Background: The complete loss of S-methyl-5′-thioadenosine phosphorylase (MTAP) expression, often due to homozygous 9p21 deletion, creates a druggable vulnerability in cancer cells. Methods: A total of 769 primary pancreatic ductal adenocarcinomas were analyzed on tissue microarrays with MTAP immunohistochemistry (IHC) and 9p21 fluorescence in situ hybridization (FISH). Intratumoral heterogeneity was assessed on a “heterogeneity” TMA containing up to nine samples from different areas of 236 primary tumor and nodal metastases, and whole sections of all tumor blocks from 19 cancers. Results: MTAP expression loss was found in 181 (37.9%) of 478 interpretable primary tumors and was unrelated to pT, pN, grade, and tumor size. MTAP expression loss was homogenous in 37.6% and heterogeneous in 1.1% of the 181 tumors, with at least three evaluable samples on the heterogeneity TMA. On whole sections, 1 of 19 tumors showed heterogeneous MTAP loss. The correlation between IHC and FISH was nearly perfect, with 98.8% of MTAP-deficient samples showing a 9p21 deletion. Conclusions: MTAP expression loss is frequent, caused by homozygous deletion, and mostly homogeneous in pancreatic ductal adenocarcinomas. Considering also their aggressive clinical behavior, pancreatic adenocarcinomas may represent an ideal cancer type for studying new drugs targeting MTAP-deficient cancer cells in clinical trials.

Backround: Anterior gradient 2 (AGR2) is a resident endoplasmic reticulum (ER) protein with a vital role in embryonal development, mucus maturation, tissue regeneration, and wound healing. Methods: To determine the prevalence and clinical significance of AGR2 expression in cancer, a tissue microarray containing 14,966 tumors from 134 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry (IHC). Results: AGR2 positivity was found in 103 of 134 tumor categories, and 83 tumor categories contained at least one strongly positive case. AGR2 expression was most frequently seen in tumors of the female genital tract, particularly adenocarcinomas (up to 100%), various breast cancer subtypes (57.1%–100%), urothelial carcinoma (74.6%–100%), adenocarcinomas of the upper and lower gastrointestinal tract (93.6%–99.6%), and pancreaticobiliary cancers (65.2%–98.2%). AGR2 positivity was slightly less common in squamous cell carcinomas (46.4%–77.3%) and mainly absent in mesenchymal and lymphoid tumors. While AGR2 expression was only weak or absent in the normal thyroid, it was moderate to strong in 46.0% of adenomas, 52.8% of follicular carcinomas, and 81.8% of papillary carcinomas of the thyroid. High AGR2 expression was strongly linked to poor ISUP ( p < 0.0001), Fuhrman ( p < 0.0001), and Thoenes ( p < 0.0001) grades as well as advanced pT stage ( p = 0.0035) in clear cell renal cell carcinoma (ccRCC). Low AGR2 expression was associated with high BRE grade in breast cancer ( p = 0.0049), nodal metastasis ( p = 0.0275) and RAS mutation ( p = 0.0136) in colorectal cancer, nodal metastasis ( p = 0.0482) in endometrioid endometrial carcinoma, high grade in noninvasive urothelial carcinoma ( p = 0.0003), and invasive tumor growth in urothelial carcinoma ( p < 0.0001). Conclusions: It is concluded that AGR2 expression occurs in a broad range of different tumor entities and that AGR2 assessment may serve as a diagnostic aid for the distinction of thyroidal neoplasms and as a prognostic marker in various cancer types.

Colorectal carcinomas are a rare but possible complication in an interposed colonic segment used for reconstruction after esophagectomy. We report the case of a patient who underwent colonic interposition surgery in childhood due to esophageal atresia and was diagnosed with colorectal adenocarcinoma of the interposed colon ~57 years later. The patient underwent gastric pull-up after thoraco-abdominal resection of the colonic interposition en bloc with the adjacent remaining esophagus.

Background: Carbohydrate antigen 19–9 (CA19‐9) is a cell surface glycoprotein widely used as a diagnostic and prognostic serum marker for monitoring pancreatic cancer. The aim of this study was to evaluate the prevalence and clinical relevance of CA19‐9 expression in human cancer. Methods: To comprehensively determine the prevalence and clinical relevance of CA19‐9 expression in cancer, a tissue microarray containing 14,966 samples from 134 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. Results: The staining results were categorized into four groups according to the percentage of CA19‐9‐positive tumor cells and the staining intensity. At least an occasional CA19‐9 positivity was found in 79 of 134 tumor categories with 66 containing at least one strongly positive case. CA19‐9 positivity was most frequent in biliopancreatic adenocarcinomas (84.4%–95.4%), adenocarcinomas of the upper and lower gastrointestinal tract (54.7%–74.4%), embryonal carcinomas of the testis (93.5%), and endometrioid endometrial carcinomas (87.5%). High CA19‐9 staining was associated with advanced pT‐stage, pN1, L1 ( p < 0.0001 each), V1 ( p = 0.0239), mismatch repair protein deficiency ( p = 0.0067), and BRAF V600E mutation ( p = 0.0005) in colorectal adenocarcinoma. Reduced CA19‐9 staining was associated with distant metastasis ( p = 0.0067) in clear cell renal cell carcinoma, advanced pT‐stage ( p = 0.0277) in papillary renal cell carcinoma, high grade ( p = 0.0129) in breast cancer and with invasive tumor growth (pTa vs. pT2‐4, p < 0.0001) and high grade ( p = 0.0367) in urothelial carcinoma. Conclusions: It is concluded that a high CA19‐9 expression, as found in pancreatic adenocarcinoma, occurs in subsets of various other cancer types. Patients with such tumors could potentially benefit from CA19‐9 serum monitoring, for example in terms of response to treatment, recurrence or predicting prognosis. Cancer type dependent associations between high or low CA19‐9 expression and aggressive tumor phenotype are in line with the complex and variable functional role described for CA19‐9 in cancer.

The stimulator of interferon genes (STING) is expressed on various cell types and tumour entities, where it might enhance antitumoural effects of the immune system and impact tumour angiogenesis. However, the clinical significance of STING expression in tumour cells as compared to tumour-associated inflammatory cells is not fully resolved. To evaluate the clinical significance of STING expression in different cell types of colorectal cancer (CRC), 1,905 patients were analysed by multiplex fluorescence immunohistochemistry in a tissue microarray format in combination with a deep learning algorithm for automated cell detection. High STING expression on tumour was associated with microsatellite instability (MSI, p<0.0001), low tumour stage (pT, p=0.0013), absence of nodal metastasis (pN, p=0.0003) and tumour localisation in the right colon (p<0.0001). Subgroup analysis of tumours with and without MSI did not show associations between STING expression on tumour cells and pT or pN. While the number of CD68^- leukocytes and macrophages was related to MSI, low pT ​and pN0, there were significant associations between a high percentage of STING-positive macrophages and CD68^- leukocytes to low pT (p<0.0001 each) and the absence of metastases for a high percentage of STING-positive macrophages (p=0.0033). In summary, our data show that high STING expression in tumour cells is strongly linked to MSI while STING expression on macrophages and CD68^- leukocytes is tightly linked to the extent of tumour-associated inflammation in CRC.

Background: Claudin 3 (CLDN3) is a transmembrane protein which forms tight junctions (TJs) together with other claudins, occludin, and junctional adhesion molecules. Because of its membranous localization CLDN3 is a potential therapeutic target. Altered CLDN3 has been proposed as a prognostic feature in lung cancer and other tumors. Material and Methods: To better understand the prevalence of expression and its impact on the prognosis of different lung cancer subtypes, we investigated CLDN3 expression by immunohistochemistry in a set of tissue microarrays containing 858 resected lung cancers. Results: CLDN3 positivity was markedly more frequent and more intense in pulmonary adenocarcinoma (AC, 95.9% positive) than in squamous cell carcinoma (SCC, 53.3%; p< 0.0001). Among 444 ACs, CLDN3 staining was strong in 64.2%, moderate in 25.0%, weak in 6.8% and negative in 4.1%. In 214 SCCs, CLDN3 staining was strong in 6.1%, moderate in 11.7%, weak in 35.5% and negative in 46.7%. Reduced CLDN3 staining was significantly linked to advanced pT stage in both AC and SCC (p< 0.0001 each). The fraction of strongly positive cases decreased markedly from pT1 (AC: 67.6%; SCC: 11.1%) to pT4 (47.2%/1.8%). Low CLDN3 expression was also linked to nodal metastasis (p=0.0339) and R+ status (p = 0.0068) in SCCs. Absent or reduced CLDN3 staining was significantly associated with shortened overall survival in pulmonary ACs (p=0.0235) and SCCs (p=0.0330). Conclusion: It is concluded that CLDN3 expression is common in lung cancer, that its level of expression is higher in AC than in SCC, and that a reduced expression level is associated with unfavorable outcome in both SCC and AC. Once anti-CLDN3 targeted drugs should prove to be safe and efficient, NSCLC may represent a major application for such treatments.