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.

Background/Objectives: Carcinoembryonic antigen (CEA) is a cell-surface glycoprotein serving as a drug target, diagnostic marker, and serum marker for cancer monitoring. However, prevalence data on CEA expression in cancer tissues vary considerably. This study was designed to determine CEA expression in normal and neoplastic tissues. Methods: A tissue microarray containing 13,725 samples from 120 different tumor types, as well as 76 different normal tissue types, was analyzed by immunohistochemistry (IHC). Results: CEA was detectable in 65 (54.2%) of 120 tumor categories, including 49 (40.8%) tumor types with at least one strongly positive case. CEA positivity was most common in colorectal adenomas (100%) and carcinomas (98.7%), other gastrointestinal adenocarcinomas (61.1–80.3%), medullary carcinomas of the thyroid (96.3%), pulmonary adenocarcinoma (73.7%), mucinous carcinomas of the ovary (79.8%) and the breast (43.2%), small-cell carcinomas of the lung (64.3%), and urinary bladder (38.9%). CEA overexpression was linked to high tumor grade and invasive growth (p < 0.0001 each) in urinary bladder cancer, and estrogen and HER2 receptor positivity (p ≤ 0.0158) in invasive breast cancer of no special type. In colorectal adenocarcinomas, reduced CEA expression was associated with mismatch repair deficiency (p < 0.0001). Conclusions: The comprehensive list of CEA-positive human tumor types demonstrates that CEA is expressed in a broad range of epithelial neoplasms, many of which might benefit from CEA serum monitoring and anti-CEA therapies.

Trichorhinophalangeal syndrome 1 (TRPS1) is a nuclear protein highly expressed in breast epithelial cells. TRPS1 immunohistochemistry (IHC) has been suggested as a breast cancer marker. To determine the diagnostic and prognostic utility of TRPS1 IHC, tissue microarrays containing 19,201 samples from 152 different tumor types and subtypes were analyzed. GATA3 IHC was performed in a previous study. TRPS1 staining was seen in 86 of 152 tumor categories with 36 containing at least one strongly positive case. TRPS1 staining predominated in various types of breast carcinomas (51%-100%), soft tissue tumors (up to 100%), salivary gland tumors (up to 46%), squamous cell carcinomas (up to 35%), and gynecological cancers (up to 40%). TRPS1 positivity occurred in 1.8% of 1083 urothelial neoplasms. In invasive breast carcinoma of no special type, low TRPS1 expression was linked to high grade (P = 0.0547), high pT (P < 0.0001), nodal metastasis (P = 0.0571), loss of estrogen receptor and progesterone receptor expression (P < 0.0001 each), and triple-negative status (P < 0.0001) but was unrelated to patient survival (P = 0.8016). In squamous cell carcinomas from 11 different sites, low TRPS1 expression was unrelated to tumor phenotype. Positivity for both TRPS1 and GATA3 occurred in 47.4% to 100% of breast cancers, up to 30% of salivary gland tumors, and 29 (0.3%) of 9835 tumors from 134 other cancer entities. TRPS1 IHC has high utility for the identification of cancers of breast (or salivary gland) origin, especially in combination with GATA3. The virtual absence of TRPS1 positivity in urothelial neoplasms is useful for the distinction of GATA3-positive urothelial carcinoma from breast cancer.

Loss of S-methyl-5′-thioadenosine phosphorylase (MTAP) expression is a common event in cancer leading to a critical vulnerability of cancer cells towards anti-cancer drugs. Homozygous MTAP deletions result in a complete expression loss that can be detected by immunohistochemistry (IHC). In this study, a tissue microarray containing 17,078 samples from 149 different tumor entities was analyzed by IHC, and complete MTAP loss was validated by fluorescence in situ hybridization. MTAP loss was observed in 83 of 149 tumor categories, including neuroendocrine neoplasms (up to 80%), Hodgkin lymphoma (50.0%), mesothelioma (32.0% to 36.8%), gastro-intestinal adenocarcinoma (4.0% to 40.5%), urothelial neoplasms (10.5% to 36.7%), squamous cell carcinomas (up to 38%), and various types of sarcomas (up to 20%) and non-Hodgkin lymphomas (up to 14%). Homozygous MTAP deletion was found in 90% to 100% of cases with MTAP expression loss in most tumor categories. However, neuroendocrine tumors, Hodgkin lymphomas, and other lymphomas lacked MTAP deletions. MTAP deficiency was significantly linked to unfavorable tumor phenotype in selected tumor entities and the presence of PD-L1 expression on tumor cells, absence of PD-L1 expression on immune cells, and a low density of CD8⁺ lymphocytes. In summary, MTAP deficiency can occur in various tumor entities and is linked to unfavorable tumor phenotype and noninflamed tumor microenvironment, but is not always related to deletions. MTAP IHC is of considerable diagnostic value for the detection of neoplastic transformation in multiple different applications.

Carboxypeptidase A1 (CPA1) is a zinc metalloprotease that is produced in pancreatic acinar cells and plays a role in cleaving C-terminal branched-chain and aromatic amino acids from dietary proteins. This study assessed the utility of immunohistochemical CPA1 staining for diagnosing pancreatic acinar cell carcinoma (ACC). A total of 12,274 tumor samples from 132 different tumor types and subtypes as well as 8 samples each of 76 different normal tissue types were interpretable by immunohistochemistry in a tissue microarray format. CPA1 was strongly expressed in acinar cells of all normal pancreas samples but not in any other normal tissues. CPA1 immunostaining was detected in 100% of 11 pancreatic ACCs and 1 mixed acinar endocrine carcinoma, but absent in 449 pancreatic ductal adenocarcinomas, 75 adenocarcinomas of the ampulla Vateri, and 11,739 other evaluable cancers from 128 different tumor entities. A weak to moderate diffuse staining of epithelial and stromal cells of cancer tissues immediately adjacent to non-neoplastic pancreatic acinar cells often occurred and was considered to be caused by the diffusion of the highly abundant CPA1 from normal acinar cells that may have suffered some autolytic cell damage. In conclusion, our data show that CPA1 is a highly sensitive and largely specific marker for normal and neoplastic pancreatic acinar cells. CPA1 immunohistochemistry greatly facilitates the otherwise often difficult diagnosis of pancreatic ACC.

Human mammaglobin-A (SCGB2A2) is a secretory protein with an unknown function that is used as a diagnostic marker for breast cancer. However, other tumors can also express mammaglobin-A. To comprehensively study patterns of mammaglobin-A expression, a tissue microarray containing 16,328 samples from 128 different tumor types as well as 608 samples of 76 different normal tissue types was analyzed using immunohistochemistry. Mammaglobin-A positivity was found in only a few normal tissues, including luminal cells of the breast as well as endocervical and endometrial glands. In tumor tissues, 37 of 128 tumor categories showed mamma-globin-A staining, 32 of which were derived from one of four organs: breast (6 tumor categories), endometrium (5 tumor categories), ovary (5 tumor categories), and salivary glands (16 tumor categories). Only five additional tumor types showed occasional weak mammaglobin positivity, including medullary thyroid cancer, teratoma of the testis, squamous cell carcinoma of the skin and pharynx, and prostatic adenocarcinoma. Among 1139 evaluable invasive breast carcinomas of no special type, low mammaglobin-A immunostaining was linked to high BRE grade (p = 0.0011), loss of estrogen and progesterone receptor expression (p < 0.0001 each), and triple-negative status (p < 0.0001) but not to patient survival. In endometrial cancer, mammaglobin-A loss was linked to an advanced tumor stage (p = 0.0198). Our data characterize mammaglobin-A as a highly specific marker for tumors derived from either the breast, female genitals, or salivary gland.