Gastric Mixed Neuroendocrine-Nonneuroendocrine Neoplasm: A rare case report

Objective: The incidence of gastric neuroendocrine neoplasms is less than 1%. They are seen as combined tumors with non-neuroendocrine neoplasms at a rate of approximately 7%. This study aims to share the case of mixed neuroendocrine and non-neuroendocrine cancer with the literature. Case: Endoscopic biopsies were taken from the tumoral mass detected in the gastric cardia region at endoscopy in a 60-year-old male patient that has complaints of weight loss and epigastric pain. Histopathological examination revealed malignant tumor infiltration that consisting of neuroendocrine cells with large nuclei and narrow cytoplasm in some areas and adenoid structures composed of atypical cells with pleomorphic large nuclei in some areas. Strong staining was observed in neuroendocrine areas with neuroendocrine markers such as synaptophysin and Chromogranin. Ki-67 proliferative index and mitotic activity were high in neuroendocrine neoplasm areas. The case was reported as a high-grade neuroendocrine-non neuroendocrine mixed neoplasm. Conclusion: Gastric Mixed Neuroendocrine-Nonneuroendocrine neoplasms are rare cases and correct diagnosis and grading are important in the treatment and patient follow-up protocol.

TGFB-Induced Factor Homeobox 1 (TGIF) Expression in Breast Cancer

Background: Breast cancer (BC) is the most frequent female cancer its which preferentially metastasizes to bone. Mechanisms of bone tropism are poorly understood, however, the transcription factor TGFB-induced factor homeobox 1 (TGIF) is involved in bone metabolism and thus of potential interest.Methods: TGIF expression was analyzed by immunohistochemistry in 1197 formalin-fixed, paraffin-embedded tissue from BC patients treated in the GAIN study with two adjuvant dose-dense schedules of chemotherapy with or without bisphosphonate ibandronate. TGIF expression was categorized into negative/low and moderate/strong staining.Results: In 1197 samples, we found associations of higher TGIF protein expression with smaller tumor size (p = 0.015), well differentiated phenotype (p < 0.001) and estrogen receptor (ER)-positive BC (p < 0.001). Patients with higher TGIF expression levels showed a significantly better disease-free (log-rank p 0.019) and overall survival (log-rank p = 0.018), but no association with time to bone metastasis as first site of relapse. Stratified univariate analysis in molecular subgroups emphasized that elevated TGIF expression was prognostic for both DFS and OS in ER-positive BC patients (DFS: log-rank p = 0.009; OS: log-rank p = 0.008) and in the HER2-negative subgroup (DFS: log-rank p = 0.004; OS: log-rank p = 0.002).Conclusions: Our findings suggest that a loss of TGIF expression is associated with BC progression, especially in luminal carcinomas.Trial registration: This clinical trial has been registered with ClinicalTrials.gov; registration number: NCT00196872.

KISS1, P53, and PTEN immunoexpressions and prediction of malignancy in endometrial intraepithelial neoplasia lesion within endometrial polyp

Objective: Aim of this study to evaluate the usefulness of phosphase and tensin homologous deleted on chromosome 10 (PTEN), p53, and kisspeptin (KISS1) immunoexpressions in predicting malignancy in endometrial intraepithelial neoplasia within the endometrial polyps. Material and method: This cross-sectional study was based on chart data from a convenience sample of patients who underwent probe curetage at the Gynecology and Obstetrics Clinic of Başkent University Ankara and Konya Practice and Research Hospitals, Turkey. A total of 169 patients were allocated into 5 groups, comprising the EIN-p group: 62 patients with an endometrial intraepithelial neoplasia lesion within an endometrial polyp, EC group: 17 patients with an endometrial carcinoma, EP-h group: 30 patients with hyperplasia on the background of the polyp but no atypia, EP group: 30 patients with endometrial polyps, and NE group: 30 patients with a normal (proliferative) endometrium. P53, PTEN, and KISS1 expressions between the groups were evaluated. Results: In the EIN-p and EC groups, P53 and KISS1 expressions were moderate or strong. In the NE, EP and EP-h groups, KISS1 was weakly stained and P53 expression was negative. The number of patients with strong p53 and KISS1 expressions in the EC group was higher and this difference was statistically significant (P < 0.001). With PTEN immunostaining, the EC and EIN-P groups were weakly stained, whereas the NE, EP, and EP-h groups had moderate or strong staining. Strong staining rates were higher in patients in the NE and EP groups than in the EP-h group (P < 0.001). Conclusion: In addition to the literature about P53 and PTEN, according to the data obtained herein, it was speculated that KISS1 may play an important role in the malignant transformation of endometrial polyps and it might be used as a predicting marker in this patient group.

Positivity for SATB2 distinguishes Islet1 positive rectal neuroendocrine tumours from pancreaticoduodenal neuroendocrine tumours

AimsDetermining the site of origin of a metastatic neuroendocrine tumour (NET) can be challenging and has important prognostic and therapeutic implications. An immunohistochemical (IHC) panel consisting of TTF1, CDX2, PAX8/PAX6 and Islet1 is often employed. However, there can be a significant IHC overlap among different primary sites. Herein, we sought to determine the utility of including Special AT-rich sequence binding protein-2 (SATB2) in the IHC panel that is used for determining the site of origin of a metastatic NET.MethodsParaffin tissue microarrays consisting of 137 primary NETs (26 lung, 22 jejunoileal, 8 appendix, 5 stomach, 4 duodenum, 17 rectum and 55 pancreas) were stained for SATB2, in addition to the well-described lineage-associated markers, such as TTF1, CDX2, PAX6 and Islet1. Additionally, a tissue microarray consisting of 21 metastatic NETs (1 lung, 1 stomach, 8 jejunoileal and 11 pancreas) was stained for TTF1, CDX2, SATB2 and Islet1. The results were recorded as no staining, weak staining and moderate to strong staining.ResultsAll appendiceal NETs and majority (88%) of the rectal NETs were positive for SATB2. All primary foregut NETs (stomach, pancreas, duodenum and lung) were negative for SATB2, except for one pulmonary NET with weak staining. However, among the metastatic tumours, 5 of 11 pancreatic NETs, 1 stomach NET, 1 lung NET and 2 of 8 jejunoileal NETs showed weak staining. Receiver operating characteristic analysis incorporating sensitivity and specificity data of IHC panel, considering moderate to strong staining as truly positive cases, showed that inclusion of SATB2 to the previously described NET IHC panel outperformed the panel without SATB2, raising the specificity for pancreaticoduodenal NETs from 81.2% to 100%, with a positive predictive value (PPV) of 100% and negative predictive value (NPV) of 82.22% (p<0.0001); for appendiceal NETs the specificity changed from 99.1% to 98.5% and sensitivity increased from 11.8% to 80%, with a PPV and NPV of 66.67% and 99.26%, respectively (p<0.0001); and for rectal NETs the specificity increased from 97.6% to 99.3% and sensitivity raised from 7.1% to 66.7%, with a PPV and NPV of 80% and 98.53%, respectively (p<0.0001).ConclusionsSATB2 stain is useful in differentiatingIslet1/PAX6 positive pancreatic and rectal NETs, as rectal NETs are typically moderately to strongly positive for SATB2 and pancreatic NETs are usually negative or weakly positive for SATB2. Moderate to strong staining for SATB2 is suggestive of an appendiceal or a rectal primary. SATB2 may complement the panel of CDX2, TTF1 and Islet1 in determining the site of origin of an NET in a metastatic setting.

Endometritis in the bitch: Immunohistochemical localization of cyclooxygenase 2

Background: In several mammals, subfertility or infertility associated with endometritis was reported. Although there have been studies about endometritis in bitches, the pathophysiological mechanisms are not completely known.Aim: This study aimed to evaluate the immunohistochemical expression of Cyclooxygenase 2 (COX2) in clinically healthy bitches with normal uterine tissue and bitches with endometritis.Methods: Forty-eight mixed breed bitches in diestrus were used. Uterine biopsies were collected for diagnosis [normal endometrium (n = 15; NE), cystic endometrial hyperplasia (n = 1), atrophy (n= 2), acute endometritis (n = 9; AE), subacute endometritis (n = 7; SE), and chronic endometritis (n = 14; CE)]. Immunostaining and quantification of positively stained cells was performed on full-thickness uterine biopsies. Data were analyzed by the GLIMMIX procedure of SAS.Results: COX2 immunostaining was scattered and restricted to cells in the stroma in bitches with NE. However, in bitches with endometritis, strong staining was observed in the luminal epithelium, glandular epithelium, and stromal cells. Staining was also observed in inflammatory cells localized in the stroma as well as inside of the glands. The percentage of COX2 positive stromal cells in bitches with AE, SE, and CE was significantly higher compared with NE (p < 0.005). In addition, the percentage of COX2 positive stromal cells in bitches with SE, and CE was significantly lower compared with AE (p < 0.003).Conclusion: COX2 could be involved in the pathophysiological mechanisms producing endometritis without the presence of cystic endometrial hyperplasia in bitches. However, further researches on this topic are required. Keywords: Bitch, COX2, Endometritis, Immunohistochemical.

NADPH Oxidase 5 upregulation is associated with lymphoma aggressiveness

SUMMARY OBJECTIVES Lymphomas are a heterogeneous set of malignant neoplasias of lymphoid B and NK/T mature and immature cells at various stages of differentiation. Genetic and molecular biology tools are used to appropriately classify the type and prognosis of the lymphomas, which have implications in therapeutic effectiveness. Among them, the nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) oxidase (NOX5) enzymes have been explored. This study analyzed the expression of NADPH oxidase 5 in lymphoma tissue according to the degree of tumor aggressiveness. METHODS Slides from 64 patients with lymphoma who had paraffin-embedded tissue available were reviewed by two independent, experienced pathologists. They classified tumors according to the WHO classification (2017). NOX5 expression in tissues was assessed by immunohistochemical staining using a tissue microarray. The assay was interpreted using a scoring system of 0, 1, 2, and 3, for cytoplasmic staining of NOX5 corresponding to negative, weak, intermediate, and strong staining, respectively. We compared the expression of NOX5 in patients with aggressive versus non-aggressive lymphomas. RESULTS NOX5 expression was positive in 100% (27/27) of aggressive lymphomas and in 19% (7/37) of non-aggressive ones. The seven patients with positive expression of NOX5 presented intermediate staining (2); strong staining (3) was observed only in tissues of aggressive lymphomas, and negative and weak staining (0 and 1) were observed only in non-aggressive lymphomas. CONCLUSIONS Aggressive lymphomas overexpress NOX5 protein. The higher NOX5 expression in aggressive lymphomas can suggest an involvement of this enzyme on the acquisition of an aggressive phenotype in lymphoid neoplasia.

Diagnostic Utility of BCOR Antibody in Clear Cell Sarcomas of Kidney

Purpose. Clear cell sarcoma of the kidney (CCSK) is an uncommon malignant renal tumor. It is the second most common renal pediatric renal malignancy after Wilms tumor. It exhibits a heterogeneous morphology, with overlapping features with its close differentials, which results in diagnostic challenges. There was no specific immunohistochemical marker in the past, to help in this regard. BCOR antibody has recently been suggested to be helpful in the differential diagnosis. We aim to study the utility of the BCOR antibody in the diagnosis of CCSK. Methods. We selected a total of 27 cases of CCSK (n = 12), Wilms tumor (n = 12), and congenital mesoblastic nephroma (n = 3). All cases were evaluated for the extent and intensity of nuclear labeling for BCOR antibody by immunohistochemistry (IHC). Results. We found that BCOR IHC was positive in 11 out of 12 cases with diffuse and strong staining in 8 of the cases. None of the cases of Wilms tumor and congenital mesoblastic nephroma were positive. Only 2 cases of Wilms tumor showed minimal and weak staining in <5% of cells. Conclusion. Diffuse and strong nuclear staining for the BCOR antibody is highly specific for CCSK among common pediatric renal malignancies. Our study confirms that BCOR IHC is a good IHC marker for the diagnosis of CCSK.

Plant poisoning leads to alpha-synucleinopathy and neuromelanopathy in kangaroos

The pathogenesis of synucleinopathies, common neuropathological lesions normally associated with some human neurodegenerative disorders such as Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy, remains poorly understood. In animals, ingestion of the tryptamine-alkaloid-rich phalaris pastures plants causes a disorder called Phalaris staggers, a neurological syndrome reported in kangaroos. The aim of the study was to characterise the clinical and neuropathological changes associated with spontaneous cases of Phalaris staggers in kangaroos. Gross, histological, ultrastructural and Immunohistochemical studies were performed to demonstrate neuronal accumulation of neuromelanin and aggregated α-synuclein. ELISA and mass spectrometry were used to detect serum-borne α-synuclein and tryptamine alkaloids respectively. We report that neurons in the central and enteric nervous systems of affected kangaroos display extensive accumulation of neuromelanin in the perikaryon without affecting neuronal morphology. Ultrastructural studies confirmed the typical structure of neuromelanin. While we demonstrated strong staining of α-synuclein, restricted to neurons, intracytoplasmic Lewy bodies inclusions were not observed. α-synuclein aggregates levels were shown to be lower in sera of the affected kangaroos compared to unaffected herd mate kangaroos. Finally, mass spectrometry failed to detect the alkaloid toxins in the sera derived from the affected kangaroos. Our preliminary findings warrant further investigation of Phalaris staggers in kangaroos, potentially a valuable large animal model for environmentally-acquired toxic synucleinopathy.

Use of Programmed Death Ligand-1 (PD-L1) Staining to Separate Sarcomatoid Malignant Mesotheliomas From Benign Mesothelial Reactions

Context.— The separation of benign from malignant mesothelial proliferations is a difficult morphologic problem. Some mesotheliomas stain for programmed death ligand-1 (PD-L1). Objective.— To determine whether PD-L1 staining can separate mesotheliomas from reactive mesothelial proliferations (RMPs). Design.— We stained 2 tissue microarrays containing in toto 62 malignant mesotheliomas and 88 RMPs, using anti-PD-L1 antibody 22C3. Staining was graded by using an immunoreactive score encompassing intensity/distribution and was divided into negative, weak, moderate, and strong. Because PD-L1 staining can be heterogeneous, we also stained 10 whole sections of sarcomatoid/desmoplastic mesotheliomas (SMMs) and 10 whole sections of spindled RMPs in the form of organizing pleuritis, the major morphologic differential of SMM. These 20 cases were not on the tissue microarrays. Results.— RMPs showed generally negative, or occasionally weak staining in either the epithelioid or spindle cell compartments, whereas moderate to strong staining was seen in 10 of 14 SMMs but only in 6 of 48 epithelioid mesotheliomas (EMMs). The difference between SMM and RMP staining was statistically significant (P &lt; .001), but between EMM and RMP was not significant. Whole section cases of organizing pleuritis showed no staining (N = 8) or weak staining (N = 2), whereas moderate/strong staining was seen in 9 of 10 whole sections of SMMs, a statistically significant difference (P = .02). There were no “hot spots” of RMP staining, suggesting that heterogeneous staining of RMPs is not a confounder. Conclusions.— Strong diffuse PD-L1 staining using antibody 22C3 supports a diagnosis of SMM when the differential diagnosis is RMPs, but PD-L1 staining is not useful for separating EMMs from RMPs.

Mixed Adenocarcinomatous and Neuroendocrine Tumor of the Urinary Bladder With Concomitant Carcinoma In Situ: A Case Report With a Comprehensive Immunohistochemical Analysis and Review of the Literature

Mixed adenoneuroendocrine carcinomas are rare and usually occur in the gastrointestinal tract. Although there have been several investigations regarding their developmental mechanism, the molecular origin of these tumors remains unclear. In this article, we present an exceedingly rare case of a mixed tumor of the urinary bladder with an adenocarcinomatous and a neuroendocrine component and a concomitant urothelial carcinoma in situ (CIS). Due to this extraordinary combination of tumor components, our goal was to extensively examine the 3 tumor components with regard to a representable common origin. Therefore, a comprehensive immunohistochemical analysis and review of the literature was performed. Besides expected outcome, our examination also revealed surprising staining results. Urothelial CIS, like the adenocarcinomatous component, showed strong staining for CDX2. In addition, parts of the adenocarcinoma were positive for synaptophysin like the neuroendocrine tumor component. All 3 components showed a significant overexpression of p53 and a moderate to strong membranous and cytoplasmatic staining for β-catenin. To our knowledge, we are the first to describe a case of a mixed tumor of the urinary bladder with an adenocarcinomatous and a neuroendocrine component and a concomitant CIS. The components share striking molecular features that argue for a common clonal origin and a development of the invasive tumor via the urothelial precursor lesion.