Morphological, immunohistochemical and genetic aspects of acinar and ductal adenocarcinoma of the prostate

Abstract: Prostate cancer is one of the most common causes of cancer-related death in developed countries. Acinar adenocarcinoma is by far the most common subtype of prostate cancer, with ductal adenocarcinoma being the second most common subtype. Biobanking of prostate cancer tissue is important for basic research, development of new biomarkers and a move towards personalized medicine. Various biobanking techniques have been described but harvesting of tissue is still often based on macroscopic identification of cancer in radical prostatectomy specimens. In the literature, the macroscopic features of prostate cancer in unfixed prostatectomy specimens are incompletely described. In our first study, we investigated the macroscopic features of identifiable tumors and their zonal distribution in 514 radical prostatectomy specimens. Grossly detected findings conclusive for cancer were seen in 52% of cases and suspicious for cancer in 24%. Macroscopic findings conclusive for cancer predicted microscopic identification of prostate cancer on microscopic examination in most cases. Cancers ≥2 mm were present somewhere on the cut surface in the majority of cases even when no suspicious or conclusive cancers had been identified macroscopically. Tumors in the transition zone of the prostate were more difficult to identify macroscopically. In our second study, we report a novel biobanking protocol for harvesting a full horizontal slice of unfixed prostate tissue from 20 radical prostatectomy specimens. In 18 of 20 cases, cancer was found in the biobanked tissue material. The biobanking protocol facilitated harvesting of a large slice of prostatic tissue, allowing studies of multifocal tumors and tumor heterogeneity. Clinical histopathological parameters could be reported from frozen sections of the biobanked material. The morphological quality, using cryogel, and the RNA quality, measured by RNA integrity number (RIN), were excellent. Ductal adenocarcinoma is a high-grade neoplasm with an adverse prognosis compared to acinar adenocarcinoma. The definition of ductal adenocarcinoma is based on histological features. Ductal adenocarcinoma usually presents in mixed tumors together with acinar adenocarcinoma. For a long time, the histogenesis and definition of ductal adenocarcinoma has been controversial. Some studies have suggested that acinar and ductal adenocarcinoma components may have a common clonal background. Expression of Programmed Death Ligand-1 (PD-L1) is a predictive biomarker for a new group of oncological drugs, immune checkpoint inhibitors. The frequency of PD-L1 expression in ductal adenocarcinoma is not well described. Deficient mismatch repair (dMMR) results in an accumulation of mutations in cancer cells. dMMR has been reported to be uncommon in prostate cancer. In our third study, we investigated the expression of PD-L1, dMMR and tumor infiltrating immune cells in acinar and ductal adenocarcinoma using a tissue microarray (TMA). PD-L1 expression in tumor cells was rare but more common in tumor infiltrating immune cells. PD-L1 expression was identified in tumor infiltrating immune cells in 29% of ductal adenocarcinomas. dMMR was rare, identified in only 5% of cases. There was a statistically significant increase in the number of CD8+ lymphocytes in ductal adenocarcinoma compared to acinar adenocarcinoma. In our final study, we investigated the clonal relationship between acinar and ductal adenocarcinoma components in mixed prostate cancers. Targeted sequencing was performed in 15 cases, followed by bioinformatic processing and manual curation of data. A common somatic denominator for both tumor components could be identified in 12 out of 15 cases indicating a common clonal origin. Increased ploidy, which is associated with advanced prostate cancer, was seen in more than half (53%) of ductal adenocarcinomas but not in any acinar adenocarcinoma. PTEN and CTNNB1 mutations were common in ductal adenocarcinoma (40%) but not seen in any acinar adenocarcinoma. In both acinar and ductal adenocarcinomas, ERG gene fusions were detected in 47%. No cases showed microsatellite instability or high tumor mutation burden. The genetic signature of ductal adenocarcinoma was consistent with its characterization of ductal adenocarcinoma as an aggressive form of prostate cancer