Primary Melanoma of the Leptomeninges with BAP1 Expression‐Loss in the Setting of a Nevus of Ota: A Clinical, Morphological and Genetic Study of 2 Cases

Sir, we read with interest the review on genetic features in leptomeningeal melanocytic tumors by Küsters‐Vandewelde et al. 8. We report herein additional molecular features found in two cases of primary leptomeningeal melanomas with ipsilateral nevi of Ota, both displaying BAP1 expression‐loss, expanding the previous data described in these rare lesions.

Case 1

A 42‐year‐old woman with a right congenital nevus of Ota (NO) involving the ocular sclera, the superior maxillary, fronto‐orbital and temporal areas was presented with seizures. A computed tomography (CT) scan showed a 3‐cm right fronto‐orbital lesion. A cutaneous biopsy showed a typical blue nevus morphology, without evidence of malignancy (Figure 1). Surgical excision was performed. Histologically, the leptomeningeal tumor showed features of melanoma and was moderately pigmented, characterized by a sheet‐like architecture, with clonal areas, composed of large, atypical, epithelioid melanocytes (Figure 2). There were two mitoses per 10 high power fields (HPF). Emboli were observed, but there was neither necrosis nor hemorrhage. The tumor cells expressed HMB45 and MelanA. Ki67 proliferative index was 15%. Nuclear BAP1 immunohistochemistry expression was completely negative in melanocytes, with positive staining of endothelial cells (Figure 3). A targeted next‐generation sequencing (MiSeq, Illumina TSCA method) was performed to analyze the 17 coding exons of BAP1 with a mean depth of 100 reads, and failed to confirm a BAP1 mutation. However, an exon 5 GNAQ (Q209H) mutation was identified. Clinical work‐up excluded a mucosal, cutaneous or uveal melanoma.

Figure 1.

HE: Cutaneous biopsy of Ota nevus: fascicles of dendritic melanocytes in a sclerotic dermis.

Figure 2.

HE: Leptomeningeal melanoma: pigmented epithelioid cells, with marked atypia.

Figure 3.

BAP1 IHC: Expression‐loss nuclear of tumoral cells with positive control cells in vessels in upper/right corner.

The aCGH profile showed monosomy of chromosome 3, gains of the entire chromosomes 4, 8 and 21, including a high‐level gain of chromosome 8q, and segmental alterations on chromosomes 1, 9 17 and X (Figure 4A).

Figure 4.

aCGH layouts: (A) Case n°1 ish cgh: dim1(p),enh1(q),dim3,enh4,enh8,dim9(pterp21.1),enh17(q22qter),enh21,dim(X)(pterp21.3); (B) Case n°2: ish cgh: dim1(p31.1p13.2),dim3,dim6(q11.1q22.31),enh8(q),enh20,dim(X).

The patient received adjuvant chemotherapy and radiotherapy. Follow‐up identified a local recurrence after 2 years which was treated by surgery, immunotherapy and radiotherapy. One year later, a new local recurrence with ethmoidal extension appeared. She received chemotherapy, but presented with rapid severe deterioration in neurological function. Magnetic resonance imaging (MRI) showed multiple bone and liver metastases. Chemotherapy was ceased and the patient was subsequently lost‐to‐follow‐up.

Case 2

A 69‐year‐old woman with a right orbital NO involving the iris, sclera and uvea, and persisting headaches, was found to have an intracranial hematoma associated with a 45‐mm right fronto‐temporal lesion. Complete surgical excision of a pigmented intra‐cranial mass, connected to the meninges, was performed. Fundoscopy showed focal pigmented retinal lesions but no evidence of choroidal melanoma. Clinical work‐up excluded a mucosal or cutaneous melanoma.

Histologically, the tumor was moderately pigmented with a lobular architecture associated with prominent vascularization and interconnecting vascular lakes (Figure 5) showing features of melanoma. A high nuclear–cytoplasmic ratio and prominent nucleoli were observed as well as multinucleation (Figure 6). There were three mitoses per 10 HPF. Areas of hemorrhage and apoptosis were identified, but there was no necrosis. The tumor cells expressed HMB45 and MelanA. Ki67 proliferative index was 12%. Nuclear BAP1 immunohistochemistry expression was completely negative in melanocytes, with positive staining of endothelial cells. An exon 4 GNAQ mutation (R183Q) and a BAP1 inactivating mutation (c.277Q>QX) were identified by NGS. aCGH showed a monosomy of chromosome 3 and X, a complete gain of chromosome 20, a high‐level gain of chromosome 8q, and segmental losses on chromosomes 1p and 6q (Figure 4B). Twenty‐one months after follow‐up, there was evidence of multifocal recurrence. The patient is currently being treated with radiotherapy and chemotherapy.

Figure 5.

Case n°2 HE: Leptomeningeal melanoma: fascicles of cells separated by hemorrhagic lakes.

Figure 6.

HE: Large, pleomorphic, pigmented, atypical melanocytes.

Discussion

NO is a dermal melanocytosis involving areas related to the first two branches of the trigeminal nerve with a higher frequency in females and Asians 12. NO is associated with ocular or leptomeningeal melanocytomas. Malignant transformations of NO occur mostly in the skin and in Caucasians 7, 14. As other blue‐like dermal melanocytosis, NO is thought to be related to GNAQ or GNA11 mutations occurring during embryogenesis, that expands the number of migrating melanoblasts 19, 20. Rarely, BRAF mutations have also been reported 10. The congenital “port‐wine stain” of the Sturge‐Weber syndrome also arises in the same site and carries exon 4 GNAQ mutations 16. Interestingly, an exon 4 GNAQ mutation was present in case 2 in which we noticed an unusual formation of wide, interconnected, intratumoral vascular lakes. This suggests that these mutations may occur in a pluripotent precursor cell that could give rise to vascular and melanocytic cells, encountered in phakomatosis pigmentovacularis.

BRCA1‐Associated Protein 1 (BAP1) is a tumor suppressor gene, member of the polycomb‐group proteins. Carriers of germline BAP1 mutations are at risk of developing cutaneous, uveal or leptomeningeal melanomas, mesotheliomas, clear cell renal cancer and various other tumor types 3, 11. NO has not been reported in this setting and neither of our patients had a history suggesting such condition. Biallelic inactivation of BAP1 in uveal melanoma is associated with an increased risk of liver metastases and is routinely tested for by either immunohistochemistry or aCGH. In the latter, monosomy 3 (BAP1 is located at 3p2.1) has been identified as a recurrent chromosomal abnormality 13, 17 linked to an adverse prognosis 5. When monosomy 3 is associated with 1q loss or 8q gains, which were present in both of our cases, the prognosis is worse 1, 3, 6, 18. Two recent studies found monosomy 3 and gain of 8q in leptomeningeal melanomas 3, 9, including one occurring in a BAP1 cancer syndrome described previously by the authors (AF, DP, VH) 3. A molecular study performed on 18 melanocytomas of the CNS reported one case combining monosomy 3, 6p gain, 8q gain, and described it as a tumor with a high proliferative index 7. No details about a potential high‐level gain of region 8q or follow‐up are available for that case. Gerami et al. reported a NO with cellular blue nevus features, showing malignant progression in the skin. Within the melanoma component, CGH showed gains involving the distal arm of chromosomes 1q, 6p, the distal arm of 9q, the distal arm of 8q, and loss of 6q 4. This profile, although displaying the recurring anomalies on chromosomes 6p/6q and 8q, did not show a monosomy 3 that could hint toward BAP1expression‐loss. The clinical follow‐up was uneventful.

One of the interesting aspects of NO is its capacity to illustrate the relationship between uveal melanoma, intradermal melanocytic proliferations and melanocytomas as has been previously proposed 2. Our results contribute to those already in the literature and suggest that malignant transformation arising in NO could have similar molecular patterns regardless of site, and share common prognostic features with uveal melanoma 5.

We recommend performing both aCGH and BAP1 immunohistochemistry when assessing leptomeningeal melanocytic tumors. Immunohistochemistry is a robust technique to detect BAP1‐expression‐loss 15, which is strongly correlated to a functional inactivation of BAP1 21. In Case 1, both monosomy 3 and expression‐loss of BAP1 were found, without the identification of a BAP1 mutation. Evaluation of BAP1 expression could be of prognostic significance, allowing more appropriate treatment and follow‐up.