Central Nervous System Melanoma Research Articles

Primary intracranial malignant melanoma in an adolescent female: a case report

BackgroundPrimary central nervous system melanoma is an extremely rare entity and even rarer in children and adolescents as compared to adults. It is often difficult to consider a diagnosis of intracranial melanoma pre-operatively without any clinical evidence of neurocutaneous melanosis.Case presentationHerein, a case of primary melanoma of the brain is reported in a 17-year-old female who presented with headache, vomiting, and focal neurological deficit in the form of left-sided facial palsy and limb weakness. A contrast-enhanced computed tomography of head was performed which revealed a heterogeneously hyperattenuating mass lesion at left gangliocapsular region showing peripheral enhancement with internal non-enhancing cystic component. The patient underwent left frontotemporal craniotomy. The diagnosis was made on histopathological examination, which showed an invasive tumor comprising of epithelioid to spindled cells arranged in sheets, nests, and singly scattered. The special stains and immunohistochemical markers proved very helpful in establishing the diagnosis.ConclusionsThe case highlights the uncommon occurrence of primary intracranial melanoma in the pediatric age group, the perplexing histological features, and the rapid and fatal course.

Melanoma of the central nervous system based on neurocutaneous melanocytosis in childhood: A rare but fatal condition.

Melanomas of the central nervous system (CNS) based on neurocutaneous melanocytosis (NCM) are exceptionally rare in childhood and have been described only sporadically. Rapidly progressive disease may represent a major challenge for treating physicians, especially given the limited knowledge about this condition. This analysis aimed to increase knowledge about the occurrence and treatment of these malignancies. Data on diagnosis, treatment, and outcome of patients aged 0-18 years with CNS melanoma based on NCM recorded in the German Registry for Rare Pediatric Tumors (STEP registry) were analyzed. Additionally, published case reports on this condition were analyzed. In STEP, five patients with leptomeningeal melanoma based on NCM were identified, with a median age at melanoma diagnosis of 3.7 years. Various multimodal treatments were performed: (partial) resection (n=4), irradiation (n=2), trametinib (n=3), different cytostatics (n=2), and anti-GD2 immunotherapy (n=1). All patients died between 0.3 and 0.8 years after diagnosis. Including published case reports, 27 patients were identified with a median age of 2.8 years at melanoma diagnosis (range: 0.2-16.6). Fourteen of 16 cases with reported data had a NRAS alteration (88%), particularly NRAS p.Q61K (85%). In the expanded cohort, no patient survived longer than 1 year after diagnosis despite multimodal therapy (including trametinib; n=9), with a median survival of 0.4 years (range 0.1-0.9). CNS melanomas based on NCM in childhood are aggressive malignancies without curative treatment to date. Therapeutic approaches must be individualized. Genetic tumor sequencing is essential to improve understanding of tumorigenesis and potentially identify new therapeutic targets.

Central Nervous System Melanoma: Report of two cases

Primary brain melanomas are exceedingly rare, and metastasis outside of the central nervous system is an uncommon occurrence. The patients initially presented with an intraparenchymal hematoma with associated symptoms. Extensive diagnostic tests did not reveal any tumor-related or vascular patterns contributing to these bleedings. A comprehensive surgical resection was conducted, and the diagnosis of Central Nervous System (CNS) melanoma was confirmed through histological examination. Despite the generally poor prognosis associated with malignant melanomas, the combination of complete surgical resection and emerging therapies is extending overall survival and enhancing the quality of life. In cases where primary brain melanoma is suspected, even in the presence of extracerebral metastasis, aggressive treatment may be a viable consideration.

Clinicopathological features, current status, and progress of primary central nervous system melanoma diagnosis and treatment.

Primary central nervous system (CNS) melanoma is an extremely rare condition, with an incidence rate of 0.01 per 100,000 individuals per year. Despite its rarity, the etiology and pathogenesis of this disease are not yet fully understood. Primary CNS melanoma exhibits highly aggressive biological behavior and presents clinically in a distinct manner from other types of melanomas. It can develop at any age, predominantly affecting the meninges as the primary site, with clinical symptoms varying depending on the neoplasm's location. Due to the lack of specificity in its presentation and the challenging nature of imaging diagnosis, distinguishing primary CNS melanoma from other CNS diseases. The combination of challenges in early detection, heightened tumor aggressiveness, and the obscured location of its origin contribute to an unfavorable prognostic outcome. Furthermore, there has been currently no consensus on a standardized treatment approach for primary CNS melanoma. Despite recent advancements in targeted therapy and immunotherapy for CNS melanoma, patients with primary CNS melanoma have limited treatment options due to their inadequate response to these therapies. Here, we provided a comprehensive summary of the epidemiology, clinical features, molecular pathological manifestations, and available diagnostic and therapeutic approaches of primary CNS melanoma. Additionally, we proposed potential therapeutic strategies for it.

Real-world efficacy and safety data of anti-PD-1 plus anti-CTLA-4 combination therapy in Chinese patients with advanced melanoma.

e21530 Background: Combination of anti-PD-1 plus anti-CTLA-4 has shown superior efficacy over monotherapy in advanced melanoma among Caucasian populations. However, it has not been evaluated in Chinese patients, and data on acral and mucosal melanoma are limited. We aimed to assess the efficacy and safety of anti-PD-1 antibody plus ipilimumab therapy in Chinese patients with advanced melanoma in clinical practice. Methods: Advanced melanoma patients treated with anti-PD-1 antibody combined with ipilimumab in Sun-Yat sen University Cancer Center from May 2015 to October 2022 were retrospectively assessed. Patient baseline characteristics, tumor responses (RECIST), progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier analysis. Toxicity was assessed to estimate safety. Results: Altogether, 86 patients were included. The primary site was cutaneous, acral, mucosal, uveal and central nervous system (CNS) in 34, 21, 20, six and five patients, respectively. Among them, 21 patients were treatment-naive, 65 patients were previously treated, and 54 patients progressed of front-line ani-PD-1 therapy. 12 patients received ipilimumab 3mg/kg combined with low dose anti-PD-1 (Nivolumab 80mg or Pembrolizumab 1mg/kg) Q3w for four doses, and the other 74 patients received standard dose of anti-PD-1 plus ipilimumab 1mg/kg Q3w therapy. There were 25(29%) patients with liver metastasis and 26(30.2%) patients with CNS metastasis at baseline. The overall response rate (ORR) was 15.1% in the whole cohort, with complete response observed in six (6%) patients, partial response in 7 (8.1%), stable disease in 28 (32.6%). The response rate in the treatment-naive and prior systemic therapy group was 23.8% and 12.3%, respectively. For those treated with anti-PD-1 followed by the anti-PD-1+ ipilimumab as subsequent therapy after disease progression, the ORR was 11.1%. The response rate for cutaneous melanoma was 23.5%, and 37.5% in the naïve group. Response rates for acral, uveal, CNS and mucosal melanoma were 19.0%, 16.7%,0% and 0% respectively. The median progression-free survival (PFS) and overall survival (OS) in all patients was 4.5 (3.6-5.4) months and 22.0 (12.4-31.6) months, respectively. The 3-year OS were 100% in patients who achieved ORR. There were no significant differences in PFS or OS for patients with cutaneous or acral melanoma. mucosal primary tumor type, liver metastasis and elevated LDH were predictive of shorter PFS and OS. CNS metastasis, previous treatment, BRAF/NRAS mutation status and sex were not found to be related to survival. Adverse events occurred in 71% of patients and 13% were grade 3 or worse. Conclusions: The efficacy of anti-PD-1+ ipilimumab combination therapy in Chinese patients tended to be inferior compared to global studies but was well tolerated. OS were good in cases with CR or PR.

Abstract 632: Exploiting pyroptosis in melanoma brain metastasis

Abstract Melanoma is the deadliest form of skin cancer due to its frequent metastasis to the brain. Melanoma brain metastases (MBM) are a significant clinical challenge, and current model systems and therapeutic strategies are poor. Inhibitors targeting the most common oncogenic driver of melanoma, BRAFV600E (BRAFi), disrupt mitogenic signaling and promote caspase-3 associated cell death. Though caspase-3 is a well-known apoptotic driver, it can also cleave Gasdermin E (GSDME) to create pore-forming N-terminal fragments that oligomerize at plasma and mitochondrial membranes and trigger pyroptosis - a form of immunogenic cell death (ICD). Our recent work illustrates the importance of GSDME mediated pyroptosis and associated immunogenicity in providing a durable therapeutic response against melanoma. Since pyroptosis can be activated by GSDME cleavage via caspase-3, and is prominent in various neuropathologies, a better understanding of the interplay between central nervous system (CNS) immune cells and BRAFi-mediated ICD is critical for designing more effective therapies against MBM. Here, we engineered a panel of inducible pyroptotic melanoma cells to model BRAFi-mediated pyroptosis. Using ex vivo CNS slice co-cultures, we found that inducible N-GSDME expression in human and murine melanoma cells drives propidium iodide uptake and release of inflammatory activators like HMGB1 and IL-1 - hallmarks of pyroptosis. Importantly, conditioned media from these pyroptotic cells stimulates a more robust phagocytic response from resident macrophages of the CNS and pyroptotic melanoma elicit stronger cytotoxicity from syngeneic CD8+ T cells, further highlighting the benefits of BRAFi-mediated ICD. Our findings provide evidence that resident CNS immune cells and peripheral T cells respond to pyroptotic melanoma, suggesting that induction of ICD should be a consideration in the development of anti-MBM therapies. Citation Format: Maria R. Cavallo. Exploiting pyroptosis in melanoma brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 632.

Oral IRAK-4 Inhibitor CA-4948 Is Blood-Brain Barrier Penetrant and Has Single-Agent Activity against CNS Lymphoma and Melanoma Brain Metastases.

An ongoing challenge in cancer is the management of primary and metastatic brain malignancies. This is partly due to restrictions of the blood-brain barrier and their unique microenvironment. These challenges are most evident in cancers such as lymphoma and melanoma, which are typically responsive to treatment in systemic locations but resistant when established in the brain. We propose interleukin-1 receptor-associated kinase-4 (IRAK-4) as a potential target across these diseases and describe the activity and mechanism of oral IRAK-4 inhibitor CA-4948. Human primary central nervous system lymphoma (PCNSL) and melanoma brain metastases (MBM) samples were analyzed for expression of IRAK-4 and downstream transcription pathways. We next determined the central nervous system (CNS) applicability of CA-4948 in naïve and tumor-bearing mice using models of PCNSL and MBM. The mechanistic effect on tumors and the tumor microenvironment was then analyzed. Human PCNSL and MBM have high expression of IRAK-4, IRAK-1, and nuclear factor kappa B (NF-κB). This increase in inflammation results in reflexive inhibitory signaling. Similar profiles are observed in immunocompetent murine models. Treatment of tumor-bearing animals with CA-4948 results in the downregulation of mitogen-activated protein kinase (MAPK) signaling in addition to decreased NF-κB. These intracellular changes are associated with a survival advantage. IRAK-4 is an attractive target in PCNSL and MBM. The inhibition of IRAK-4 with CA-4948 downregulates the expression of important transcription factors involved in tumor growth and proliferation. CA-4948 is currently being investigated in clinical trials for relapsed and refractory lymphoma and warrants further translation into PCNSL and MBM.

Primary Intracranial Malignant Melanoma Mimicking Meningioma—Report of Two Cases

AbstractPrimary intracranial melanoma is uncommon and accounts for only approximately 1% of all cases of melanoma. This is interesting to neuro-oncologists and neurosurgeons because the clinical and radiological patterns of these tumors can mimic the presence of meningioma. Primary central nervous system melanomas have rarely been reported with less than 25 cases reported till date. We report two cases of the primary intracranial melanoma that even though very rare should be kept as a differential diagnosis when meningioma is suspected.

Fatal GNAQ-mutated CNS melanoma in an adolescent with nevus of Ota.

Nevus of Ota is an uncommon benign mesodermal melanosis that involves the first and second divisions of the trigeminal nerve. Primary non-cutaneous melanoma often involves distinct genetic mutations compared to cutaneous melanoma. In primary central nervous system (CNS) melanomas associated with nevus of Ota, somatic mutations most commonly occur at the Q209 and R183 residues of GNAQ and likely induce tumorigenesis through upregulation of the MAP kinase pathway. This case underscores the importance of elucidating neurologic symptoms early in patients with nevus of Ota, as a delayed presentation of CNS melanoma could portend a devastating outcome.

Ultrastructural and clinical features of central nervous system melanoma:Analysis of nine cases

ABSTRACT To investigate the ultrastructural and clinical characteristics of melanoma of the central nervous system (CNS). The clinical and electron microscopy pathology data of nine patients with melanoma surveyed from 1993 to 2017 were analyzed. All the CNS melanomas were confirmed by transmission electron microscopy (TEM), including eight cases of primary melanomas and one case of metastatic melanoma. In this study, four stage II melanosomes were intracranial space-occupying, three of which were malignant melanoma, the other one was melanoma. Among the five stage IV melanosomes, four cases were intraspinal space-occupying, the other one was intracranial space-occupying, and the pathological diagnoses were all melanoma. At present, TEM is an important tool for the diagnosis of CNS melanomas. Malignant melanoma has high malignancy and recurrence rate and poor prognosis, while benign melanoma with relatively low recurrence rate, so we speculate that patients with mainly immature melanosomes are more likely to exhibit recurrence.

Clincial Response of Central Nervous System Melanoma to Anti-PD1 Therapy in 2 Melanoma Patients

The first patient is a 76-year-old man who presented in June 2015 with aphasia and right hemiparesis. Imaging revealed a 3.5 × 3 × 1.3 cm left parietal mass. The patient underwent a craniotomy and pathology confirmed BRAF V600E mutant melanoma. He did not have a previous diagnosis of a primary melanoma. Subsequent PET imaging in August showed no evidence of systemic disease. Surveillance brain MRI in November showed several new nodular areas of enhancement along the dura and inter hemispheric falx, with CT of the body again not demonstrating other sites of disease. He was treated with whole brain radiation in December of 2015 (37.5 Gy, 15 fractions). In late January 2016 an MRI was done demonstrating mild progression of the anterior falcine dural metastatic disease. Given the progression was not significant and the patient was asymptomatic a watchful waiting approach was planned with a close follow-up MRI. Repeat MRI in March showed stable changes, thus surveillance continued.

[Current research analysis and prospects on sensitization effect of artesunate on anti-cancer radiotherapy and chemotherapy].

The wide application of artemisinins in the treatment of multiple cancers reflects the advantages of traditional Chinese medicine used in this field. The existing basic and clinical studies have revealed that artesunate can effectively suppress the malignant progression of breast cancer,colon cancer,leukemia,melanoma,ovarian cancer,prostate cancer,kidney cancer and various tumors in central nervous system. The pharmacological mechanisms of artesunate against cancers are reflected in many aspects,such as inhibiting tumor cell proliferation,invasion and metastasis,inducing tumor cell apoptosis and autophagy,regulating cell signal transduction and inhibiting tumor angiogenesis. Meanwhile,growing experimental evidences have indicated that artesunate has been used for the sensitization of radiotherapy with X-ray,β-ray,γ-ray and~(60)Co γ-ray,as well as chemotherapy with cisplatin,carboplatin and doxorubicin.This review collected basic and clinical studies on the sensitization effect of artesunate on anti-cancer radiotherapy and chemotherapy published on PubMed and CNKI during April 2000 and February 2019,and summarized the clinical positioning and application of artesunate,with the aim to provide a more comprehensive explanation on the sensitization effect of artesunate on anti-cancer radiotherapy and chemotherapy,and offer the inspiration and ideas for the development of radiotherapy and chemotherapy sensitizers,as well as cancer resistance reversal agents.

Primary Malignant Melanoma of the Brain: A Population-Based Study

Primary melanocytic neoplasms of the central nervous system (CNS) are rare and account for 1%of all melanomas. This study used the Surveillance, Epidemiology, and End Results (SEER) database to evaluate the epidemiology of primary CNS melanoma and further characterize their treatment. Data from the National Cancer Institute SEER program, collected from 1973-2015, were retrospectively analyzed. A total of 86 records of malignant melanoma cases with CNS as the primary site were identified, and 54 patients were studied based on the inclusion criteria. Demographic, tumor, and treatment regimen effectiveness were studied. A total of 54 patients were included in this study. Tumors were distributed evenly in size and localized primarily to the cerebral meninges and spinal cord. A total of 13% of patients underwent biopsy, 40.7% gross total resection (GTR), 7.4% subtotal resection (STR), 46.3% radiation therapy (RT), and 27.3% chemotherapy (CT) in a variety of treatment combinations. GTR alone and STR+RT resulted in increased disease-specific survival compared to biopsy alone, but no survival benefit was found with biopsy with RT and/or CT as well as STR alone. To our knowledge, this is the largest single database study completed for primary malignant melanoma of the CNS. The study identified the need for tumor resection for the proper treatment of these lesions, particularly GTR. GTR could be paired with adjuvant RT or RT+ CT providing survival benefit as well. In cases when GTR is unable to be completed, STR+ RT provides significant improvement in survival compared to biopsy alone.

Incidence, Outcomes and Predictors of Primary Central Nervous System Melanoma: A SEER-Based Study

Primary central nervous system (pCNS) melanoma is an extremely rare malignant tumor. We explored the incidence, outcomes, and predictors of pCNS melanoma. We queried the Surveillance, Epidemiology, and End Results database to identify all patients diagnosed with pCNS melanoma during 1973-2015. Overall survival (OS) was obtained by using the Kaplan-Meier curves. Log-rank test was used to compare survival across groups of age, sex, race, tumor location, size, surgical resection, radiotherapy, chemotherapy and year of diagnosis. Cox regression was used for univariate and multivariate analysis of survival. A total of 84 pCNS melanomas were identified with a 5-year OS of 37.7%. The overall age-adjusted incidence rate was 0.52 per 10,000,000 person-years. Age ≤19 years (vs. age 20-59 years, hazard ratio [HR]= 2.37, 95% confidence interval [CI]: 1.11-5.07, P= 0.03) and intracranial location (vs. intraspinal, HR= 1.98, 95% CI: 1.04-3.77, P= 0.04) were associated with decreased survival rate. Gross total resection surgery (vs. partial resection, HR= 0.31, 95% CI: 0.15-0.66, P= 0.002) was associated with improved survival rate. There was no significant association between other demographic characteristics, tumor size, therapy methods, year of diagnosis, and OS. The overall age-adjusted incidence rate of pCNS melanoma is 0.52 per 10,000,000 person-years. Age ≤19 years and intracranial tumor location are independent risk factors of low survival rate, whereas gross total resection is associated with better survival rate.

Primary versus Secondary Central Nervous System Melanoma: a Diagnostic Dilemma and Report of a Case

Primary versus Secondary Central Nervous System Melanoma: a Diagnostic Dilemma and Report of a Case

Neurocutaneous melanosis with pulmonary metastasis: looking beyond the skin

Neurocutaneous melanosis are neuroectodermal disorders characterized by giant congenital melanocytic nevus or multiple (≥3) nevus’s associated with melanocytic leptomeningeal tumour. Central nervous system tumour can be benign or malignant and usually presents at an early age. The neurological manifestation includes raised intracranial pressure, seizures and spinal cord compression. The dissemination of malignant nevomelanocytes to the peritoneal cavity has been observed with ventriculoperitoneal shunt placement in neurocutaneous melanosis. We report an infant of neurocutaneous melanosis with primary central nervous system melanoma and its metastasis to the lung in view of rarity.

SCALP Syndrome associated with central nervous system melanoma

<scp>SCALP</scp> Syndrome associated with central nervous system melanoma

Systemic Tolerance Mediated by Melanoma Brain Tumors Is Reversible by Radiotherapy and Vaccination

Immune responses to antigens originating in the central nervous system (CNS) are generally attenuated, as collateral damage can have devastating consequences. The significance of this finding for the efficacy of tumor-targeted immunotherapies is largely unknown. The B16 murine melanoma model was used to compare cytotoxic responses against established tumors in the CNS and in the periphery. Cytokine analysis of tissues from brain tumor-bearing mice detected elevated TGFβ secretion from microglia and in the serum and TGFβ signaling blockade reversed tolerance of tumor antigen-directed CD8 T cells. In addition, a treatment regimen using focal radiation therapy and recombinant Listeria monocytogenes was evaluated for immunologic activity and efficacy in this model. CNS melanomas were more tolerogenic than equivalently progressed tumors outside the CNS as antigen-specific CD8 T cells were deleted and exhibited impaired cytotoxicity. Tumor-bearing mice had elevated serum levels of TGFβ; however, blocking TGFβ signaling with a small-molecule inhibitor or a monoclonal antibody did not improve survival. Conversely, tumor antigen-specific vaccination in combination with focal radiation therapy reversed tolerance and improved survival. This treatment regimen was associated with increased polyfunctionality of CD8 T cells, elevated T effector to T regulatory cell ratios, and decreased TGFβ secretion from microglia. These data suggest that CNS tumors may impair systemic antitumor immunity and consequently accelerate cancer progression locally as well as outside the CNS, whereas antitumor immunity may be restored by combining vaccination with radiation therapy. These findings are hypothesis-generating and warrant further study in contemporary melanoma models as well as human trials.

Objective Ki-67 Index Quantification In Non-Breast Tumors – Preliminary Data In Timisoara, Romania

Introduction/ Background The immunohistochemical expression of the Ki-67 protein is routinely used for diagnostic and grading purposes of various tumors. The most common use of automation process for Ki-67 quantification is represented by breast tumors. Aims We aimed to analyze the accuracy of digital quantification of Ki-67 expression in non-breast tumors. Methods We selected all the available Ki-67 stained slides done in 2014 at the County Emergency Hospital Timisoara, Ro- mania, excluding breast tumors. Images of the stained slides (10 images/slide on average, depending on the size of the specimen) were acquired on a Leica DMD108. We performed preprocessing (autolevels) in IrfanView and Ki-67 quantification in Fiji (ImageJ distribution) using ImmunoRatio plugin. Results Proper image segmentation was identified on 25 cases. The best segmentation was obtained in lymphoid and central nervous system (CNS) tumors. Lower Ki-67 values than the ones manually reported were identified in 16/25 cases (64%). Interestingly, digital quantification showed all 7 lymphoid cases to have a lower Ki-67 index than manually reported, while 6/9 CNS had higher Ki67 indices using automation processing. Valid digital quantification was not possible on skin, cervical and urothelial tumors, as regions of interest could not be defined to restrain the area to be evaluated. C o nclusion: Our preliminary study shows that ImmunoRatio plugin for Fiji in combination with IrfanView preprocessing are free, easy to use and powerful tools to obtain an objective Ki-67 index in non-mammary tumors: CNS, lymphoid, soft tissue, neuroendocrine tumors, choriocarcinomas and malignant melanomas.

Primary intracranial malignant melanoma in an adolescent girl: A case report

Primary intracranial malignant melanoma is a very rare tumor, and most of the central nervous system melanomas are metastatic diseases. Diagnosis needs extensive dermatological, opthalmological, and radiological workup to exclude metastatic melanoma. Histologically, it should be differentiate from benign melanocytic lesions, pigmented choroid plexus carcinoma, and pigmented papillary medulloblastoma. Here, we are reporting a case of primary malignant melanoma of posterior fossa in an adolescent girl diagnosed in squash cytology as well as in histology and confirmed by immunohistochemistry and by excluding metastatic melanoma.