Primary Melanocytic Lesions Research Articles

CD8-Lymphocytic Phenotype Significance in Primary Multiple and Familial Melanoma with Various CDKN2A Mutational Status.

Background and Objectives: In the realm of the rising incidence of cutaneous and mucous melanoma, CDKN2A mutations characterize familial and multiple primary melanoma cases. The involvement of tumor-infiltrating lymphocytes (TILs) is interconnected with survival rates, but may extend even further. The aim of this study is to verify the accuracy of the classical "naked eye" count of CD8-positive T cells comprised within the tumoral population and peritumoral infiltrate versus that obtained via a special software run by the aid of artificial intelligence (AI), used to determine the percentage of CD8-positive TILs. Materials and Methods: The present retrospective cross-sectional study conducted over a period of 5 years (2018-2022) focused on patients diagnosed with mucous and/or cutaneous melanoma, with a positive family history for melanoma, or personal antecedents of primary malignant melanocytic lesions. The 23 selected cases were diagnosed histopathologically, tested for CDKN2A mutations through fluorescent hybridization in situ, and CD8 immunohistochemistry was performed. The included slides were evaluated both manually (naked-eye examination) and automatically (via QuPath platform) for quantifying the CD8-positive TILs. Results: The number of CD8-positive TILs in melanoma samples has been more accurately identified through the use of an AI-mediated software as compared to the human-eye evaluation performed by experimental pathologists. A higher percentage of CD8-positive intratumoral lymphocytes versus stromal lymphocytes was positively associated with more numerous metastatic sites. Conclusions: The CD8 lymphocytic phenotype harbors major significance in the context of familial and multiple primary melanoma and may comprise a cost-effective investigation meant to help in the establishment of melanoma prognosis and response to immunotherapy.

Primary melanocytic melanoma of foramen magnum

Meningeal melanocytomas are a group of benign tumors that arise from the leptomeningeal melanocytes. According to the World Health Organization, they belong to primary melanocytic lesions. These rare lesions pose a diagnostic challenge to a neurosurgeon, especially in the absence of cutaneous melanosis and often because it masquerades as other benign tumors on imaging. Complete microsurgical excision, proper histological diagnosis, and diligent search for primary are essential for the complete cure. One of the rare complications of high-grade melanoma is a thromboembolic event which can prove catastrophic despite a complete surgical excision. We report a case of a 39-year-old male who was diagnosed with foramen magnum melanoma and eventually succumbed to thromboembolic complication despite an uneventful total excision.

Melanocytic lesions of the central nervous system: a case series.

Melanocytic lesions of the central nervous system (CNS) are an infrequent, broad and diverse group of entities, both benign and malignant, found in all age groups, with imaging findings ranging from well-circumscribed focal lesions to diffuse leptomeningeal involvement. On MRI, they are usually distinguished by a high signal on T1WI sequences, given the paramagnetic effect of melanin, thus making it difficult to differentiate among them. To describe the imaging and epidemiological characteristics of a retrospective series of CNS melanocytic lesions. MR images of 23 patients with CNS melanocytic lesions diagnosed between January 2012 and June 2018 were analyzed. Most patients were female (14/23; 61%), with a median age of 47 years (range: 3 weeks to 72 years). The primary melanocytic lesions accounted for 8/19 cases (42.1%), which included neurocutaneous melanosis, meningeal melanocytomas and primary malignant melanomas. Secondary melanocytic lesions (metastatic) accounted for 10/19 cases (52.6%). There was one case of a tumor with secondary melanization, from a melanocytic neuroectodermal tumor of infancy. There were also four cases of primary ocular melanomas. The most frequent findings were the cerebral location, high T1WI signal and marked contrast-enhancement. The present review describes the wide variety of melanocytic lesions that could affect the CNS, emphasizing the MRI characteristics. Knowledge of the imaging, clinical and epidemiological characteristics of CNS melanocytic lesions is essential for their correct interpretation, given the significant overlap between lesion features and the variable prognosis.

PRAME expression in 155 cases of metastatic melanoma.

PRAME (preferentially expressed antigen in melanoma) is a promising immunohistochemical marker in distinguishing benign from malignant primary cutaneous melanocytic lesions and lymph node deposits. We hypothesize that PRAME may also reliably identify melanoma metastases that are clinically detected in skin, lymph nodes, or small intestine. A total of 155 cases of metastatic melanoma to lymph node (N = 54) and non-lymph node (N = 101) sites were stained with an antibody against PRAME. Nuclear expression was scored in tumor cells as negative, 1% to 25% (1+), 26% to 50% (2+), 51% to 75% (3+), or 76% to 100% (4+). PRAME expression was seen in 151/155 (97.4%) cases, with 4+ expression in 64 cases (41.3%), 3+ expression in 46 cases (29.7%), 2+ expression in 18 cases (11.6%), and 1+ expression in 23 cases (14.8%). Lymph node metastases were more likely to show lower expression as compared to metastases to other anatomic sites (P = 0.003). A high level of PRAME immunoreactivity was identified in this cohort of metastatic melanoma. Lymph node metastases showed more focal or absent PRAME expression as compared to metastases to other sites. Overall, PRAME is a useful tool for confirming the diagnosis of melanoma in a metastatic setting, in both nodal and visceral deposits.

Genomic profiling of melanomas of unknown primary.

e21048 Background: Approximately 2-10% of metastatic melanoma patients present without an identifiable primary melanocytic lesion. These melanomas of unknown primary (MUP) are clinically classified into stage III or stage IV based upon extent of spread of metastatic disease. Previous studies, evaluating MUP using a limited sequencing of BRAF, NRAS, and KIT, have shown a similar frequency of mutations as cutaneous samples. Methods: We identified and performed retrospective chart review on 43 patients treated at the University of Colorado who presented with a melanoma of unknown primary. We excluded patient who presented with a preceding pigmented lesion treated with excision or cryotherapy without a histological diagnosis. After informed consent, DNA was extracted from the tumor samples of these 43 patients. Whole exome sequencing (WES) was performed with exome capture on an Illumina HiSeq sequencer. Results: Our cohort showed a male predominance at 58.1%. The median age at diagnosis was 50.6 years. In our cohort, 93% were Caucasian, while 4.7% were Hispanic and 2.3% were of unknown ethnic origin. 9.3% of patient had a family history of melanoma. Sun exposure was documented in 39.5% of patients and its presence was associated with an increased survival (Median OS of 3.7 vs 1.3 years, p = 0.026). Patients with stage III melanoma had an increased survival (Median OS of 6.8 vs 1.3 years, p = 0.013). Genomic analysis showed mutational pattern similar to cutaneous melanoma with 50% harboring a BRAF mutation, 12% with an NRAS mutation, and 19% carrying an NF1 variant. We found mutational signatures for each tumor and classified each against a larger cohort of cutaneous, mucosal and acral melanomas. Conclusions: We present the genomic data of a large cohort of MUP. The mutational profile of MUP is consistent with other cutaneous melanomas.

Adipophilin expression in cutaneous malignant melanoma.

The lipogenic pathway is upregulated in cancer cells, including melanomas. However, the pathological significance of cellular lipids in melanocytic lesions has yet to be determined. In this study, we evaluated intracytoplasmic lipid droplets in melanocytic nevi (MNs) and malignant melanomas via immunohistochemical analysis of adipophilin (ADP), which coats lipid droplets. One hundred primary cutaneous melanocytic lesions [33 MNs, 17 melanomas in situ (MIS), and 50 invasive melanomas (IMs)] were immunostained for ADP. The intensity score (IS) and proportion score (PS) of ADP staining in each case was recorded semiquantitatively on a scale of 0 to 3+. High ADP expression (IS2/3+ and PS2/3+) was observed in 27 primary cutaneous melanocytic lesions that consisted of 23 IMs, three MISs, and one MN. Consequently, high ADP expression was associated with malignancy (38.8% vs. 3.0%; p < 0.0001). Among the IMs, high ADP expression was more prevalent in pT3/4 than pT1/2 (63.3% vs. 23.8%; p = 0.01) and Stage 3/4 than Stage 1/2 (76.9% vs. 36.8%; p = 0.02). The majority of the melanocytic lesions with high ADP expression were malignant melanomas in our cohort. Therefore, ADP expression may serve as a sensitive diagnostic marker for malignant melanoma.

Mutation analysis of metastatic melanomas in the central nervous system: results of a panel of 5 genes in 48 cases.

Melanocytic lesions in the central nervous system (CNS) may be primary to the site but are more commonly metastases from cutaneous primaries. In fact, melanomas are one of the most common malignancies that can metastasize to the brain, and some patients may not have a diagnosis of melanoma prior to the discovery of the CNS lesion. In such cases, identifying the primary site may be challenging. We reviewed the archives of a large referral center for melanocytic tumors involving the CNS and selected 48 patients for this study based on our inclusion criteria. We used sequencing to identify mutation status of these tumors and compared these with clinicopathological features. Mutations in exon 9, 11, 13, 17, and 18 of KIT gene, exon 15 of BRAF gene, exon 2 and 3 of NRAS gene, exon 4 and 5 of GNAQ and GNA11 genes were analyzed. Mutations in BRAF-exon 15 were the most common among tumors (58.3%). NRAS-exon 2 and NRAS-exon 3 mutations were detected in 3 and 7 cases, respectively. GNAQ-exon 4, GNAQ-exon 5 and GNA11-exon 5 mutation were present in 1 tumor each. Eight tumors were wild type for all 5 genes, and 6 of these were not known primary despite a work-up and clinical follow-up. Only 1 of these tumors showed a mutation in exon 11 of KIT gene. When compared to primary melanocytic lesions of the CNS, metastatic melanomas were characterized by BRAF gene mutations and wild-type GNAQ and GNA11 genes.

OT-07 * PRIMARY CENTRAL NERVOUS SYSTEM MELANOCYTIC LESIONS IN CHILDHOOD: EXPERIENCE AT NATIONAL INSTITUTE OF PEDIATRICS IN MEXICO

INTRODUCTION: Primary central nervous system (CNS) melanocytic tumors are extremely uncommon in children. Annual incidence is 1 per 10 million population and carry a poor prognosis. Herein we present two cases treated at our institution, a leading pediatric oncology center in Mexico. METHODS: Our first patient was a 1 year-old female who began with non-convulsive status epilepticus and no fever history. Right frontoparietal leptomeningeal enhancement was evident on MRI, and a primary leptomeningeal melanoma was diagnosed according to biopsy. Radiotherapy did not improved her condition and further neurologic deterioration ensued. The second patient was a 6 year old male with a history of headache and vomiting, and left sided hemiparesis was evident at admission. MRI showed an ill-defined right temporal lobe lesion with mass effect and leptomeningeal involment. Immature cells were isolated on cerebrospinal fluid (CSF) and a primary malignant melanocytic lesion was diagnosed on brain biopsy. Later he developed refractory status epilepticus and died of septic shock. DISCUSSION: Although melanocytes are normally present in the nervous system, primary melanocytic tumors are extremely uncommon, being less than 0.1% of all CNS tumors in children. Three mayor variants are distinguished: diffuse melanocytosis, meningeal melanocytoma and malignant melanoma. Complete surgical resection is not always possible, while the efficacy of radiotherapy and chemotherapy remain controversial. CONCLUSION: Our experience shows that these lesions are extremely rare in our population and cannot be safely resected. Diagnosis is made by biopsy exclusively and neurologic deterioration eventually occurs despite radiotherapy.

Primary malignant melanoma of the pleura with rapid progression: A case report and literature review.

A primary melanocytic lesion arising from the pleura is a rare occurrence. This is the case report of a 36-year-old female patient with a primary pleural melanocytic tumor. The positron emission tomography/computed tomography scan revealed multiple nodular soft tissue thickenings of the left hemipleura and a large amount of pleural effusion in the left hemithorax. The results of the histological examination confirmed the diagnosis of melanoma. The disease progressed 4 months following immunotherapy and chemotherapy and the patient succumbed to the disease 2 months later. This type of tumor appears to exhibit a highly aggressive biological behavior and responds poorly to immunotherapy and chemotherapy, which are characteristics similar to those exhibited by melanomas arising in other regions.

Comparative cytogenetic characterization of primary canine melanocytic lesions using array CGH and fluorescence in situ hybridization

Comparative cytogenetic characterization of primary canine melanocytic lesions using array CGH and fluorescence in situ hybridization

Comparative cytogenetic characterization of primary canine melanocytic lesions using array CGH and fluorescence in situ hybridization.

Melanocytic lesions originating from the oral mucosa or cutaneous epithelium are common in the general dog population, with up to 100,000 diagnoses each year in the USA. Oral melanoma is the most frequent canine neoplasm of the oral cavity, exhibiting a highly aggressive course. Cutaneous melanocytomas occur frequently, but rarely develop into a malignant form. Despite the differential prognosis, it has been assumed that subtypes of melanocytic lesions represent the same disease. To address the relative paucity of information about their genomic status, molecular cytogenetic analysis was performed on the three recognized subtypes of canine melanocytic lesions. Using array comparative genomic hybridization (aCGH) analysis, highly aberrant distinct copy number status across the tumor genome for both of the malignant melanoma subtypes was revealed. The most frequent aberrations included gain of dog chromosome (CFA) 13 and 17 and loss of CFA 22. Melanocytomas possessed fewer genome wide aberrations, yet showed a recurrent gain of CFA 20q15.3-17. A distinctive copy number profile, evident only in oral melanomas, displayed a sigmoidal pattern of copy number loss followed immediately by a gain, around CFA 30q14. Moreover, when assessed by fluorescence in situ hybridization (FISH), copy number aberrations of targeted genes, such as gain of c-MYC (80% of cases) and loss of CDKN2A (68% of cases), were observed. This study suggests that in concordance with what is known for human melanomas, canine melanomas of the oral mucosa and cutaneous epithelium are discrete and initiated by different molecular pathways.

Primary Gastric Melanoma: Wait, I Thought the Stomach Did Not Have Any Melanocytes!

Introduction: We report a case of a patient who presented with abdominal pain and decreased ability to tolerate food, and was found to have melanoma in the gastric mucosa. We highlight the difficulty of diagnosing primary gastric melanoma with certainty, given its rarity and theoretical implausibility, as normal gastric epithelium lacks melanocytes. We also briefly review several pathophysiologic and embryologic hypotheses for this phenomenon. A 50-year-old Hispanic male presented to our clinic with epigastric pain and decreased ability to tolerate food. An EGD revealed a large, irregular ulcerated gastric mass extending 1.5 to 2 cm from the gastroesophageal junction to the antrum. The mass was biopsied, and immunohistochemical stains showed the tumor cells were positive for melan-A, HMB45 and vimentin, confirming melanoma. A thorough search for another possible primary lesion, consisting of a complete skin examination and positron emission tomography (PET), did not identify a clear primary site of melanoma. The PET scan revealed uptake involving the gastric walls and lymph nodes in the perigastric, retroperitoneal and left supraclavicular regions. BRAF analysis was positive for a V600 mutation. The patient subsequently underwent palliative jejunostomy placement and was evaluated by medical oncology. Primary gastric melanoma is extremely rare (with only a handful of cases reported in the literature), likely due to the lack of melanocytes in normal gastric epithelium. Therefore, when melanoma is encountered in the stomach, it is crucial to search for a primary melanocytic lesion that may have metastasized to the stomach. While gastrointestinal involvement by melanoma has been found in up to 60% of autopsies of patients who have died with primary cutaneous melanoma, melanoma located primarily in the gastric mucosa is an uncommon occurrence. Several pathophysiologic mechanisms have been suggested. Ectopic migration of melanocyte precursors or differentiation of the APUD cells to melanocytes have been suggested as possible mechanisms. Spontaneous regression of primary melanoma has also been recognized, and it is possible that our patient’s gastric melanoma may have represented a metastasis from primary lesion that had spontaneously regressed. The median overall survival for primary melanoma of the GI tract is 17 months; for primary melanoma of the stomach, 5 months. There is little consensus on therapy for patients with primary GI melanoma, but treatment with complete excision may provide long-term disease-free survival. Vemurafenib, a BRAF kinase inhibitor, has been shown to improve both overall and progression-free survival in patients with metastatic melanoma with the BRAF V600E mutation

Histopathological atlas and proposed classification for melanocytic lesions in Tyr::NRasQ61K; Cdkn2a−/− transgenic mice

Reference EPFL-ARTICLE-188431doi:10.1111/pcmr.12115View record in Web of Science Record created on 2013-09-09, modified on 2017-05-12

NEVOS RECORRENTES – UMA REVISÃO DE 5 ANOS

A persistência de uma lesão melanocítica, em local onde tenha sido previamente excisado um nevo me- lanocítico pode colocar, clínica e histologicamente, problemas no diagnóstico diferencial com melanoma, designado por alguns autores como ‘pseudomelanoma’. Neste estudo, os autores pretendem realizar uma análise comparativa entre os achados clínicos e histopatológicos das lesões melanocíticas primárias e dos nevos recorrentes. Procura-se também avaliar eventuais factores predisponentes para este fenómeno.PALAVRAS-CHAVE – Nevo recorrente; Pseudomelanoma; Melanoma; Regressão.

Primäre amelanotische meningeale Melanomatose

Primary melanocytic lesions of the central nervous system are rare. The spread of melanoma cells primarily into the meningeal layers is referred to as meningeal melanomatosis. A few case reports about either intracranial or intraspinal primary meningeal melanoma were published in the past. The amelanotic variation of primary melanoma in the central nervous system is a very rare event and so far no cases of primary amelanotic meningeal melanomatosis have been described in the current literature. We present a case with combined multiple intracranial and intraspinal primary malignant amelanotic melanomas.

P-REX1, a Rac guanine exchange factor, links melanocyte development and melanoma progression

P-REX1, a Rac guanine exchange factor, links melanocyte development and melanoma progression

Leptomeningeal melanocytosis in an adult male without large congenital nevi: a rare and atypical case of neurocutaneous melanosis

Leptomeningeal melanocytosis is a primary melanocytic lesion of the central nervous system that is characterized by diffuse melanocytic infiltration of the leptomeninges. It is seen almost exclusively in children with large congenital nevi and together the findings form a dermatologic syndrome known as neurocutaneous melanosis. We report a rare and atypical case of a 31-year-old adult male with no evident congenital melanocytic lesions who presented with neurologic symptoms and was found to have leptomeningeal melanocytosis. The brain biopsy demonstrated a conspicuous but benign-appearing melanocytic infiltrate that was discordant with the severity of the patient's symptoms. Ultimately, the patient was suspected to represent a case of former fruste neurocutaneous melanosis. Herein the relevant clinical and histopathologic features are discussed along with a brief review of the literature.

Improved discrimination of melanotic schwannoma from melanocytic lesions by combined morphological and GNAQ mutational analysis

The histological differential diagnosis between melanotic schwannoma, primary leptomeningeal melanocytic lesions and cellular blue nevus can be challenging. Correct diagnosis of melanotic schwannoma is important to select patients who need clinical evaluation for possible association with Carney complex. Recently, we described the presence of activating codon 209 mutations in the GNAQ gene in primary leptomeningeal melanocytic lesions. Identical codon 209 mutations have been described in blue nevi. The aims of the present study were to (1) perform a histological review of a series of lesions (initially) diagnosed as melanotic schwannoma and analyze them for GNAQ mutations, and (2) test the diagnostic value of GNAQ mutational analysis in the differential diagnosis with leptomeningeal melanocytic lesions. We retrieved 25 cases that were initially diagnosed as melanotic schwannoma. All cases were reviewed using established criteria and analyzed for GNAQ codon 209 mutations. After review, nine cases were classified as melanotic schwannoma. GNAQ mutations were absent in these nine cases. The remaining cases were reclassified as conventional schwannoma (n = 9), melanocytoma (n = 4), blue nevus (n = 1) and lesions that could not be classified with certainty as melanotic schwannoma or melanocytoma (n = 2). GNAQ codon 209 mutations were present in 3/4 melanocytomas and the blue nevus. Including results from our previous study in leptomeningeal melanocytic lesions, GNAQ mutations were highly specific (100%) for leptomeningeal melanocytic lesions compared to melanotic schwannoma (sensitivity 43%). We conclude that a detailed analysis of morphology combined with GNAQ mutational analysis can aid in the differential diagnosis of melanotic schwannoma with leptomeningeal melanocytic lesions.

Targeting X-Linked Inhibitor of Apoptosis Protein to Increase the Efficacy of Endoplasmic Reticulum Stress-Induced Apoptosis for Melanoma Therapy

Melanoma remains notoriously resistant to current chemotherapeutics, leaving an acute need for novel therapeutic approaches. The aim of this study was to determine the prognostic and therapeutic significance of X-linked inhibitor of apoptosis protein (XIAP) in melanoma through correlation of XIAP expression with disease stage, RAS/RAF mutational status, clinical outcome, and susceptibility to endoplasmic reticulum (ER) stress-induced cell death. XIAP expression and N-RAS/B-RAF mutational status were retrospectively determined in a cohort of 55 primary cutaneous melanocytic lesions selected and grouped according to the American Joint Committee on Cancer staging system. Short hairpin RNA interference of XIAP was used to analyze the effect of XIAP expression on ER stress-induced apoptosis in response to fenretinide or bortezomib in vitro. The results showed that XIAP positivity increased with progressive disease stage, although there was no significant correlation between XIAP positivity and combined N-RAS/B-RAF mutational status or clinical outcome. However, XIAP knockdown significantly increased ER stress-induced apoptosis of melanoma cells in a caspase-dependant manner. The correlation of XIAP expression with disease stage, as well as data showing that XIAP knockdown significantly increases fenretinide and bortezomib-induced apoptosis of metastatic melanoma cells, suggests that XIAP may prove to be an effective therapeutic target for melanoma therapy.

The diagnostic dilemma of primary central nervous system melanoma

Melanomas are malignant neoplasms of melanocytes developing predominantly in the skin, but occasionally arising from eyes, mucous membranes, and the central nervous system (CNS). The CNS can be affected by a spectrum of melanocytic lesions ranging from diffuse neurocutaneous melanosis, to a focal and benign neoplasm (melanocytoma), and to an overtly malignant tumor (melanoma). Primary melanocytic lesions involving the CNS are typically concentrated in the perimedullary and high cervical region. Primary CNS melanoma cannot be reliably distinguished from metastatic melanoma on neuroimaging and histopathological characteristics alone: its diagnosis is established only after exclusion of secondary metastatic disease from a cutaneous, mucosal or retinal primary. We present two patients with primary CNS melanoma and discuss relevant issues, available treatment options, and expected outcomes. Awareness of disease spectrum and clinico-biological differences may be used to guide therapeutic decision-making for a patient with a proven or suspected primary CNS melanoma.