Pediatric Primary Intracranial Malignant Melanoma: Case Report and Literature Review

Introduction: Primary intracranial malignant melanoma (PIMM) is an extremely rare primary brain tumor with most cases diagnosed in adults. To date, there are only a few cases reported in the pediatric population. Owing to its infrequency, there are no established guidelines to treat this aggressive neoplasm. Recent insights suggest that PIMM are molecularly different between adults and children, whereby NRAS mutations drive tumor growth in the latter group. We present a unique case of PIMM in a pediatric patient and discuss the case in corroboration with current literature. Case Presentation: A previously well 15-year-old male presented with progressive symptoms of raised intracranial pressure. Neuroimaging reported a large solid-cystic lesion with significant mass effect. He underwent gross total resection of the lesion that was reported to be a PIMM with pathogenic single nucleotide variant NRAS p.Gln61Lys. Further workup for cutaneous, uveal, and visceral malignant melanoma was negative. A trial of whole-brain radiotherapy followed by dual immune checkpoint inhibitors was commenced. Despite concerted efforts, the patient had aggressive tumor progression and eventually demised from his disease. Conclusion: We therein report a case of pediatric PIMM, in the context of the patient’s clinical, radiological, histopathological, and molecular findings. This case highlights the therapeutic difficulties faced in disease management and contributes to the very limited pool of medical literature for this devastating primary brain tumor.


Introduction
Primary intracranial malignant melanoma (PIMM) is a very rare brain tumor, constituting only 1% of all melanoma cases [1,2].This aggressive neoplasm is thought to arise from the melanocytes of leptomeninges and has a purported incidence of less than 3% of all pediatric cancers [3,4].In children, there is often a strong association with neurocutaneous melanosis [5].At the time of this writing, there is a paucity of publications on pediatric PIMM [6,7] as it has been mostly reported in the adult population [6].Owing to its infrequency, there is firstly, a lack of established guidelines for adjuvant treatment in pediatric PIMM; and next, there are no previous randomized trials available to guide management of affected patients [8,9].We report a unique case of PIMM in a pediatric patient and discuss its nuances in corroboration with existing literature.

Case Presentation
A previously well 15-year-old male presented with a month's history of progressively worsening headaches associated with vomiting and photophobia.Magnetic resonance imaging (MRI) of his brain identified a 7.1 × 5 × 4.8 cm intra-axial solid-cystic heterogeneously contrast-enhancing mass centered in the right frontal lobe, associated with significant mass effect.Of note, there were also nodular foci along bilateral cerebral hemispheres that were hyperintense on pre-contrast T1-weighted sequences and isointense to grey matter on T2-weighted images (shown in Fig 1,2).Additional MRI screening of his whole spine did not show radiological evidence of drop metastases.An ophthalmological examination confirmed bilateral papilledema.
He underwent craniotomy and gross total excision of the brain tumor.Intraoperatively, an extremely hemorrhagic intra-axial lesion with a pigmented appearance was encountered.The initial impression of the pigmentation was due to previous hemorrhage.The patient's postoperative recovery was unremarkable and there was resolution of his initial complaints of headaches, vomiting, and visual disturbance.Histopathology showed diffuse sheets of epithelioid tumor cells with large oval nuclei bearing prominent nucleoli, and moderate amounts of eosinophilic cytoplasm (shown in Fig. 3).There was extensive pigmentation consistent with melanosis.Immunohistochemical staining showed positive reactivity for S-100 protein and melanocytic markers HMB45 and melan-A (shown in Fig. 4) while glial markers glial fibrillary acid protein and OLIG2 were negative.Overall, the features were consistent with those of PIMM [10].Molecular genomic profiling was performed via AmpliSeq™ for Illumina ® Childhood Cancer Panel, a pediatric pan-cancer next-generation sequencing targeted panel specific for the study of the most common variants associated with childhood and young adult cancer types [11].This identified the following: a pathogenic single nucleotide variant NRAS p.Gln61Lys (Tier 1A) and a variant of uncertain significance IKZF p.Val341del (Tier 3).Additional tests included microsatellite instability which did not show significant instability, and tumor mutation burden which was low (summarized in Table 1).A follow-up fluorodeoxyglucosepositron emission tomography scan did not demonstrate any other suspicious extracranial lesions.In view of the diagnosis, the patient had further assessments by the Dermatology and Ophthalmology specialists to look for coexisting cutaneous and uveal melanomas.There was no clinical evidence of oculodermal melanocytosis or other congenital nevus.After much discussion, recommendations by the multidisciplinary neuro-oncology tumor board (MDT) was for whole brain radiotherapy (WBRT) 30 Gy in 10 fractions, to be followed by dual immune checkpoint inhibitors for synergistic effect-the latter adapted from a phase IIIb/IV clinical trial for advanced melanoma [12].In event of disease relapse, a MEK inhibitor as monotherapy would be considered.The decision for primary WBRT instead of fractionated stereotactic radiotherapy (RT) was based on the presence of extensive intracranial disease that was deemed non-resectable [13].Next, immune checkpoint inhibitor therapy had been previously cited as a feasible approach to NRAS-mutant melanomas [14].Preclinical studies already suggested that tumors with NRAS driver mutations have tumor microenvironments differentially responsive to immune checkpoint inhibitors compared to that BRAF-mutant melanomas [15,16].In addition, there was limited evidence for upfront mitogen-activated protein kinase kinase (MEK) inhibitor monotherapy in advanced NRAS melanoma at the time of this writing [14].Therefore, the decision was to withhold its use for the time being.
He underwent 4 cycles of Nivolumab and Ipilimumab (Nivolumab 3 mg/kg and Ipilimumab 1 mg/kg), followed by maintenance phase of 4-weekly Nivolumab.Initial surveillance neuroimaging during this treatment period demonstrated stability of the intracranial lesions.Approximately 6 months after diagnosis, there was tumor recurrence seen in the followup scans.Repeat resection of his previous left frontal lesion was performed.Postoperatively, trametinib, a MEK inhibitor was commenced.However, there was minimal therapeutic response; and furthermore, there was continued clinical and radiological disease progression (shown in Fig. 5).After a trial of trametinib for 4 weeks, decision was made for palliation in view of medical futility.The patient eventually passed away at approximately 8 months after diagnosis.

Discussion
PIMM is an uncommon, highly aggressive cancer with poor prognosis [9,21].Overall survival is reported to be between 9 and 24 months [22].At the time of this writing, up to 250 cases of PIMM have been reported [23][24][25][26], with less than a handful cases of PIMM in children [5,7,8,24].Data from a population-based study using the National Cancer Institute SEER program in USA collected from 1973 to 2015 observes that the incidence of PIMM peaks during the fourth and fifth decades of life [23][24][25].The mean age for PIMM is 45.8 years (minimum 12 years, maximum 82 years), and patients are predominantly male (33; 61.1%) [25].Put together, it should be emphasized that cases of PIMM in children are very rare [5,7,8,[12][13][14][15].A list of these patients from contemporary literature is summarized in Table 2.
Often, PIMM is a diagnosis of exclusion that is made when skin or uveal melanocytic lesions are not found to account for a primary malignancy [27][28][29].As they are very uncommon, these tumors are often misdiagnosed as other brain disease entities on initial neuroimaging [2,9,29].For affected patients, MRI of the neuroaxis is essential as this is the imaging modality that demonstrates features specific to the disease [30,31].In malignant intracranial melanoma cells, the melanin produces superfluous metal ion complexes that shorten the T1-weighted and T2-weighted relaxation times [30].Broadly speaking, these tumors are divided into 4 subtypes according to the melanin content of the tumors resulting in different MRI features.Based on Isikar et al. [30] study, intracranial melanoma is likely to have the following imaging patterns: melanotic (T1-hyperintense and T2-hypointense); amelanotic (T1-hypo or isotense and T2-hyper or isointense), indeterminate (mixed pattern or do not conform to criteria of the previous 2 patterns), and hematoma (MRI features of hematoma only).Here, the most common are lesions characterized by a high signal intensity on non-contrasted T1weighted sequences and low signal intensity on T2-weighted sequences, as demonstrated in our patient's scans [30].
Presently, the recommended first line of management is surgical excision of the tumor [5,12].Studies report that PIMM patients who underwent gross total resection have a significantly longer survival time in comparison to those with subtotal resection, or biopsy [17,23].Separately, the role of adjuvant therapy has not been significantly associated with prolonging survival [24].RT has traditionally been considered as a palliative treatment option indicated only for advanced cases or disseminated disease [32].Furthermore, in vitro studies suggest that cells from metastatic melanoma lesions are more radioresistant than those from primary tumors [33].Nonetheless, some publications report that RT for residual tumor and leptomeningeal disease is associated with improved survival [23].Under   such circumstances, RT can be administered either as WBRT or fractionated doses to the surgical cavity postoperatively [8].With regard to our patient, the rationale for a more palliative approach for his postoperative RT regimen (that is, 30 Gy in 10 fractions) was due to the extent of satellite and leptomeningeal disease at initial diagnosis.
Following that, there is no standard chemotherapy or immunotherapy established for PIMM.Most treatment paradigms are often extrapolated from adult-based studies on advanced malignant melanoma with brain metastases and subsequently, formulated on a case-by-case basis [12,23,34].As reflected in our patient, a consensus is reached  only after thorough discussions at a designated MDT to agree upon the next step of management.Despite concerted efforts, his overall survival was still dismal.Malignant melanomas originate from melanocytes and may either be primary tumors derived from melanoblasts of neural crest origin, typically seen in the leptomeninges [35], or secondary neoplasms originating from cutaneous sites that metastasize intracranially [24].Specifically for PIMM, diagnosis may be delayed owing to the lack of clinically observable cutaneous melanosis [8].According to their pathological behavior, PIMM may be classified into 2 subtypes: first, the diffuse type that infiltrates the pia mater extensively and usually involves the subarachnoid space; and next, the solitary type that presents as a discrete, nodular mass [23].Microscopically, PIMMs show melanotic differentiation and appear similar to malignant melanomas elsewhere in the body [9].Recent insights demonstrate that PIMMs are triggered by overexpression of the neuroblastoma RAS viral oncogene (NRAS) in melanocytes of the leptomeninges during embryogenesis and that somatic mutations in the NRAS oncogene are risk factors to develop PIMM in children [21].Also, additional alterations affecting BRAF (v-raf murine sarcoma viral oncogene homolog B1), TERT (telomerase reverse transcriptase), GNAQ (G protein subunit alpha Q), SF3B1 (splicing factor 3b subunit 1), and EIF1AX (eukaryotic translation initiation factor 1A X-linked) genes have also been observed [36].Furthermore, advances in molecular profiling demonstrate that the genetic drivers of PIMM tend to involve mutations in GNAQ in adults [37], while somatic mutations in NRAS are more common in children [21].These findings are similarly demonstrated in our patient whereby molecular interrogation of his tumor identifies a pathogenic single nucleotide variant in NRAS p.Gln61Lys.This is consistent with existing reports in the literature and supports the hypothesis that somatic oncogenic mutations in NRAS of intracranial melanocytes lead to pediatric PIMM [21].
Preclinical research utilizing a mouse PIMM model with NRAS mutations has shown that these tumor cells are susceptible to MEK inhibitors-suggesting potential targeted therapy for affected patients [21].Briefly, the mitogen-activated protein kinase (MAPK) cascade is an intracellular signaling pathway involved in the regulation of cellular proliferation and the survival of tumor cells.Several different mutations, involving NRAS, exert an oncogenic effect by activating the MAPK pathway, resulting in an increase in cellular proliferation.These mutations have become targets for new therapeutic strategies in melanoma and other cancers [38].Nevertheless, we are now aware there is increasing evidence that for NRAS-mutant melanomas, effective treatment requires more than MEK inhibition alone [39].To date, no clinical trial has identified any MEK inhibitor to be effective as monotherapy against tumors with NRAS mutations [40].Besides involvement of the of the MAPK pathway, these patients often have simultaneous disturbances in cell cycle regulation-adding on another layer of therapeutic difficulty [14,41].Overall, the use of MEK inhibitors for clinical use is still a work in progress, and not fully established in PIMM patients at this stage.
Following that, this challenging case has also made us cognizant of other clinical gaps for PIMM.One of them is the issue of disease progression which occurs in many patients, even after treatment [42].For our patient, we would have preferred a modality to allow closer disease surveillance during the course of his treatment.At present, regular MRI surveillance is the main modality to follow-up patients to evaluate disease status.Despite its use in routine clinical practice, frequent neuroimaging is costly to patients and healthcare systems [43,44].As a step toward overcoming this issue, the use of circulating tumor DNA has been explored used as a marker of disease status in several cancers, including metastatic melanoma [45][46][47].This noninvasive real-time biomarker has been promising as a clinical tool to accurately reflect tumor burden in certain cancer types, provide prognostic information and as a monitoring tool for treatment response [48][49][50].Therefore, the development of serum biomarkers that can aid clinicians in detecting progressive disease will be useful in this context [51].In meantime, we are hopeful that the use of circulating tumor DNA for patients with PIMM will be implemented into routine clinical management in the near future.

Conclusion
The authors therein report a pediatric patient with PIMM and highlight the therapeutic challenges faced in disease management.This case adds to the very limited pool of medical literature for this devastating primary brain tumor.As the way forward for patient care, we reinstate the need for collaborative clinical and in-depth molecular studies at a global level.Lim/Tan/Wong/Chang/Fortier/Cheong/ Ng/Low and, or their legal guardians signed a written, IRB-approved informed consent form prior to enrollment to participate in this study.The consent to publish clinical/medical information is included as part of the written, informed consent form in this study.For this case report, written informed consent was obtained from the parent of the patient for publication of the details of their medical case and any accompanying images.A copy of the consent form is available upon request.

Fig. 1 .Fig. 2 .
Fig. 1.Representative MRI brain axial images in T2-weighted (a), pre-contrast T1-weighted (b) and post-contrast T1weighted (c) sequences depicting a large solid-cystic mass in the anterior right frontal lobe.Its solid component shows hyperintense signal in pre-contrast T1-weighted sequence (b), and heterogeneous contrast enhancement in the post-contrast T1-weighted sequence (c).There are hypointense signal changes with foci of susceptibility in the T2-weighted sequence (a).Of note, there is a nodular focus (red arrow) that is hyperintense without susceptibility in the pre-contrast T1-weighted image (b).This finding is consistent with the melanotic pattern of intracranial melanoma.

Fig. 3 .
Fig. 3. Hematoxylin and eosin-stained photomicrograph of tumor demonstrating diffuse sheets of epithelioid tumor cells with large oval nuclei bearing prominent nucleoli, and moderate amounts of eosinophilic cytoplasm, with extensive melanin pigmentation (magnification, ×400).

Fig. 5 .
Fig. 5. Representative post-contrast T1-weighted MRI images at time of tumor recurrence and dissemination.a MRI axial image depicting heterogeneously enhancing lesion in the previous right frontal lobe surgical cavity.Next, MRI sagittal images of the patient's spine showing multiple enhancing nodules along the thoracic spine (b) and in the thecal sac (c), consistent with drop metastases (red arrows).

Table 1 .
Summary of additional molecular investigations for patient's tumor

Table 2 .
Summary of pediatric PIMM cases in the literature