Malignant Melanoma of the Oral Cavity: An Aggressive and Rare Entity.

It is exceptionally unusual to see oral malignant melanoma, which is highly aggressive with dismal prognosis. A 61-year-old female patient presented with hyperpigmented and hemorrhagic areas in the anterior mandible. Microscopically, positive Immunohistochemistry staining with monoclonal antibody Human Melanoma Black (HMB45) and S100 protein, confirmed the diagnosis as malignant melanoma.

Establishment and Validation of Prognostic Nomograms for Nonmetastatic Melanoma of the Limbs-A SEER-Based Study.

BACKGROUND: Malignant melanoma, a highly aggressive skin cancer, has remarkable incidence and mortality nowadays. This study aims to explore prognostic factors associated with nonmetastatic cutaneous melanoma of the limbs and to develop nomograms for predicting overall survival (OS) and cancer-specific survival (CSS). METHODS: The study cohort was derived from the Surveillance, Epidemiology, and End Results database. Univariate Cox regression, Lasso regression, and multivariate Cox regression analyses were conducted to identify prognostic factors and construct nomograms. The receiver operating characteristic (ROC) curve, time-dependent C-index, calibration curve, decision curve analysis (DCA) and Kaplan-Meier method were used to evaluate the accuracy and clinical applicability of the nomograms. RESULTS: A total of 15,606 patients were enrolled. Multivariate analysis identified several prognostic factors for OS and CSS including age, sex, histologic type, N stage, tumor thickness, depth of invasion, mitotic rate, ulceration, surgery of primary site, systemic therapy, race, and number of lymph nodes examined. A nomogram incorporating 12 independent predictors for OS was developed, with a C-index of 0.866 (95% confidence interval [CI]: 0.858-0.874) in the training cohort and 0.853 (95% CI: 0.839-0.867) in validation. For CSS, 10 independent predictors and one related factor were included, yielding a C-index of 0.913 (95% CI: 0.903-0.923) in the training cohort and 0.922 (95% CI: 0.908-0.936) in validation. The ROC curve, time-dependent C-index, calibration curve, DCA, and K-M plot demonstrated favorable discrimination, calibration, and clinical utility. CONCLUSION: The developed nomograms provide a precise and personalized predictive tool for risk management of patients with nonmetastatic limb melanoma.

Glut-1-Negative Choroidal Malignant Melanoma with Liver Metastasis Recurrence 12 Years after Surgery without FDG Accumulation in a Recurrent Lesion on FDG-PET/CT: a Case Report.

Choroidal malignant melanoma is a rare malignant tumor that develops in adult eyeballs. It causes early lymph node and distant metastasis. Fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (CT) is widely used for screening malignant melanoma metastases. We encountered a 58-year-old man with choroidal malignant melanoma in whom liver metastasis recurred 12 years after surgery, without any observable FDG accumulation. Immunostaining revealed the absence of glucose transporter type 1 (GLUT-1) expression, crucial for intracellular FDG uptake. The lack of FDG accumulation in the lesion could be attributed to the diminished cellular FDG uptake due to the absence of GLUT-1 expression.

Trends in Melanoma Mortality in Serbia: A 22-Year Population-Based Study.

Background: We aimed to investigating the sex-specific and age-specific melanoma mortality trends observed on the territory of Serbia between 2000 and 2021. Methods: This population-based study used data from the Statistical Office of the Republic of Serbia database during the period 2000-2021. The calculation of the gender and age-standardized rates (ASR) was performed. We used a regression analysis complete with linear trend model. Results: The mean ASR was 1.77 per 100,000 people, meaning that male mortality rates (2.24 per 100,000) was higher than female mortality rates (1.34 per 100,000). During the observation period, a rising trend in mortality from melanoma skin cancer was reported. Observed by gender, the change of melanoma mortality trend was significant in men (P=0.021), but not in women (P=0.747). The annual growth rate of ASRs values was 1.43%. A increase in the melanoma mortality rate was observed since 2000 by 2.44% annually in males and by 2.79% annually in females. Mortality rates were increasing in both sexes as they aged, and the greatest number of deaths was recorded in the group of those aged 80 yr or above (16.25 per 100,000 for men; 10.45 per 100,000 for women). Conclusion: Our study findings underline the importance of launching more effective public health awareness campaigns to educate people about the dangers of melanoma and its symptoms' detection along with establishing a diagnosis at an early stage of the disease, especially among male patients and those at an advanced age.

Malignant Melanoma in the Groin Masquerading as a Vascular Tumour: A Rare Cytodiagnosis.

Malignant melanoma (MM) is an aggressive cutaneous neoplasm tending to metastasise anywhere within the body. It frequently metastasises to the draining lymph nodes. A distinct presentation of MM occurs when metastatic lesions appear in the regional lymph nodes, while the primary tumour remains clinically undetected. Fine needle aspiration cytology (FNAC) is highly sensitive, rapid, and cost-effective. The utility of the FNAC procedure is well established in the patient's diagnostic workup. However, the Indian data on the cytodiagnosis and cytomorphology of metastatic MM are very scarce. We submit a clinicopathological profile of a rare case in a 68-year-old male, where FNAC from an inguinal mass led to the diagnosis of metastatic MM, which mimicked clinically as a vascular tumour. The present case highlights MM's unusual clinical presentation and cytomorphological details through FNAC.

Role of spexin and DARS2 as potential biomarkers in basal cell carcinoma and cutaneous malignant melanoma diagnosis, and as therapeutic targets.

Basal cell carcinoma (BCC) is a slowly progressive, locally aggressive and rarely metastasizing cancer, and although its mortality is low, its morbidity and cost of disease are high. While BCC is more common, cutaneous malignant melanoma (CMM) is significant due to its higher mortality rate. These patients can be treated, but recurrence, metastasis and mortality may occur in such patients. Various environmental, phenotypic and genotypic factors, especially ultraviolet (UV) radiations, play a role in the etiology of BCC and CMM. Histopathological examination continues to be the "gold standard" in their diagnosis. Spexin (SPX) and DARS2 are newly discovered proteins linked to many diseases, including cancer. These proteins may have an effect on the development and expression of skin cancers such as BCC and CMM. In this study, we evaluated the potential of SPX and DARS2 expressions as immunohistochemical biomarkers in the differential diagnosis of BCC and CMM. This study was conducted retrospectively using samples taken from the pathology laboratory. A total of 180 patient samples were used. The control group consisted of healthy skin tissues of the patients, and the other groups consisted of BCC and CMM tissues of the same patients. Tissue samples of all three groups were evaluated immunohistochemically with SPX and DARS2. The immunoreactivity of SPX was found to be higher in BCC and CMM tissue samples than in healthy skin tissues in the control group. DARS2 immunoreactivity was found to be higher in CMM tissues compared to the other two groups, and statistically significant in BCC tissues when compared with healthy control group tissues. SPX can be used as an immunohistochemical biomarker in the diagnosis of BCC and CMM. Since DARS2 expression is statistically more significant in CMM tissues than in BCC tissues, it can be used in differential diagnosis.

Immune Checkpoint Inhibitors and Endocrine Disruption: A Case of Hyponatremia and Adrenal Insufficiency.

Immune checkpoint inhibitors, such as pembrolizumab, have transformed cancer therapy by enhancing the immune system's ability to combat tumors, but they can also lead to immune-related adverse events, including adrenal insufficiency. This case report presents a 52-year-old male with a history of malignant melanoma who developed adrenal insufficiency after four months of pembrolizumab therapy. The patient was admitted with symptoms of malaise, vomiting, abdominal pain, and poor appetite. Laboratory tests revealed significant metabolic abnormalities including hyponatremia, hypokalemia, and elevated thyroid-stimulating hormone. Further endocrine evaluation confirmed the diagnosis of secondary adrenal insufficiency, likely due to pembrolizumab-induced inflammation of the pituitary gland. The patient was treated with corticosteroid replacement therapy, leading to clinical improvement, and pembrolizumab was discontinued due to the risk of worsening adrenal insufficiency. This case underscores the importance of early recognition and management of adrenal insufficiency in patients receiving pembrolizumab. While the exact cause of pembrolizumab-induced adrenal insufficiency is not fully understood, it may involve an autoimmune attack on cells in the pituitary gland. Prompt identification and treatment are essential to prevent potentially life-threatening complications, and this case highlights the need for clinicians to maintain a high level of awareness for adrenal insufficiency in patients presenting with nonspecific symptoms during or after immunotherapy.

Primary Anorectal Mucosal Melanoma: A Unique Presentation of Mucosal Melanomas.

Anorectal mucosal melanoma (AMM) is a rare and highly aggressive malignancy. It frequently presents with nonspecific symptoms, often resulting in delayed diagnosis and poor prognosis. This report describes the case of a 60-year-old male who presented with a painful para-anal papule that progressed to a fistula. Histopathological and immunohistochemical analyses confirmed AMM. Imaging revealed a locally advanced tumor without distant metastasis. Due to the locally advanced nature of the disease, a multidisciplinary team recommended neoadjuvant radiotherapy. This case highlights the diagnostic and therapeutic challenges associated with AMM and emphasizes the importance of a tailored, multidisciplinary approach. Surgical resection remains the cornerstone of treatment, with neoadjuvant therapy potentially improving surgical outcomes in advanced cases.

Modeling tumor-immune interactions using hybrid spheroids and microfluidic platforms for studying tumor-associated macrophage polarization in melanoma.

Tumor-associated macrophages (TAMs), as key components of tumor microenvironment (TME), exhibit phenotypic plasticity in response to environmental cues, causing polarization into either pro-inflammatory M1 phenotypes or immunosuppressive M2 phenotypes. Although TAM has been widely studied for its crucial involvement in the initiation, progression, metastasis, and immune regulation of cancer cells, there have been limited attempts to understand how the metastatic potentials of cancer cells influence TAM polarization within TME. Here, we developed a miniaturized TME model using a 3D hybrid system composed of murine melanoma cells and macrophages, aiming to investigate interactions between cancer cells exhibiting various metastatic potentials and macrophages within TME. The increase in spheroid size within this model was associated with a reduction in cancer cell viability. Examining macrophage surface marker expression and cytokine secretion indicated the development of diverse TMEs influenced by both spheroid size and the metastatic potential of cancer cells. Furthermore, a high-throughput microfluidic platform equipped with trapping systems and hybrid spheroids was employed to simulate the tumor-immune system of complex TMEs and for comparative analysis with traditional 3D culture models. This study provides insight into TAM polarization in melanoma with different heterogeneities by modeling cancer-immune systems, which can be potentially employed for immune-oncology research, drug-screening, and personalized-therapy. STATEMENT OF SIGNIFICANCE: This study presents the development of a 3D hybrid spheroid system designed to model tumor-immune interactions, providing a detailed analysis of how melanoma cell metastatic potential influences tumor-associated macrophage (TAM) polarization. By utilizing a microfluidic platform, we are able to replicate and investigate the complex tumor-immune system of the tumor microenvironments (TMEs) under continuous flow conditions. Our model holds significant potential for high-throughput drug screening and personalized medicine applications, offering a versatile tool for advancing cancer research and treatment strategies.

An uncommon case of anorectal malignant melanoma (ARMM): Clinical presentation and surgical outcome.

INTRODUCTION AND IMPORTANCE: Anorectal mucosal melanoma (ARMM) is a rare disease with a poor prognosis. However, surgery is often difficult, due to the lentiginous growth pattern of such melanoma. CASE PRESENTATION: A 61 years old lady presented with anal pain for 1 year, associated with painless fresh per rectal bleeding post defecation and altered bowel habit. Physical examination showed hyperpigmentation at the anal verge, extending to the dentate line. CT, MRI and PET imaging showed localised disease. She underwent pelvic exanteration and radical lymph node dissection with gracilis flap coverage. Post operatively, she recovers well, and was discharged well on day 8. HPE came back as malignant melanoma, with 1 out 12 lymph nodes involved. She was subsequently referred to oncology, started on pembrolizumab immunotherapy. CLINICAL DISCUSSION: Anorectal melanoma is an aggressive disease, often present with delayed diagnosis. Multiple imaging has been proposed, however none is standardized to diagnose ARMM. Immunohistochemical stains such as S-100 protein, MelanA and tyrosinase and with HMB-45 help in diagnosis and are sensitive for melanocytic differentiation. Surgery excision remains the most common and superior initial treatment for ARMM. One retrospective study done to compare different treatment modalities has shown that patients with surgical excision and radiation therapy had the highest median survival at 32.3 months but surgical excision remains the single best modality for ARMM. CONCLUSION: Suspicious hyperpigmentation at the anal region should raise clinical awareness. Surgical excision with optimal margin is indicated to achieve favourable symptom control, reduce local recurrence and improve survival rate.

Pannexin 1 crosstalk with the Hippo pathway in malignant melanoma.

In this study, we explored the intricate relationship between Pannexin 1 (PANX1) and the Hippo signaling pathway effector, Yes-associated protein (YAP). Analysis of The Cancer Genome Atlas (TCGA) data revealed a significant positive correlation between PANX1 mRNA and core Hippo components, YAP, TAZ, and Hippo scaffold, IQGAP1, in invasive cutaneous melanoma and breast carcinoma. Furthermore, we demonstrated that PANX1 expression is upregulated in invasive melanoma cell lines and is associated with increased YAP protein levels. Notably, our investigations uncovered a previously unrecognized interaction between endogenous PANX1 and the Hippo scaffold protein IQGAP1 in melanoma cells. Moreover, our findings revealed that IQGAP1 exhibits differential expression in melanoma cells and plays a regulatory role in cellular morphology. Functional studies involving PANX1 knockdown provided compelling evidence that PANX1 modulates YAP protein levels and its co-transcriptional activity in both melanoma and breast carcinoma cells. Importantly, our study showcases the potential therapeutic relevance of targeting PANX1, as pharmacological inhibition of PANX1 using selective FDA-approved inhibitors or PANX1 knockdown reduced YAP abundance in melanoma cells. Furthermore, our Clariom™ S analysis unveiled key genes implicated in cell proliferation, such as neuroglin1 (NRG1), ß-galactoside binding protein, galectin-3 (LGALS3), that are affected in PANX1-deficient cells. In summary, our investigation delves into the intricate interplay between PANX1 and YAP in the context of invasive melanoma, offering valuable insights into potential therapeutic strategies for effective treatment.

Primary nipple melanoma in a patient with breast cancer: A diagnosis to consider.

Melanoma in situ of the nipple is an uncommon diagnosis, with only a few reports in the literature. Due to the variety of pathologies that can affect the nipple-areola complex, the diagnosis can be challenging. In this case report we describe a patient with cosmetic bilateral breast implants who presented with eczema of the left nipple-areola complex and suspicious microcalcifications in the lower inner quadrant of the ipsilateral breast on mammography, subsequently diagnosed with nipple melanoma and concomitant ductal carcinoma in situ.

[Effects of the COVID-19 pandemic on inpatient dermatosurgery in Germany : Retrospective evaluation of the surgical cases from nine dermatology clinics]. / Auswirkungen der COVID-19-Pandemie auf die stationäre Dermatochirurgie in Deutschland : Retrospektive Auswertung der operativen Fälle aus neun Hautkliniken.

INTRODUCTION: Currently, only little data is available on the impact of the COVID-19 pandemic on inpatient dermatosurgical care in German dermatological clinics. METHODS: A retrospective analysis of all dermatosurgical cases that were treated in inpatient setting in nine German dermatological clinics in four federal states in 2019, 2020 and 2021 was performed. The diagnoses were recorded using the ICD-10 codes. In addition, demographic data such as age, gender and the length of inpatient stay were analysed. RESULTS: In 2019, 2020 and 2021, a total of 10,739, 9185 and 9828 dermatosurgical inpatients were treated respectively. Thus, the reduction of inpatient dermatosurgical cases was 14.5% in 2020 and 8.5% in 2021 compared to 2019. Inpatient surgical treatment of melanoma decreased by 10.1% of cases in 2020. This decrease was only 1.4% in 2021 compared to 2019. The number of inpatient surgeries performed for benign lesions such as melanocytic nevi or viral warts reduced sharply in both pandemic years. CONCLUSION: Our data show for the first time how inpatient care for the entire spectrum of dermatosurgical diseases developed during the COVID-19 pandemic in Germany. After the initial marked decline in inpatient dermatosurgical cases in 2020, there was less difference in 2021 compared to 2019. This trend can be interpreted as an indication that there is still a strong need for inpatient dermatosurgical care that cannot yet be met on an outpatient basis.

Thermosensitive hyaluronic acid-manganese-capsaicin complex nanogel improving NKG2D/CAR-T melanoma treatment through adjusting tumor microenvironment.

Intratumorally injection of CAR-T cells to treat melanoma can reduce the incidence of systemic side effects and ensure an adequate concentration of CAR-T cells. However, few targeting ligands and hostile tumor microenvironment (TME) inhibit the CAR-T cells' survival and infiltration. An in situ hyaluronic acid­manganese-capsaicin complex nanogel (HA-Mn-CAP Gel) was designed by forming complex nanogel based on the main skeleton material of hyaluronic acid (HA). It targeted CD44 and TRPV1 receptors through HA and CAP, concentrated and released Mn at melanoma, subsequently relieving the hypoxia in the tumor and increasing the expression of CAR-T cells' specific ligands. Cell experiments showed that HA-Mn-CAP Gel significantly enhanced the expression of representative NKG2D ligands (MICA/B and ULBP2/5/6) >2.7 times on A375 melanoma cells. Sequential administration of HA-Mn-CAP Gel and NKG2D/CAR-T increased the tumor inhibition rate about 1.5 times that of the NKG2D/CAR-T group in melanoma-bearing NSG mice. The results of immunohistochemistry and immunofluorescence assays showed that the combined HA-Mn-CAP Gel and NKG2D/CAR-T significantly increased the proliferation and infiltration of T cells, especially for CD8+ cells. Therefore, the new promising strategy of increasing the target ligand expression and adjusting TME before administering CAR-T cells is suitable for treating solid tumors.

The Expression of miR-211-5p in Sentinel Lymph Node Metastases of Malignant Melanoma Is a Potential Marker for Poor Prognosis.

Metastatic primary cutaneous melanoma is a frequently fatal disease despite recent therapeutic advances. Biomarkers to stratify patients' prognosis are lacking. MicroRNAs (miRNAs) are small, non-coding RNAs. We aimed to determine the expression of miR-211-5p in primary tumors and metastases of malignant melanoma and its potential use as a prognostic biomarker. We performed in situ hybridization for miRNA-211-5p on 109 FFPE melanoma samples from 76 patients, including 31 paired primary tumor/metastasis samples. For validation, we performed in silico analyses of TCGA skin cutaneous melanoma (SKCM) cohort. High miR-211-5p expression was more frequent in primary tumors (70.8%) compared to metastases (39.3%). In metastases, it was associated with a significantly worse overall survival. Data from TCGA SKCM cohort confirmed that high miR-211-5p expression in melanoma metastases, but not primary tumors, is associated with worse overall survival. MiR-211-5p expression in metastases is associated with a shorter survival, emphasizing the potential of miR-211-5p as a risk predictor for a less favorable clinical outcome in metastatic disease. In situ hybridization could be implemented in a routine laboratory workflow and can be performed on diagnostic tissue.

Recurrent melanoma 25 years after initial diagnosis, presenting as metastatic disease early after heart transplantation.

BACKGROUND: Cancer survivors (CS) comprise a particularly high-risk group for both de-novo and recurrent malignancies after solid organ transplantation. CASE PRESENTATION: We report a case of relapsed melanoma, presented as metastatic disease seven months after heart transplantation in a patient who had an early-stage melanoma resected 25 years prior. Treatment with a combination of dabrafenib, a BRAF inhibitor, and trametinib, a mitogen-activated protein kinase (MEK) inhibitor resulted in a near-complete metabolic response, without major adverse effects. CONCLUSION: This case demonstrates the increased risk of recurrence in CS with melanoma, which can persist decades after cancer diagnosis. These patients may be amenable to treatment using modern treatment modalities in oncology.

Genetically predicted metabolites mediate the association between lipidome and malignant melanoma of skin.

Objective: To investigate the causal relationship between lipidome and malignant melanoma of skin (MMOS), while identifying and quantifying the role of metabolites as potential mediators. Methods: A two-sample Mendelian randomization (MR) analysis of lipid species (n=7174) and MMOS was performed using pooled data from genome-wide association studies (GWAS). In addition, we quantified the proportion of metabolite-mediated lipidome effects on MMOS by two-step MR. Results: This study identified potential causal relationships between 11 lipids and MMOS, and 40 metabolites and MMOS, respectively. Phosphatidylethanolamine (18:0_18:2) levels mined from 179 lipids by MR Analysis increased the risk of MMOS (OR: 1.962; 95%CI:1.298,2.964; P=0.001). There is no strong evidence for a relationship between genetically predicted MMOS and phosphatidylethanolamine (18:0_18:2) levels (P=0.628). The proportion of gene predictions for phosphatidylethanolamine (18:0_18:2) levels mediated by 1-stearoyl-(glycosylphosphatidylinositol) GPI (18:0) levels was 12.40%. Conclusion: This study identifies 1-stearoyl-GPI (18:0) levels as a potential mediator that may mediate the causal relationship between phosphatidylethanolamine (18:0_18:2) levels and MMOS, This provides direction for the investigation of MMOS, but further research of other possible potential mediators is still needed.

Tumor lysis syndrome signal with the combination of encorafenib and binimetinib for malignant melanoma: a pharmacovigilance study using data from the FAERS database.

Objective: To investigate the potential association between tumor lysis syndrome (TLS) and drugs for the treatment of malignant melanoma (MM). Methods: Reports of TLS recorded in the FDA Adverse Event Reporting System (FAERS) (January 2004-2023q3) were identified. Demographic and clinical characteristics were described, and disproportionality signals were assessed through the Reporting Odds Ratio (ROR) and Information Component (IC). The latency of TLS with anticancer drugs was described based on parametric models. Subgroup analysis was conducted to explore the differences of TLS signals in different age and sex. Results: We found 5 (1.49%), 59 (17.61%), 79 (23.58%), 19 (5.67%), 13 (3.88%), 13 (3.88%), 33 (9.85%), 49 (14.63%), 16 (4.78%) TLS reports with pembrolizumab, nivolumab, ipilimumab, dabrafenib, vemurafenib, dacarbazine, "encorafenib and binimetinib", "nivolumab and ipilimumab", "dabrafenib and trametinib", respectively. The combination of encorafenib and binimetinib showed the strongest signal of TLS (IC025 = 3.98). The median days of latency of TLS with combination of encorafenib and binimetinib is 2 days, which was much shorter than nivolumab (22.0 days) and ipilimumab (21.5 days). TLS cases associated with drugs for MM were predominantly recorded in females and aged 25-65 years. After excluding confounding factors such as pre-existing diseases and co-treated drugs, the disproportionate signal of TLS with "encorafenib and binimetinib" remained strong. Conclusions: Stronger disproportionate signal of TLS was detected in MM patients using the combination of encorafenib and binimetinib than other drugs. Further research is needed to investigate the underlying mechanisms and identify patient-related predisposing factors to support safe prescribing of the combination of encorafenib and binimetinib.

A Unique Case of High-Grade Dedifferentiated Melanoma Without a Known Primary Site.

Melanoma is a malignant neoplasm that arises in melanocytes, pigment-producing cells present primarily in the skin. However, not all malignant melanomas originate from the skin, and the other sites of origin include the uveal (eye) or mucosa (rectal or oral); it can have different patterns of mutations. While targeted therapies and immunotherapies have transformed the treatment of this disease in the metastatic setting, resistance mechanisms can still pose challenges for patients and their healthcare providers. We present a case of a male patient with metastatic melanoma and discuss its clinical presentation, diagnostic workup, treatment options, and outcomes. By exploring the complexities of this multifaceted disease process, clinicians and researchers can gain valuable insights into potential areas for improved management strategies. Ultimately, we should aim to deepen our understanding of melanoma and work towards better patient outcomes.

Amelanotic Malignant Melanoma With Atypical Divergent Neuroendocrine Differentiation: A Report of an Unusual and Rare Case of Anorectal Bleeding.

Melanocytes located between the anal transition zone and the dentate line of the anal canal can give rise to the uncommon malignant tumor known as anal melanoma. It has a fast-paced clinical course and can masquerade as several common anorectal symptoms, such as hemorrhoids or rectal ulcers. In melanoma, divergent differentiation is a very uncommon phenomenon. The diagnosis of melanoma is difficult with histopathology sections alone (hematoxylin and eosin, H&E). Special stains and ancillary immunohistochemistry investigations are useful in these situations. A 60-year-old female patient presented to the surgical outpatient department with complaints of anorectal bleeding. After clinical evaluation, a growth in the anorectal region was identified, and a biopsy was taken from the growth. Histopathological and subsequent immunohistochemical analysis of the biopsy material was done at the Department of Pathology. A diagnosis of amelanotic melanoma with atypical and divergent neuroendocrine differentiation involving the anorectal region was rendered. Histologically, this tumor showed extremely pleomorphic polygonal to elongated spindle cells that co-expressed neuroendocrine markers and were positive for S100, HMB-45, and Melan-A. This case presented many diagnostic challenges at both the histomorphological level and the immunohistochemical expression profile analysis. We will go into great depth regarding the diagnostic challenges in this instance and provide an outline of our approach. The immunohistochemical and prognostic importance of this case will also be covered.