Abstract
Primary diffuse leptomeningeal melanomatosis (PDLMM) is an extremely rare and aggressive cancer type for which best treatment strategies remain to be elucidated. Herein, we present current and prospective diagnostic strategies and treatment management of PDLMM. Against the background of an extensive literature review of published PDLMM cases and currently employed therapeutic strategies, we present an illustrative case of a pediatric patient suffering from PDLMM. We report the first case of a pediatric patient with PDLMM who received combination treatment including trametinib and everolimus, followed by intravenous nivolumab and ipilimumab with concomitant intensive intraventricular chemotherapy, resulting in temporary significant clinical improvement and overall survival of 7 months. Following this clinical experience, we performed a comprehensive literature review, identifying 26 additional cases. By these means, we provide insight into current knowledge on clinical and molecular characteristics of PDLMM. Analysis of these cases revealed that the unspecific clinical presentation, such as unrecognized increased intracranial pressure (present in 67%), is a frequent reason for the delay in diagnosis. Mortality remains substantial despite diverse therapeutic approaches with a median overall survival of 4 months from diagnosis. On the molecular level, to date, the only oncogenic driver reported so far is mutation of NRAS (n = 3), underlining a close biological relation to malignant melanoma and neurocutaneous melanosis. We further show, for the first time, that this somatic mutation can be exploited for cerebrospinal fluid liquid biopsy detection, revealing a novel potential biomarker for diagnosis and monitoring of PDLMM. Last, we use a unique patient derived PDLMM cell model to provide first insights into in vitro drug sensitivities. In summary, we provide future diagnostic and therapeutic guidance for PDLMM and first insights into the use of liquid biopsy and in vitro models for this orphan cancer type.
Highlights
Primary diffuse leptomeningeal melanomatosis (PDLMM), a primary meningeal melanocytic tumor, is an extremely rare and highly aggressive disease for which standardized treatment and cure are still lacking
We present a rare case of pediatric primary diffuse leptomeningeal melanomatosis, discuss the therapeutic approach, and provide a comprehensive analysis of clinical course and molecular characteristics of PDLMM
The lumbar puncture led to an immediate improvement in clinical symptoms, indicative of increased intracranial pressure (ICP)
Summary
Primary diffuse leptomeningeal melanomatosis (PDLMM), a primary meningeal melanocytic tumor, is an extremely rare and highly aggressive disease for which standardized treatment and cure are still lacking. According to the 2016 WHO classification, melanoblasts can give rise to four groups of neoplasms: the circumscribed melanocytoma (benign) or melanoma (malignant) and the primary diffuse leptomeningeal melanocytosis (PDLMC, benign) or melanomatosis (PDLMM, malignant), which exhibit distinct molecular profiles [1,2]. Brain metastases of malignant melanoma (MM) are more frequent than all of these entities together, highlighting the importance of studies exploring the translational potential of knowledge based on MM research to melanocytic CNS tumors. MM ranks among the malignancies with the highest mutational burden and is classified into four genomic groups based on the presence of distinct oncogenic drivers: mutant BRAF (50% of all melanomas), mutant N-/K-/H-RAS (25%), mutant NF1 (15%), and triplewildtype (5%) [3,4]. At least BRAF and NRAS mutations are found in benign naevi, highlighting the importance of additional somatic mutations, which are often found in CDKN2A, PTEN, TERT promoter or TP53 [4,5]
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