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Avelumab, a programmed cell death ligand 1 blocking antibody, was approved for its first indication in Japan in September 2017 to treat unresectable Merkel cell carcinoma (MCC). Given that the pivotal JAVELIN Merkel 200 study only included a few Japanese patients, this post-marketing surveillance (PMS) evaluated the safety and effectiveness outcomes of patients with MCC who received avelumab in general clinical practice in Japan. This prospective, non-comparative, multicenter PMS included data from all patients with unresectable MCC who received avelumab between November 22, 2017 (avelumab launch date) and October 31, 2019. The primary objective was to evaluate avelumab safety (i.e., adverse events [AEs], adverse drug reactions [ADRs], and ADRs of safety specifications). The secondary objective was to evaluate avelumab effectiveness (i.e., objective response rate and overall survival [OS] rate). Seventy-five evaluable patients were included, of whom 81.3% experienced AEs of any grade (57.3% experienced AEs of grade ≥ 3; 41.3% experienced AEs of grade 5) and 61.3% experienced ADRs (14.7% experienced ADRs of grade ≥ 3; no grade 5 ADRs were observed). The most common ADRs were pyrexia (18.7%), infusion related reaction (10.7%), and chills (6.7%). The most common ADRs of safety specifications were infusion reactions (any grade: n = 21 [28.0%]; grade 3 or 4: n = 3 [4.0%]), thyroid dysfunction (n = 7 [9.3%]), and hepatic function disorders (n = 4 [5.3%]). The median observation period was 51 weeks. An objective response was achieved by 34/75 patients (45.3%; complete response, 24.0%; partial response, 21.3%) and 6- and 12-month OS rates were 77.7% and 59.6%, respectively. This PMS confirmed the clinical tolerability and effectiveness of avelumab in patients with MCC, with no new safety concerns. The risk-benefit profile of avelumab was comparable with that observed in clinical trials and remains favorable for use in general clinical practice in Japan.
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Anticuerpos Monoclonales Humanizados , Carcinoma de Células de Merkel , Neoplasias Cutáneas , Humanos , Carcinoma de Células de Merkel/tratamiento farmacológico , Carcinoma de Células de Merkel/patología , Japón , Anticuerpos Monoclonales/efectos adversos , Estudios Prospectivos , Neoplasias Cutáneas/patología , Vigilancia de Productos ComercializadosRESUMEN
Background: Anti-programmed cell death protein 1 (PD-1) monotherapy is one of the standard systemic therapies for advanced melanoma; however, the efficacy of salvage systemic therapies after PD-1 monotherapy failure (PD-1 MF), particularly in acral melanoma (AM), the main clinical melanoma type in Japanese patients, is unclear. This study aimed to investigate the efficacy of salvage systemic therapies in Japanese patients with AM after PD-1 MF. Patients and methods: The study included 108 patients with advanced AM (palm and sole, 72; nail apparatus, 36) who underwent salvage systemic therapy at 24 Japanese institutions. We mainly assessed the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: Thirty-six (33%) patients received ipilimumab, 23 (21%) received nivolumab and ipilimumab (nivo/ipi), 10 (9%) received cytotoxic chemotherapy, 4 (4%) received BRAF and MEK inhibitors (BRAFi/MEKi), and the remaining 35 (32%) continued with PD-1 monotherapy after disease progression. The ORRs in the ipilimumab, nivo/ipi, cytotoxic chemotherapy, and BRAFi/MEKi groups were 8, 17, 0, and 100%, respectively. The nivo/ipi group showed the longest OS (median, 18.9 months); however, differences in ORR, PFS, and OS between the groups were insignificant. The OS in the nivo/ipi group was higher in the palm and sole groups than in the nail apparatus group (median: not reached vs. 8.7 months, p < 0.001). Cox multivariate analysis demonstrated that nail apparatus melanoma independently predicted unfavorable PFS and OS (p = 0.006 and 0.001). The total OS (from PD-1 monotherapy initiation to death/last follow-up) was insignificant between the groups. Conclusion: Nivo/ipi was not more effective than cytotoxic chemotherapy and ipilimumab after PD-1 MF in patients with advanced AM. The prognosis after PD-1 MF would be poorer for nail apparatus melanoma than for palm and sole melanoma.
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BACKGROUND: Although anti-PD-1 antibody monotherapy (PD-1) is commonly used to treat advanced acral melanoma (AM), its efficacy is limited. Further, data on the efficacy of PD-1 plus anti-CTLA-4 antibody (PD-1+CTLA-4) for the treatment of AM are limited. Therefore, we compared the efficacy of PD-1+CTLA-4 and PD-1 in the treatment of Japanese patients with advanced AM. METHODS: This retrospective study evaluated patients with advanced AM who were treated with PD-1 or PD-1+CTLA-4 as first-line immunotherapy in 24 Japanese institutions between 2014 and 2020. Treatment efficacy focussing on the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) was compared between the two groups. RESULTS: In total, 254 patients (palm and sole melanoma [PSM], n = 180; nail apparatus melanoma [NAM], n = 74) were included. Among the patients with PSM, the ORR (19% vs. 31%; P = 0.44), PFS (5.9 vs. 3.2 months; P = 0.74), and OS (23.1 vs. not reached; P = 0.55) did not differ significantly between the PD-1 and PD-1+CTLA-4 groups. Among the patients with NAM, the ORR (61% vs. 10%; P < 0.001) was significantly higher and PFS was longer (6.4 vs. 3.8 months; P = 0.10) in the PD-1+CTLA-4 group than in the PD-1 group. Cox multivariate analysis demonstrated that PD-1+CTLA-4 is an independent predictor of a favourable PFS in patients with NAM (P = 0.002). CONCLUSIONS: The efficacy of PD-1+CTLA-4 is not superior to that of PD-1 for the treatment of advanced PSM. However, PD-1+CTLA-4 may be more efficacious than PD-1 for the treatment of advanced NAM.
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Melanoma , Receptor de Muerte Celular Programada 1 , Humanos , Estudios Retrospectivos , Ipilimumab/efectos adversos , Japón , Melanoma/tratamiento farmacológico , Inmunoterapia , Factores Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Melanoma Cutáneo MalignoAsunto(s)
Artritis Psoriásica , Fármacos Dermatológicos , Enfermedades Pulmonares Intersticiales , Anticuerpos Monoclonales Humanizados/efectos adversos , Artritis Psoriásica/tratamiento farmacológico , Fármacos Dermatológicos/efectos adversos , Humanos , Enfermedades Pulmonares Intersticiales/inducido químicamente , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Resultado del TratamientoRESUMEN
BACKGROUND: Immune checkpoint inhibitors (ICIs) have a lower efficacy in mucosal melanoma (MUM) than in cutaneous melanoma. The use of combination treatments with radiotherapy (RT) to improve the efficacy in MUM, however, requires further investigation. METHODS: We retrospectively evaluated 225 advanced MUM patients treated with anti-PD-1 monotherapy (PD1; 115) or anti-PD-1 + anti-CTLA-4 combination therapy (PD1+CTLA4; 42) with or without RT (56 and 12, respectively). Treatment efficacy was estimated by determining the objective response rate (ORR) and survival rate with the Kaplan-Meier analysis. RESULTS: The baseline characteristics between the two groups in each ICI cohort were similar, except for Eastern Cooperative Oncology Group performance status in the PD1 cohort. No significant differences in ORR, progression-free survival (PFS), and overall survival (OS) were observed between the PD1 alone and PD1+RT groups in the PD1 cohort (ORR 26% versus 27%, P > 0.99; median PFS 6.2 versus 6.8 months, P = 0.63; median OS 19.2 versus 23.1 months, P = 0.70) or between the PD1+CTLA alone and PD1+CTLA4+RT groups in the PD1+CTLA4 cohort (ORR 28% vs 25%, P = 0.62; median PFS 5.8 versus 3.5 months, P = 0.21; median OS 31.7 versus 19.8 months, P = 0.79). Cox multivariate analysis indicated that RT in addition to PD1 or PD1+CTLA4 did not have a positive impact on the PFS or OS. CONCLUSIONS: A prolonged survival benefit with RT in combination with ICIs was not identified for advanced MUM patients, although RT may improve local control of the tumour and relieve local symptoms.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de Cabeza y Cuello/terapia , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Melanoma/terapia , Membrana Mucosa/patología , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Antígeno CTLA-4/antagonistas & inhibidores , Quimioradioterapia/métodos , Quimioradioterapia/estadística & datos numéricos , Femenino , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/patología , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Estimación de Kaplan-Meier , Masculino , Melanoma/mortalidad , Melanoma/patología , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Supervivencia sin Progresión , Estudios RetrospectivosRESUMEN
Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine carcinoma of the skin associated with Merkel cell polyomavirus and immunosuppression. Although MCC incidence is rising worldwide, MCC has not been sufficiently investigated in Japan. This study aimed to determine MCC demographics in Japan, including incidence, age, sex, location, spontaneous regression, and pure/combined MCC. Using PubMed and Igaku Chuo Zasshi, 847 MCC cases between 1985 and 2015 were extracted, and the main epidemiological characteristics were described. The mean age of all patients was 77.5 years. Regarding the characterized lesions, 63.0% were located on the head and neck, 5.2% on the trunk, 12.6% on the upper limb, 15.1% on the lower limb, 3.5% on the buttocks, and 0.6% on the genitals. Histopathological information regarding the presence of other malignancies could be retrieved in 611 cases, and a coexisting malignancy, mainly squamous cell carcinoma and Bowen's disease, was present in 14.2%. Subcutaneous MCC was observed in 31 patients with a male : female ratio of 1.07 (16 men/15 women). Nodal lesions with unknown primary tumor location were described in 19 patients with a male : female ratio of 0.9 (nine men/10 women) and a mean age of 77.7 years. Of 640 evaluable cases, spontaneous regression developed in 9.1%. Among those 58 patients, the male : female ratio was 1:2.1 in 56 evaluable cases (18 men/38 women). Merkel cell polyomavirus was assessed in 180 patients, and the virus was detected in 31.1% and not detected in 68.9% of the patients. MCC is a rare disease in Japan, with incidence rates and male : female ratios differing from those in the USA and European countries. Besides, this study reveals the high frequency of subcutaneous MCC and MCC with divergent differentiation patterns and spontaneous regression in Japan compared to other countries.
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Carcinoma de Células de Merkel , Poliomavirus de Células de Merkel , Neoplasias Cutáneas , Anciano , Demografía , Femenino , Humanos , Japón , MasculinoRESUMEN
ABSTRACT: In skin containing hair follicles, specialized epithelial structures known as "touch domes (TDs)" are located where the Merkel cells are clustered. We explored the histogenetic relationship between intraepidermal and dermal Merkel cell carcinomas (MCCs) and investigated which transformed progenitor cells can develop into intraepidermal MCC. We encountered an association between an extremely rare case of dermal and intraepidermal MCC with squamous cell carcinoma, which was examined using standard immunohistochemical methods with various epithelial, neuroendocrine, and TD markers including several immunohistochemical markers. Differential expression levels of CK20 and CD56 were found between intraepidermal and dermal MCCs, indicating molecularly distinct MCC populations. CK15 and CK17, expressed in TDs, were partially expressed in the intraepidermal neuroendocrine component at the tumor periphery in intraepidermal MCC with squamous cell carcinoma. These differences may suggest that the origin of dermal and intraepidermal MCCs is different under pathological conditions. We hypothesize that intraepidermal MCC is derived from tissue-specific stem cells localized within TDs.
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Carcinoma de Células de Merkel/patología , Carcinoma de Células Escamosas/patología , Queratinas/análisis , Células de Merkel/patología , Neoplasias Complejas y Mixtas/patología , Células Madre Neoplásicas/patología , Neoplasias Cutáneas/patología , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Carcinoma de Células de Merkel/química , Carcinoma de Células Escamosas/química , Linaje de la Célula , Femenino , Humanos , Inmunohistoquímica , Células de Merkel/química , Neoplasias Complejas y Mixtas/química , Células Madre Neoplásicas/química , Neoplasias Cutáneas/químicaAsunto(s)
Antígeno B7-H1/antagonistas & inhibidores , Carcinoma de Células de Merkel , Infecciones por Virus de Epstein-Barr , Neoplasias Cutáneas , Adulto , Carcinoma de Células de Merkel/radioterapia , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/diagnóstico , Herpesvirus Humano 4 , Humanos , Masculino , Neoplasias Cutáneas/radioterapiaRESUMEN
BACKGROUND: Merkel cell carcinoma (MCC) is a rare and highly malignant skin cancer. Some cases have a good prognosis and spontaneous regression can occur. Reported prognostic markers, such as Merkel cell polyoma virus infection or programmed death ligand-1 (PD-L1) expression, remain insufficient for precisely estimating the vastly different patient outcomes. We performed RNA sequencing to evaluate the immune response and comprehensively estimate prognostic values of immunogenic factors in patients with MCC. METHODS: We collected 90 specimens from 71 patients and 53 blood serum samples from 21 patients with MCC at 10 facilities. The mRNA was extracted from formalin-fixed paraffin-embedded tissues. Next-generation sequencing, immunohistochemical staining and blood serum tests were performed. RESULTS: Next-generation sequencing results classified MCC samples into two types: the 'immune active type' was associated with better clinical outcomes than the 'cell division type'. Expression of the glucose-6-phosphate dehydrogenase (G6PD) gene was highly significantly upregulated in the 'cell division type'. Among 395 genes, G6PD expression correlated with the presence of lymph node or distant metastases during the disease course and significantly negatively correlated with PD-L1 expression. Immunohistochemical staining of G6PD also correlated with disease-specific survival and exhibited less heterogeneity compared with PD-L1 expression. G6PD activity could be measured by a blood serum test. The detection values significantly increased as the cancer stage progressed and significantly decreased after treatment. CONCLUSIONS: G6PD expression was an immunohistochemically and serum-detectable prognostic marker that negatively correlated with immune activity and PD-L1 levels, and could be used to predict the immunotherapy response.
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Antígeno B7-H1/inmunología , Carcinoma de Células de Merkel/inmunología , Glucosafosfato Deshidrogenasa/inmunología , Neoplasias Cutáneas/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/biosíntesis , Antígeno B7-H1/genética , Carcinoma de Células de Merkel/genética , Carcinoma de Células de Merkel/metabolismo , Carcinoma de Células de Merkel/patología , Femenino , Expresión Génica , Glucosafosfato Deshidrogenasa/genética , Humanos , Masculino , Persona de Mediana Edad , ARN Neoplásico/genética , ARN Neoplásico/metabolismo , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Regulación hacia ArribaRESUMEN
BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is the second most common type of skin cancer. Few patients with cSCC experience metastases, but the prognosis of advanced cSCC (acSCC) is dismal. Evidence regarding systemic therapy for acSCC is limited. Therefore, we aimed to determine the most effective systemic treatment for acSCC. PATIENTS AND METHODS: This retrospective study involved 16 Japanese institutions. We documented patient and tumour characteristics and disease course of patients with acSCC who received systemic therapy between 1st January 2006 and 31st December 2015. We compared the overall survival (OS) and progression-free survival (PFS) for (1) platinum versus non-platinum groups, (2) radiation plus chemotherapy first-line therapy (RCT) versus non-RCT groups and (3) platinum-based RCT versus non-platinum-based RCT groups. RESULTS: Although the use of platinum-based systemic therapy was not associated with statistically significant improvements in PFS and OS, there were significant differences between the RCT and non-RCT groups (PFS: p < 0.001, OS: p = 0.003). In the subgroup analysis, RCT significantly prolonged PFS and OS in the nodal SCC (nSCC) group. For the RCT and non-RCT groups, the median OS was 110 and 14 months, respectively, and the 5-year OS rate was 54% and 21%, respectively. CONCLUSION: RCT could improve OS in patients with nSCC. However, further multicenter prospective studies are needed to establish evidence for superiority of RCT.
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Antineoplásicos/uso terapéutico , Carcinoma de Células Escamosas/mortalidad , Quimioradioterapia/mortalidad , Cisplatino/uso terapéutico , Radioterapia/mortalidad , Neoplasias Cutáneas/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapia , Tasa de SupervivenciaAsunto(s)
Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinoma de Células de Merkel/mortalidad , Neoplasias Cutáneas/mortalidad , Piel/patología , Anciano , Anciano de 80 o más Años , Biopsia , Carcinoma de Células de Merkel/patología , Carcinoma de Células de Merkel/cirugía , Femenino , Humanos , Japón/epidemiología , Estimación de Kaplan-Meier , Masculino , Pronóstico , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/cirugíaRESUMEN
The cellular origin of Merkel cell carcinoma (MCC) is controversial. We previously hypothesized that MCC originates from hair follicle stem cells or Merkel cell (MC) progenitors residing within the hair follicle bulge. Examination of three cases of combined MCC led to the unexpected discovery that numerous keratin 20 (CK20)-positive MCs within the squamous cell carcinoma (SCC) component of combined MCC appeared morphologically normal with dendritic and oval shapes. Moreover, one extremely rare case of combined SCC and MCC showed both intra-epidermal and dermal MCCs. These three cases represent the first documentation of MC hyperplasia in MCC, besides various benign follicular neoplasms associated with MC hyperplasia. Therefore, to elucidate the proliferating potential of MCs and their histogenetic relationship with MCCs, we further investigated these cases based on pathological observations. We identified numerous cells co-expressing CK20 and the proliferation marker Ki-67, identical to the morphological and immunohistochemical features of normal MCs. This finding indicated that MCs can no longer be considered as pure post-mitotic cells. Instead, they have proliferative potential under specific conditions in the diseased or wounded skin, or adjacent to various skin tumors, including MCC. Intimate co-existence of two malignant cell components composed of intradermal and intra-epidermal MCCs, with the proliferation of normal-appearing MCs in the same lesion, lends support to the hypothesis that MCs and MCC cells are derived from MC progenitors residing within the hair follicle bulge. Specifically, MCCs are derived from transformed MC progenitors with potential for dual-directional differentiation towards neuroendocrine and epithelial lineages.
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Carcinoma de Células de Merkel/patología , Proliferación Celular , Células de Merkel/fisiología , Anciano , Anciano de 80 o más Años , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Queratina-20/inmunología , Antígeno Ki-67 , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Coloración y EtiquetadoRESUMEN
Merkel cell carcinoma is a rare neuroendocrine carcinoma of the skin that is associated with Merkel cell polyomavirus (MCPyV). The clinical appearance and demographic characteristics of this tumor have been described using the mnemonic AEIOU: asymptomatic, expanding rapidly, immune suppression, older than 50 years, and ultraviolet-exposed fair skin. In addition, MCC can be categorized based on morphology as pure MCC or combined MCC that exhibits neuroendocrine and other phenotypic elements. There is limited information regarding the clinical characteristics and prognosis of combined MCC. This retrospective study aimed to identify factors, such as ulceration or hyperkeratosis, that could predict MCPyV status and morphological variants. Twenty patients with MCC were divided into groups based on MCPyV status and morphology: MCPyV-positive or MCPyV-negative MCC and pure or combined MCC. The patients' MCPyV status was immunohistochemically determined using the CM2B4 antibody to the MCPyV large T-antigen. The patients' clinicopathological characteristics were evaluated to identify predictors of MCPyV-negative MCC and combined MCC. The presence of ulceration/hyperkeratosis predicted the presence of MCPyV-negative MCC (80% of cases) and combined MCC (50% of cases). None of the 10 patients with MCPyV-positive MCC had ulceration/hyperkeratosis. The clinical presence of ulceration/hyperkeratosis may help guide the diagnosis of MCPyV-negative MCC and combined MCC.
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Carcinoma de Células de Merkel/virología , Poliomavirus de Células de Merkel , Neoplasias Cutáneas/virología , Anciano , Anciano de 80 o más Años , Carcinoma de Células de Merkel/complicaciones , Carcinoma de Células de Merkel/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Piel/patología , Neoplasias Cutáneas/complicaciones , Neoplasias Cutáneas/patología , Úlcera/etiologíaRESUMEN
OPINION STATEMENT: Merkel cell carcinoma (MCC) is a rare but highly aggressive neuroendocrine carcinoma of the skin, with frequent recurrences, metastasis, and a high mortality rate. For primary or locoregional MCC, a wide local excision followed by radiation therapy is the basic treatment modality for preventing recurrence at the primary site and involved lymph nodes. Cytotoxic chemotherapy has been commonly used to treat patients with metastatic MCC, but not as an adjuvant therapy for high-risk resected MCC. Although MCC is often chemotherapy-sensitive in the first-line setting, responses are rarely durable and most patients subsequently relapse and develop metastasis. Treatment with checkpoint inhibitors (CPIs) has shown a major advancement in the treatment of advanced MCC. Systemic therapy against programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) is associated with a high objective response rate (ORR), prolonged durable responses, and good tolerability in advanced-stage MCC. CPIs are now included in the National Comprehensive Cancer Network (NCCN) guidelines for the treatment of patients with metastatic MCC. Multiple clinical trials of CPIs administered as monotherapy or in combination with other agents or modalities, including the adjuvant setting, are ongoing. Immunotherapy offers a promising future for patients with MCC. In this review, we present an overview of emerging data on immunotherapy, especially CPIs of the PD-1/PD-L1 pathway, for patients with advanced MCC.
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Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Células de Merkel/tratamiento farmacológico , Inmunoterapia/métodos , Neoplasias Cutáneas/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Carcinoma de Células de Merkel/patología , Terapia Combinada/métodos , Humanos , Recurrencia Local de Neoplasia/prevención & control , Nivolumab/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias Cutáneas/patologíaRESUMEN
Merkel cell carcinoma (MCC) is a rare but more lethal cutaneous cancer than melanoma. However, spontaneous regression of a number of MCC has been reported, although the cause of this regression remains unclear. In most cases, MCC regresses after a surgical procedure, for example, biopsy. Herein, we report a case of Merkel cell polyomavirus-negative MCC coincident with squamous cell carcinoma (SCC) that underwent true spontaneous regression without biopsy. One month after the patient's first visit, clinical examination revealed that the tumor had not grown, but its surface showed changes in texture and color. Histopathologically, the excised specimen was indicative of MCC coincident with SCC and showed extensive necrosis in the upper portion of the tumor, numerous caspase-3-positive apoptotic cells, an accumulation of CD68-positive foam cells and vascular invasion. These findings suggested that the tumor had regressed. We hypothesize that extensive coagulative necrosis resulting from an insufficient local blood supply triggered the shedding of some products or components of MCC and SCC, which in turn induced antitumor immunity against both lesions.