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Primary Central Nervous System Malignant Melanoma in Children

A Case Series and Review of the Literature

Choi, Daniel K., MD, MS*; Pillay-Smiley, Natasha, DO; Marzec, Sarah, MD, MA; Wadhwani, Nitin R., MD§; DiPatri, Arthur J., MD; Tomita, Tadanori, MD; Lulla, Rishi R., MD

Journal of Pediatric Hematology/Oncology: November 2018 - Volume 40 - Issue 8 - p 616–619
doi: 10.1097/MPH.0000000000001092
Clinical and Laboratory Observations

We describe 2 cases of rapidly progressive primary central nervous system malignant melanoma, and summarize 18 previously reported cases of this extremely rare tumor in children. Both patients presented with focal neurologic symptoms, with no evidence of skin or other organ system involvement. One patient was treated with temozolomide and etoposide, whereas the other was treated with multiple surgical resections, radiation therapy, and a trial of ipilimumab. New molecularly targeted and immune-based therapies used in metastatic melanoma in adults are potential new treatment options, but their efficacy and safety in pediatric patients needs to be established.

*Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of Illinois at Chicago College of Medicine

Department of Pediatrics, Division of Hematology/Oncology/Stem Cell Transplantation

§Department of Pathology, Division of Pediatric Pathology

Department of Neurological Surgery, Division of Pediatric Neurosurgery, Ann & Robert H. Lurie Children’s Hospital of Chicago/Northwestern University Feinberg School of Medicine, Chicago, IL

Division of Oncology, Cincinnati Children’s Hospital, Cincinnati, OH

The authors declare no conflict of interest.

Reprints: Daniel K. Choi, MD, MS, Division of Pediatric Hematology/Oncology, University of Illinois at Chicago College of Medicine, 840 S Wood Street, M/C 856, Chicago, IL 60612 (e-mail:

Received May 31, 2017

Accepted October 8, 2017

Primary central nervous system (CNS) malignant melanomas are rare, accounting for only 1% of all melanoma cases in adults.1This tumor is even rarer in children, limited to a handful of case reports. To date, 18 cases of children with primary CNS malignant melanoma have been reported.2–9In general, melanocytic neoplasms of the CNS are classified into 4 major groupings per the 2016 World Health Organization (WHO) criteria: meningeal melanocytosis (formerly diffuse leptomeningeal melanocytosis), meningeal melanocytoma, meningeal melanomatosis, and meningeal melanoma (formerly malignant melanoma).10 Primary CNS malignant melanoma presents a diagnostic as well as therapeutic challenge given the dearth of previous cases, the aggressive nature of the tumor, and a lack of consensus with regard to optimal treatment. We present cases of a 3-year-old boy and 17-year-old boy, both with the diagnosis of primary CNS malignant melanoma. We review the limited data on treatment for this tumor, including novel agents used in the treatment of cutaneous melanoma with metastases to the CNS.

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Patient 1 was a 17-year-old boy with a history of congenital deafness who presented with acute onset mental status change, slurred speech, headache, and vomiting. Initial imaging at a referring hospital revealed a “4 cm right frontoparietal intracranial hemorrhage with localized edema and midline shift.” The patient was emergently transferred to our institution’s intensive care unit, where his physical examination was notable for a left facial droop and left upper extremity weakness. A complete blood count and coagulation panel were all age appropriate. A computed tomographic (CT) angiogram was negative for any vascular malformation. The patient’s examination and mental status improved, and he was discharged to inpatient rehabilitation along with seizure prophylaxis.

The patient was followed every 2 weeks by his primary neurosurgeon. The patient presented acutely 2 months later with similar symptoms of headache and vomiting. A repeat head CT scan and subsequent magnetic resonance imaging (MRI) revealed a “3.1×2.8 cm enhancing lesion in the right frontoparietal lobe.” The patient was started emergently on dexamethasone, and the lesion was resected via an open craniotomy (Fig. 1). The pathology of the tumor showed pleomorphic cells with dark pigment that were diffusely positive for HMB-45 and Melan-A, and negative for hemosiderin, synaptophysin, and glial fibrillary acidic protein (Fig. 2), consistent with a malignant melanoma. The patient had a complete skin and ophthalmologic examination which were normal. The patient had a MRI spine and lumbar puncture which were consistent with metastatic disease. Therefore the patient was diagnosed with primary CNS malignant melanoma.





As the patient’s care plan was being prepared, he again presented 4 weeks later with focal neurologic findings and a MRI obtained showed “marked interval worsening of hemorrhagic changes in the right frontoparietal lobes, with surrounding vasogenic edema.” Symptoms improved with a dexamethasone burst and surgical intervention was not necessary. Before radiation therapy could be initiated, the patient presented with another acute hemorrhage to the tumor area requiring surgical intervention. Upon recovery, he was treated with 26.1 cGy in 4 fractions. Compassionate use ipilimumab (a monoclonal antibody against cytotoxic T-lymphocyte–associated antigen 4 [CTLA-4]) was started at 300 mg (3 mg/kg) concurrent with radiation.

Approximately 1 month after initiating treatment, the patient presented with symptoms of obstructive hydrocephalus, purulent drainage from his surgical incision, and progressive disease at his primary site. Although the primary disease site in the right frontoparietal lobe slightly decreased in size, there was an increase in vasogenic edema, as well as an increase in metastatic foci in the suprasellar cistern and superior tectum, as well as new enhancement in the bilateral internal auditory canals. The patient’s infection was treated, but the patient had a progressive decline in mental status. With continued progression of his disease and lack of viable surgical options, the patient was eventually transitioned to a hospice facility for supportive end-of-life care. The patient passed away 5 months after his initial presentation.

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Patient 2 was a 3-year-old boy with a past medical history of prematurity at 29 weeks who presented with new onset seizure. Imaging revealed mild hydrocephalus and he was discharged and advised to follow-up with neurosurgery as an outpatient. One month later he presented again in status epilepticus. He was admitted to a referring hospital intensive care unit, where initial imaging showed worsening hydrocephalus requiring emergent ventriculopertitoneal shunt placement. Given a history of recent exposure to tuberculosis, he was treated empirically for tuberculous meningitis while serum and cerebrospinal fluid (CSF) studies were sent. His bone marrow, CSF, and serum were negative for infectious markers and malignancy. He remained inpatient for 1 month and his seizures abated with medication. Given a negative initial workup but a residual left hemiparesis, a MRI of the brain was repeated which now showed diffuse right frontotemporal meningeal enhancement.

At this point the patient was transferred to our institution, and a subsequent biopsy of a meningeal focus confirmed the diagnosis of primary CNS melanoma based on pathologic staining showing cells diffusely positive for HMB-45 and Melan-A. CSF examination was negative for malignant melanoma. The patient also had a complete skin and ophthalmologic examination which were normal. A CT of the chest, abdomen, pelvis, and MRI of the spine, as well as repeat CSF examination were all negative for metastatic disease. However, a rereview of the CSF did demonstrate the presence of atypical pigmented cells.

Upfront radiation therapy was considered, however given the patient’s metastatic disease in the CSF, craniospinal radiation at doses >45 Gy could not be achieved in the spine. As melanoma has been shown to be resistant to doses <60 Gy, and after discussions with the child’s parents, radiation was not performed in an effort to maximize quality of life. An oral palliative chemotherapy regimen was chosen in an effort to maintain quality of life. Temozolomide was given at 150 mg/m2 for 5 days each month. Etoposide was given at 50 mg/m2 daily ×14 days per month. Despite complications of a right frontal lobe hematoma and hemorrhage into the subarachnoid space, the patient was ultimately discharged home and tolerated chemotherapy well as an outpatient. However, the patient ultimately passed away 6 months from the time of initial presentation.

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We present 2 children with acute onset of neurologic symptoms who underwent extensive infectious and malignant evaluations and were eventually diagnosed with primary CNS melanoma by biopsy. Both of these patients suffered intracranial hemorrhage post resection and had quick disease progression despite chemotherapy and/or radiation.

Primary CNS malignant melanoma is a rare tumor overall. The more common presentation of CNS melanoma is as metastatic disease from a primary cutaneous lesion. The estimated incidence of cutaneous melanoma in children is 1% to 3% of all pediatric malignancies, and metastatic disease to the CNS has been reported in 1 case series in 18% (3/17) patients at the time of relapse.11In our review of the literature to date, there have only been ∼250 cases of primary CNS malignant melanoma reported.12We have identified 10 case reports of 18 children below 18 years of age with primary CNS malignant melanoma (Table 1). It is likely this is a slight underestimate of the true number of cases as there has been little consensus on diagnostic criteria for primary CNS malignant melanoma until recently by the WHO.



Primary CNS malignant melanomas can occur in either the brain or spine (60 spinal cases have been reported, 1 in a pediatric patient).6,13 Early in embryologic development, melanoblasts, which are derived from neural crest cells, can migrate anywhere along the neuraxis and have the potential to undergo malignant transformation.

Symptoms at presentation are often correlated with the location of the tumor, and can include intracranial hypertension, hydrocephalus, neurologic deficits secondary to nerve compression, intracranial hemorrhage, and seizure activity.14 Spinal cord primary tumors generally involve the thoracic spine (~60% of cases), but cervical and lumbar involvement have also been reported.13

The melanin content in melanocytic neoplasms gives these tumors certain characteristic radiological findings. Specifically, these tumors tend to be hyperintense on T1-weighted and FLAIR images, and hypointense on T2-weighted imaging.14At a gross histologic level, this tumor is often black in color, but can be dark-brown or blue. At the microscopic level, these tumors have morphologic features quite similar to cutaneous melanoma, including high cellularity, often with tissue invasion and/or hemorrhage. These tumors typically are immunohistochemically positive for melanin, S-100, and HMB-45. Cytogenetic abnormalities seen in cutaneous melanoma have also been found in primary CNS melanoma, and include mutations in the BRAF, NRAS, and CDKN2A genes, and abnormalities in the short arm of chromosome 6.13,14 Recently, Pedersen et al7 postulated that acquisition of somatic mutations in NRAS in CNS melanocytes is a predisposing risk factor to primary melanoma of the CNS in children based on a mouse model of the disease.

Diagnosis can be difficult as other primary CNS tumors can contain melanin, including schwannomas, medulloblastomas, and certain gliomas.15 A critical step in diagnosis is to conduct a thorough search for a non-CNS primary melanoma, including detailed dermatologic and ophthalmologic examinations. CT of the chest/abdomen/pelvis is also indicated as primary melanoma can occur in the soft tissues (particularly gastrointestinal tissue).

There is little consensus on treatment for primary CNS malignant melanoma in the adult literature. In the first large case report on melanocytic tumors of the CNS, Brat et al4 reported on 13 cases of primary CNS malignant melanoma. Primary resection of the tumor was the initial therapy of choice in all 13 cases, with 6 patients also receiving radiation therapy. Currently, therapeutic modalities have still focused on primary resection followed by radiation therapy, particularly in cases of incomplete resection.12–14 Radiation doses have varied from 30 to 60 cGy.14 The role of adjuvant chemotherapy has not been established in the treatment of primary CNS malignant melanoma, although multiple different agents including intrathecal agents have been used.16

Metastatic melanoma has traditionally been difficult to treat, with 1-year survival reported at <33%, with median survival of <1 year.17,18 Until recently, interleukin-2 (IL-2) was the only approved treatment for metastatic melanoma. Ipilimumab was approved in 2011 by the FDA for use in metastatic melanoma. Ipilimumab is a human monoclonal antibody to CTLA-4, an immunosuppressive receptor on T cells. Blockade of CTLA-4 has been shown in studies to potentiate the antitumor activity of cytotoxic T cells. In its first phase III trial in adults, Hodi et al17 reported median overall survival was 10.1 and 10.0 months with ipilimumab and ipilimumab plus gp100, respectively, versus 6.4 months in the gp100 only group (gp100 is an adjuvant vaccine believed to potentiate IL-2 against melanoma cells). In the most mature data to date, Prieto et al18 demonstrated an overall survival of 25% at 5 years, with a median survival of 16 months in patients receiving ipilimumab + IL-2. Prieto and colleagues also noted durable responses in adult patients from 54 to 99 months. Ipilimumab is not currently approved for use in children, and to our knowledge, our patient is the first reported case of the use of ipilimumab for melanoma, metastatic or otherwise, in a pediatric patient.

Another emerging group of agents for metastatic melanoma includes inhibitors of V600E mutated BRAF such as vemurafenib and dabrafenib, and trametinib (a MEK inhibitor). BRAF, a part of the MAP kinase pathway, is a mutation often found in malignant melanoma. In a recent phase III trial randomizing 675 adult patients with BRAF-mutated metastatic melanoma to receive either vemurafenib or dacarbazine, vemurafenib therapy gave a 48% response rate and led to improved overall survival.19 Recently, immunotherapy with inhibitors for program cell death 1 (PD-1) and its ligand (PD-Ll) have shown promising therapeutic activity, and are now approved for the treatment of metastatic melanoma in adults. Although immune-based therapies like ipilimumab and targeted BRAF inhibitors like vemurafenib present exciting potential treatments for adults with metastatic melanoma, their efficacy in either metastatic melanoma or primary CNS malignant melanoma in children requires further investigation.

Reported outcomes in primary CNS malignant melanoma are variable in the adult literature. In their case series of 26 primary CNS malignant melanomas of the spine, Kim et al20 reported all 26 patients underwent resection, 11 of whom received additional radiation therapy, ultimately with 19/26 patients surviving. However, Brat et al4 reported that in 9/13 patients with primary CNS malignant melanoma had recurrence of their disease, and 5/9 died within 12 months of starting treatment. As seen in Table 1, there are too few pediatric cases to determine the optimal treatment modality and/or prognosis.

In summary, we present 2 cases of primary CNS malignant melanoma in a child and adolescent. Primary CNS malignant melanoma is an extremely rare tumor in children, with no consensus on the best treatment modalities. Surgical resection and radiotherapy are the current standard treatments. New molecularly targeted and immune-based therapies used in metastatic melanoma in adults are providing potential new options for treatment, but their efficacy and safety still need to be evaluated in pediatric patients.

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central nervous system malignant melanoma; pediatric brain tumor; melanoma

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