further explored clinically and/or genetically.

1. Carney JA. Psammomatous melanotic schwannoma. A distinctive, heritable tumor with special associations, including cardiac myxoma and the Cushing syndrome. Am J Surg Pathol. 1990;14(3):206-22.
2. Kirschner LS, Carney JA, Pack SD, et al. Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Nat Genet. 2000;26(1):89-92.
3. Koelsche C, Hovestadt V, Jones DT, et al. Melanotic tumors of the nervous system are characterized by distinct mutational, chromosomal and epigenomic profiles. Brain Pathol. 2015;25(2):202-8.
4. Torres-Mora J, Dry S, Li X, Binder S, Amin M, Folpe AL. Malignant melanotic schwannian tumor: a clinicopathologic, immunohistochemical, and gene expression profiling study of 40 cases, with a proposal for the reclassification of “melanotic schwannoma.” Am J Surg Pathol. 2014;38(1):94-105.
5. Wilkes D, McDermott DA, Basson CT. Clinical phenotypes and molecular genetic mechanisms of Carney complex. Lancet Oncol. 2005;6(7):501-8.