Search Results (205)

Background/Objectives: Merkel cell polyomavirus (MCPyV) is a ubiquitous virus strictly associated with Merkel cell carcinoma (MCC), a rare and aggressive skin cancer. MCPyV oncogenic properties are associated mainly with early protein expression, integration, and LT truncation. MCPyV can also interact with DNA Damage Response (DDR) mechanisms, contributing to oncogenesis and tumor progression. In this work, we investigated the correlation between MCPyV and MCC and evaluated the mRNA expression profiles of DDR genes in virus-positive and -negative tumors. Methods: A total of 19 formalin-fixed paraffin-embedded biopsies were acquired from patients diagnosed with MCC. After DNA and RNA extraction, the DNA was used for MCPyV detection via qPCR and for sequencing analysis of the early, late, and non-coding control viral regions and the extracted RNA was used for MCPyV transcripts, miRNA detection and for the evaluation of several DDR genes expression such as ATM, ATR, CHK1, CHK2, H2AX, Rad51, p53, and p21, in MCPyV-positive and -negative samples via reverse transcription, PCR, and qPCR. Results: MCPyV presence was detected in 11/19 samples, all characterized by viral integration, LT truncation, and early region expression only. Furthermore, higher mRNA levels of DDR genes were observed in MCPyV-positive tumors compared with the negative ones. Conclusions: Our findings support the role of MCPyV in MCC formation and suggest its involvement in the transcriptional regulation of DDR genes, which may influence tumor progression. Understanding the molecular interplay between MCPyV and the DDR may guide future research into plausible novel diagnostic and therapeutic strategies for virus-induced tumors. Full article

Background: Merkel cell carcinoma (MCC) is a rare malignancy of the skin caused by Merkel cell polyomavirus (80% of cases) or by ultraviolet (UV) sun exposure (20% of cases). The isoprenoid biosynthesis pathway (IBP) is an essential metabolic pathway shown to be upregulated in tumorigenesis, causing aberrant activation of Ras and Rho GTPases and resulting in unregulated cellular proliferation and survival. Methods: Through the use of pharmacological inhibitors of the IBP, we assessed the role of the IBP and its downstream targets in viral-positive and viral-negative MCC cell lines. To identify the most critical IBP intermediates, cellular metabolic activity, cell death and cell cycle distribution were measured after IBP perturbation. Results: Across all cell lines, treatment with IBP inhibitors, especially fluvastatin, decreased metabolic activity; however, perturbation of different intermediates resulted in variable responses between viral-positive and viral-negative cell lines. Conclusions: Our findings demonstrate varying dependence on the IBP between viral-positive and viral-negative MCC and highlight the importance of cellular dynamics when determining a treatment regimen for patients with MCC. Full article

Background and Objectives: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin malignancy associated with high rates of recurrence and disease-specific mortality. Although adjuvant platinum–etoposide chemotherapy is used in high-risk disease, the optimal number of treatment cycles has not been established. Materials and Methods: This multicenter retrospective cohort study included 104 patients with resected high-risk MCC (pathological stage IIB–III) treated at Israeli medical centers between September 1985 and February 2021. Patients were assigned to one of three treatment groups: radiotherapy alone, four cycles of platinum–etoposide plus radiotherapy, or six cycles of platinum–etoposide plus radiotherapy. The chemotherapy regimen consisted of cisplatin or carboplatin combined with etoposide in 21-day cycles, with the first two cycles administered concurrently with radiotherapy. Primary endpoints were disease-free survival (DFS) and overall survival (OS), analyzed using the Kaplan–Meier method and multivariable Cox proportional hazards regression. Results: Four cycles of adjuvant platinum–etoposide combined with radiotherapy were associated with the most favorable survival outcomes at all follow-up time points. Five-year DFS and OS in the four-cycle group were 65% (95% CI: 58–72%) and 75% (95% CI: 68–82%), respectively, compared with 55% and 60% in the six-cycle group, and 40% and 45% in the radiotherapy-only group (p < 0.001). The survival advantage of four cycles over radiotherapy alone was sustained at 10- and 20-year follow-up (p < 0.0001). In patients with stage III disease and nodal involvement, the four-cycle group achieved a median DFS of 93 months and a median OS of approximately 110 months, significantly exceeding outcomes in both the six-cycle and radiotherapy-alone groups. No statistically significant survival benefit from chemotherapy was identified in the small subgroup of patients with stage IIB/T4N0 disease. Conclusions: In patients with high-risk resected MCC, the addition of adjuvant platinum–etoposide chemotherapy to radiotherapy significantly improves DFS and OS, with the greatest benefit observed in patients with stage III disease and lymph node involvement. Four cycles represent an optimal treatment duration, delivering durable long-term survival benefit without the need for more prolonged chemotherapy exposure. These findings support a risk-adapted multimodality approach and provide real-world evidence to guide adjuvant therapy decisions in this rare and aggressive malignancy. Full article

Background: Prenylated chalcones are recognized for their beneficial nutritional properties and have attracted increasing interest due to their anticancer activities, which involve various mechanisms and pathways. In the current study, we investigated the influence of prenylated chalcone xanthohumol (XH) and its two minor derivatives xanthohumol C (XHC) and 1″,2″-dihydroxantohumol C (DHXHC) on the formation of reactive oxygen species (ROS), causing oxidative stress. Concomitantly, we studied the effect of mitochondrial transmembrane potential changes on human skin cancer, namely Merkel cell carcinoma (MCC13). Methods: The cancer cells were treated with the mentioned compounds for 24 and 48 h at various concentrations. Results: Our findings showed that ROS generation was dose-dependent at 24 h for xanthohumol, whereas for xanthohumol C and 1″2″-dihydroxanthohumol C, a significant increase in ROS occurred only at the highest concentration (100 μM) after 48 h. Mitochondrial membrane potential was significantly diminished by all the compounds. Conclusions: Taken together, our results indicate that the aforementioned chalcones exhibit cytotoxic activity against the MCC13 cell line and may be promising candidates for further investigation as anticancer agents. Full article

Merkel Cell Polyomavirus is an oncogenic virus associated with Merkel Cell Carcinoma (MCC). However, considering viral detection in respiratory specimens and similarities between MCC and neuroendocrine lung cancer, its plausible role in the respiratory tract is disputed. MCPyV-mediated oncogenesis involves viral antigens interfering with host signaling as a DNA Damage Response (DDR). In the current study, respiratory models, including lung cancer cell lines (A549 and H1299), and non-malignant bronchial systems (HBEC-KT and a 2D ALI model) were used to investigate DDR genes’ expression following MCPyV infection. Once the capability to support viral replication and transcription was assessed using qPCR and RT-qPCR, respectively, the mRNA levels of DDR genes, including ATM, ATR, Chk1, Chk2, H2AX, Rad51, p53 and p21, were examined. Our findings showed MCPyV replication in all cellular systems, as proven by the detection of viral DNA and transcripts. Viral infection induced an overexpression of DDR genes, suggesting a role of the virus in manipulating DDR to favor its replication or contribute to tumor progression. These preliminary results provide in vitro models for studying the interplay between MCPyV and DDR within malignant and non-malignant contexts across the respiratory tract, laying the basis for future research exploring the clinical relevance of DDR activation in virus-driven malignancies. Full article

Background: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer, with prognosis influenced by tumor location and primary status. This study evaluated clinicopathological features and survival outcomes in patients with MCC from multiple centers in Israel. Methods: Data on demographics, tumor characteristics, lymph node (LN) involvement, treatment, and survival were collected. Patients were stratified by primary tumor status (known vs. unknown) and tumor location (sun-exposed vs. non-sun-exposed). Disease-free survival (DFS) and overall survival (OS) were estimated using Kaplan–Meier analysis, and multivariate analyses were performed. Results: The cohort included 80 patients diagnosed with stage 3 (with LN involvement) MCC, of whom 52 (65%) had primary MCC with lymph node involvement, and 28 patients (35%) with unknown primary MCC. The majority were male (81.3%), with a median age of 71.2 years (range, 37–92). The median DFS and OS for the entire cohort were 24 and 32 months, respectively. Patients with unknown primary tumors had longer DFS (34 vs. 18 months; p = 0.0503) and OS (43 vs. 28 months; p = 0.0362) compared with those with known primary MCC. Non-sun-exposed tumors were associated with longer median DFS (32 vs. 18.5 months; p = 0.0663) and OS (41 vs. 23 months; p = 0.0353). Five-year survival analysis showed improved outcomes in patients with unknown primary tumors (DFS 54% vs. 35%, p = 0.04; OS 57% vs. 42%, p = 0.03) and in non-sun-exposed tumors (DFS 51% vs. 33%, p = 0.05; OS 57% vs. 40%, p = 0.04). Conclusions: Unknown primary status and non-sun-exposed tumor location are potentially associated with improved long-term survival in patients with MCC. These findings highlight the prognostic importance of tumor origin and anatomical site in MCC management. Full article

Background: Merkel cell carcinoma (MCC) is a rare, aggressive primary cutaneous neuroendocrine carcinoma with a marked propensity for early regional lymph node metastasis. Although MCC most often arises on sun-exposed head and neck skin in older adults, tumors of the lower extremity are uncommon and may be mistaken for benign hemorrhagic lesions. Case presentation: A 54-year-old woman developed a rapidly enlarging, hemorrhagic mass in the left suprapatellar thigh. Magnetic resonance imaging demonstrated an extracompartmental subcutaneous soft-tissue mass without quadriceps muscle invasion. Wide local excision including the quadriceps fascia was performed. Histopathologic examination showed a dermal/subcutaneous small blue round cell neoplasm with brisk mitotic activity. Immunohistochemistry demonstrated diffuse cytoplasmic synaptophysin positivity, paranuclear dot-like CK20 reactivity, chromogranin A positivity, and negative MCPyV staining; TTF-1, S100, melan-A, HMB-45, and hematolymphoid markers were negative. Staging positron emission tomography/computed tomography identified ipsilateral inguinal nodal involvement. Therapeutic inguinal lymph node dissection revealed metastatic MCC in one of four lymph nodes without extranodal extension. The final stage was pT3 pN1b cM0 (AJCC 8th edition), corresponding to stage IIIB disease. Adjuvant radiotherapy (57 Gy in 20 fractions) was delivered to the primary bed and ipsilateral inguinal basin. The patient remains disease-free at 5-year follow-up. Conclusions: Lower-extremity MCC can mimic hemorrhagic or post-traumatic lesions, contributing to diagnostic delay. Persistent or rapidly enlarging “hematoma-like” lesions warrant early biopsy, and timely pathologic nodal staging is essential. Multimodal management can achieve durable control even in node-positive disease Full article

Background: Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neuroendocrine malignancy. The prognostic impact of sun exposure at the primary tumor site in localized and locally advanced MCC remains incompletely defined. We aimed to compare clinicopathologic characteristics and survival outcomes between sun-exposed and non-sun-exposed MCC in a large, multi-center Israeli cohort. Methods: We retrospectively identified 249 patients diagnosed with localized or locally advanced MCC between January 1985 and December 2020. Of these, 225 patients met eligibility criteria and were included in the analysis: 142 with sun-exposed primary tumors (cohort A) and 83 with non-sun-exposed tumors (cohort B). Baseline characteristics included age, sex, tumor size, lymph node (LN) involvement at diagnosis, disease-free survival (DFS), and overall survival (OS). Results: Median age at diagnosis was similar between cohorts (~73 years), with a male predominance in both groups. LN involvement was significantly more frequent in non-sun-exposed tumors compared with sun-exposed tumors (57.0% vs. 30.0%, p < 0.001), while tumor size distribution did not differ significantly. Median DFS was numerically longer in sun-exposed patients (58.0 vs. 47.8 months, p ≈ 0.18), whereas median OS favored non-sun-exposed patients (89.7 vs. 79.7 months, p ≈ 0.21), though neither difference reached statistical significance overall. Females demonstrated longer DFS and OS than males across both cohorts. Among LN-negative patients, non-sun-exposed tumors were associated with significantly improved OS (105.9 vs. 91.4 months, p ≈ 0.03), particularly in males. Primary tumor size further stratified outcomes: non-sun-exposed patients had significantly superior OS for tumors <2 cm and both improved DFS and OS for tumors ≥2 cm. Conclusions: In this large real-world MCC cohort, sun exposure status was associated with distinct patterns of nodal involvement and survival in clinically relevant subgroups. Non-sun-exposed MCC demonstrated favorable survival outcomes, particularly in LN-negative disease and across tumor size categories, suggesting underlying biological differences that merit further investigation. Full article

Background and Clinical Significance Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin malignancy. Early diagnosis is essential to optimize therapeutic strategies and improve prognosis. However, the role of high-frequency ultrasound (HFUS) in the diagnostic and follow-up phases of MCC remains under-investigated and underutilized in clinical practice. Case Presentation We present a case of MCC initially referred to a physiatric outpatient clinic for a functional disorder of the third finger, where HFUS revealed a well-circumscribed, hypoechoic subdermal lesion with central and peripheral vascularity. Surgical excision, histopathology, and immunohistochemistry confirmed the diagnosis of Merkel cell carcinoma. The HFUS findings were correlated with histological features, and a structured sonographic follow-up protocol was established postoperatively. Conclusions This case highlights the diagnostic and prognostic potential of HFUS in MCC, especially in early detection, surgical planning, and longitudinal follow-up. A multidisciplinary approach integrating ultrasound imaging, surgery, and pathology may enhance diagnostic accuracy and patient management. Full article

The incidence of melanoma and non-melanoma skin cancers (NMSCs) is increasing worldwide. While NMSCs are more common, melanoma remains the most challenging because of its higher aggressiveness. Although the use of sunscreens is key in high-risk populations, it provides limited protection, which highlights the need for alternative solutions. In this review, we discuss current evidence on chemopreventive therapies, as well as their efficacy and adverse events, including immunocompetent and immunosuppressed patients. Acitretin, nicotinamide, 5-fluorouracil, and photodynamic therapy have shown overall promising results in actinic keratosis and squamous cell carcinoma. Nevertheless, more research is needed to establish their efficacy, particularly in melanoma, Merkel cell carcinoma, and cutaneous lymphoma, due to their higher mortality rates. Full article

Background and Objectives: Merkel cell carcinoma (MCC) is a rare, aggressive, invasive cutaneous neuroendocrine carcinoma. It commonly affects the skin of the extremities and head and neck regions in elderly patients. In situ MMC represents MMC confined to the epidermis. Incipient MCC is a descriptive term that represents in situ MCC with early focal dermal microinvasion. In situ MCC and incipient MCC have a much better prognosis than MCC. In this study, we aimed to address the clinicopathologic features of early lesions of MCCs, including both incipient and in situ forms. Methods: We conducted a PubMed search using the following keywords: (“Merkel cell carcinoma” OR “Merkel carcinoma” OR “Merkel” OR “MCC”) AND (“in situ” OR “incipient” OR “intraepidermal”) AND (“skin” OR “cutaneous”. The inclusion criteria included (i) human studies, and (ii) case reports and series published in the English language with the above-mentioned search keywords. Studies not meeting all inclusion criteria were excluded. Results: Incipient and in situ MCCs are extremely rare events (15 case reports). They usually appear as tiny (2 mm to 6 mm) erythematous papules or nodules over the skin. Immunohistology (for CK20, EMA, and neuroendocrine markers) was required to establish the diagnosis of these lesions. Conclusions: MCCs carry a significantly high mortality rate due to their aggressive nature. However, for in situ MCC and incipient MCC, local surgical excision is usually curative, and the prognosis is excellent. Therefore, dermatologists and dermatopathologists should remain vigilant for these forms of early lesions of MCCs. This will help with early detection and prompt treatment. Full article

MicroRNAs (miRNAs) have emerged as critical post-transcriptional regulators in melanoma and non-melanoma skin cancers (NMSCs), yet their full biological and clinical significance remains incompletely defined. This review synthesizes current evidence on miRNA dysregulation across basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), Merkel cell carcinoma (MCC), and melanoma, emphasizing their diagnostic, prognostic, and therapeutic relevance. In BCC, distinct miRNA expression signatures differentiate tumor tissue from normal skin and correlate with histopathological subtypes. miR-383-5p, miR-4705, miR-145-5p, and miR-18a show strong diagnostic potential, while downregulation of miR-34a is consistently associated with greater tumor aggressiveness. Subtype-specific profiles further delineate superficial versus infiltrative lesions, highlighting miRNAs as markers of tumor behavior. cSCC similarly demonstrates characteristic miRNA alterations. miR-31 is markedly upregulated during the transition from actinic keratosis to invasive carcinoma, whereas high miR-205 and low miR-203 levels correlate with poor and favorable prognosis, respectively. Regarding MCC, many miRNAs such as miR-375 and miR-182 may present a clinical value for potential biomarkers, as they are upregulated in MCC. Merkel cell carcinoma has also been linked with Merkel cell polyomavirus (MCPyV). Melanoma exhibits a complex miRNA landscape, including oncogenic miR-18a-5p and miR-146a, and tumor-suppressive miR-128-3p. Several miRNAs correlate with metastatic potential, BRAF mutation status, and therapeutic resistance, particularly miR-181a/b, underscoring their potential as predictive biomarkers. Overall, current evidence supports miRNAs as promising diagnostic, prognostic, and predictive biomarkers in cutaneous oncology. Standardized methodologies and large-scale validation remain essential for their integration into routine clinical practice. Full article

Ageing is sustained by a complex network of cellular and molecular mechanisms. The main mechanisms are cellular senescence, telomere attrition, gene expression changes, metabolic dysregulations, oxidative stress and epigenetic modifications such as DNA methylation. All these networks can harbor the initiation of age-related diseases, skin cancer included. The studies published in the last years linking ageing and skin cancers focus on basal and squamous carcinomas, melanomas and Merkel cell carcinomas. Our review will focus on skin melanomas as one of the aggressive skin cancers along with Merkel cell carcinomas. Several long-term studies conducted on large populations have shown that in elderly individuals melanoma related to photo-exposure has doubled in the last decade. The clinic-pathological pattern of skin melanomas is different in aged patients and is guided also by immune-related mechanisms. Besides sun exposure, metabolic deregulations and obesity can be risk factors in melanomas. Controversial results were published on obesity risk in melanomas; however, the adipose tissue favors increased cytokines and growth factors production contributing to melanoma aggressiveness. Moreover, immunotherapy that is not offered in geriatric patients as often as in young ones has proven to be as efficient as in younger ones, although the aged-related co-morbidities can impede the immunotherapy choice. Without being exhaustive, our review has synthesized current research and critically assessed the links between aging as a normal physiological process to the initiation and propagation of skin cancers, focusing on cutaneous melanoma. The review highlights the differences at various levels of skin melanoma developed in aged patients compared to younger one and gives the general outlines for diagnosis, prognosis and therapeutical approaches in aged patients. Full article

Background and Clinical Significance: Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine cutaneous malignancy with increasing incidence among elderly, immunocompromised patients or individuals exposed to ultraviolet radiation. Case Presentation: We present the case of an 84-year-old Caucasian male with no history of immunosuppression, who was admitted for asthenia, dysphagia, weight loss, and generalized weakness. Clinical and imaging investigations revealed a violaceous tumor on the right arm and disseminated metastases affecting the liver, spleen, bones and lymph nodes. A liver biopsy confirmed a small round blue cell neoplasm suggestive for MCC, although immunohistochemistry could not be performed due to the patient’s fulminant deterioration and death within 12 days of admission. Conclusions: This case is notable for its exceptionally rapid progression, particularly splenic involvement, and absence of known immunosuppressive factors. It highlights the existence of highly proliferative MCC subtypes with potential for bypassing classical metastatic pathways. Early clinical suspicion and prompt histological evaluation are essential for diagnosis, although the prognosis remains poor in advanced stages. Due to fulminant deterioration, immunohistochemistry could not be performed; therefore, the diagnosis is highly suggestive based on clinical, imaging, and morphological correlation. Full article

Background/Objectives: Parotid incidentalomas are increasingly detected during brain MRI and PET-CT, particularly in patients with serious diseases such as cancer. This study aimed to evaluate the clinical significance of incidentally identified parotid lesions. Methods: We retrospectively reviewed the records of 44,952 patients (≥19 years) who underwent brain MRI and 10,957 who underwent PET-CT between January 2014 and December 2023. The incidence, imaging findings, and pathological results of parotid incidentalomas were analyzed. Results: Among 44,952 brain MRIs, 100 incidental parotid lesions (0.22%) were detected, compared with 92 lesions (0.84%) among 10,957 PET-CT scans. The mean patient age was slightly higher in the PET-CT group. Of the MRI-detected lesions, 35 patients underwent further evaluation and 14 underwent surgery, with final pathology confirming only benign tumors, including pleomorphic adenomas, Warthin tumors, and basal cell adenomas. In contrast, among 23 PET-CT patients who underwent additional evaluation, 7 had surgery, and final pathology revealed both benign and malignant tumors. Malignant cases included mucoepidermoid carcinoma, metastatic Merkel cell carcinoma, metastatic sebaceous carcinoma, and adenoid cystic carcinoma. Notably, two patients with initially benign cytology and negative PET-CT findings were later confirmed to have malignancies after surgery, Primary sites of metastatic disease included the thyroid, cervix, head and neck, and skin. Conclusions: Most parotid incidentalomas detected on brain MRI are benign and may be managed conservatively. However, incidentalomas identified on PET-CT require thorough evaluation, as they may indicate metastatic disease or a second primary malignancy, particularly in patients with head and neck or skin cancers. Full article