PAX8 expression in cancerous and non-neoplastic tissue: a tissue microarray study on more than 17,000 tumors from 149 different tumor entities.

PAX8 plays a role in development of the thyroid, kidney, and the Wolffian and Mullerian tract. In surgical pathology, PAX8 immunohistochemistry is used to determine tumors of renal and ovarian origin, but data on its expression in other tumors are conflicting. To evaluate PAX8 expression in normal and tumor tissues, a tissue microarray containing 17,386 samples from 149 different tumor types and 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. PAX8 results were compared with previously collected data on cadherin 16 (CDH16). PAX8 positivity was found in 40 different tumor types. The highest rate of PAX8 positivity was found in thyroidal neoplasms of follicular origin (98.6-100%), gynecological carcinomas (up to 100%), renal tumors (82.6-97.8%), and urothelial neoplasms (2.3-23.7%). Important tumors with near complete absence of PAX8 staining (< 1%) included all subtypes of breast cancers, hepatocellular carcinomas, gastric, prostatic, pancreatic, and pulmonary adenocarcinomas, neuroendocrine neoplasms, small cell carcinomas of various sites, and lymphomas. High PAX8 expression was associated with low tumor grade in 365 non-invasive papillary urothelial carcinomas (p < 0.0001) but unrelated to patient outcome and/or tumor phenotype in clear cell renal cell carcinoma, high-grade serous ovarian cancer, and endometrioid endometrial carcinoma. For determining a renal tumor origin, sensitivity was 88.1% and specificity 87.2% for PAX8, while sensitivity was 85.3% and specificity 95.7% for CDH16. The combination of PAX8 and CDH16 increased specificity to 96.8%. In conclusion, PAX8 immunohistochemistry is a suitable diagnostic tool. The combination of PAX8 and CDH16 positivity has high specificity for renal cell carcinoma.

Prevalence of S-methyl-5'-thioadenosine Phosphorylase (MTAP) Deficiency in Human Cancer: A Tissue Microarray Study on 13,067 Tumors From 149 Different Tumor Types.

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.

KLK7 expression in human tumors: a tissue microarray study on 13,447 tumors.

BACKGROUND: Kallikrein-related peptidase 7 (KLK7) is a chymotrypsin-like serine protease which is essential for the desquamation of corneocytes and thus plays a pivotal role in maintaining skin homeostasis. In cancer, KLK7 overexpression was suggested to represent a route for metastasis through cleavage of cell junction and extracellular matrix proteins of cancer cells. METHODS: To comprehensively determine KLK7 protein expression in normal and neoplastic tissues, a tissue microarray containing 13,447 samples from 147 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. RESULTS: KLK7 positivity was found in 64 of 147 tumor categories, including 17 tumor categories with at least one strongly positive case. The highest rate of KLK7 positivity was found in squamous cell carcinomas from various sites of origin (positive in 18.1%-63.8%), ovarian and endometrium cancers (4.8%-56.2%), salivary gland tumors (4.8%-13.7%), bilio-pancreatic adenocarcinomas (20.0%-40.4%), and adenocarcinomas of the upper gastrointestinal tract (3.3%-12.5%). KLK7 positivity was linked to nodal metastasis (p = 0.0005), blood vessel infiltration (p = 0.0037), and lymph vessel infiltration (p < 0.0001) in colorectal adenocarcinoma, nodal metastasis in hepatocellular carcinoma (p = 0.0382), advanced pathological tumor stage in papillary thyroid cancer (p = 0.0132), and low grade of malignancy in a cohort of 719 squamous cell carcinomas from 11 different sites of origin (p < 0.0001). CONCLUSIONS: These data provide a comprehensive overview on KLK7 expression in normal and neoplastic human tissues. The prognostic relevance of KLK7 expression and the possible role of KLK7 as a drug target need to be further investigated.

Stimulator of Interferon Genes Protein (STING) Expression in Cancer Cells: A Tissue Microarray Study Evaluating More than 18,000 Tumors from 139 Different Tumor Entities.

Stimulator of interferon genes protein (STING) activates the immune response in inflammatory cells. STING expression in cancer cells is less well characterized, but STING agonists are currently being evaluated as anticancer drugs. A tissue microarray containing 18,001 samples from 139 different tumor types was analyzed for STING by immunohistochemistry. STING-positive tumor cells were found in 130 (93.5%) of 139 tumor entities. The highest STING positivity rates occurred in squamous cell carcinomas (up to 96%); malignant mesothelioma (88.5%-95.7%); adenocarcinoma of the pancreas (94.9%), lung (90.3%), cervix (90.0%), colorectum (75.2%), and gallbladder (68.8%); and serous high-grade ovarian cancer (86.0%). High STING expression was linked to adverse phenotypes in breast cancer, clear cell renal cell carcinoma, colorectal adenocarcinoma, hepatocellular carcinoma, and papillary carcinoma of the thyroid (p < 0.05). In pTa urothelial carcinomas, STING expression was associated with low-grade carcinoma (p = 0.0002). Across all tumors, STING expression paralleled PD-L1 positivity of tumor and inflammatory cells (p < 0.0001 each) but was unrelated to the density of CD8+ lymphocytes. STING expression is variable across tumor types and may be related to aggressive tumor phenotype and PD-L1 positivity. The lack of relationship with tumor-infiltrating CD8+ lymphocytes argues against a significant IFN production by STING positive tumor cells.

Soluble adenylyl cyclase is an acid-base sensor in rainbow trout red blood cells that regulates intracellular pH and haemoglobin-oxygen binding.

AIM: To identify the physiological role of the acid-base sensing enzyme, soluble adenylyl cyclase (sAC), in red blood cells (RBC) of the model teleost fish, rainbow trout. METHODS: We used: (i) super-resolution microscopy to determine the subcellular location of sAC protein; (ii) live-cell imaging of RBC intracellular pH (pHi) with specific sAC inhibition (KH7 or LRE1) to determine its role in cellular acid-base regulation; (iii) spectrophotometric measurements of haemoglobin-oxygen (Hb-O2) binding in steady-state conditions; and (iv) during simulated arterial-venous transit, to determine the role of sAC in systemic O2 transport. RESULTS: Distinct pools of sAC protein were detected in the RBC cytoplasm, at the plasma membrane and within the nucleus. Inhibition of sAC decreased the setpoint for RBC pHi regulation by ~0.25 pH units compared to controls, and slowed the rates of RBC pHi recovery after an acid-base disturbance. RBC pHi recovery was entirely through the anion exchanger (AE) that was in part regulated by HCO3 --dependent sAC signaling. Inhibition of sAC decreased Hb-O2 affinity during a respiratory acidosis compared to controls and reduced the cooperativity of O2 binding. During in vitro simulations of arterial-venous transit, sAC inhibition decreased the amount of O2 that is unloaded by ~11%. CONCLUSION: sAC represents a novel acid-base sensor in the RBCs of rainbow trout, where it participates in the modulation of RBC pHi and blood O2 transport though the regulation of AE activity. If substantiated in other species, these findings may have broad implications for our understanding of cardiovascular physiology in vertebrates.

The physiological significance of plasma-accessible carbonic anhydrase in the respiratory systems of fishes.

Carbonic anhydrase (CA) activity is ubiquitously found in all vertebrate species, tissues and cellular compartments. Most species have plasma-accessible CA (paCA) isoforms at the respiratory surfaces, where the enzyme catalyzes the conversion of plasma bicarbonate to carbon dioxide (CO2) that can be excreted by diffusion. A notable exception are the teleost fishes that appear to lack paCA at their gills. The present review: (i) recapitulates the significance of CA activity and distribution in vertebrates; (ii) summarizes the current evidence for the presence or absence of paCA at the gills of fishes, from the basal cyclostomes to the derived teleosts and extremophiles such as the Antarctic icefishes; (iii) explores the contribution of paCA to organismal CO2 excretion in fishes; and (iv) the functional significance of its absence at the gills, for the specialized system of O2 transport in most teleosts; (v) outlines the multiplicity and isoform distribution of membrane-associated CAs in fishes and methodologies to determine their plasma-accessible orientation; and (vi) sketches a tentative time line for the evolutionary dynamics of branchial paCA distribution in the major groups of fishes. Finally, this review highlights current gaps in the knowledge on branchial paCA function and provides recommendations for future work.

Frequency of Androgen Receptor Positivity in Tumors: A Study Evaluating More Than 18,000 Tumors.

Androgen receptor (AR) is a transcription factor expressed in various normal tissues and is a therapeutic target for prostate and possibly other cancers. A TMA containing 18,234 samples from 141 different tumor types/subtypes and 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. AR positivity was found in 116 tumor types including 66 tumor types (46.8%) with ≥1 strongly positive tumor. Moderate/strong AR positivity was detected in testicular sex cord-stromal tumors (93.3-100%) and neoplasms of the prostate (79.3-98.7%), breast (25.0-75.5%), other gynecological tumors (0.9-100%), kidney (5.0-44.1%), and urinary bladder (5.4-24.2%). Low AR staining was associated with advanced tumor stage (pTa versus pT2-4; p < 0.0001) in urothelial carcinoma; advanced pT (p < 0.0001), high tumor grade (p < 0.0001), nodal metastasis (p < 0.0001), and reduced survival (p = 0.0024) in invasive breast carcinoma; high pT (p < 0.0001) and grade (p < 0.0001) in clear cell renal cell carcinoma (RCC); and high pT (p = 0.0055) as well as high grade (p < 0.05) in papillary RCC. AR staining was unrelated to histopathological/clinical features in 157 endometrial carcinomas and in 221 ovarian carcinomas. Our data suggest a limited role of AR immunohistochemistry for tumor distinction and a prognostic role in breast and clear cell RCC and highlight tumor entities that might benefit from AR-targeted therapy.

Epithelial Cell Adhesion Molecule (EpCAM) Expression in Human Tumors: A Comparison with Pan-Cytokeratin and TROP2 in 14,832 Tumors.

EpCAM is expressed in many epithelial tumors and is used for the distinction of malignant mesotheliomas from adenocarcinomas and as a surrogate pan-epithelial marker. A tissue microarray containing 14,832 samples from 120 different tumor categories was analyzed by immunohistochemistry. EpCAM staining was compared with TROP2 and CKpan. EpCAM staining was detectable in 99 tumor categories. Among 78 epithelial tumor types, the EpCAM positivity rate was ≥90% in 60 categories-including adenocarcinomas, neuroendocrine neoplasms, and germ cell tumors. EpCAM staining was the lowest in hepatocellular carcinomas, adrenocortical tumors, renal cell neoplasms, and in poorly differentiated carcinomas. A comparison of EpCAM and CKpan staining identified a high concordance but EpCAM was higher in testicular seminomas and neuroendocrine neoplasms and CKpan in hepatocellular carcinomas, mesotheliomas, and poorly differentiated non-neuroendocrine tumors. A comparison of EpCAM and TROP2 revealed a higher rate of TROP2 positivity in squamous cell carcinomas and lower rates in many gastrointestinal adenocarcinomas, testicular germ cell tumors, neuroendocrine neoplasms, and renal cell tumors. These data confirm EpCAM as a surrogate epithelial marker for adenocarcinomas and its diagnostic utility for the distinction of malignant mesotheliomas. In comparison to CKpan and TROP2 antibodies, EpCAM staining is particularly common in seminomas and in neuroendocrine neoplasms.

Staining pattern of specific and cross-reacting Melan-A antibodies: A comparative study on 15,840 samples from 133 human tumor types.

The Melan-A (melanocyte antigen) protein, also termed 'melanoma antigen recognized by T cells 1' (MART-1) is a protein with unknown function whose expression is specific for the melanocyte lineage. Antibodies against Melan-A are thus used for identifying melanocytic tumors, but some Melan-A antibodies show an additional - diagnostically useful - cross-reactivity against an unspecified protein involved in corticosteroid hormone synthesis. To comprehensively compare the staining patterns of a specific and a cross-reactive Melan-A antibody in normal and neoplastic tissues, tissue microarrays containing 15,840 samples from 133 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types were analyzed by immunohistochemistry. For the Melan-A-specific antibody 'Melan-A specific' (MSVA-900M), Melan-A positivity was seen in 96.0% of 25 benign nevi, 93.0% of 40 primary and 86.7% of 75 metastatic melanomas, 82.4% of 85 renal angiomyolipomas as well as 96.4% of 84 neurofibromas, 2.2% of 46 granular cell tumors, 1.0% of 104 schwannomas, and 1.1% of 87 leiomyosarcomas. The cross-reactive antibody 'Melan-A+' (MSVA-901M+) stained 98.1% of the tumors stained by 'Melan-A specific'. In addition, high positivity rates were seen in sex-cord-stroma tumors of the ovary (35.3%-100%) and the testis (86.7%) as well as for adrenocortical neoplasms (76.3%-83.0%). Only nine further tumor groups showed Melan-A+ staining, including five different categories of urothelial carcinomas. Our data provide a comprehensive overview on the staining patterns of specific and cross-reactive Melan-A antibodies. The data demonstrate that both antibodies are highly useful for their specific purpose. It is important for pathologists to distinguish these two Melan-A antibody subtypes for their daily work.

Hippocampal astrocytes induce sex-dimorphic effects on memory.

Astrocytic receptors influence cognitive function and can promote behavioral deficits in disease. These effects may vary based on variables such as biological sex, but it is not known if the effects of astrocytic receptors are dependent on sex. We leveraged in vivo gene editing and chemogenetics to examine the roles of astrocytic receptors in spatial memory and other processes. We show that reductions in metabotropic glutamate receptor 3 (mGluR3), the main astrocytic glutamate receptor in adults, impair memory in females but enhance memory in males. Similarly, increases in astrocytic mGluR3 levels have sex-dependent effects and enhance memory in females. mGluR3 manipulations also alter spatial search strategies during recall in a sex-specific manner. In addition, acute chemogenetic stimulation of Gi/o-coupled or Gs-coupled receptors in hippocampal astrocytes induces bidirectional and sex-dimorphic effects on memory. Thus, astrocytes are sex-dependent modulators of cognitive function and may promote sex differences in aging and disease.

Regulation of sexual commitment in malaria parasites - a complex affair.

Malaria blood stage parasites commit to either one of two distinct cellular fates while developing within erythrocytes of their mammalian host: they either undergo another round of asexual replication or they differentiate into nonreplicative transmissible gametocytes. Depending on the state of infection, either path may support or impair the ultimate goal of human-to-human transmission via the mosquito vector. Malaria parasites therefore evolved strategies to control investments into asexual proliferation versus gametocyte formation. Recent work provided fascinating molecular insight into shared and unique mechanisms underlying the control and environmental modulation of sexual commitment in the two most widely studied malaria parasite species, Plasmodium falciparum and P. berghei. With this review, we aim at placing these findings into a comparative mechanistic context.

TRPS1 is a Highly Sensitive Marker for Breast Cancer: A Tissue Microarray Study Evaluating More Than 19,000 Tumors From 152 Different Tumor Entities.

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.

Astrocytes in selective vulnerability to neurodegenerative disease.

Selective vulnerability of specific brain regions and cell populations is a hallmark of neurodegenerative disorders. Mechanisms of selective vulnerability involve neuronal heterogeneity, functional specializations, and differential sensitivities to stressors and pathogenic factors. In this review we discuss the growing body of literature suggesting that, like neurons, astrocytes are heterogeneous and specialized, respond to and integrate diverse inputs, and induce selective effects on brain function. In disease, astrocytes undergo specific, context-dependent changes that promote different pathogenic trajectories and functional outcomes. We propose that astrocytes contribute to selective vulnerability through maladaptive transitions to context-divergent phenotypes that impair specific brain regions and functions. Further studies on the multifaceted roles of astrocytes in disease may provide new therapeutic approaches to enhance resilience against neurodegenerative disorders.

Cadherin-17 (CDH17) expression in human cancer: A tissue microarray study on 18,131 tumors.

Cadherin-17 (CDH17) is a membranous cell adhesion protein predominantly expressed in intestinal epithelial cells. CDH17 is therefore considered a possible diagnostic and therapeutic target. This study was to comprehensively determine the expression of CDH17 in cancer and to further assess the diagnostic utility of CDH17 immunohistochemistry (IHC). A tissue microarray containing 14,948 interpretable samples from 150 different tumor types and subtypes as well as 76 different normal tissue types was analyzed by IHC. In normal tissues, a membranous CDH17 staining was predominantly seen in the epithelium of the intestine and pancreatic excretory ducts. In tumors, 53 of 150 analyzed categories showed CDH17 positivity including 26 categories with at least one strongly positive case. CDH17 positivity was most common in epithelial and neuroendocrine colorectal neoplasms (50.0%-100%), other gastrointestinal adenocarcinomas (42.7%-61.6%), mucinous ovarian cancer (61.1%), pancreatic acinar cell carcinoma (28.6%), cervical adenocarcinoma (52.6%), bilio-pancreatic adenocarcinomas (40.5-69.8%), and other neuroendocrine neoplasms (5.6%-100%). OnIy 9.9% of 182 pulmonary adenocarcinomas were CDH17 positive. In colorectal adenocarcinomas, reduced CDH17 staining was linked to high pT (p = 0.0147), nodal metastasis (p = 0.0041), V1 (p = 0.0025), L1 (p = 0.0054), location in the right colon (p = 0.0033), and microsatellite instability (p < 0.0001). The CDH17 expression level was unrelated to tumor phenotype in gastric and pancreatic cancer. In summary, our comprehensive overview on CDH17 expression in human tumors identified various tumor entities that might often benefit from anti-CDH17 therapies and suggest utility of CDH17 IHC for the distinction of metastatic gastrointestinal or bilio-pancreatic adenocarcinomas (often positive) from primary pulmonary adenocarcinomas (mostly negative).

Expression of the MSPDBL2 antigen in a discrete subset of Plasmodium falciparum schizonts is regulated by GDV1 but may not be linked to sexual commitment.

The Plasmodium falciparum merozoite surface protein MSPDBL2 is a polymorphic antigen targeted by acquired immune responses, and normally expressed in only a minority of mature schizonts. The potential relationship of MSPDBL2 to sexual commitment is examined, as variable mspdbl2 transcript levels and proportions of MSPDBL2-positive mature schizonts in clinical isolates have previously correlated with levels of many sexual stage parasite gene transcripts, although not with the master regulator ap2-g. It is demonstrated that conditional overexpression of the gametocyte development protein GDV1, which promotes sexual commitment, also substantially increases the proportion of MSPDBL2-positive schizonts in culture. Conversely, truncation of the gdv1 gene is shown to prevent any expression of MSPDBL2. However, across diverse P. falciparum cultured lines, the variable proportions of MSPDBL2 positivity in schizonts do not correlate significantly with variable gametocyte conversion rates, indicating it is not involved in sexual commitment. Confirming this, examining a line with endogenous hemagglutinin-tagged AP2-G showed that the individual schizonts expressing MSPDBL2 are mostly different from those expressing AP2-G. Using a selection-linked integration system, modified P. falciparum lines were engineered to express an intact or disrupted version of MSPDBL2, showing the protein is not required for sexual commitment or early gametocyte development. Asexual parasite multiplication rates were also not affected by expression of either intact or disrupted MSPDBL2 in a majority of schizonts. Occurring alongside sexual commitment, the role of the discrete MSPDBL2-positive schizont subpopulation requires further investigation in natural infections where it is under immune selection. IMPORTANCE: Malaria parasites in the blood are remarkably variable, able to switch antigenic targets so they may survive within humans who have already developed specific immune responses. This is one of the challenges in developing vaccines against malaria. MSPDBL2 is a target of naturally acquired immunity expressed in minority proportions of schizonts, the end stages of each 2-day replication cycle in red blood cells which contain merozoites prepared to invade new red blood cells. Results show that the proportion of schizonts expressing MSPDBL2 is positively controlled by the expression of the regulatory gametocyte development protein GDV1. It was previously known that expression of GDV1 leads to increased expression of AP2-G which causes parasites to switch to sexual development, so a surprising finding here is that MSPDBL2-positive parasites are mostly distinct from those that express AP2-G. This discrete antigenic subpopulation of mostly asexual parasites is regulated alongside sexually committed parasites, potentially enabling survival under stress conditions.

Steroidogenic Acute Regulatory Protein Is a Useful Marker for Sex-Cord-Stroma Tumors and Normal and Neoplastic Adrenocortical Tissue.

CONTEXT.­: Steroidogenic acute regulatory (StAR) protein is a mitochondrial transport protein with a critical regulatory role for steroid hormone production. The tissue distribution of StAR expression is limited to few human normal tissues. OBJECTIVE.­: To assess the diagnostic and prognostic value of StAR immunohistochemistry analysis. DESIGN.­: A tissue microarray containing 19 202 samples from 152 different tumor types and subtypes and 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. RESULT.­: StAR immunostaining occurred in 198 (1.2%) of the 17 135 analyzable tumors. StAR expression was observed in 27 of 152 tumor categories, 9 of which included at least 1 strongly positive case. The highest rate of StAR positivity occurred in Leydig cell tumors of the testis and the ovary (100%), steroid cell tumors of the ovary (100%), adrenocortical carcinomas (93%) and adenomas (87%), Sertoli-Leydig cell tumors (67%) and granulosa cell tumors of the ovary (56%), as well as seminomas (7%). Nineteen other tumor entities showed-a usually weak-StAR positivity in less than 6% of cases. A comparison with preexisting Melan-A (a melanocyte antigen) data revealed that StAR was more often positive in adrenocortical neoplasms and in Leydig cell tumors while StAR (but not Melan-A) was negative in Sertoli cell tumors. CONCLUSIONS.­: Our data provide a comprehensive overview on the patterns of StAR immunostaining in human tumors and suggest a diagnostic utility of StAR immunohistochemistry for supporting a diagnosis of Leydig cell tumors or of normal or neoplastic adrenocortical tissue.

GAD2 Is a Highly Specific Marker for Neuroendocrine Neoplasms of the Pancreas.

Glutamate decarboxylase 2 (GAD2) is the most important inhibitory neurotransmitter and plays a role in insulin-producing ß cells of pancreatic islets. The limitation of GAD2 expression to a few normal cell types makes GAD2 a potential immunohistochemical diagnostic marker. To evaluate the diagnostic utility of GAD2 immunohistochemistry, a tissue microarray containing 19,202 samples from 152 different tumor entities and 608 samples of 76 different normal tissue types was analyzed. In normal tissues, GAD2 staining was restricted to brain and pancreatic islet cells. GAD2 staining was seen in 20 (13.2%) of 152 tumor categories, including 5 (3.3%) tumor categories containing at least 1 strongly positive case. GAD2 immunostaining was most commonly seen in neuroendocrine carcinomas (58.3%) and neuroendocrine tumors (63.2%) of the pancreas, followed by granular cell tumors (37.0%) and neuroendocrine tumors of the lung (11.1%). GAD2 was only occasionally (<10% of cases) seen in 16 other tumor entities including paraganglioma, medullary thyroid carcinoma, and small cell neuroendocrine carcinoma of the urinary bladder. Data on GAD2 and progesterone receptor (PR) expression (from a previous study) were available for 95 pancreatic and 380 extrapancreatic neuroendocrine neoplasms. For determining a pancreatic origin of a neuroendocrine neoplasm, the sensitivity of GAD2 was 64.2% and specificity 96.3%, while the sensitivity of PR was 56.8% and specificity 92.6%. The combination of PR and GAD2 increased both sensitivity and specificity. GAD2 immunohistochemistry is a highly useful diagnostic tool for the identification of pancreatic origin in case of neuroendocrine neoplasms with unknown site of origin.

Outcome of Epilepsy Surgery in MRI-Negative Patients Without Histopathologic Abnormalities in the Resected Tissue.

BACKGROUND AND OBJECTIVE: Patients with presumed nonlesional focal epilepsy-based on either MRI or histopathologic findings-have a lower success rate of epilepsy surgery compared with lesional patients. In this study, we aimed to characterize a large group of patients with focal epilepsy who underwent epilepsy surgery despite a normal MRI and had no lesion on histopathology. Determinants of their postoperative seizure outcomes were further studied. METHODS: We designed an observational multicenter cohort study of MRI-negative and histopathology-negative patients who were derived from the European Epilepsy Brain Bank and underwent epilepsy surgery between 2000 and 2012 in 34 epilepsy surgery centers within Europe. We collected data on clinical characteristics, presurgical assessment, including genetic testing, surgery characteristics, postoperative outcome, and treatment regimen. RESULTS: Of the 217 included patients, 40% were seizure-free (Engel I) 2 years after surgery and one-third of patients remained seizure-free after 5 years. Temporal lobe surgery (adjusted odds ratio [AOR]: 2.62; 95% CI 1.19-5.76), shorter epilepsy duration (AOR for duration: 0.94; 95% CI 0.89-0.99), and completely normal histopathologic findings-versus nonspecific reactive gliosis-(AOR: 4.69; 95% CI 1.79-11.27) were significantly associated with favorable seizure outcome at 2 years after surgery. Of patients who underwent invasive monitoring, only 35% reached seizure freedom at 2 years. Patients with parietal lobe resections had lowest seizure freedom rates (12.5%). Among temporal lobe surgery patients, there was a trend toward favorable outcome if hippocampectomy was part of the resection strategy (OR: 2.94; 95% CI 0.98-8.80). Genetic testing was only sporadically performed. DISCUSSION: This study shows that seizure freedom can be reached in 40% of nonlesional patients with both normal MRI and histopathology findings. In particular, nonlesional temporal lobe epilepsy should be regarded as a relatively favorable group, with almost half of patients achieving seizure freedom at 2 years after surgery-even more if the hippocampus is resected-compared with only 1 in 5 nonlesional patients who underwent extratemporal surgery. Patients with an electroclinically identified focus, who are nonlesional, will be a promising group for advanced molecular-genetic analysis of brain tissue specimens to identify new brain somatic epilepsy genes or epilepsy-associated molecular pathways.

Prostein expression in human tumors: a tissue microarray study on 19,202 tumors from 152 different Tumor entities.

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.

Comparison of INSM1 immunostaining with established neuroendocrine markers synaptophysin and chromogranin A in over 14,000 neuroendocrine and non-neuroendocrine tumors.

INSM1 is a transcription factor protein which is increasingly used as an immunohistochemical marker for neuroendocrine differentiation. To determine the prevalence of INSM1 expression in tumors and its expression pattern in normal tissues, tissue microarrays containing 14,908 samples from 117 different tumor types/subtypes as well as 76 different normal tissues were analyzed by immunohistochemistry. INSM1 was positive in 89.2% of 471 neuroendocrine neoplasms (NEN) and in 3.5% of 11,815 non-neuroendocrine neoplasms that were successfully analyzed. At least an occasional weak INSM1 positivity was observed in 59 different non-neuroendocrine tumor entities, of which 15 entities contained at least one case with strong INSM1 staining. A comparison with synaptophysin and chromogranin A staining revealed that in NEN, synaptophysin showed the highest sensitivity (93.3%), followed by INSM1 (89.2%) and chromogranin A (87.5%). In neuroendocrine carcinomas (NEC), sensitivity was highest for INSM1 (88.0%), followed by synaptophysin (86.5%) and chromogranin A (66.4%). If INSM1 was used as an additional marker, the sensitivity for detecting neuroendocrine differentiation in NEN increased from 96.6% (synaptophysin and chromogranin A) to 97.2% (synaptophysin, chromogranin A and INSM1). Our study shows that INSM1 is a useful additional marker for neuroendocrine differentiation with high sensitivity, particularly in NEC.