Undifferentiated Melanoma Research Articles

A Comparative Genomic Study of Conventional and Undifferentiated Melanoma

Undifferentiated melanoma, defined as melanoma that has lost all usual phenotypic and immunohistochemical characteristics of conventional melanoma, can pose significant diagnostic challenges. Molecular studies have advanced our understanding of undifferentiated melanoma by demonstrating that a subset of these tumors harbors known melanoma driver alterations in genes such as BRAF, NRAS, and NF1. However, there is a paucity of data describing genetic alterations that may distinguish undifferentiated melanoma from conventional melanoma. In this study, we directly compared the genomic profiles of undifferentiated melanoma to a cohort of conventional melanomas, including 14 undifferentiated melanoma cases (comprised of 2 primary cases, 2 cutaneous recurrences, and 10 metastases) and a cohort of 127 conventional melanomas including primary, recurrent, and metastatic cases. Targeted sequencing of 447 cancer-associated genes was performed, including identification of mutations and copy number alterations. NRAS was the most frequent melanoma driver in undifferentiated melanoma (8/14 cases, 57%), although notably, only 1 undifferentiated melanoma harbored an NRAS Q61R mutation. Compared with the conventional melanoma cohort, undifferentiated melanoma demonstrated statistically significant enrichment of pathogenic activating RAC1 mutations (6/14 total cases, 43%), including P29S (4/6 cases), P29L (1/6 cases), and D11E (1/6 cases). In addition to providing insight into the molecular pathogenesis of undifferentiated melanoma, these findings also suggest that RAS Q61R immunohistochemistry may have limited utility for its diagnosis. The presence of recurrent RAC1 mutations in undifferentiated melanoma is also to be noted as these alterations may contribute to mitogen-activated protein kinase pathway–targeted therapy resistance. Furthermore, the RAC1 alterations identified in this cohort have been shown to drive a melanocytic to mesenchymal switch in melanocytes, offering a possible explanation for the undifferentiated phenotype of these melanomas.

Single-cell RNA sequencing reveals melanoma cell state-dependent heterogeneity of response to MAPK inhibitors

Melanoma is a heterogeneous cancer influenced by the plasticity of melanoma cells and their dynamic adaptations to microenvironmental cues. Melanoma cells transition between well-defined transcriptional cell states that impact treatment response and resistance. In this study, we applied single-cell RNA sequencing to interrogate the molecular features of immunotherapy-naive and immunotherapy-resistant melanoma tumours in response to exvivo BRAF/MEK inhibitor treatment. We confirm the presence of four distinct melanoma cell states - melanocytic, transitory, neural-crest like and undifferentiated, and identify enrichment of neural crest-like and undifferentiated melanoma cells in immunotherapy-resistant tumours. Furthermore, we introduce an integrated computational approach to identify subsets of responding and nonresponding melanoma cells within the transcriptional cell states. Nonresponding melanoma cells are identified in all transcriptional cell states and are predisposed to BRAF/MEK inhibitor resistance due to pro-inflammatory IL6 and TNFɑ signalling. Our study provides a framework to study treatment response within distinct melanoma cell states and indicate that tumour-intrinsic pro-inflammatory signalling contributes to BRAF/MEK inhibitor resistance. This work was supported by Macquarie University, Melanoma Institute Australia, and the National Health and Medical Research Council of Australia (NHMRC; grant 2012860, 2028055).

Assessment of The Utility of The Sarcoma DNA Methylation Classifier In Surgical Pathology.

Diagnostic classification of soft tissue tumors is based on histology, immunohistochemistry, genetic findings, and radiologic and clinical correlations. Recently, a sarcoma DNA methylation classifier was developed, covering 62 soft tissue and bone tumor entities. The classifier is based on large-scale analysis of methylation sites across the genome. It includes DNA copy number analysis and determines O 6 methylguanine DNA methyl-transferase methylation status. In this study, we evaluated 619 well-studied soft tissue and bone tumors with the sarcoma classifier. Problem cases and typical examples of different entities were included. The classifier had high sensitivity and specificity for fusion sarcomas: Ewing, synovial, CIC -rearranged, and BCOR -rearranged. It also performed well for leiomyosarcoma, malignant peripheral nerve sheath tumors (MPNST), and malignant vascular tumors. There was low sensitivity for diagnoses of desmoid fibromatosis, neurofibroma, and schwannoma. Low specificity of matches was observed for angiomatoid fibrous histiocytoma, inflammatory myofibroblastic tumor, Langerhans histiocytosis, schwannoma, undifferentiated sarcoma, and well-differentiated/dedifferentiated liposarcoma. Diagnosis of lipomatous tumors was greatly assisted by the detection of MDM2 amplification and RB1 loss in the copy plot. The classifier helped to establish diagnoses for KIT-negative gastrointestinal stromal tumors, MPNSTs with unusual immunophenotypes, and undifferentiated melanomas. O 6 methylguanine DNA methyl-transferase methylation was infrequent and most common in melanomas (35%), MPNSTs (11%), and undifferentiated sarcomas (11%). The Sarcoma Methylation Classifier will likely evolve with the addition of new entities and refinement of the present methylation classes. The classifier may also help to define new entities and give new insight into the interrelationships of sarcomas.

PRAME Expression Is a Useful Tool in the Diagnosis of Primary and Metastatic Dedifferentiated and Undifferentiated Melanoma.

Although mostly recognized in the metastatic setting dedifferentiated and undifferentiated melanomas are increasingly recognized as cutaneous and, less commonly, mucosal primary tumors. Their diagnosis is challenging and dependent on sampling and recognition of a conventional melanoma precursor and/or detection of a mutation in a conventional melanoma driver gene. PRAME immunohistochemistry has recently become an important ancillary tool in the separation of melanoma from benign nevi, but no comprehensive studies exist regarding its value in the detection of dedifferentiated and undifferentiated melanomas and their separation from atypical fibroxanthoma and pleomorphic dermal sarcoma, the main differential diagnoses on sun-damaged skin. After retrieval from archival files, we performed PRAME immunohistochemistry on 11 primary and 10 metastatic dedifferentiated and undifferentiated melanomas, 11 atypical fibroxanthomas, and 10 pleomorphic dermal sarcomas. Nuclear staining was assigned extent (ranging from 0 to 4 and reflecting the percentage of PRAME-positive tumor nuclei) and intensity scores (graded as absent, weak, moderate, and strong, with assigned scores ranging from 0 to 3) with combined scores ranging from 0 to 7. Both primary and metastatic dedifferentiated and undifferentiated melanomas showed strong and diffuse nuclear PRAME staining with median combined scores of 7. Strong and diffuse staining was also seen in all conventional melanoma precursors except for desmoplastic melanoma. In contrast, PRAME staining in atypical fibroxanthoma and pleomorphic dermal sarcoma was patchy and weak with median combined scores of 2. Our data emphasize the diagnostic utility of PRAME staining as a first screening tool in the detection and workup of dedifferentiated and undifferentiated melanomas, both in the primary and metastatic settings. PRAME immunohistochemistry is particularly helpful as it is also positive in tumors without a recognizable conventional melanoma precursor and in those associated with desmoplastic melanomas, where PRAME is typically found to be negative.

Single cell profiling of tumour biopsies and heterogeneity in response of dedifferentiated melanoma.

64 Background: Patients with advanced BRAFV600-mutant melanoma can be treated with immune checkpoint inhibitors or combination BRAF/MEK inhibitors. The sequence of these therapies can influence response to second-line treatment. Patients who progress on first-line PD1 blockade have poorer outcomes on BRAF/MEK inhibitors compared to patients who are treatment-naïve. Thus, defining the molecular features that are modified by therapy and that influence subsequent treatment responses require thorough characterization. Methods: In this study, tumor biopsies from five BRAF-mutant melanoma patients progressing on anti-PD1 (PROG) and five BRAF-mutant treatment-naïve (NAÏVE) patients were dissociated and treated ex vivo with BRAF/MEK inhibitors (dabrafenib+trametinib (DT)) before flow cytometry profiling and single cell transcriptome sequencing. Results: DT treatment did not alter tumor or immune cell proportions but effectively inhibited MAPK signaling by decreasing phosphorylated S6 levels in tumor cells within 8/10 melanoma samples. Single cell RNA-sequencing of the tumor dissociates identified four distinct melanoma differentiation states (e.g. melanocytic, transitory, neural crest-like and undifferentiated). The proportions of these cell states differed between tumor specimens, and were not affected by DT treatment. The neural crest-like and undifferentiated melanoma cells were enriched in PROG compared to NAIVE tumor samples and all differentiation states responded, albeit variably. For instance, MAPK inhibition after DT treatment was less pronounced in undifferentiated melanoma cells. Importantly, within the undifferentiated cell state, we identified a proportion of melanoma cells capable of responding to DT, and comparison of responding vs non-responding undifferentiated cells showed enrichment of pro-inflammatory IL-6 and TNFα signaling in the non-responding population. Elevated IL-6 and TNFα pathway activity correlated with decreased potency to MAPK inhibition, indicating that increased IL-6 and TNFα signaling in undifferentiated melanoma may contribute to resistance to MAPK inhibition. Conclusions: Ex vivo treatment of tumor dissociates coupled with single cell transcriptome sequencing identified cell state-specific responses to MAPK inhibition. Resistance to MAPK inhibition may be driven, in part, by tumor-intrinsic pro-inflammatory IL-6 and TNFα signalling.

Dedifferentiated and undifferentiated melanomas: a practical approach to a challenging diagnosis

Dedifferentiation, defined as the loss of cellular features of terminal differentiation resulting in a more primitive, unspecialized phenotype, is a rare phenomenon in melanoma and more commonly observed in the metastatic setting than in primary melanomas. The diagnosis of dedifferentiated melanoma poses a significant challenge, and the tumors need to be carefully sampled and worked up to identify any residual morphologic, immunohistochemical, or molecular evidence of their melanocytic lineage. This article reviews our current knowledge of the clinical, histopathological, immunohistochemical, and molecular features of these rare tumors and provides a practical diagnostic approach and discussion of the relevant differential diagnoses and associated diagnostic pitfalls.

Undifferentiated and Dedifferentiated Metastatic Melanomas Masquerading as Soft Tissue Sarcomas: Mutational Signature Analysis and Immunotherapy Response

The distinction between undifferentiated melanoma (UM) or dedifferentiated melanoma (DM) from undifferentiated or unclassifiable sarcoma can be difficult and requires the careful correlation of clinical, pathologic, and genomic findings. In this study, we examined the utility of mutational signatures to identify patients with UM/DM with particular attention as to whether this distinction matters for treatment because the survival of patients with metastatic melanoma has dramatically improved with immunologic therapy, whereas durable responses are less frequent in sarcomas. We identified 19 cases of UM/DM that were initially reported as unclassified or undifferentiated malignant neoplasm or sarcoma and submitted for targeted next-generation sequencing analysis. These cases were confirmed as UM/DM by harboring melanoma driver mutations, UV signature, and high tumor mutation burden. One case of DM showed melanoma in situ. Meanwhile, 18 cases represented metastatic UM/DM. Eleven patients had a prior history of melanoma. Thirteen of 19 (68%) of the tumors were immunohistochemically completely negative for 4 melanocytic markers (S100, SOX10, HMB45, and MELAN-A). All cases harbored a dominant UV signature. Frequent driver mutations involved BRAF (26%), NRAS (32%), and NF1 (42%). In contrast, the control cohort of undifferentiated pleomorphic sarcomas (UPS) of deep soft tissue exhibited a dominant aging signature in 46.6% (7/15) without evidence of UV signature. The median tumor mutation burden for DM/UM vs UPS was 31.5 vs 7.0 mutations/Mb (P < .001). A favorable response to immune checkpoint inhibitor therapy was observed in 66.6% (12/18) of patients with UM/DM. Eight patients exhibited a complete response and were alive with no evidence of disease at the last follow-up (median 45.5 months). Our findings support the usefulness of the UV signature in discriminating DM/UM vs UPS. Furthermore, we present evidence suggesting that patients with DM/UM and UV signatures can benefit from immune checkpoint inhibitor therapy.

Integrating Molecular Sequencing Into the Pathological Diagnosis of Clinically Suspected Non–Small Cell Lung Carcinomas

Cancer panel sequencing has been rapidly adopted into clinical practice for the detection of actionable genetic variants in advanced non–small cell lung carcinomas. Unexpected molecular results may lead to reexamination of the clinical diagnosis; however, this scenario has not been systematically evaluated. We reviewed cancer panel next-generation sequencing results from 1007 consecutive patients performed for the clinical indication of non–small cell lung carcinoma along with the corresponding clinical history and anatomical pathology findings. The final integrative diagnosis was a cancer of extrapulmonary origin in 12 of 1007 patients (1.2%). Molecular evidence supporting the final diagnoses included the detection of an UV radiation–associated mutational signature (n = 6), gene fusions (n = 2), and mutations (n = 4). The integrative diagnoses included undifferentiated melanoma, cutaneous squamous cell, and basal cell carcinomas, thyroid carcinoma, urothelial carcinoma, hepatocellular carcinoma, pancreatic adenocarcinoma, intrahepatic cholangiocarcinoma, and synovial sarcoma. A small but nonnegligible proportion of clinically suspected non–small cell lung carcinomas had a final diagnosis of cancer of extrapulmonary origin after clinical next-generation sequencing. The integration of clinical, microscopic, and molecular evidence can aid diagnosis and guide personalized oncology care.

Undifferentiated Melanoma: A Rare Phenomenon and a Challenging Diagnosis

Abstract Introduction/Objective Undifferentiated melanoma is defined as a primary or metastatic melanoma lacking histologic and immunophenotypic features of melanoma. Dedifferentiated melanoma shows transition between undifferentiated and conventional melanoma components. Dedifferentiation and transdifferentiation (implying dedifferentiation with heterologous elements) in melanoma are exceedingly rare and occur mostly in metastatic deposits. The purpose of this report is to describe a case of undifferentiated melanoma that proved to be a diagnostic challenge and to highlight the importance of the multimodality approach and utilization of advanced diagnostic tools in reaching an accurate diagnosis. Methods/Case Report Methods: A 43-year-old white male who was diagnosed with metastatic melanoma on the right axillary biopsy at a local hospital presented to our institution with a rapidly enlarging 30 cm peritoneal mass. He underwent debulking surgery to lower his tumor burden. On pathologic evaluation, the tumor showed a heterogeneous appearance ranging from highly cellular fascicles of spindle cells to sheets of primitive round cells and epithelioid cells with abundant eosinophilic cytoplasm. One metastatic focus showed heterologous cartilaginous differentiation. This morphologic appearance elicited the differential diagnosis of metastatic melanoma, primitive neuroectodermal tumor, synovial sarcoma, and metastatic germ cell tumor with somatic transformation. Immunochemical staining showed the tumor cells to be positive for SALL4, CD99 (patchy), and TLE1 (patchy) and negative for pan-cytokeratin, S100, SOX- 10, HMB-45, desmin, myogenin, DOG1, CD 117, CDX2, TTF-1, PAX-8, CK7, CK20, chromogranin, CD30, and OCT4. Fluorescence in situ hybridization for EWSR1, SS18(SYT), and isochromosome 12p were negative. BRAF gene mutation analysis detected p.V600E / p.V600D. Subsequently, a diagnosis of undifferentiated melanoma was rendered after expert consultation. Unfortunately, the patient passed away 1 month after surgery. Results (if a Case Study enter NA) NA. Conclusion Diagnosis of undifferentiated melanoma by the conventional H&amp;E and immunohistochemical profile is extremely challenging. Multimodality approach and utilization of advanced diagnostic tools such as molecular studies are helpful in this regard.

The utility of molecular testing in the recognition of undifferentiated metastatic melanoma

Background: Undifferentiated melanoma is an under-recognised phenomenon, often classified as undifferentiated pleomorphic sarcoma even when arising in the context of previous melanoma.1 Identification of undifferentiated melanoma is important for appropriate ancillary treatment. Molecular testing represents a useful tool that can help identify this entity.

Primary de-differentiated, trans-differentiated and undifferentiated melanomas: overview of the clinicopathological, immunohistochemical and molecular spectrum.

Primary cutaneous and mucosal melanoma shows a wide histological spectrum. The correct diagnosis depends upon the demonstration of melanocytic differentiation by recognition of an associated in-situ component or immunohistochemical evidence of a melanocytic phenotype using conventional melanocytic markers, such as S-100, SOX10, Melan-A and HMB-45. Exceptionally, melanomas lose their melanocytic phenotype, at least focally, and show differentiation towards other lineages. Review of the literature shows that de- and trans-differentiation in melanoma is rare but probably under-recognised and under-reported. These often large and frequently ulcerated tumours affect adults and show a wide anatomical distribution, including mucosal sites, although there is a predilection for sun-damaged skin of the head and neck. Histologically, the tumours are biphasic and contain a pre-existing conventional melanoma. The de-differentiated component closely resembles atypical fibroxanthoma, both morphologically and immunohistochemically. Trans-differentiated melanoma may show rhabdomyosarcomatous or spindle cell carcinomatous features. Undifferentiated melanomas are similar tumours in which the conventional melanoma component is absent. Their diagnosis depends entirely upon the clinical context and identification of a classical melanoma driver gene mutation, i.e. BRAF V600E. The diagnosis of these rare and unusual tumours is challenging, and requires thorough tumour sampling and recognition of the background of a pre-existing but often focal conventional melanoma together with molecular analysis.

270 Phenotypic plasticity of melanocytes derived from human adult skin

In previous work we have shown that adult human melanocytes cultured in a defined, specific mitogen-free medium, Mel-mix became bipolar, unpigmented and highly proliferative. Furthemore, in these cells the expression of TRP-1 and c-kit disappeared and EGFR receptor and nestin expression was detected, indicating a phenotypic switch toward dedifferentiation. In the present work we used high throughput mRNA sequencing analysis to compare the dedifferentiated melanocytes to mature cells. Immunohistochemistry showed the loss of MITF and Sox-10 expression in the dedifferentiated cells and flow cytrometry detected the expression of characteristic markers of mesenchymal stem cells. During dedifferentiation the expression of E-cadherin was reduced and the expression of fibronectin and oncofoetal fibronectin was elevated, confirmed by western blot. The dedifferentiated melanocytes were able to differentiate into adipogenic, osteogenic and chondrogenic phenotype given the appropriate in vitro environment. The extensive characterization of these cells revealed relevant similarities with undifferentiated melanoma cells, indicating that phenotype switching driven by environmental factors is a general characteristic of melanocytes that can occur independent of malignant transformation. These in vitro dedifferentiated melanocytes can be used to investigate the non-genetic plasticity of melanoma cells, a process that play a crucial role in metastasis, dormant cancer cell development and in therapy resistance.

Dedifferentiated and Undifferentiated Melanomas: Report of 35 New Cases With Literature Review and Proposal of Diagnostic Criteria.

Dedifferentiated melanoma (DM) and undifferentiated melanoma (UM) is defined as a primary or metastatic melanoma showing transition between conventional and undifferentiated components (DM) or lacking histologic and immunophenotypic features of melanoma altogether (UM). The latter is impossible to verify as melanoma by conventional diagnostic tools alone. We herein describe our experience with 35 unpublished cases to expand on their morphologic, phenotypic, and genotypic spectrum, along with a review of 50 previously reported cases (total: 85) to establish the diagnostic criteria. By definition, the dedifferentiated/undifferentiated component lacked expression of 5 routinely used melanoma markers (S100, SOX10, Melan-A, HMB45, Pan-melanoma). Initial diagnoses (known in 66 cases) were undifferentiated/unclassified pleomorphic sarcoma (n=30), unclassified epithelioid malignancy (n=7), pleomorphic rhabdomyosarcoma (n=5), other specific sarcoma types (n=6), poorly differentiated carcinoma (n=2), collision tumor (n=2), atypical fibroxanthoma (n=2), and reactive osteochondromatous lesion (n=1). In only 11 cases (16.6%) was a diagnosis of melanoma considered. Three main categories were identified: The largest group (n=56) comprised patients with a history of verified previous melanoma who presented with metastatic DM or UM. Axillary or inguinal lymph nodes, soft tissue, bone, and lung were mainly affected. A melanoma-compatible mutation was detected in 35 of 48 (73%) evaluable cases: BRAF (n=20; 40.8%), and NRAS (n=15; 30.6%). The second group (n=15) had clinicopathologic features similar to group 1, but a melanoma history was lacking. Axillary lymph nodes (n=6) was the major site in this group followed by the lung, soft tissue, and multiple site involvement. For this group, NRAS mutation was much more frequent (n=9; 60%) than BRAF (n=3; 20%) and NF1 (n=1; 6.6%). The third category (n=14) comprised primary DM (12) or UM (2). A melanoma-compatible mutation was detected in only 7 cases: BRAF (n=2), NF1 (n=2), NRAS (n=2), and KIT exon 11 (n=1). This extended follow-up study highlights the high phenotypic plasticity of DM/UM and indicates significant underrecognition of this aggressive disease among general surgical pathologists. The major clues to the diagnosis of DM and UM are: (1) presence of minimal differentiated clone in DM, (2) earlier history of melanoma, (3) undifferentiated histology that does not fit any defined entity, (4) locations at sites that are unusual for undifferentiated/unclassified pleomorphic sarcoma (axilla, inguinal, neck, digestive system, etc.), (5) unusual multifocal disease typical of melanoma spread, (6) detection of a melanoma-compatible gene mutation, and (7) absence of another genuine primary (eg, anaplastic carcinoma) in other organs.

Mutational analysis of undifferentiated melanoma

Mutational analysis of undifferentiated melanoma

The Use of Molecular Studies for Diagnosis of Undifferentiated Tumors

Malignant melanoma (MM) is an aggressive heterogeneous skin cancer with phenotypic, immunoprofile, and molecular diversity. Some tumors may be undifferentiated, with loss of immunohistochemical markers and a less differentiated lesion status. These authors explored the immunoprofile and genetic landscape of 14 metastatic undifferentiated melanomas. These melanomas were more frequent in males (median age, 67 years), one with an unknown primary. …

Matrix softness regulates plasticity of tumour-repopulating cells via H3K9 demethylation and Sox2 expression.

Tumour-repopulating cells (TRCs) are a self-renewing, tumorigenic subpopulation of cancer cells critical in cancer progression. However, the underlying mechanisms of how TRCs maintain their self-renewing capability remain elusive. Here we show that relatively undifferentiated melanoma TRCs exhibit plasticity in Cdc42-mediated mechanical stiffening, histone 3 lysine residue 9 (H3K9) methylation, Sox2 expression and self-renewal capability. In contrast to differentiated melanoma cells, TRCs have a low level of H3K9 methylation that is unresponsive to matrix stiffness or applied forces. Silencing H3K9 methyltransferase G9a or SUV39h1 elevates the self-renewal capability of differentiated melanoma cells in a Sox2-dependent manner. Mechanistically, H3K9 methylation at the Sox2 promoter region inhibits Sox2 expression that is essential in maintaining self-renewal and tumorigenicity of TRCs both in vitro and in vivo. Taken together, our data suggest that 3D soft-fibrin-matrix-mediated cell softening, H3K9 demethylation and Sox2 gene expression are essential in regulating TRC self-renewal.

Small molecule targeting of RhoC‐regulated gene transcription in metastatic, undifferentiated melanoma

Melanoma is the most dangerous form of skin cancer with the majority of deaths arising from metastatic disease. Recent evidence implicates Rho‐activated gene transcription, mediated by the nuclear localization of the transcriptional coactivator, megakaryoblastic leukemia‐1 (MKL1), in melanoma metastasis. Here, we examine correlates of Rho expression and activity as well as markers of differentiation, migration, morphology, and tumorigenicity in a panel of human metastatic melanoma cell lines. Three melanoma lines with evidence of high Rho activity also show an aggressive and undifferentiated phenotype. These melanomas selectively overexpress RhoC but not RhoA and also have increased expression of mRNA for P75, a neural crest stem cell marker and decreased expression of melanocytic differentiation markers, MITF and TYR. To target the Rho/MKL transcriptional mechanism, we have developed a small molecule inhibitor of Rho‐regulated transcription. CCG‐203971, at low μM concentrations blocks nuclear localization of MKL, produces a more melanocyte‐like cellular morphology, decreases MKL target gene expression, and inhibits cellular migration of aggressive undifferentiated melanoma cells. These data link melanoma cell differentiation with Rho activity and support targeting the Rho/MKL transcriptional pathway as a novel approach to melanoma therapeutics. (Supported by NIH –T32‐GM007767)

Merkel cell carcinoma: a distinct lesion of the eyelid

Merkel cell carcinoma (trabecular cell carcinoma) is a rare, distinct, primitive, neuroendocrine malignancy of the skin, usually affecting elderly patients. It develops from Merkel cells and nearly one out of every 10 Merkel cell carcinomas occurs in the eyelids and periocular region. The tumor manifests itself clinically as a bulging lesion near the lid margin, painless, reddish colored with teleangiectatic blood vessels on the surface. Histologically, the tumor can mimic malignant lymphoma, undifferentiated melanoma, sebaceous carcinoma or cutaneous metastases of pulmonary microcytoma. Immunohistochemical studies with antibodies to neuron-specific enolase, cytokeratins and neurosecretory granules are necessary to differentiate these tumors. One third of all Merkel cell carcinomas result in death. In the present paper, we present data on the clinical features, treatment and long-term follow-up of three patients.