2023 Volume 10 Pages 315-320
Meningeal melanocytomas of the central nervous system, although typically benign, rarely undergo malignant transformations. A 46-year-old man presented with headache and nausea 4 years after gross total resection of a craniovertebral junction meningeal melanocytoma at another hospital. The initial clinical course was previously reported.1) Computed tomography revealed the presence of multiple intracranial mass lesions. Furthermore, magnetic resonance imaging showed multiple intracranial lesions and meningeal dissemination. A biopsy was performed for a circumflex lesion located in the right frontal lobe. Pathological examination showed anaplastic changes and a Ki-67 index of 33%. Based on the pleomorphic changes and high mitotic activity, the patient was diagnosed with primary cerebral malignant melanoma. The patient received four cycles of nivolumab (80 mg) and ipilimumab (165 mg), followed by whole-brain radiotherapy (37.5 Gy). However, the disease progressed after the third cycle. Genome analysis revealed GNAQ Q209P and SF3B1 R625C mutations, but no treatments related to these gene mutations were available. Despite the seven cycles of nivolumab therapy, the patient eventually passed away 9 months after surgery. This case was a rare example of malignant transformation and leptomeningeal melanomatosis in a meningeal melanocytoma. It highlights the importance of careful follow up after gross total resection. Identification of molecular alterations can lead to better detection of melanocytic melanomas with poor prognosis and high risk of recurrence and metastasis. It can also facilitate the development of novel therapeutic options for these patients.
Meningeal melanocytomas, a rare variant of melanoma that accounts for <0.1% of all brain tumors, are characterized by their benign nature and potential for cure through complete surgical excision.2) However, meningeal melanocytomas rarely undergo malignant transformation or exhibit a metastatic behavior. To date, the incidence of malignant transformation and the ideal treatment approach for meningeal melanocytomas remain unclear. We herein present a case of malignant transformation and leptomeningeal melanomatosis in a craniovertebral junction (CVJ) meningeal melanocytoma and review relevant literature.
A 46-year-old man underwent gross total resection (GTR) for a CVJ meningeal melanocytoma at another hospital 4 years ago. The initial clinical course was previously reported.1) He presented to our hospital with acute severe headache and nausea. He was then referred to our department after computed tomography revealed multiple intracranial mass lesions. Magnetic resonance imaging (MRI) revealed multiple intracranial lesions and meningeal dissemination, exhibiting hyperintensity on T1-weighted images, hypointensity on T2-weighted images, and no enhancement following gadolinium administration (Fig. 1A-C). Furthermore, MRI showed no evidence of recurrence at the initial surgical site (Fig. 1D, E). A biopsy was performed for a circumflex lesion in the right frontal lobe (Fig. 2).
MRI showing multiple lesions and meningeal dissemination. The lesions were hyperintense on axial T1-weighted images (A) and hypointense on axial T2-weighted images (B). (C) Contrast-enhanced T1-weighted image showing no obvious enhancement. (D, E) Axial T2-weighted and gadolinium-enhanced T1-weighted images showing no evidence of recurrence at the site of previous surgery.
Intraoperative findings. (A) Melanin pigmentation can be observed on the cerebral surface. (B) A blackish-gray tumor was identified at the time of central removal, and a biopsy was performed.
Histopathological analysis revealed that the tumor cells were significantly pleomorphic with abundant eosinophilic cytoplasm. Most of the tumor cells contained melanin. The nuclei were irregular in shape and had prominent nucleoli. A high mitotic rate of 15 per 10 HPF was recorded. Necrosis and hemorrhage were also observed. Immunohistochemical studies were positive for S-100, human melanoma black-45. The Ki-67 labeling index was approximately 33%, compared with 4% in the initial pathology (Fig. 3). Based on these findings, the patient was diagnosed with melanoma. There was no evidence of metastases outside the central nervous system.
Malignant transformation in meningeal melanocytoma; histopathological and immunohistochemical findings. (A) Proliferation of large, severely dysplastic cells with prominent nucleoli. Some of the cells are spindle-shaped and prominently pleomorphic. Most of the tumor cells contain melanin (hematoxylin and eosin staining, 100×). (B) Pleomorphic tumor cells and numerous multinucleated cells (hematoxylin and eosin staining, 400×). (C) Most tumor cells react with HMB-45. (D) S-100 positive of tumor cells. (E) High Ki-67 labeling index (33%).
Two weeks after biopsy, the patient received four cycles of nivolumab (80 mg) and ipilimumab (165 mg). Whole-brain radiation therapy was administered, with a planned dose of 37.5 Gy in 15 fractions. However, disease progression occurred after the third treatment cycle. FoundationOne CDx (F1CDx) (Foundation Medicine, Inc., Cambridge, MA, USA) genetic analysis revealed alternations in the guanine nucleotide-binding protein G subunit alpha q (GNAQ) Q209P and SF3B1 R625C genes, but no anticancer drugs related to these mutations were available. The F1CDx test also designed the tumor as microsatellite-stable and revealed an intermediate tumor mutation burden of 9 mutations per megabase. Despite the seven cycles of nivolumab (240 mg), the disease progressed, and the patient eventually passed away 9 months after surgery.
Meningeal melanocytomas are rare and typically benign neoplasms that arise from neuroectodermal melanocytes derived from the neural crest.3) First reported by Limas and Tio in 1972, melanocytomas are derived from leptomeningeal melanocytes, not from meningothelial cells.4) Meckel's cave and the cerebellopontine angle are the most common locations of melanocytomas.5)
Malignant transformationMeningeal melanocytoma rarely undergo malignant transformation, with only nine cases reported in literature (Table 1).6-13) Six of these cases, including our case, underwent GTR. This indicates the possibility of malignant transformation even after GTR. The time to malignant transformation ranges from 6 months to 5 years. Wang et al. reported that the initial Ki-67 index for melanocytomas was 1%-2%, which increased to 20% at the time of recurrence.10) Roser et al. demonstrated a shorter disease course, with an increase in the Ki-67 index of 10% in 9 months.7) It is unknown whether the cases with faster malignant transformation differed from those with longer disease courses. Although the factors associated with malignant transformation remain unknown, San-Miguel et al. recently reported that loss of heterozygosity for the BRCA1 gene was associated with an increased proliferative index in the case of cerebellopontine angle meningeal melanocytoma that recurred thrice despite GTR.14) Seven cases had leptomeningeal melanomatosis. Furthermore, five of the reported patients with malignant transformation eventually died, whereas four developed tumor progression. In some cases, the tumor can metastasize to other organs, including the liver, pancreas, and bones.8,12)
Reported cases of meningeal melanocytoma with malignant transformation
| Reference | Age (years)/Sex | Location of primary tumor | Surgery of primary tumor | Primary pathology/Ki-67 | Duration between the last confirmed benign pathology to the confirmed malignant transformation | Recurrence | Ki-67 of secondaty pathology | Adjuvant therapy | Outcome |
|---|---|---|---|---|---|---|---|---|---|
| Bev, bevacizumab; C, cervical vertebra; GTR, gross total resection; Ipi, ipilimumab; NA, not available; Niv, nivolumab; Pemb, pembrolizumab; PR, partial resection; RS, radiosurgery; RT, radiotherapy; S, sacral; STR, subtotal resection; Th, thoracic; TMZ, temozolomide; WBRT, whole-brain radiotherapy | |||||||||
| Uozumi et al. (2003)6) | 49/M | Lt. frontal lobe | PR | Meningeal melanocytoma/0-1% | 60 months | Lt. frontal lobe Leptomeningeal melanomatosis |
5%-10% | - | Died 6 months after confirmed malignant transformation |
| Roser et al. (2004)7) | 37/F | Petroclival area | STR | Meningeal melanocytoma/5% | 7 months | Petroclival area Leptomeningeal melanomatosis |
25% | WBRT (40.8 Gy)/TMZ 200 mg/m2 | Died 4 months after confirmed malignant transformation |
| Wang et al. (2008)8) | 57/M | An intradural extramedullary lesion (L5-S1 level) | GTR | Meningeal melanocytoma/NA | 12 months | L5-S1 level Leptomeningeal melanomatosis distant metastases (liver, left 9th rib) |
NA | RT (50 Gy) | Still alive 5 months after confirmed malignant transformation |
| Perrini et al. (2010)9) | 79/F | An intramedullary lesion (Th10-11 level) | GTR | Intermediate-grade meningeal melanocytoma/1-4% | 24 months | Th11 level | 15% | - | Still alive 6 months after confirmed malignant transformation |
| Wang et al. (2011)10) | 32/M | Rt. temporal lobe | GTR | Meningeal melanocytoma/1-2% | 36 months | Rt. temporal lobe | 20% | - | Still alive 12 months after confirmed malignant transformation |
| Gempt et al. (2011)11) | 71/F | Rt. frontal lobe | PR | Meningeal melanocytoma/2% melanoma/12% |
- | Rt. frontal lobe Leptomeningeal melanomatosis |
- | WBRT | Still alive 18 months after confirmed malignant transformation |
| Küsters-Vandevelde et al. (2017)12) | 43/F | Rt. parietal lobe | GTR | Intermediate-grade meningeal melanocytoma/5% | 32 months | 1st: Rt. frontal lobe 2nd: Rt.temporal lobe 3rd: Distant metastases (liver, pancreas) 4th: Rt.temporal lobe Leptomeningeal melanomatosis |
10% | 1st: RT 2nd: RS 3rd: TMZ 200 mg/m2 4th: RS/Ipi |
Died 31 months after confirmed malignant transformation |
| Deng et al. (2022)13) | 19/F | A dumbell-shaped lesion (C1-2 level) | GTR | Meningeal melanocytoma/1-2% | 6 months | 1st: C2 level 2nd: Intracranial multiple metastases Leptomeningeal melanomatosis |
5%-10% | 1st: Pemb+Bev+TMZ 2nd: CSI (30 Gy)/Pemb+Bev+Ipi/Intrathecal Ipi |
Died 2months after the last chemotherapy |
| Our case | 44/M | Craniovertebral Junction | GTR | Meningeal melanocytoma/4% | 45 months | Intracranial multiple metastases Leptomeningeal melanomatosis |
33% | WBRT (37.5 Gy)/Niv+Ipi | Died 9 months after confirmed malignant transformation |
As previously discussed, malignant transformation and recurrence can occur despite GTR. Thus, previous studies have also demonstrated the role of adjuvant radiotherapy in these cases. Prasad et al. reported that a combination of GTR and radiotherapy led to very low recurrence rates, but the difference was not significant.15) They also reported that GTR and CVJ or posterior fossa tumors were significantly associated with low recurrence rates. Ricchizzi et al. reported that the combination of GTR and adjuvant radiotherapy may be considered only for cases with high mitotic activity.16) In the present case, because GTR was achieved and the Ki-67 index was low, it was appropriate to follow up the patient without radiotherapy.
Adjuvant therapy for malignant meningeal melanocytomasRecurrence and malignant meningeal melanocytomas poorly respond to adjuvant therapy and have a poor prognosis. Chemotherapeutic and immunotherapeutic agents, including temozolomide,17) cisplatin-fotemustine,14)methotrexate,18) nivolumab,5) ipilimumab,12) and pembrolizumab-bevacizumab-ipilimumab,13) have previously been used with radiotherapy. However, tumor progression was observed in all but one patient. In our case, nivolumab and ipilimumab were administered in combination with radiotherapy, but the patient did not respond.
Molecular features of meningeal melanocytomasSeveral genetic mutations, including GNAQ, GNA11, BRAF, and NRAS, have recently been identified in meningeal melanocytomas.15,19,20) The molecular profile of primary leptomeningeal melanocytic neoplasms differs from that of cutaneous melanomas and is more similar to that of uveal melanomas (UMs) and blue nevi.21) This indicates that GNAQ and GNA11 are typically mutated in leptomeningeal melanocytic neoplasms, although BRAF and the TERT promoter mutations are uncommon. A previously published series showed that GNAQ mutations are thought to be present in 39% of melanocytomas and 17% of primary leptomeningeal melanomas, whereas GNA11 mutations are thought to be present in 17% of melanocytomas and 19% of primary leptomeningeal melanomas.22) Thus, GNAQ and GNA11 have been identified as promising therapeutic targets. These genes cause constitutive activation of the MAPK and PI3K/AKT pathways, leading to the use of downstream targeted therapies against effector proteins, including MEK and AKT. Selumetinib, an oral selective MEK1/2 inhibitor, was compared with temozolomide and dacarbazine chemotherapy, but it exhibited limited clinical activity (objective response rates of 14% and 3%, respectively). Trametinib, an MEK inhibitor, was tested alone and in combination with the AKT inhibitor, GSK2141795.23) The objective response rates for trametinib-alone (n = 18) and combination (n = 21) groups were 5.5% and 4.8%, respectively, suggesting that the combination did not improve clinical outcomes. The median progression-free survival was 3.6 months for both groups. Existing anticancer drugs and novel targeted therapies based on genetic mutations have not proven to be effective, and there is an urgent need for newer treatments.
In our case, we were also able to find a mutation in SF3B1. SF3B1 is the largest subunit of the SF3B complex promoting efficient mRNA splicing.24) Previous studies reported that the GNAQ, GNA11, and NRAS genes contribute to the early stages of carcinogenesis, whereas SF3B1 mutations occur later in the oncogenic process.25) These mutations impact hotspot codons, which are linked to certain cancer types. For instance, codon 700 alterations are typically observed in chronic lymphocytic leukemia and myelodysplastic syndromes, but the involvement of codon 625 in UMs is substantially more common.25,26)SF3B1 codon 625 mutations can be found in 20% of UMs.27) Griewank et al. suggested that SF3B1-mutant tumors should be considered as intermediate-risk tumors owing to their potential for metastasis.28) Melanie et al. reported that all patients with the SF3B1 mutation displayed aggressive behaviors and leptomeningeal seeding immediately after diagnosis despite one case being identified as melanocytoma.21) To date, it remains unclear how this mutation may affect the course and prognosis of the disease. However, as more unique therapies emerge, knowledge of the mutational status of meningeal melanoma is necessary. Splicing modulators are becoming more popular because of the role of SF3B1 in splicing. Furthermore, protein arginine methyltransferase 5 inhibitors and nonsense-mediated mRNA degradation inhibitors may be effective against SF3B1 mutations.29,30)
In summary, we demonstrated the first case of GNAQ and SF3B1 double mutation that has malignant transformation and leptomeningeal melanomatosis in CVJ meningeal melanocytoma. A careful follow up after GTR is crucial, and knowledge of the mutational status of meningeal melanoma like GNAQ and SF3B1 is necessary to understand molecular features and to consider the treatment for individual cases.
The patient provided written informed consent.
The authors have no conflicts of interest to report regarding the materials, methods, and findings of this study.
