RARE DISEASE
Cutaneous neuroendocrine carcinoma
Cutaneous neuroendocrine carcinoma
Cutaneous neuroendocrine carcinoma
Synonyms: MCC, Merkel cell carcinoma
Synonyms: MCC, Merkel cell carcinoma
Synonyms: MCC, Merkel cell carcinoma
Drug discovery
15
drugs
With orphan designations
Overview
Cutaneous neuroendocrine carcinoma (CNEC), primarily Merkel cell carcinoma (MCC), is a rare, aggressive malignancy arising from neuroendocrine cells in sun-exposed skin. It presents as rapidly growing, painless nodules, often in elderly or immunocompromised individuals. Diagnosis requires biopsy and immunohistochemistry (CK20+/TTF-1– in most cases). Prognosis remains poor due to high recurrence and metastatic rates, with staging (tumor size, nodal/distant spread) being the strongest survival predictor [1][2][12].
Therapies
Localized disease: Wide excision ± adjuvant radiation (reduces recurrence) [8][14]
Advanced/metastatic: Immune checkpoint inhibitors (avelumab, pembrolizumab) as first-line systemic therapy; chemotherapy (carboplatin/etoposide) reserved for refractory cases [8][18][13]
Emerging options: Targeted therapies (VEGF inhibitors), peptide receptor radionuclide therapy (PRRT) [8][13][18]
Categories: rare endocrine diseases, rare neoplastic diseases, rare skin diseases
Research Papers
1,668 drug discovery papers about Cutaneous neuroendocrine carcinoma, with 4 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,668 drug discovery papers about Cutaneous neuroendocrine carcinoma, with 4 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-14 | Merkel cell carcinoma: A clinically oriented mini-review for dermatologists.
Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous neuroendocrine malignancy with mortality rates exceeding melanoma at comparable stages. Its incidence is increasing worldwide, particularly among elderly, immunosuppressed, and fairskinned individuals. Clinically, MCC often presents as a rapidly enlarging, asymptomatic nodule on sun-exposed skin, although atypical locations and morphologic variants may delay recognition. This clinically oriented mini-review summarizes current evidence most relevant to dermatologists regarding the epidemiology, risk factors, clinical presentation, histopathology, immunohistochemical diagnosis, staging, imaging, prognostic factors, circulating biomarkers, and treatment of MCC. Diagnosis relies on histopathology and immunohistochemistry, with cytokeratin 20 and Merkel cell polyomavirus (MCPyV)-related markers playing important roles in distinguishing MCC from other small round blue cell tumors. Imaging modalities, particularly FDG-PET/CT, are essential for accurate staging and surveillance. Prognosis is influenced by tumor size, stage, immune status, age, and viral status. Emerging biomarkers such as circulating tumor DNA and MCPyV oncoprotein antibody titers are increasingly relevant for disease monitoring. Management is stage-specific and multidisciplinary, involving surgical excision, radiotherapy, and immune checkpoint inhibitors such as avelumab, pembrolizumab, nivolumab, and retifanlimab, which have improved outcomes in advanced disease. MCC is an uncommon but highly lethal skin cancer that requires early recognition, accurate staging, and multidisciplinary management. Dermatologists should be aware of both classic and atypical presentations to avoid delayed diagnosis. Recent advances in imaging, biomarkers, and immunotherapy have improved disease monitoring and treatment, but important global disparities remain in access to diagnostic tools and modern therapies.
2026-08-07 | Clinical Reasoning: A 79-Year-Old Man With Subacute Onset Involuntary Facial Movements and Discoordination.
A 79-year-old man with metastatic Merkel cell carcinoma undergoing cancer-directed treatment was admitted to the hospital with 1 week of bilateral upper and lower extremity tremor and nearly continuous involuntary facial movements. These abnormal movements of his face, head, and limbs were exacerbated by purposeful movement. Examination revealed dysarthria with tremulous speech, intention tremors of the head and all extremities, distally diminished vibration sense with hyporeflexia, bilateral upper extremity dysdiadochokinesis, bilateral lower extremity dysmetria on heel-to-shin testing, and truncal ataxia. MRI of the brain showed no acute abnormalities. CSF and serum testing showed evidence of CNS inflammation with a CSF lymphocytic pleocytosis and elevated total protein. Diagnosis was ultimately made using serum and CSF studies. Here, we discuss the differential diagnosis of 2 weeks of diffuse intention tremor, involuntary facial movements, and ataxia. We discuss the workup, diagnosis, acute and nonacute management of this condition, as well as important clinical points regarding the broader category into which this diagnosis falls.
2026-07-29 | An immunocompetent model of MCPyV-driven Merkel cell carcinoma reveals tumor evolution under immune selection.
Merkel cell carcinoma (MCC) is a neuroendocrine skin tumor that is frequently driven by integration of Merkel cell polyomavirus (MCPyV). In MCC, the MCPyV genome is truncated, but expression of the viral tumor antigens, truncated large tumor antigen (LTT) and small tumor antigen (sT), is maintained and drives uncontrolled proliferation. We introduced constitutive expression of the MCPyV T antigens (TAs) into primary mouse dermal fibroblasts (MDFs) to determine whether these cells are susceptible to MCPyV-driven transformation. TA expression alone in MDFs induced key MCC markers, cytokeratin-20 (CK20) and Sry-box transcription factor 2 (SOX2), and promoted anchorage-independent growth indicative of cellular transformation. Subcutaneous implantation of TA-transformed fibroblasts produced high-grade MCC-like tumors that grew persistently in immunodeficient NSG mice but not in immunocompetent C57BL/6 mice. Serial in vivo passaging of the tumor cell line enhanced tumor growth, reduced expression of p53-target genes and MHC-1, and was accompanied by a shift in T antigen isoform expression, with decreased LTT and increased sT expression. Our data demonstrate that MCPyV-driven tumors acquire immune-evasive adaptions during tumor progression in vivo and suggest that the anti-tumor immune response exerts selective pressure in MCC that favors expression of sT rather than LTT. The model established in this study provides a unique platform for studying evolution of MCPyV-driven tumors under immune pressure and identifying mechanisms of immune evasion in MCC that could be used to develop new therapeutic strategies. MCPyV tumor antigen expression transforms mouse dermal fibroblasts to generate MCC-like tumors. Serial in vivo passaging reveals tumor evolution under immune pressure, providing a model to study immune evasion mechanisms in MCC.
2026-07-28 | The Nicotinic Acetylcholine Receptor-Macrophage Axis in Merkel Cell Carcinoma: Evidence, Limitations, and Therapeutic Hypotheses.
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin malignancy characterized by high mortality and a rising incidence. Although immune checkpoint inhibitors have significantly improved patient outcomes, many patients exhibit primary or acquired resistance, frequently in the setting of an immunosuppressive tumor microenvironment (TME) enriched for myeloid populations. This review synthesizes current evidence and proposes a testable model in which nicotinic acetylcholine receptor (nAChR) signaling may intersect with tumor-associated macrophage (TAM) biology to reinforce immune exclusion in MCC. Direct MCC-specific evidence currently supports nAChR-subunit expression in tumor tissues and the association of CD163+/CD14+/S100A8+ myeloid populations with resistance to PD-1 pathway blockade; however, functional nAChR signaling in MCC tumor cells, TAMs, or dendritic cells has not yet been demonstrated. We therefore distinguish established MCC observations from mechanistic hypotheses extrapolated from macrophage biology, cholinergic anti-inflammatory signaling, and other cancer models. Within this framework, α7-nAChR signaling on TAMs may activate the cholinergic anti-inflammatory pathway and favor suppressive myeloid states, whereas α3- and α5-containing receptors detected in MCC tumor cells may represent tumor-cell-associated candidates for future mechanistic testing. By integrating evidence on TAM plasticity, spatial immune exclusion, and cholinergic signaling, we propose that the nAChR-macrophage axis is a rational but unproven therapeutic hypothesis that warrants systematic validation in MCC models.
2026-07-28 | Cutaneous Malignancies Metastatic to the Female Genital Tract and Pelvic Lymph Nodes: Analysis of Metastatic Patterns and Pathogenesis.
Background/Objectives: Metastases from cutaneous malignancies to the female genital tract and pelvic lymph nodes are rare clinical entities that frequently masquerade as primary gynecologic tumors, leading to significant diagnostic challenges. The distinction between primary and metastatic disease is critical, yet complex, given the varying patterns of spread exhibited by different skin cancers. This study aims to provide a tumor-specific overview of these metastatic patterns to guide diagnosis and therapy. Methods: We conducted a narrative review informed by a systematic literature search of MEDLINE/PubMed, Embase, Scopus, and Web of Science for records regarding primary cutaneous melanoma, cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC), Merkel cell carcinoma (MCC), and cutaneous lymphomas metastasizing to the female genital tract (FGT) or pelvic lymph nodes. Data were synthesized qualitatively to identify organotropic patterns, diagnostic pitfalls, and management outcomes across these distinct malignancies. Results: The analysis reveals distinct metastatic niches: cutaneous melanoma shows a predilection for the ovary, often mimicking epithelial ovarian carcinoma, whereas cSCC and MCC typically involve pelvic lymph nodes via contiguous spread from inguinal basins. Histologic evaluation with broad immunohistochemical panels is mandatory to confirm the diagnosis, as imaging alone lacks specificity. Crucially, the introduction of immune checkpoint inhibitors and targeted therapies has significantly improved survival in advanced melanoma, cSCC, and MCC, altering the role of pelvic surgery. Conclusions: Management of cutaneous malignancies metastatic to the pelvis is shifting from a focus on radical surgery to a systemic-first approach. Pelvic metastasectomy should be reserved for selected oligometastatic cases or symptom control within a multidisciplinary framework. Clinicians must maintain a high index of suspicion in patients with a history of skin cancer to avoid overtreatment and optimize quality of life.
2026-08-14 | Merkel cell carcinoma: A clinically oriented mini-review for dermatologists.
Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous neuroendocrine malignancy with mortality rates exceeding melanoma at comparable stages. Its incidence is increasing worldwide, particularly among elderly, immunosuppressed, and fairskinned individuals. Clinically, MCC often presents as a rapidly enlarging, asymptomatic nodule on sun-exposed skin, although atypical locations and morphologic variants may delay recognition. This clinically oriented mini-review summarizes current evidence most relevant to dermatologists regarding the epidemiology, risk factors, clinical presentation, histopathology, immunohistochemical diagnosis, staging, imaging, prognostic factors, circulating biomarkers, and treatment of MCC. Diagnosis relies on histopathology and immunohistochemistry, with cytokeratin 20 and Merkel cell polyomavirus (MCPyV)-related markers playing important roles in distinguishing MCC from other small round blue cell tumors. Imaging modalities, particularly FDG-PET/CT, are essential for accurate staging and surveillance. Prognosis is influenced by tumor size, stage, immune status, age, and viral status. Emerging biomarkers such as circulating tumor DNA and MCPyV oncoprotein antibody titers are increasingly relevant for disease monitoring. Management is stage-specific and multidisciplinary, involving surgical excision, radiotherapy, and immune checkpoint inhibitors such as avelumab, pembrolizumab, nivolumab, and retifanlimab, which have improved outcomes in advanced disease. MCC is an uncommon but highly lethal skin cancer that requires early recognition, accurate staging, and multidisciplinary management. Dermatologists should be aware of both classic and atypical presentations to avoid delayed diagnosis. Recent advances in imaging, biomarkers, and immunotherapy have improved disease monitoring and treatment, but important global disparities remain in access to diagnostic tools and modern therapies.
2026-08-07 | Clinical Reasoning: A 79-Year-Old Man With Subacute Onset Involuntary Facial Movements and Discoordination.
A 79-year-old man with metastatic Merkel cell carcinoma undergoing cancer-directed treatment was admitted to the hospital with 1 week of bilateral upper and lower extremity tremor and nearly continuous involuntary facial movements. These abnormal movements of his face, head, and limbs were exacerbated by purposeful movement. Examination revealed dysarthria with tremulous speech, intention tremors of the head and all extremities, distally diminished vibration sense with hyporeflexia, bilateral upper extremity dysdiadochokinesis, bilateral lower extremity dysmetria on heel-to-shin testing, and truncal ataxia. MRI of the brain showed no acute abnormalities. CSF and serum testing showed evidence of CNS inflammation with a CSF lymphocytic pleocytosis and elevated total protein. Diagnosis was ultimately made using serum and CSF studies. Here, we discuss the differential diagnosis of 2 weeks of diffuse intention tremor, involuntary facial movements, and ataxia. We discuss the workup, diagnosis, acute and nonacute management of this condition, as well as important clinical points regarding the broader category into which this diagnosis falls.
2026-07-29 | An immunocompetent model of MCPyV-driven Merkel cell carcinoma reveals tumor evolution under immune selection.
Merkel cell carcinoma (MCC) is a neuroendocrine skin tumor that is frequently driven by integration of Merkel cell polyomavirus (MCPyV). In MCC, the MCPyV genome is truncated, but expression of the viral tumor antigens, truncated large tumor antigen (LTT) and small tumor antigen (sT), is maintained and drives uncontrolled proliferation. We introduced constitutive expression of the MCPyV T antigens (TAs) into primary mouse dermal fibroblasts (MDFs) to determine whether these cells are susceptible to MCPyV-driven transformation. TA expression alone in MDFs induced key MCC markers, cytokeratin-20 (CK20) and Sry-box transcription factor 2 (SOX2), and promoted anchorage-independent growth indicative of cellular transformation. Subcutaneous implantation of TA-transformed fibroblasts produced high-grade MCC-like tumors that grew persistently in immunodeficient NSG mice but not in immunocompetent C57BL/6 mice. Serial in vivo passaging of the tumor cell line enhanced tumor growth, reduced expression of p53-target genes and MHC-1, and was accompanied by a shift in T antigen isoform expression, with decreased LTT and increased sT expression. Our data demonstrate that MCPyV-driven tumors acquire immune-evasive adaptions during tumor progression in vivo and suggest that the anti-tumor immune response exerts selective pressure in MCC that favors expression of sT rather than LTT. The model established in this study provides a unique platform for studying evolution of MCPyV-driven tumors under immune pressure and identifying mechanisms of immune evasion in MCC that could be used to develop new therapeutic strategies. MCPyV tumor antigen expression transforms mouse dermal fibroblasts to generate MCC-like tumors. Serial in vivo passaging reveals tumor evolution under immune pressure, providing a model to study immune evasion mechanisms in MCC.
2026-07-28 | The Nicotinic Acetylcholine Receptor-Macrophage Axis in Merkel Cell Carcinoma: Evidence, Limitations, and Therapeutic Hypotheses.
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin malignancy characterized by high mortality and a rising incidence. Although immune checkpoint inhibitors have significantly improved patient outcomes, many patients exhibit primary or acquired resistance, frequently in the setting of an immunosuppressive tumor microenvironment (TME) enriched for myeloid populations. This review synthesizes current evidence and proposes a testable model in which nicotinic acetylcholine receptor (nAChR) signaling may intersect with tumor-associated macrophage (TAM) biology to reinforce immune exclusion in MCC. Direct MCC-specific evidence currently supports nAChR-subunit expression in tumor tissues and the association of CD163+/CD14+/S100A8+ myeloid populations with resistance to PD-1 pathway blockade; however, functional nAChR signaling in MCC tumor cells, TAMs, or dendritic cells has not yet been demonstrated. We therefore distinguish established MCC observations from mechanistic hypotheses extrapolated from macrophage biology, cholinergic anti-inflammatory signaling, and other cancer models. Within this framework, α7-nAChR signaling on TAMs may activate the cholinergic anti-inflammatory pathway and favor suppressive myeloid states, whereas α3- and α5-containing receptors detected in MCC tumor cells may represent tumor-cell-associated candidates for future mechanistic testing. By integrating evidence on TAM plasticity, spatial immune exclusion, and cholinergic signaling, we propose that the nAChR-macrophage axis is a rational but unproven therapeutic hypothesis that warrants systematic validation in MCC models.
2026-07-28 | Cutaneous Malignancies Metastatic to the Female Genital Tract and Pelvic Lymph Nodes: Analysis of Metastatic Patterns and Pathogenesis.
Background/Objectives: Metastases from cutaneous malignancies to the female genital tract and pelvic lymph nodes are rare clinical entities that frequently masquerade as primary gynecologic tumors, leading to significant diagnostic challenges. The distinction between primary and metastatic disease is critical, yet complex, given the varying patterns of spread exhibited by different skin cancers. This study aims to provide a tumor-specific overview of these metastatic patterns to guide diagnosis and therapy. Methods: We conducted a narrative review informed by a systematic literature search of MEDLINE/PubMed, Embase, Scopus, and Web of Science for records regarding primary cutaneous melanoma, cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC), Merkel cell carcinoma (MCC), and cutaneous lymphomas metastasizing to the female genital tract (FGT) or pelvic lymph nodes. Data were synthesized qualitatively to identify organotropic patterns, diagnostic pitfalls, and management outcomes across these distinct malignancies. Results: The analysis reveals distinct metastatic niches: cutaneous melanoma shows a predilection for the ovary, often mimicking epithelial ovarian carcinoma, whereas cSCC and MCC typically involve pelvic lymph nodes via contiguous spread from inguinal basins. Histologic evaluation with broad immunohistochemical panels is mandatory to confirm the diagnosis, as imaging alone lacks specificity. Crucially, the introduction of immune checkpoint inhibitors and targeted therapies has significantly improved survival in advanced melanoma, cSCC, and MCC, altering the role of pelvic surgery. Conclusions: Management of cutaneous malignancies metastatic to the pelvis is shifting from a focus on radical surgery to a systemic-first approach. Pelvic metastasectomy should be reserved for selected oligometastatic cases or symptom control within a multidisciplinary framework. Clinicians must maintain a high index of suspicion in patients with a history of skin cancer to avoid overtreatment and optimize quality of life.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
15 orphan drug designations for Cutaneous neuroendocrine carcinoma, including 4 approved therapies.
15 orphan drug designations for Cutaneous neuroendocrine carcinoma, including 4 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
a humanized bispecific monoclonal antibody against PD-L1 and 4-1BB | antibodies | FDA | 2024-11-20 | — | Nanjing Leads Biolabs Co., Ltd. |
topotecan liposome injection | small molecules | FDA | 2024-03-21 | — | Fujifilm Pharmaceuticals U.S.A., Inc. |
Retifanlimab [ZYNYZ] | antibodies | EMA | 2023-01-13 | 2024-04-24 | Incyte Biosciences Distribution B.V. |
bi-specific fragment crystallizable region (Fc) fusion protein containing cluster of differentiation 80 ectodomain as an N-terminal moiety and interleukin-2 variant as a C-terminal moiety conjugated with human immunoglobulin G4 Fc | proteins | FDA | 2022-10-17 | — | GI Innovation, Inc. |
Navtemadlin | small molecules | EMA | 2022-01-14 | — | Yes Pharmaceutical Development Services GmbH |
cavrotolimod | oligonucleotides | FDA | 2021-03-01 | — | Exicure, Inc. |
retifanlimab-dlwr [Zynyz] | antibodies | FDA | 2020-10-26 | 2023-03-22 | Incyte Corporation |
navtemadlin | small molecules | FDA | 2020-04-08 | — | Kartos Therapeutics, Inc. |
activated natural killer[aNK]) | cell therapies | FDA | 2017-03-15 | — | ImmunityBio, Inc. |
pembrolizumab [Keytruda] | antibodies | FDA | 2016-12-28 | 2018-12-19 | MSD International Business GmbH |
Live-attenuated non-replicative Pseudomonas aeruginosa strain expressing large T antigen of Merkel cell polyomavirus | vaccines | EMA | 2016-11-18 | — | APCure SAS |
Avelumab [Bavencio] | antibodies | EMA | 2015-12-14 | — | Merck Europe B.V. |
avelumab (Recombinant human monoclonal IgG1 antibody against programmed death ligand-1) [Bavencio] | antibodies | FDA | 2015-09-21 | 2017-03-23 | EMD Serono Research and Development Institute, Inc. |
Lorvotuzumab mertansine [IMGN901 (BB-10901 and huN901-DM1)] | antibodies | EMA | 2010-06-09 | — | ImmunoGen Europe Limited |
maytansinoid DM1-conjugated humanized monoclonal antibody N901 | antibodies | FDA | 2010-03-02 | — | ImmunoGen, Inc. |
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