Undifferentiated gastrointestinal tract carcinomas are rare highly aggressive neoplasms with frequent but not obligatory rhabdoid features. Recent studies showed loss of SMARCB1 (INI1), a core ...subunit of the SWI/SNF chromatin remodeling complex, in 50% of tested cases. However, the molecular pathways underlying histologically similar but SMARCB1-intact cases are unknown. We herein analyzed 13 cases for expression of 4 SWI/SNF complex subunits SMARCB1, SMARCA2, SMARCA4, and ARID1A and the mismatch-repair proteins MLH1, MSH2, MSH6, and PMS2 by immunohistochemistry. Patients included 12 men and 1 woman aged 32 to 81 years (median, 57 y). Site of origin was colon (5), small bowel (2), stomach (3), small+large intestine (1), small intestine+ampulla of Vater (1), and esophagogastric junction (1). All tumors showed anaplastic large to medium-sized cells with variable rhabdoid features, pleomorphic giant cells, and, rarely, spindle cell foci. Abortive gland formation was seen in 3 cases and bona fide glandular component in 1 case. Most cases strongly expressed vimentin and variably pancytokeratin. In total, 12/13 cases (92%) showed loss of at least 1 SWI/SNF component. Loss of SMARCB1 (5/13), SMARCA2 (10/13), SMARCA4 (2/13), and ARID1A (2/13) was observed either in combination or isolated. SMARCA2 loss was isolated in 5 cases and coexisted with lost SMARCB1 in 5 cases (all 5 SMARCB1-deficient tumors showed loss of SMARCA2 as well). Co-inactivation of SMARCB1 and SMARCA4 or of SMARCA2 and SMARCA4 was not observed. Two mismatch-repair–deficient cases (MLH1/PMS2) showed concurrent loss of SMARCB1, SMARCA2, and (one of them) ARID1A. This study illustrates for the first time loss of different components of the SWI/SNF complex other than SMARCB1 in undifferentiated gastrointestinal carcinomas including novel SMARCA4-deficient and SMARCA2-deficient cases. Our results underline the close link between SWI/SNF deficiency and the aggressive rhabdoid phenotype. Frequent loss of SMARCA2 possibly points to fragility/vulnerability of the SWI/SNF complex as a consequence of lost core subunit SMARCB1. The exact molecular mechanisms underlying co-inactivation of different SWI/SNF subunits merit further investigations.
The rapid development of pathology is in contrast to a shortage of qualified staff. The aims of the present study are to compile basic information on the numbers of German physicians in pathology and ...to compare it with the situation in Europe and overseas. In addition, model calculations will shed light on the effects of part-time working models. Various publicly accessible databases (EuroStat) as well as publications of medical associations and professional associations of European countries and the USA/Canada were examined. In addition, a survey was carried out among the institutes of German universities. Figures from 24 European countries and the USA/Canada were evaluated. With one pathologist per 47,989 inhabitants, the density of pathologists in Germany in relation to the population is the second-lowest in Europe (average: 32,018). Moreover, the proportion of pathologists among the physicians working in Germany is the lowest in Europe and at the same time lower than in the USA and Canada (Germany: 1:200, USA: 1:70, Canada: 1:49). The ratio of pathologists to medical specialists is shifted in the same direction. The survey among university pathologists revealed a relevant increase in the workload over the last 10 years. The majority of institutes can manage this workload only with considerable difficulties. With a ratio between specialists and residents of 1:1, the university institutes show a high commitment in the area of training. The results of this study indicate a shortage of pathologists in Germany that could lead to a bottleneck in large parts of the health system.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Endoscopic resection is the standard treatment for superficial esophageal cancer. Data on early adenocarcinoma (EAC) are widely restricted to endoscopic mucosal resection (EMR), whereas large studies ...have been published on endoscopic submucosal dissection (ESD) for early squamous cell carcinoma (ESCC). ESD has potential advantages regarding en bloc and R0 resection rates, which have been demonstrated for ESCC. However, studies have failed to confirm these advantages in EAC. The aim of this study was to investigate the efficacy of ESD in early esophageal cancer.
A total of 111 early esophageal cancers (87 EACs and 24 ESCCs) were resected by ESD at a German tertiary referral center. A total of 60 EACs were resected within Barrett's segments ≤ M3. Resection rates, complications, and follow-up data were recorded prospectively.
En bloc resection rates were 95.4 % for EAC and 100 % for ESCC (P = 0.575), and R0 resection rates were 83.9 % and 91.7 %, respectively (P = 0.515). The R0 resection rate was higher in Barrett's ≤ M3 vs. > M3 (90 % vs. 70.4 %; P = 0.029). The curative resection rate was 72.4 % for EAC vs. 45.8 % for ESCC (P = 0.026). Endoluminal recurrence was observed in 2.4 % of EACs (8 % in Barrett's > M3, 0 % in Barrett's ≤ M3), and 0 % of ESCCs. Complications included strictures (11.7 %) and bleedings (0.9 %), but no perforation. Disease-specific survival was 97.7 % (EAC) and 95.8 % (ESCC), and overall survival was 96.6 % (EAC) and 66.7 % (ESCC) over a mean follow-up period of 24.3 months and 38.0 months, respectively.
ESD was shown to be a safe resection method, achieving high R0 resection rates in both EAC and ESCC. Recurrence rates were low. To improve R0 resection within long Barrett's segments, diagnosis of the lateral extension of the lesion needs to be improved.
Ever declining autopsy rates have been a concern of pathologists as well as clinicians for decades. Notably, in the field of oncology, data on autopsies and discrepancies between clinical and ...autoptic diagnoses are particularly scarce. In this retrospective study, we show the effect of a simple catalog of measures consisting of a different approach to obtain consent for autopsy, structured conferencing, and systematic teaching of residents, as well as a close collaboration between clinicians and pathologists on the numbers of autopsies, especially of oncological patients. Additionally, postmortem examination protocols from the years 2015 until 2019 were analyzed, regarding rates of discrepancies between clinical and autoptic causes of death in this category of patients. Autopsy numbers could be significantly increased from a minimum in 2014 (60 autopsies) to a maximum in 2018 (142 autopsies) (
p
< 0.0001). In the 67 autopsies of oncological cases, a high rate of 51% of major discrepancy between clinical and autoptic causes of death could be detected. In contrast to the general reported decline of autopsy rates, we present rising autopsy numbers over the past 5 years with an increasing number of oncological cases who underwent a postmortem examination. The high percentage of major discrepancies between clinical and autopsy diagnosis is in contrast to an expected decrease of major discrepancies in times of precise diagnostic methods and underlines the importance of autopsies to ensure high quality in diagnostics and therapy not only in the field of oncology.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Progressive respiratory failure and hyperinflammatory response is the primary cause of death in the coronavirus disease 2019 (COVID-19) pandemic. Despite mounting evidence of disruption of the ...hypothalamus-pituitary-adrenal axis in COVID-19, relatively little is known about the tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to adrenal glands and associated changes. Here we demonstrate adrenal viral tropism and replication in COVID-19 patients. Adrenal glands showed inflammation accompanied by inflammatory cell death. Histopathologic analysis revealed widespread microthrombosis and severe adrenal injury. In addition, activation of the glycerophospholipid metabolism and reduction of cortisone intensities were characteristic for COVID-19 specimens. In conclusion, our autopsy series suggests that SARS-CoV-2 facilitates the induction of adrenalitis. Given the central role of adrenal glands in immunoregulation and taking into account the significant adrenal injury observed, monitoring of developing adrenal insufficiency might be essential in acute SARS-CoV-2 infection and during recovery.
Gene fusions involving the
NUTM1
gene (
NUT
) represent defining genetic markers of a highly aggressive carcinoma type with predilection for the midline structures of children and young adults, hence ...the original description as NUT midline carcinoma. Recent studies have increasingly documented involvement of the
NUTM1
gene in the pathogenesis of other entities as well. We herein describe two cases of auditory canal carcinomas with features of porocarcinoma, both harboring a newly described
YAP1-NUTM1
gene fusion. Patients were males aged 28 and 82 years who presented with slowly growing lesions in the external auditory canal. Histologic examination showed monomorphic basaloid and squamoid cells arranged into organoid solid aggregates, nests, ducts, small cysts, and focal pseudocribriform pattern with variable mitotic activity, infiltrative growth, and focal squamous differentiation, particularly in the most superficial part of the tumor. Immunohistochemistry revealed consistent reactivity for CK5, p63 and SOX10 and diffuse aberrant expression of TP53. CK7 expression was limited to a few luminal ductal cells. The androgen receptor and S100 were negative. Next generation sequencing (TruSight RNA fusion panel, Illumina) revealed the same
YAP1-NUTM1
gene fusion in both tumors, which was subsequently confirmed by NUT-FISH and the monoclonal anti-NUT antibody. These cases represent a novel contribution to the spectrum of NUT-rearranged head and neck malignancies. This adnexal carcinoma variant should not be confused with the highly lethal NUT carcinoma based on NUT immunoreactivity alone.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Recently, we discovered the recurrent genomic rearrangement t(4;9)(q13;q31) enabling upregulation of the transcription factor Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3) through enhancer ...hijacking as the oncogenic driver event in acinic cell carcinoma (AciCC) of the salivary glands. In the current study, we evaluated the usefulness of NR4A3 immunostaining and NR4A3 fluorescence in situ hybridization (FISH) in the differential diagnosis of AciCC, comparing a total of 64 AciCCs including 17% cases with high-grade transformation, 29 secretory (mammary analog) carcinomas (MASC), and 70 other salivary gland carcinomas. Nuclear NR4A3 immunostaining was a highly specific (100%) and sensitive (98%) marker for AciCC with only 1 negative case, whereas NR4A3 FISH was less sensitive (84%). None of the MASCs or other salivary gland carcinomas displayed any nuclear NR4A3 immunostaining. The recently described HTN3-MSANTD3 gene fusion was observed in 4 of 49 (8%) evaluable AciCCs, all with nuclear NR4A3 immunostaining. In summary, NR4A3 immunostaining is a highly specific and sensitive marker for AciCC, which may be especially valuable in cases with high-grade transformation and in “zymogen granule”-poor examples within the differential diagnostic spectrum of AciCC and MASC.
Complement plays an important role in the direct defense to pathogens, but can also activate immune cells and the release of pro-inflammatory cytokines. However, in critically ill patients with ...COVID-19 the immune system is inadequately activated leading to severe acute respiratory syndrome (SARS) and acute kidney injury, which is associated with higher mortality. Therefore, we characterized local complement deposition as a sign of activation in both lungs and kidneys from patients with severe COVID-19. Using immunohistochemistry we investigated deposition of complement factors C1q, MASP-2, factor D (CFD), C3c, C3d and C5b-9 as well as myeloperoxidase (MPO) positive neutrophils and SARS-CoV-2 virus particles in lungs and kidneys from 38 patients who died from COVID-19. In addition, tissue damage was analyzed using semi-quantitative scores followed by correlation with complement deposition. Autopsy material from non-COVID patients who died from cardiovascular causes, cerebral hemorrhage and pulmonary embolism served as control (n=8). Lung injury in samples from COVID-19 patients was significantly more pronounced compared to controls with formation of hyaline membranes, thrombi and edema. In addition, in the kidney tubular injury was higher in these patients and correlated with lung injury (r=0.361*). In autopsy samples SARS-CoV-2 spike protein was detected in 22% of the lungs of COVID-19 patients but was lacking in kidneys. Complement activation was significantly stronger in lung samples from patients with COVID-19
the lectin and alternative pathway as indicated by deposition of MASP-2, CFD, C3d and C5b9. Deposits in the lung were predominantly detected along the alveolar septa, the hyaline membranes and in the alveolar lumina. In the kidney, complement was significantly more deposited in patients with COVID-19 in peritubular capillaries and tubular basement membranes. Renal COVID-19-induced complement activation occurred
the lectin pathway, while activation of the alternative pathway was similar in both groups. Furthermore, MPO-positive neutrophils were found in significantly higher numbers in lungs and kidneys of COVID-19 patients and correlated with local MASP-2 deposition. In conclusion, in patients who died from SARS-CoV-2 infection complement was activated in both lungs and kidneys indicating that complement might be involved in systemic worsening of the inflammatory response. Complement inhibition might thus be a promising treatment option to prevent deregulated activation and subsequent collateral tissue injury in COVID-19.
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