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Abstract Background Claudin-3 (CLDN3) participates in the formation of the tight-junctions (TJs) that regulate intercellular permeability. Altered CLDN3 expression has been linked to tumor progression in multiple tumor types. Despite its widespread expression in normal epithelial cells, CLDN3 is considered an attractive drug target candidate, since it may be more accessible in cancer cells than in normal cells due to their less orchestrated cell growth. Methods To comprehensively determine the prevalence of CLDN3 expression in cancer, a tissue microarray containing 14,966 samples from 133 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. Results CLDN3 immunostaining was observed in 8,479 (68.9%) of 12,314 analyzable tumors, including 11.6% with weak, 6.2% with moderate, and 51.1% with strong positivity. CLDN3 staining was found in 96 of 133 tumor categories, 80 of which contained at least one strongly positive case. CLDN3 positivity was most seen in neuroendocrine neoplasms (92–100%) and in adenocarcinomas (67–100%), tumors of the female genital tract, including various subtypes of ovarian and endometrial carcinoma (up to 100%), as well as different subtypes of breast cancer (95.3–100%). CLDN3 positivity was less common in squamous cell carcinomas (0–43.2%) and mainly absent in melanoma, mesenchymal, and hematolymphatic neoplasms. In clear cell renal cell carcinoma (ccRCC), low CLDN3 was strongly linked to poor ISUP (p

ABSTRACT 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

Abstract Background Prostein (P501S), also termed solute carrier family 45 member 3 (SLC45A3) is an androgen regulated protein which is preferentially expressed in prostate epithelial cells. Because of its frequent expression in prostate cancer, prostein was suggested a diagnostic prostate cancer marker. Methods In order to comprehensively assess the diagnostic utility of prostein immunohistochemistry, a tissue microarray containing 19,202 samples from 152 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. Results Prostein immunostaining was typically cytoplasmic, granular and perinuclear. Prostein positivity was seen in 96.7% of 419 prostate cancers including 78.3% with strong staining. In 16,709 extra-prostatic tumors, prostein positivity was observed in 7.2% of all cases but only 0.3% had a strong staining. Overall, 50 different extra-prostatic tumor categories were prostein positive, 12 of which included at least one strongly positive case. Extra-prostatic tumors with highest rates of prostein positivity included different subtypes of salivary gland tumors (7.6-44.4%), neuroendocrine neoplasms (15.8-44.4%), adenocarcinomas of the gastrointestinal tract (7.3-14.8%), biliopancreatic adenocarcinomas (3.6-38.7%), hepatocellular carcinomas (8.1%), and adenocarcinomas of other organs (up to 21%). Conclusions Our data provide a comprehensive overview on prostein expression in human cancers. Prostein is a highly sensitive prostate cancer marker occurring in > 96% of prostate cancers. Because prostein can also be expressed in various other tumor entities, classifying of a tumor mass as a prostate cancer should not be based on prostein positivity alone.

Background/Objectives: Trefoil factor 1 (TFF1) plays a role in the mucus barrier. Methods: To evaluate the prevalence of TFF1 expression in cancer, a tissue microarray containing 18,878 samples from 149 tumor types and 608 samples of 76 normal tissue types was analyzed through immunohistochemistry (IHC). Results: TFF1 staining was detectable in 65 of 149 tumor categories. The highest rates of TFF1 positivity were found in mucinous ovarian carcinomas (76.2%), colorectal adenomas and adenocarcinomas (47.1–75%), breast neoplasms (up to 72.9%), bilio-pancreatic adenocarcinomas (42.1–62.5%), gastro-esophageal adenocarcinomas (40.4–50.0%), neuroendocrine neoplasms (up to 45.5%), cervical adenocarcinomas (39.1%), and urothelial neoplasms (up to 24.3%). High TFF1 expression was related to a low grade of malignancy in non-invasive urothelial carcinomas of the bladder (p = 0.0225), low grade of malignancy (p = 0.0003), estrogen and progesterone receptor expression (p < 0.0001), non-triple negativity (p = 0.0005) in invasive breast cancer of no special type, and right-sided tumor location (p = 0.0021) in colorectal adenocarcinomas. Conclusions: TFF1 IHC has only limited utility for the discrimination of different tumor entities given its expression in many tumor entities. The link between TFF1 expression and parameters of malignancy argues for a relevant biological role of TFF1 in cancer. TFF1 may represent a suitable therapeutic target due to its expression in only a few normal cell types.

Abstract Placental alkaline phosphatase (PLAP) is commonly expressed at high levels in testicular germ cell tumors. PLAP immunohistochemistry (IHC) is thus often used to confirm this diagnosis, especially in cases of putative metastasis. However, other tumors can also express PLAP. To comprehensively determine PLAP expression in normal and tumor tissue, a tissue microarray containing 16,166 samples from 131 different tumor types and subtypes as well as 608 samples from 76 different normal tissue types was analyzed by IHC. Moderate to strong PLAP positivity was found in 27 (21%) of 131 different tumor types including seminoma (96%), embryonal carcinoma (85%), and yolk sac tumors of the testis (56%); endometrioid carcinoma of the endometrium (28%) and the ovary (20%); gastric adenocarcinoma (22%); serous carcinoma (not otherwise specified) of the ovary (17%) and the uterus (11%); adenocarcinoma of the ampulla of Vater (15%); carcinosarcoma of the ovary (11%) and the uterus (8%); esophageal adenocarcinoma (10%); invasive urothelial carcinoma (4%); cholangiocarcinoma (2%); and adenocarcinoma of the lung (1%). Low‐level PLAP immunostaining, often involving only a small fraction of tumor cells, was seen in 21 additional tumor entities. The clinical significance of PLAP expression may vary between tumor types as high PLAP expression was linked to advanced pathological tumor stage (p = 0.0086), nodal metastasis (p = 0.0085), and lymphatic (p = 0.0007) and blood vessel invasion (p = 0.0222) in colorectal cancer, but to low pathological tumor stage in endometrial cancer (p = 0.0043). In conclusion, our data identify several tumor entities that can show PLAP expression at comparable levels to testicular germ cell tumors. These tumor entities need to be considered in cases of PLAP‐positive metastasis. Low‐level PLAP expression can be found in various other tumor entities and should generally not be viewed as a strong argument for germ cell neoplasia.

Chymotrypsin-like elastase family member 3B (CELA3B, elastase-3B) is a pancreatic enzyme with digestive function in the intestine. Since RNA analyses of normal tissues suggest that CELA3B expression is limited to the pancreas, the potential diagnostic utility of CELA3B immunohistochemistry for the distinction of pancreatic from extrapancreatic cancers and in the distinction of acinar cell carcinoma from ductal adenocarcinoma was assessed. CELA3B expression was successfully analyzed in 13,223 tumor samples from 132 different tumor types and subtypes as well as 8 samples each of 76 different normal tissue types by immunohistochemistry in a tissue microarray format (TMA). In normal tissues, CELA3B immunostaining was only seen in acinar cells and in a fraction of ductal cells of the pancreas as well as on some apical membranes of surface epithelial cells of the intestine. Among tumors, CELA3B immunostaining was seen in 12 of 16 (75%) acinar cell carcinoma of the pancreas including 6 cases with strong staining (37.5%) as well as in 5 of 13,207 other tumors (0.04%). These included 1.2% of 91 adenoid cystic carcinomas, 1.2% of 246 mucoepidermoid carcinomas and 0.8% of 127 acinic cell carcinomas of salivary glands. Our data show a good sensitivity (75%) and a high specificity (99.9%) of CELA3B immunohistochemistry for diagnosing acinar cell carcinoma of the pancreas.

Abstract Background The E-Cadherin gene (CDH1, Cadherin 1), located at 16q22.1 encodes for a calcium-dependent membranous glycoprotein with an important role in cellular adhesion and polarity maintenance. Methods To systematically determine E-Cadherin protein expression in normal and cancerous tissues, 14,637 tumor samples from 112 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types were analyzed by immunohistochemistry in a tissue microarray format. Results E-Cadherin was strongly expressed in normal epithelial cells of most organs. From 77 tumor entities derived from cell types normally positive for E-Cadherin, 35 (45.5%) retained at least a weak E-Cadherin immunostaining in ≥99% of cases and 61 (79.2%) in ≥90% of cases. Tumors with the highest rates of E-Cadherin loss included Merkel cell carcinoma, anaplastic thyroid carcinoma, lobular carcinoma of the breast, and sarcomatoid and small cell neuroendocrine carcinomas of the urinary bladder. Reduced E-Cadherin expression was linked to higher grade (p = 0.0009), triple negative receptor status (p = 0.0336), and poor prognosis (p = 0.0466) in invasive breast carcinoma of no special type, triple negative receptor status in lobular carcinoma of the breast (p = 0.0454), advanced pT stage (p = 0.0047) and lymph node metastasis in colorectal cancer (p

Abstract Background Cytokeratin 18 (CK18) is an intermediate filament protein of the cytokeratin acidic type I group and is primarily expressed in single-layered or “simple” epithelial tissues and carcinomas of different origin. Methods To systematically determine CK18 expression in normal and cancerous tissues, 11,952 tumor samples from 115 different tumor types and subtypes (including carcinomas, mesenchymal and biphasic tumors) as well as 608 samples of 76 different normal tissue types were analyzed by immunohistochemistry in a tissue microarray format. Results CK18 was expressed in normal epithelial cells of most organs but absent in normal squamous epithelium. At least an occasional weak CK18 positivity was seen in 90 of 115 (78.3%) tumor types. Wide-spread CK18 positivity was seen in 37 (31.9%) of tumor entities, including adenocarcinomas of the lung, prostate, colon and pancreas as well as ovarian cancer. Tumor categories with variable CK18 immunostaining included cancer types arising from CK18 positive precursor cells but show CK18 downregulation in a fraction of cases, tumor types arising from CK18 negative precursor cells occasionally exhibiting CK18 neo-expression, tumors derived from normal tissues with variable CK18 expression, and tumors with a mixed differentiation. CK18 downregulation was for example seen in renal cell cancers and breast cancers, whereas CK18 neo-expression was found in squamous cell carcinomas of various origins. Down-regulation of CK18 in invasive breast carcinomas of no special type and clear cell renal cell carcinomas (ccRCC) was related to adverse tumor features in both tumors (p ≤ 0.0001) and poor patient prognosis in ccRCC (p = 0.0088). Up-regulation of CK18 in squamous cell carcinomas was linked to high grade and lymph node metastasis (p

Abstract Background Tumor protein 63 (p63) is a transcription factor of the p53 gene family involved in differentiation of several tissues including squamous epithelium. p63 immunohistochemistry is broadly used for tumor classification but published data on its expression in cancer is conflicting. Methods To comprehensively catalogue p63 expression, tissue microarrays (TMAs) containing 12,620 tissue samples from 115 tumor entities and 76 normal tissue types were analyzed. Results p63 expression was seen in various normal tissues including squamous epithelium and urothelium. At least occasional weak p63 positivity could be detected in 61 (53%) of 115 different tumor types. The frequencies of p63 positivity was highest in squamous cell carcinomas irrespective of their origin (96–100%), thymic tumors (100%), urothelial carcinomas (81–100%), basal type tumors such as basal cell carcinomas (100%), and various salivary gland neoplasias (81–100%). As a rule, p63 was mostly expressed in cancers derived from p63 positive normal tissues and mostly not detectable in tumors derived from p63 negative cancers. However, exceptions from this rule occurred. A positive p63 immunostaining in cancers derived from p63 negative tissues was unrelated to aggressive phenotype in 422 pancreatic cancers, 160 endometrium cancers and 374 ovarian cancers and might be caused by aberrant squamous differentiation or represent stem cell properties. In 355 gastric cancers, aberrant p63 expression occurred in 4% and was linked to lymph node metastasis (p = 0.0208). Loss of p63 in urothelial carcinomas - derived from p63 positive urothelium - was significantly linked to advanced stage, high grade (p

Background: Adequate preoperative information can lessen patient anxiety. Delivering sufficient information during a personal interview, however, is time consuming, and therefore a relevant economical aspect. We investigated whether video information given to the patient before the pre-anesthetic interview has an influence on the patient's anxiety and the duration of the interview. Method: We randomized 302 patients undergoing different types of anesthesia. In all, 151 patients watched a short video with general information about the anticipated anesthesia procedure. Afterward, all patients had a standard pre-anesthetic interview. Patients' anxiety and satisfaction with pre-anesthesia care were assessed after the interview using a visual analogue scale. The duration of the interview was documented. Student t-test and P < 0.05 for differences between the groups. Results: There was no difference in gender, age, ASA physical status, previous anesthesia experience, and the planned anesthesia procedure between the two groups. No difference in anxiety and satisfaction with pre-anesthesia care was observed. The duration of the pre-anesthetic interview was also not different between the groups. Discussion: Preoperative multimedia information did not reduce anxiety or increase the patient satisfaction undergoing anesthesia. The video containing general information did not save time in the pre-anesthetic interview.

Abstract Background Epithelial splicing regulatory protein 1 (ESRP1) and 2 (ESRP2) regulate alternative splicing events of various pre-mRNAs. Some of these targets play a role in cancer-associated processes, including cytoskeleton reorganization and DNA-repair processes. This study was undertaken to estimate the impact of ESRP1 and ESRP2 alterations on prostate cancer patient prognosis. Methods A tissue microarray made from 17,747 individual cancer samples with comprehensive, pathological, clinical and molecular data was analyzed by immunohistochemistry for ESRP1 and ESRP2. Results Nuclear staining for ESRP1 was seen in 38.6% (36.0% low, 2.6% high) of 12,140 interpretable cancers and in 41.9% (36.4% low, 5.3% high) of 12,962 interpretable cancers for ESRP2. Nuclear protein expression was linked to advanced tumor stage, high Gleason score, presence of lymph node metastasis, early biochemical recurrence, and ERG-positive cancers (p

Abstract Background TFAP2D is a transcription factor important for modulating gene expression in embryogenesis. Its expression and prognostic role in prostate cancer has not been evaluated. Methods Therefore, a tissue microarray containing 17,747 prostate cancer specimens with associated pathological, clinical, and molecular data was analyzed by immunohistochemistry to assess the role of TFAP2D. Results TFAP2D expression was typically increased in prostate cancer as compared to adjacent non-neoplastic glands. TFAP2D staining was considered negative in 24.3% and positive in 75.7% of 13,545 interpretable cancers. TFAP2D staining was significantly linked to advanced tumor stage, high classical and quantitative Gleason grade, lymph node metastasis, and a positive surgical margin (p ≤ 0.0045). TFAP2D positivity was more common in ERG fusion positive (88.7%) than in ERG negative cancers (66.8%; p

Abstract Survivin is an inhibitor of apoptosis. Aberrant survivin expression occurs in malignant tumors and has often been linked to unfavorable patient outcome. Here we analyzed 12 432 prostate cancers by immunohistochemistry. Survivin immunostaining was regularly expressed at high levels in normal prostate epithelium but expression was often reduced in prostate cancers. Among 9492 evaluable prostate cancers, 9% expressed survivin strongly, 19% moderately, 28% weakly, and 44% lacked it. Loss of cytoplasmic survivin was seen in advanced tumor stage, higher Gleason score, preoperative PSA levels, and Ki‐67 labeling index, and associated with earlier PSA recurrence (P

p16 (CDKN2A) is a member of the INK4 class of cell cycle inhibitors, which is often dysregulated in cancer. However, the prevalence of p16 expression in different cancer types is controversial. 15,783 samples from 124 different tumor types and 76 different normal tissue types were analyzed by immunohistochemistry in a tissue microarray format. p16 was detectable in 5,292 (45.0%) of 11,759 interpretable tumors. Except from adenohypophysis in islets of Langerhans, p16 staining was largely absent in normal tissues. In cancer, highest positivity rates were observed in uterine cervix squamous cell carcinomas (94.4%), non-invasive papillary urothelial carcinoma, pTaG2 (100%), Merkel cell carcinoma (97.7%), and small cell carcinomas of various sites of origin (54.5%-100%). All 124 tumor categories showed at least occasional p16 immunostaining. Comparison with clinico-pathological data in 128 vulvar, 149 endometrial, 295 serous ovarian, 396 pancreatic, 1365 colorectal, 284 gastric, and 1245 urinary bladder cancers, 910 breast carcinomas, 620 clear cell renal cell carcinomas, and 414 testicular germ cell tumors revealed only few statistically significant associations. Comparison of human papilloma virus (HPV) status and p16 in 497 squamous cell carcinomas of different organs revealed HPV in 80.4% of p16 positive and in 20.6% of p16 negative cancers (p

Background: Mucin 5AC (MUC5AC) belongs to the glycoprotein family of secreted gel-forming mucins and is physiologically expressed in some epithelial cells. Studies have shown that MUC5AC is also expressed in several cancer types suggesting a potential utility for the distinction of tumor types and subtypes. Methods: To systematically determine MUC5AC expression in normal and cancerous tissues, a tissue microarray containing 10 399 samples from 111 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. Results: MUC5AC was expressed in normal mucus-producing cells of various organs. At least weak MUC5AC positivity was seen in 44 of 111 (40%) tumor entities. Of these 44 tumor entities, 28 included also tumors with strong positivity. MUC5AC immunostaining was most commonly seen in esophageal adenocarcinoma (72%), colon adenoma (62%), ductal adenocarcinoma of the pancreas (64%), mucinous carcinoma of the ovary (46%), diffuse gastric adenocarcinoma (44%), pancreatic ampullary adenocarcinoma (41%), intestinal gastric adenocarcinoma (39%), and bronchioloalveolar carcinoma (33%). Clinically relevant tumors with complete or almost complete absence of MUC5AC staining included small cell carcinoma of the lung (0% of 17), clear cell renal cell carcinoma (0% of 507), papillary thyroid carcinoma (0% of 359), breast cancer (2% of 1097), prostate cancer (2% of 228), soft tissue tumors (0.1% of 968), and hematological neoplasias (0% of 111). Conclusion: The highly standardized analysis of a broad range of cancers identified a ranking order of tumors according to their relative prevalence of MUC5AC expression.

Uroplakin 3B (Upk3b) is involved in stabilizing and strengthening the urothelial cell layer of the bladder. Based on RNA expression studies, Upk3b is expressed in a limited number of normal and tumor tissues. The potential use of Upk3b as a diagnostic or prognostic marker in tumor diagnosis has not yet been extensively investigated. A tissue microarray containing 17,693 samples from 151 different tumor types/subtypes and 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. In normal tissues, Upk3b expression was largely limited to mesothelial cells, urothelial umbrella cells, and amnion cells. In tumor tissues, Upk3b was detectable in only 17 of 151 (11.3%) of tumor types. Upk3b expression was most frequent in mesotheliomas (82.1% of epithelioid and 30.8% of biphasic) and in urothelial tumors of the urinary bladder, where the positivity rate decreased from 61.9% in pTaG2 (low grade) to 58.0% in pTaG3 (high grade) and 14.6% in pT2-4 cancers. Among pT2-4 urothelial carcinomas, Upk3b staining was unrelated to tumor stage, lymph node status, and patient prognosis. Less commonly, Upk3b expression was also seen in Brenner tumors of the ovary (10.8%), as well as in four other subtypes of ovarian cancer (0.9–10.6%). Four additional tumor entities showed a weak to moderate Upk3b positivity in less than 5% of cases. In summary, Upk3b immunohistochemistry is a useful diagnostic tool for the distinction of mesotheliomas from other thoracic tumors and the visualization of normal mesothelial and umbrella cells.

Angiotensin-converting enzyme 2 (ACE2) is a regulator in the renin-angiotensin system. ACE2 expression was analysed immunohistochemically in 15,306 samples from 119 tumour types and in 608 samples of 76 normal tissue types. In normal tissue, ACE2 was most abundant in testis and corpus luteum, kidney, small intestine and capillaries of selected organs. At least an occasional weak ACE2 positivity of tumour cells was seen in 83 of 119 (70%) tumour types. ACE2 tumour cell positivity was particularly frequent in papillary (94%) and clear cell (86%) renal cell carcinoma, colorectal adenocarcinoma (81%), mucinous ovarian cancer (61%), cholangiocarcinoma (58%), hepatocellular carcinoma (56%), and in adenocarcinomas of the stomach (47%), pancreas (42%), and the lung (35%). ACE2-positive capillaries were found in 409/12,644 (3%) of analysable tumours, most frequently in tumours with endocrine/neuroendocrine activity. Presence of ACE2-positive capillaries was linked to low stage in papillary thyroid cancer and low grade in neuroendocrine neoplasms. In conclusion, ACE2 expression can occur both in tumour cells and tumour-associated capillaries in a broad variety of different tumour types at highly variable frequencies.

Abstract Background Animal model experiments have suggested a role of the DNA repair protein ERCC1 (Excision Repair Cross-Complementation Group 1) in prostate cancer progression. Methods To better understand the impact of ERCC1 protein expression in human prostate cancer, a preexisting tissue microarray (TMA) containing more than 12,000 prostate cancer specimens was analyzed by immunohistochemistry and data were compared with tumor phenotype, PSA recurrence and several of the most common genomic alterations (TMPRSS2:ERG fusions: deletions of PTEN, 6q, 5q, 3p). Results ERCC1 staining was seen in 64.7% of 10,436 interpretable tissues and was considered weak in 37.1%, moderate in 22.6% and strong in 5% of tumors. High-level ERCC1 staining was linked to advanced pT stage, high Gleason grade, positive lymph nodes, high pre-operative serum PSA, and positive surgical margin status (p

Mesothelin (MSLN) represents an attractive molecule for targeted cancer therapies. To identify tumors that might benefit from such therapies, tissue microarrays including 15,050 tumors from 122 different tumor types and 76 healthy organs were analyzed for MSLN expression by immunohistochemistry. Sixty-six (54%) tumor types showed at least occasional weak staining, including 50 (41%) tumor types with at least one strongly positive sample. Highest prevalence of MSLN positivity had ovarian carcinomas (serous 97%, clear cell 83%, endometrioid 77%, mucinous 71%, carcinosarcoma 65%), pancreatic adenocarcinoma (ductal 75%, ampullary 81%), endometrial carcinomas (clear cell 71%, serous 57%, carcinosarcoma 50%, endometrioid 45%), malignant mesothelioma (69%), and adenocarcinoma of the lung (55%). MSLN was rare in cancers of the breast (7% of 1138), kidney (7% of 807), thyroid gland (1% of 638), soft tissues (0.3% of 931), and prostate (0 of 481). High expression was linked to advanced pathological tumor (pT) stage (p < 0.0001) and metastasis (p < 0.0001) in 1619 colorectal adenocarcinomas, but unrelated to parameters of malignancy in 1072 breast-, 386 ovarian-, 174 lung-, 757 kidney-, 171 endometrial-, 373 gastric-, and 925 bladder carcinomas. In summary, numerous important cancer types with high-level MSLN expression might benefit from future anti-MSLN therapies, but MSLN’s prognostic relevance appears to be limited.