Abstract
There exist relatively sparse and conflicting data on high-level microsatellite instability (MSI-H) and deficient mismatch repair (dMMR) in cutaneous malignancies. We aimed to determine the expression profiles of MMR proteins (MSH2, MSH6, MLH1, and PMS2) in different progression stages of cutaneous squamous cell carcinoma (cSCC, 102 patients in total) by immunohistochemistry, and search for MSI-H in patients with low-level MMR or dMMR using multiplex-PCR. Low-level MMR protein expression was observed in five patients: One patient with primary cSCC < 2 mm thickness and low-level MLH1, three patients with primary cSCC > 6 mm (including one with low-level MSH2, as well as MSH6 expression, and two with low-level PMS2), and one patient with a cSCC metastasis showing low-level MSH2 as well as MSH6. Intergroup protein expression analysis revealed that MLH1 and MSH2 expression in actinic keratosis was significantly decreased when compared to Bowen’s disease, cSCC < 2 mm, cSCC > 6 mm, and cSCC metastasis. In cases with low-level MMR, we performed MSI-H tests revealing three cases with MSI-H and one with low-level MSI-L. We found low-level MMR expression in a small subset of patients with invasive or metastatic cSCC. Hence, loss of MMR expression may be associated with tumour progression in a small subgroup of patients with non-melanoma skin cancer.
Highlights
Non-melanoma skin cancer (NMSC) is one of the most common human cancers, with steadily rising incidences
We studied 102 patients with, in total, actinic keratoses (AK), Bowen’s disease (BD), invasive cutaneous squamous cell carcinoma (cSCC) < 2 mm tumour thickness, invasive cSCC > 6 mm tumour thickness, and 20 cSCC metastases, (Table 1)
Intergroup protein expression analysis revealed that MLH1 and MSH2 in AK was significantly (p = 0.014 and p = 0.0065, respectively) decreased when compared to BD, cSCC < 2 mm, cSCC > 6 mm (99.5% and 99.2%), and cSCC metastases (cSCC-M) (99.4% and 98.6%, respectively)
Summary
Non-melanoma skin cancer (NMSC) is one of the most common human cancers, with steadily rising incidences. The main subtypes of NMSC, basal cell carcinoma and cutaneous squamous cell carcinoma (cSCC), account for about 99% of all NMSCs [1]. CSCC can be curatively managed by means of surgery. Advanced cSCC, which cannot be treated by surgery and/or radiotherapy, may be a life-threatening condition [2]. A novel treatment approach with the immune checkpoint inhibitor (ICI) cemiplimab, a potent monoclonal antibody directed against programmed cell death 1 protein (PD-1) receptor, has been approved as monotherapy for adult patients with metastatic or locally advanced cSCC who are not candidates for surgery or radiotherapy. Recent data suggest that about 50% of patients may durably respond to PD-1 inhibitors such as cemiplimab, pembrolizumab, and nivolumab [2,3]
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