Usefulness of ulceration and hyperkeratosis as clinical predictors of Merkel cell polyomavirus‐negative and combined Merkel cell carcinoma: A retrospective study

Nagase, Kotaro; Kimura-Kaku, Hiromi; Inoue, Takuya; Shinogi, Taro; Narisawa, Yutaka

doi:10.1111/1346-8138.14743

Cited by 5 publications

(4 citation statements)

References 35 publications

(69 reference statements)

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“…In this study, ulceration was present in 29.5% (23/55) of primary tumors, with previous reports ranging between 6.7-40% [23][24][25][26]28]. Ulceration associated with absence of the virus and a high N:CD8, with the latter suggesting that ulceration may contribute to a tumor-supporting microenvironment by attracting neutrophils to the wound and surrounding tumor cells, in line with what has been previously shown in melanoma [16,29]. Neutrophils, inflammation and UV exposure can suppress the levels and functions of CD8 lymphocytes and induce inflammation and a local immune-suppressive microenvironment [30,31].…”

Section: Discussionsupporting

confidence: 90%

Tumor Ulceration, Reduced Infiltration of CD8-Lymphocytes, High Neutrophil-to-CD8-Lymphocyte Ratio and Absence of MC Virus are Negative Prognostic Markers for Patients with Merkel Cell Carcinoma

Naseri

Steiniche

Georgsen

et al. 2020

Cancers

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(1) Background: Merkel cell carcinoma (MCC) is caused by the Merkel cell polyomavirus and UV radiation. Understanding of the underlying biology is limited, but identification of prognostic markers may lead to better prognostic stratification for the patients. (2) Methods: Ninety patients diagnosed with MCC (1996–2012) were included. Virus status was estimated by polymerase chain reaction (qPCR) and immunohistochemistry (IHC). Ulceration status, PD-L1, cd66b neutrophils, cd8 lymphocytes and biomarkers of vascularization (cd34 endothelial cells) and migration (e-cadherin) were estimated by IHC and analyzed with digital pathology. (3) Results: Virus was present in 47% of patient samples and correlated with lower E-cadherin expression (p = 0.0005), lower neutrophil-to-CD8 lymphocyte ratio (N:CD8 ratio) (p = 0.02) and increased PD-L1 expression (p = 0.03). Ulceration was associated with absence of virus (p = 0.03), increased neutrophil infiltration (p < 0.0001) and reduced CD8 lymphocyte infiltration (p = 0.04). In multivariate analysis, presence of virus (p = 0.01), ulceration (p = 0.05) and increased CD8 lymphocyte infiltration (p = 0.001) showed independent prognostic impacts on MCC-specific survival. (3) Conclusions: In this study, we found that a high N:CD8 ratio, ulceration, virus-negative status and absence of CD8 lymphocytes are negative prognostic markers. Accurate prognostic stratification of the patients may be important in the clinical setting for determination of adjuvant treatment.

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Section: Discussionsupporting

confidence: 90%

Tumor Ulceration, Reduced Infiltration of CD8-Lymphocytes, High Neutrophil-to-CD8-Lymphocyte Ratio and Absence of MC Virus are Negative Prognostic Markers for Patients with Merkel Cell Carcinoma

Naseri

Steiniche

Georgsen

et al. 2020

Cancers

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“…However, information is scarce in the literature regarding the relationship between clinical features such as erosion, ulceration, or hyperkeratosis and histopathological subtypes. Clinicians should pay attention to the presence or absence of ulceration or hyperkeratosis because it is an important clinical predictor of MCPyV‐negative and combined MCC 42 . Because the erosion/ulcer type tended to be larger in size compared to the non‐erosion/ulcer type, necrotic MCC changes due to external irritation/trauma or insufficient blood supply of the surface area are possible.…”

Section: Discussionmentioning

confidence: 99%

“…Merkel cell carcinoma is usually described as firm-elastic and painless red to livid hemispherical tumors that can develop rapidly without specific clinical features. 12,[38][39][40][41] Because we noticed in a small case series that ulceration and hyperkeratosis clinically indicated MCPyV-negative and combined MCC, 42 we focused in the current Japanese cases on the presence or absence of skin surface symptoms such as erosion/ulceration. In this study, 30% of cases presented with erosion or ulcer.…”

Section: Discussionmentioning

confidence: 99%

Merkel cell carcinoma: A systematic review of the demographic and clinical characteristics of 847 cases in Japan

Shinogi

Nagase

Inoue

et al. 2021

The Journal of Dermatology

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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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“…[ 26 ] Pure MCCs are localized in the dermis with no epidermal involvement, whereas combined MCC often exhibit epithelial changes, such as ulceration and hyperkeratosis. [ 27 ] Patients with combined MCC, comparing with those with pure MCC were older (median 76.5 vs 69 years) and had more nonmelanoma skin cancer (85% vs 25%), malignant extracutaneous tumors (25% vs 5%), and immunodeficient states (77% vs 35%). Patients with combined MCC had more metastases (77% vs 40%) and shorter survival (41 vs 54 months) than those with pure MCC.…”

Section: Classificationmentioning

confidence: 99%

A review on the oncogenesis of Merkel cell carcinoma: Several subsets arise from different stages of differentiation of stem cell

Zhu

Yin

et al. 2023

Medicine

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Merkel cell carcinoma (MCC), a rare primary cutaneous neuroendocrine neoplasm, is extremely aggressive and has a higher mortality rate than melanoma. Based on Merkel cell polyomavirus (MCPyV) status and morphology, MCCs are often divided into several distinct subsets: pure MCPyV-positive, pure MCPyV-negative, and combined MCC. MCPyV-positive MCC develops by the clonal integration of viral DNA, whereas MCPyV-negative MCC is induced by frequent ultraviolet (UV)-mediated mutations, that are characterized by a high mutational burden, UV signature mutations, and many mutations in TP53 and retinoblastoma suppressor gene ( RB1 ). Combined MCC consists of an intimate mix of MCC and other cutaneous tumor populations, and is usually MCPyV-negative, with rare exceptions. Based on the existing subsets of MCC, it is speculated that there are at least 4 stages in the natural history of stem cell differentiation: primitive pluripotent stem cells, divergent differentiated stem cells, unidirectional stem cells, and Merkel cells (or epidermal/adnexal cells). In the first stage, MCPyV may integrate into the genome of primitive pluripotent stem cells, driving oncogenesis in pure MCPyV-positive MCC. If MCPyV integration does not occur, the stem cells enter the second stage and acquire the ability to undergo multidirectional neuroendocrine and epidermal (or adnexal) differentiation. At this stage, accumulated UV-mediated mutations may drive the development of combined MCC. In the third stage, the stem cells differentiate into unidirectional neuroendocrine stem cells, UV-mediated mutations can induce carcinogenesis in pure MCPyV-negative MCC. Therefore, it has been speculated that several subsets of MCCs arise from different stages of differentiation of common stem cells.

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Usefulness of ulceration and hyperkeratosis as clinical predictors of Merkel cell polyomavirus‐negative and combined Merkel cell carcinoma: A retrospective study

Cited by 5 publications

References 35 publications

Tumor Ulceration, Reduced Infiltration of CD8-Lymphocytes, High Neutrophil-to-CD8-Lymphocyte Ratio and Absence of MC Virus are Negative Prognostic Markers for Patients with Merkel Cell Carcinoma

Tumor Ulceration, Reduced Infiltration of CD8-Lymphocytes, High Neutrophil-to-CD8-Lymphocyte Ratio and Absence of MC Virus are Negative Prognostic Markers for Patients with Merkel Cell Carcinoma

Merkel cell carcinoma: A systematic review of the demographic and clinical characteristics of 847 cases in Japan

A review on the oncogenesis of Merkel cell carcinoma: Several subsets arise from different stages of differentiation of stem cell

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