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Immunohistochemical analysis of mismatch repair (MMR) protein expression is widely used to identify tumors with a deficient MMR (dMMR). MMR proteins (MLH1/PMS2 and MSH2/MSH6) work as functional heterodimers, which usually leads to the loss of expression in only one functional MMR heterodimer. Recently, there have been studies showing the simultaneous loss of immunoexpression in proteins of both heterodimers. Yet, this phenomenon has been rarely investigated. In this study, we retrospectively considered cases of different digestive system cancers (gastric cancer, ampullary cancer, small bowel cancer, colorectal cancer), which were immunohistochemically tested for dMMR within a 4-year period at our university hospital (n=352). Of the 103 cases showing dMMR, 5 cases (1.4% of all, 5.1% of dMMR cases) showed a concurrent loss of MLH1, PMS2 and MSH6 immunoexpression, whereas in the other 98 dMMR cases only one MMR heterodimer was affected. MLH1-/PMS2-/MSH6- cancer cases almost arose throughout the entire digestive tract: from the gastric antrum to the left colic flexur. To provide a comprehensive molecular characterization of this MLH1-/PMS2-/MSH6- immunophenotype, tumors were analyzed for microsatellite instability, MLH1 promotor hypermethylation and BRAF exon 15 status. Furthermore, we performed next-generation sequencing focusing on genes related to DNA repair. Here, we could detect pathogenic germline variants as well as multiple sporadic mutations in different genes involved in MMR and homologous recombination repair (HRR) respectively. The affected MMR/HRR-related genes were: ATM, BARD1, BRCA1, CDK12, CHEK1, CHEK2, FANCA, MLH1, MSH6, PALB2, TP53. Considering the biologic function of HRR/MMR proteins as potential drug targets and the low frequency of most of these mutations in digestive system cancers in general, their common occurrence in our MLH1-/PMS2-/MSH6- cases seems to be even more noteworthy, highlighting the need for recognition, awareness and further investigation of this unusual IHC staining pattern.

The high mortality of COVID-19 is mostly attributed to acute respiratory distress syndrome (ARDS), whose histopathological correlate is diffuse alveolar damage (DAD). Furthermore, severe COVID-19 is often accompanied by a cytokine storm and a disrupted response of the adaptive immune system. Studies aiming to depict this dysregulation have mostly investigated the peripheral cell count as well as the functionality of immune cells. We investigated the impact of SARS-CoV-2 on antigen-presenting cells using multiplexed immunofluorescence. Similar to MERS-CoV and SARS-CoV, SARS-CoV-2 appears to be impairing the maturation of dendritic cells (DCs). DC maturation involves a switch in surface antigen expression, which enables the cells' homing to lymph nodes and the subsequent activation of T-cells. As quantitative descriptions of the local inflammatory infiltrate are still scarce, we compared the cell population of professional antigen-presenting cells (APC) in the lungs of COVID-19 autopsy cases in different stages of DAD. We found an increased count of myeloid dendritic cells (mDCs) in later stages. Interestingly, mDCs also showed no significant upregulation of maturation markers in DAD-specimens with high viral load. Accumulation of immature mDCs, which are unable to home to lymph nodes, ultimately results in an inadequate T-cell response.