Primary intracranial malignant melanomas in solitary type: a tertiary center experience

Purpose: Solitary type primary intracranial malignant melanoma (PIMM) is extremely rare but fatal. The optimal treatment algorithm according to clinical relevance of symptoms and outcomes is unclear. This series emphasized the prognostic factors of solitary PIMM and established the treatment algorithm for this rare disease. Methods: Patients with solitary PIMMs were pathologically verified and treated with neurosurgical tumor resection. All solitary PIMMs recruited at our institute received multidisciplinary team care. We analyzed the clinical findings and prognostic factors. Results: The study cohort included 10 patients. PIMMs in solitary type impacted middle-aged populations with male predominance in Taiwan. Most patients (80%) presented a single tumor initially. Six patients had pro-gressed to multiplicity after the initial treatment. Rates of tumor bleeding and leptomeningeal metastasis seeding (LS) are high in solitary PIMMs. Patients who had gross-total resection (GTR) had better survival than those who had incomplete resection, with median overall survival (OS) rates of 170.4 months vs. 5.23 months (p = 0.004). Multiplicity, eloquent area involvement, initial tumor bleeding, LS, hydrocephalus, and Karnofsky Performance Score < 80 at diagnosis were associated with negative outcomes in progression-free survival and OS. Adjuvant radiotherapy for patients who had LS and for those who cannot undergo grossly total tumor removal resulted in a good outcome. Conclusions: GTR demonstrated better outcomes for solitary PIMM. For recurrent tumors, aggressively repeated surgical resection remained beneficial for selected cases. Adjuvant radiotherapy was a treatment option for LS following operation. We proposed a possible treatment algorithm for solitary PIMM.


Introduction
Malignant melanomas arising in the brain are rare but aggressive. These tumors arise from melanocytes of the leptomeninges, which developed from melanoblasts in the neural crest [1]. Few case reports on these tumors could be reviewed by Medline or PubMed. Most of the reviewed cases about intracranial melanoma referred to metastatic melanomas [2]. The most common primary sites were cutaneous or mucosal lesions. One article reported that among 67 central nervous system (CNS) melanoma reports, 53 cases referred to tumors from the cerebral area [3]. The treatment response to conventional chemotherapy or radiotherapy was limited. Recently, the immune checkpoint inhibitors, had been shown to be effective and safe in systemic disease. But the response of intracranial disease remained unclear.
We recruited cases with only cerebral malignant melanoma without any other extracranial lesions after systemic workup, and these were confirmed by pathologists as PIMMs in solitary type. The solitary PIMMs, which were initially measurable by image studies, previously described by Rodriguez et al [4]. These patients with possibly resectable lesions have longer survival time than diffuse type and metastatic intracranial malignant melanomas (MIMM). Aggressive treatment is necessary to deal with this vital disease before it leads to rapid deterioration.
Here, we present 10 cases diagnosed as PIMM in solitary type without other primary sites. This study does not include neurocutaneous melanosis. They all had higher rates of tumor apoplexy and leptomeningeal seeding (LS), which are the special presentations of PIMMs [5]. Although the poor prognosis related to LS, multidisciplinary treatments were applied. We reviewed the clinical features, radiological, surgical, and histological findings and analyzed the possible variables influencing the prognosis.

Materials and methods
From 1993 to 2016, 17 patients aged > 18 years old at the time of diagnosis were considered to have solitary intracranial malignant melanoma after surgical resection and pathologic confirmation. The clinical or pathological findings were reviewed by multidisciplinary specialists at our institute. The specialists included dermatologist, neurosurgeons, neuro-oncologists, radiation oncologists, nuclear medicine physicians, Tumor hemorrhage in the brain CT was a special presentation of solitary PIMM that led to rapidly conscious disturbance and neurosurgical emergency in case 9. (B) Melanin deposits in surrounding meninges were noticed in case 9. White arrows showed the mixture of hematoma and melanoma. (C) Tumor was adjacent to eloquent area and major vessels, preventing case 5 from undergoing total tumor removal. (D) Intensity modulated radiation therapy was delivered with the help of CT to residual tumor area with adequate margins. Normal brain tissue was spared as much as possible. T1-weighted brain MRI with contrast highlighted the residual tumor with leptomeningeal seeding in case 5 after the treatment (white arrows). (E) The solitary PIMM spread to the other parts of the brain by leptomeningeal seeding (LS). Infratentorial meninges were compromised from supratentorial PIMM in case 3. White arrows showed leptomeningeal tumor seeding at left tentorium. (F) End-stage LS caused diffuse metastatic melanoma in cerebellum in case 8. (G) Diffuse LS also led to CSF disturbance and hydrocephalus in case 8. (H) After VP shunt insertion for palliative treatment, the hydrocephalus temporally improved. However, another tumor bleeding (white arrows) was noted during follow-up in case 8. Histopathologic examinations for the solitary-type PIMM. (I) Routine hematoxylin and eosinstain showed neoplastic epithelioid cells with prominent nucleoli and pigmentation in blood clots. (J) S100 expression increased. radiologists, and neuro-pathologists. Seven patients who had skin or mucosal lesions outside CNS were excluded. Ten patients were included in this study. Their pathologic and clinical data were retrospectively analyzed. Tumor size, location, surgical procedures, and adjuvant therapies were documented along with the progression-free survival (PFS) and overall survival (OS) of each patient. These patients were followed up in the outpatient clinic or through telephone interviews. The latest follow-up was in February 2020. Statistical analyses were performed using the log-rank test and Kaplan-Meier survival analysis for the categorical variables. We conducted all statistical analysis using SPSS ver. 22.0 (IBM Corp.). Statistical significance was set at p < 0.05. The data, including pathologic findings, demographic factors, and other related information were collected from the electronic medical records after Institutional Review Board Approval in Chang Gung Medical Foundation Institutional (IRB file No. 201800203B0D001).

Clinical data at presentation
The ages of the patients at diagnosis ranged from 22 years old to 57 years old (median, 32.8 years old). Eight patients (80%) were male. The most frequent symptoms or signs were headache, increased intracranial pressure, and limb weakness. Eight (80%) had single lesion, whereas the other two (20%) had multiple lesions initially. The tumor size ranged from 1.8 cm to 5.8 cm in diameter. Six (60%) of these lesions were located in the temporal lobe, followed by frontal, parietal, occipital, and cerebellum. Five (50%) patient had lesions over the eloquent area before neurosurgery (Fig. 1C). At the time of definite diagnosis, six (60%) had congenital melanocytic nevi over the skin, which proved to be benign according to pathological biopsy. Eight patients (80%) had combined tumor hemorrhage by pre-operative image studies (Fig. 1AB). Three patients had LS including one had cavernous sinus involvement according to operative findings (Fig. 1E). Only four patients (40%) carried on performing normal activities and work without special care according to Karnofsky performance status (KPS) at diagnosis. A summary of the patients' characteristics is listed in Table 1. Diagnosis was made by regular hematoxylin and eosin stain. Immunohistochemical studies confirmed positive human melanoma black-45 and S100 ( Fig. 1I-L).

Treatment
Gross total resection (GTR) was achieved in four patients (40%). Five (50%) had incomplete resection (IR) and one (10%) had biopsy, only because the disease was at the terminal stage with diffuse leptomeningeal seeding and hydrocephalus (Fig. 1FG). Six (60%) had received post-operative radiotherapy with 54-60 cGy in 18-30 fractions. Adjuvant chemotherapy was performed after gross total tumor removal in cases 1 and 3, with dacarbazine-based regimen (250 mg/m2/ day IV for 5 days). Seven patients (70%) had repeated surgical excision due to recurrence. One patient had 9 episodes of surgical intervention between February 1993 and March 2007 for repeated tumor bleeding, including a VP shunt implantation.

PFS and OS
Nine (90%) recurrence events occurred in their clinical course and eight (80%) deaths were recorded in last follow-up. The median followup period was 52 (Fig. 1M). The 1 and 3 year OS rates were 60% and 40%, respectively. At the last follow-up in February 2020, two survivors underwent GTR initially.

Discussion
Primary malignant melanomas of the CNS are life-threatening. They account for 1% of all cases of melanoma [13]. These tumors were derived from melanocytes and can normally be found in the leptomeninges [12]. All organs of the CNS including the spinal cord [21] could be sites of the primary malignant melanomas, although extremely rare. PIMM only comprises 0.07% among all CNS tumors [16]. All melanomas are immuno reactive for HMB-45 and S-100 protein. According to the World Health Organization classification of primary brain tumors [22,23], malignant melanoma was diagnosed with high mitotic activity rather than primary melanocytic neoplasms. The PIMMs are cytologically similar to melanomas arising in other sites.
Some studies revealed the difference of primary CNS melanomas and other sites on the molecular level. GNAQ gene at codon 209 and GNA11 are a frequent event in primary melanocytic neoplasms of the CNS [24,25]. Other mutations in BAP1 [26], SF3B1 [27] and EIF1AX [28] have also been identified. In a targeted next generation sequencing study presented by van de Nes et al. [29], primary CNS melanocytic tumors were concluded to have GNAQ or GNA11 mutations. In cutaneous melanomas, mutations such as BRAF V600 and NRAS were frequently detected [30,31]. However, in van de Nes's study, all the BRAF V600 and NRAS in primary CNS melanomas were wild type. These molecular differences implied the clinical deviations between PIMM and MIMM and may help achieve a definite diagnosis in the future.
Solitary type PIMMs are differentiated from the diffuse type by a nodular mass according to pathological behavior [8,32,33]. When diffuse PIMMs infiltrate the pia mater and subarachnoid space, which leads to an unfavorable outcome and subtotal tumor resection, solitary PIMMs can potentially be subjected to aggressive treatment that could lead to longer survival [4]. In our series, we used clinical examination and image studies to exclude primary sites other than the CNS before the diagnosis was established. 18-fluoro-D-glucose positron emission tomography ( 18 F-FDG PET) was introduced in 2010. All of our patients diagnosed after 2010 had a negative extracranial finding by PET. To our knowledge, this single institute experience is the first study to focus on solitary-type PIMMs.

Tumor bleeding and LS in solitary PIMMs
The relative risk of hemorrhagic stroke was 1.45 in the first year after melanoma diagnosis by a Danish review, [34]. The bleeding risk of melanoma in the brain was higher than others [35,36]. A previous study reveals a tumor bleeding rate of 39.6% [37]. In our series, tumor apoplexy accounts for 80% in solitary PIMMs, and it contributes to recurrence and unfavorable outcomes. As tumor apoplexy leads to increased intracranial pressure or rapid deterioration in solitary PIMMs,  LS is a critical complication occurred in 30% of our patients at diagnosis and increased to 90% in the lifetime. LS is always followed by tumor apoplexy, and it indicated the involvement of tumor cells in the cerebrospinal fluid (CSF) and leptomeninges [38]. PIMMs originate from melanocytes in the leptomeninges. Thus, it is not surprising that LS is a direct route of tumor spread. Statistically, such presentation contributes to recurrence and unfavorable outcomes.
Tumor bleeding and LS are two unique characteristics of solitary PIMMs that are unusual in other solid intracranial tumors. We supposed that distal LS is promoted by blood-brain barrier and blood-tumor barrier connection and is achieved by tumor bleeding [39][40][41]. Fragile blood-tumor barrier in solitary PIMMs contributes to tumor apoplexy. For patients with advanced solitary PIMMs, LS-related hydrocephalus presented and only palliative treatments can be performed (Fig. 1H).

Neurosurgical tumor removal
In the reviews by Li et al. [14] and Aria et al. [17], gross tumor resection was most important to survival. Patients who underwent gross tumor resection had a significantly longer survival (>22 months) [17] or overall 40.8% survival rate in 3 years than those who did not [14]. In our study, patients who were able to receive GTR had satisfactory median survival (66 months), which was significantly better than patients without GTR (4.5 months). Seven (70%) of our patients underwent a second surgical excision. Four (40%) of them underwent a third excision. One of our patients had surgical excision for 8 times and had a survival rate of 170 months. The surgical interval of each recurrence was 4-41 months, within a period of 169 months. This patient finally expired due to LS and tumor bleeding. Aggressive surgical treatment, completely gross resection, and even more episodes of repeated excision were the key for longer survival regardless of tumor size or location.
Adjuvant radiotherapy following tumor resection was beneficial to survival in metastatic melanomas from systemic sites and in PIMM [14,42]. In our series, patients with LS who are not amenable to GTR showed a trend of better outcomes after adjuvant radiotherapy. * Log rank test analysis reaches significance.   Emerging studies also supported that stereotactic radiosurgery (SRS) instead of whole brain radiotherapy (WBRT) in combination with immune therapies or targeted therapy may be effective. However, this approach needs prospective studies to identify the effect of these novel regimens with radiation therapy [43]. Higher KPS at diagnosis implied lower neurological invasion and higher capability to received adjuvant Table 4 Studies about primary intracranial malignant melanoma. therapy after neurosurgery.

Treatment algorithm
Most of previous case reviews of PIMMs were mixed cases of leptomeningeal carcinomatosis and solitary cases [6,14,15,17]. In our presentation, we focused on solitary-type PIMMs. The solitary tumor for surgical attempt was first considered after initial workup. We proposed a treatment algorithm for solid brain melanoma according to both current evidence and our findings (Fig. 3). When the patient presented with solid brain melanoma, systemic workup included the following: dermatologist consultation, confirmatory biopsy examinations, and PET study. When solitary PIMMs were confirmed and reviewed by multidisciplinary tumor board, surgical total resection was performed by neurosurgeons when the eloquent area was not involved. If complete resection was not executed, focal radiotherapy as adjuvant therapy was scheduled to deal with the residual tumor and LS. Intensity-modulated radiation therapy (IMRT) was the major treatment option in our team's work, and it avoided neurologic decline and preserved better neurologic function (Fig. 4).
When tumor recurrence was observed by the follow-up MRI images, GTR was still the first choice of treatment if feasible. When diffuse LS occurred, focal radiotherapy may not be applicable. Stereotactic radiosurgery (SRS) is an alternative approach. WBRT could be considered if patient and the family understood the consequent injury to neurological function caused by radiation. Terminal stage was indicated when hydrocephalus was present in the images which indicated the refractory condition to curative procedures. Cerebrospinal fluid (CSF) cytology could be considered to identify diffuse leptomeningeal spread [44]. In our cases, 2 had sent CSF cytology and 1 was positive for malignancy. The presence of CSF involvement indicated carcinomatosis and hospice care. When metastasis was confirmed, palliative treatments inclu-ding□ventriculo-peritoneal (VP) shunt, supportive care, or immunotherapy would be considered. In patients with hydrocephalus, the prognosis is dismal (range from 0.7 to 8.1 months in our study). Multidisciplinary team care in our institute all followed this treatment algorithm. Multimodality management following surgical resection was discussed in combined meetings before it was put in practice.

Prospective therapy
Dacarbazine (DTIC)-based chemotherapies were used for other metastatic melanomas. Li et al. concluded that chemotherapy was beneficial for PIMMs [14]. DTIC has an effectiveness of 16% to 20%. However, in uveal melanoma, DTIC-based chemotherapies are ineffective [45]. In a review of blood-brain and blood-tumor barriers, melanoma cells displayed a vessel co-option phenotype [40], which was different from that of lung cancer. The systemic therapies need to overcome barriers of the neurovascular unit. In our study, adjuvant chemotherapy showed limited survival benefit.
BRAF kinase inhibitors, including vemurafenib, showed efficacy on BRAF V600 mutation-positive melanoma even when combined with MEK inhibitors [46]. Dabrafenib plus trametinib had a good but short response to BRAFV600-mutant melanoma with brain metastases [47]. However, the incidence of BRAF V600 mutation in PIMM was low in a previous study [29]. We checked BRAF V600 mutation routinely after the approval of vemurafenib and dabrafenib. The checkpoint inhibition with an anti-programmed cell death 1 (PD-1) antibody (pembrolizumab, nivolumab) in combination with the anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody ipilimumab had good efficacy on metastatic melanomas [48]. The nivolumab concentrations ranged from 35 ng/ml to 150 ng/ml with a CSF/serum ratio of 0.88%-1.9% [49]. Two phase II studies with the combination nivolumab and ipilimumab revealed clinically meaningful intracranial efficacy on metastatic melanoma [50,51]. A systemic review suggested that ipilimumab and nivolumab are active in melanoma brain metastases [52]. However, their efficacies on PIMM remained unclear. More randomized trials would be very desirable.

Limitation
Due to extremely rare, we could analyze only 10 cases in our institute across the previous 20 years. The treatment guidelines of melanoma were much different since 1990 s. Considering this small number of cases, multivariate analysis with Cox regression model was not applicable. We need more randomized clinical trials or meta-analysis to achieve better evidence in the future.

Conclusion
We report 10 cases of solitary PIMMs in our institute. Tumor apoplexy and LS were the unique characteristics of these entities. Grosstotal resection and single tumor were associated with better survival. Although the prognosis remained poor, aggressive surgical resection with adjuvant radiotherapy was the most promising treatment. Fig. 4. Intensity-modulated radiation therapy for case 9 who was unable to received total tumor resection due to eloquent cortex involvement. (A) Adjuvant radiotherapy plan for control of recurrent tumor and LS. (B)The radiation intensity of each beam is modulated to protect the eloquent area and to decrease the spectrum of vital tissue toxicities.

Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.