Endometrioid endometrial adenocarcinoma: an increase of G3 cancers?

PURPOSE: Endometrial cancer can be divided into two types: endometrioid Type 1 (G1, G2) has a hormonal driven etiology, while Type 2 is more aggressive (G3 endometrioid, clear cell and serous cancer type) and estrogen independent. We noticed an increase of more aggressive G3 endometrioid endometrial adenocarcinomas. This observation is of relevance for daily clinical practice because therapy depends on the histopathological grading and myometrial invasion. G3 cancers or myometrial invasion of more than 50% should be hysterectomized including bilateral adnexectomy with pelvine and paraaortal lymphadenectomy. In G1/G2 and lower infiltration levels, hysterectomy with adnexectomy without lymphadenectomy is sufficient. METHODS: Data of the ASF Statistic were used to analyze the changes in the incidences of patients with endometrioid cancer, grading groups and their first diagnosed stages between 2006 and 2014. RESULTS: 2611 patients, with 243-341 women per year, were analyzed. The number of diagnosed G1 tumors increased from 25 to 37% and the G3 tumors from 18 to 32%, whereas the G2 cancers decreased from 58 to 31%. Despite the rise of G3 tumors, an increase in age at diagnosis was not observed. The proportions of initial diagnosed stages (FIGO I-IV) in each grading remained constant over time. CONCLUSION: Potential consequences in treatment recommendations and prognosis urge attention to the detected increase of G3 endometrioid cancers.

[Clinical autopsies in Switzerland : A status report]. / Klinische Obduktionen in der Schweiz : Ein Statusbericht.

BACKGROUND: The number of autopsies has been steadily declining worldwide over the past decades. The reasons for this are diverse. Legislation regarding opposition and consent rules does not appear to have had a significant impact on the autopsy rates. Above all, structural causes and the attitude of the medical profession are the reasons for this decline. The main argument for a high autopsy rate is the identification of diagnostic errors; however, diagnostic discrepancies are relatively independent of the rate of autopsies performed. At the University Hospital (UniversitätsSpital) Zurich it could be shown in a study that from 1972-2002 the frequency of relevant diagnostic discrepancies (classes I and II) decreased from 30% to 7%. OBJECTIVE: The aim of this article is to present the necessity of a stable autopsy rate and to examine the situation of the autopsy in Switzerland. MATERIAL AND METHODS: For this purpose, the importance of autopsies in the fields of quality assurance of medical diagnostics, cancer statistics, medical research as well as further education of doctors in Switzerland is shown. Efforts are being made by the pathologists to counteract the declining autopsy rates. RESULTS AND DISCUSSION: Declining autopsy numbers have a significant influence on cancer statistics. The rate of newly discovered tumors in autopsies in Switzerland decreased from 42% in 1980 to 17% in 2010. Pediatric autopsies are an important tool for quality assurance of medical diagnostics in neonatology and pediatrics in Switzerland, but the rate of autopsies carried out is also declining. Postmortem magnetic resonance imaging (MRI) examinations (virtopsy) could increase the acceptance of the parents for an autopsy in the future. Autopsies make an important contribution in research and in documentation of therapy-associated side effects and they are an important component of further education of the upcoming medical generations.

[The pathology of adverse events with immune checkpoint inhibitors]. / Pathologie der Nebenwirkungen von Immune-Checkpoint-Inhibitoren.

BACKGROUND: Immunotherapy has gained importance with the development of new effective cancer treatments. Immune checkpoint inhibitors (ICI) are monoclonal antibodies that promote T­cell mediated tumor immune rejection. Checkpoint blockade also carries the risk of inducing autoimmune reactions ("immune related adverse events", irAEs). The diagnosis and classification of irAEs constitute a new and important field in pathology. AIM: Practice-oriented review of the diagnosis and classification of irAEs. MATERIALS AND METHODS: Structured, selective literature review based on PubMed und UpToDate ® online. RESULTS: The most common irAEs affect the skin, the gastrointestinal tract, the liver, and the respiratory system. The correct diagnosis and classification of irAEs by an interdisciplinary care team is essential for appropriate therapy and the prevention of long-term sequelae. Other important irAEs affect the endocrine organs, the heart, the joints, the kidneys and the nervous system. Because of their rarity and/or limited options for bioptic diagnosis, only limited data on the morphology and pathophysiology of these irAEs are currently available. Autopsies carried out after ICI therapy constitute an important element of quality control and allow better documentation of the incidence and pathogenesis of irAEs. DISCUSSION: Pathology plays a central role in the diagnosis and treatment of irAEs. Future studies may contribute to a better mechanistic understanding of irAEs for individualized knowledge-based risk assessment.

[Motility disorders of the esophagus]. / Motilitätsstörungen des Ösophagus.

Motility disorders of the esophagus comprise a heterogeneous spectrum of diseases. Primary malformations of the esophagus are now amenable to improved surgical and gastroenterological therapies; however, they often lead to persistent long-term esophageal dysmotility. Achalasia originates from impaired relaxation of the gastroesophageal sphincter apparatus. Systemic diseases may give rise to secondary disorders of esophageal motility. A number of visceral neuromuscular disorders show an esophageal manifestation but aganglionosis rarely extends into the esophagus. The growing group of myopathies includes metabolic and mitochondrial disorders with increasing levels of genetic characterization and incipient emergence of therapeutic strategies. Esophagitis with an infectious etiology causes severe dysmotility particularly in immunocompromised patients. Immunologically mediated inflammatory processes involving the esophagus are increasingly better understood. Finally, rare tumors and tumor-like lesions may impair esophageal motor function.

[Embolization of hydrophilic guide wire coating]. / Embolisation von Katheterbeschichtung in das Myokard.

The number of interventional cardiovascular procedures has been rising steadily. Such procedures include the intravascular insertion of catheters and guide wires. These devices consist of a metallic core and coil that may be covered by hydrophilic coating to ease crossability and control for challenging lesions. We report two cases where insertion of a ChoICE® PT guide wire into the coronary artery led to embolization of the hydrophilic coating material with occlusion of small intramyocardial arteries.

Beyond hematoxylin and eosin: the importance of immunohistochemical techniques for evaluating surgically resected constipated patients.

Chronic constipation requiring surgical ablation for intractability is often a frustrating condition from the pathologist's point of view. In fact, limiting the histological examination to only hematoxylin-eosin staining usually yields only the information that there are no abnormalities. By employing some simple and widely available immunohistochemical methods, discussed in this review, it is possible to gather data that may help in explaining the pathophysiological basis of constipation in these patients.

Clinical and molecular practice of European thoracic pathology laboratories during the COVID-19 pandemic. The past and the near future.

BACKGROUND: This study evaluated the consequences in Europe of the COVID-19 outbreak on pathology laboratories orientated toward the diagnosis of thoracic diseases. MATERIALS AND METHODS: A survey was sent to 71 pathology laboratories from 21 European countries. The questionnaire requested information concerning the organization of biosafety, the clinical and molecular pathology, the biobanking, the workload, the associated research into COVID-19, and the organization of education and training during the COVID-19 crisis, from 15 March to 31 May 2020, compared with the same period in 2019. RESULTS: Questionnaires were returned from 53/71 (75%) laboratories from 18 European countries. The biosafety procedures were heterogeneous. The workload in clinical and molecular pathology decreased dramatically by 31% (range, 3%-55%) and 26% (range, 7%-62%), respectively. According to the professional category, between 28% and 41% of the staff members were not present in the laboratories but did teleworking. A total of 70% of the laboratories developed virtual meetings for the training of residents and junior pathologists. During the period of study, none of the staff members with confirmed COVID-19 became infected as a result of handling samples. CONCLUSIONS: The COVID-19 pandemic has had a strong impact on most of the European pathology laboratories included in this study. Urgent implementation of several changes to the organization of most of these laboratories, notably to better harmonize biosafety procedures, was noted at the onset of the pandemic and maintained in the event of a new wave of infection occurring in Europe.

Differences in the action and metabolism between retinol and retinoic acid in B lymphocytes.

We have previously reported on the dependency of activated B lymphocytes for retinol. Here we confirm and extend these findings that cells deprived of retinol perish in cell culture within days, displaying neither signs of apoptosis nor of cell cycle arrest. Cell death can be prevented by physiological concentrations of retinol and retinal, but not by retinoic acid or three synthetic retinoic acid analogues. To exclude the possibility that retinoic acid is so rapidly degraded as to escape detection, we have tested its stability in intra- and extracellular compartments. Contrary to expectation, we find that retinoic acid persists for longer (t 1/2 3 d) in cultures than retinol (t 1/2 1 d). Furthermore, despite the use of sensitive trace-labeling techniques, we cannot detect retinoic acid or 3,4-didehydroretinoic acid among retinol metabolites. However, retinol is converted into several new retinoids, one of which has the ability to sustain B cell growth in the absence of an external source of retinol, supporting the notion of a second retinol pathway. We have also determined which of the known retinoid-binding proteins are expressed in B lymphoblastoid cells. According to results obtained with polymerase chain reaction-assisted mRNA detection, they transcribe the genes for cellular retinol- and cellular retinoic acid-binding proteins, for the nuclear retinoic acid receptors, RAR-alpha, -gamma, and RXR-alpha, but not RAR-beta. Our findings that B cells do not synthesize retinoic acid or respond to exogenous retinoic acid on the one hand, but on the other hand convert retinol to a novel bioactive form of retinol, suggest the existence of a second retinoid pathway, distinct from that of retinoic acids.

Expression of the Rai (Shc C) adaptor protein in the human enteric nervous system.

The adaptor protein Rai (ShcC/N-Shc) is almost exclusively present in the nervous system, although little is documented about its expression in the gut and the enteric nervous system (ENS). As Rai is a physiological substrate of Ret, an important factor for the development of ENS, we have evaluated the expression of Rai in the ENS in various segments of the human gastrointestinal tract. The expression of Rai was assessed by immunohistochemistry in disease-free human gut samples (oesophagus, stomach, small bowel and colon) obtained from subjects undergoing surgical procedures. Rai was not expressed in the epithelia or lymphoid tissue, whereas a moderate level of expression was observed in the endothelial cells of blood vessels and on the outer membrane of smooth muscle cells in both the muscularis mucosae and the muscularis propria. In the ENS, strong positivity was observed only in enteric glial cells, overlapping with GFAP and S100. In conclusion, Rai is expressed in the human gut, especially in the enteric glial cells. We conclude that Rai may provide an additional marker for this cell type.

Helicobacter-negative gastritis: polymerase chain reaction for Helicobacter DNA is a valuable tool to elucidate the diagnosis.

BACKGROUND: Helicobacter-negative gastritis has been increasingly reported. Molecular techniques as the polymerase chain reaction (PCR) may detect bacterial DNA in histologically negative gastritis. AIM: To evaluate of Helicobacter PCR in gastric biopsies for the daily diagnostics of Helicobacter-negative gastritis. METHODS: Over a 5-year period, routine biopsies with chronic gastritis reminiscent of Helicobacter infection, but negative by histology, were tested by using a H. pylori specific PCR. Subsequently, PCR-negative samples were re-evaluated using PCR for other Helicobacter species. RESULTS: Of the 9184 gastric biopsies, 339 (3.7%) with histological-negative gastritis and adequate material were forwarded to PCR analysis for H. pylori and 146 (43.1%) revealed a positive result. In 193 H. pylori DNA-negative biopsies, re-analysis using PCR primers for other Helicobacter species, revealed further 23 (11.9%) positive biopsies, including 4 (2.1%) biopsies with H. heilmannii sensu lato. PCR-positive biopsies showed a higher overall inflammatory score, more lymphoid follicles/aggregates and neutrophils (P < 0.05). No Helicobacter DNA was found in control biopsies of 48 patients with neither primer set (P < 0.0001). In 274 patients with an endoscopic description, detection of H. pylori DNA was associated with ulcers and erosions (P < 0.01). Over all, in 339 histologically-negative gastric biopsies, Helicobacter DNA was detected in 169 (49.9%) samples with at least one primer set. CONCLUSION: Molecular testing offers a sensitive and specific diagnosis to a selected group of patients, in whom adequate searches for bacteria by conventional histology have resulted in the unsatisfactory diagnosis of H. pylori-negative gastritis.

Cytomegalovirus infection and graft rejection in renal transplantation.

BACKGROUND: Cytomegalovirus (CMV) infection and CMV disease have been associated with acute and chronic graft rejection. The introduction of the sensitive CMV antigenemia pp65 assay for detection of CMV infection allowed us to study the time course of CMV infection and acute rejection and the long-term outcome in renal transplant recipients with and without a CMV risk constellation. METHODS: Prospective single center study including 48 renal transplant recipients at risk for CMV infection (donor and/or recipient CMV seropositive) and a control group of 36 CMV seronegative recipients of CMV seronegative kidney donors. Evidence of CMV infection was monitored by the CMV antigenemia pp65 assay every 1 to 2 weeks and compared with the occurrence of acute rejection in the posttransplant period and graft function at 5 years. RESULTS: CMV infection developed in 83% (40/48) of patients of the CMV risk group within 4 months posttransplant. A total of 18 of patients experienced an acute rejection episode (control group 16/36; P=0.65). In 12/18 CMV infection followed rejection and in three patients antigenemia preceded the diagnosis of rejection. In three patients CMV antigenemia remained negative. Five-year follow up: Patient survival (44/48 vs. 31/36; P=0.48), graft survival (38/48 vs. 27/36; P=0.79), number of patients with at least one acute rejection episode: CMV risk group: 42.1%, control group 51% (P=0.46), serum creatinine: CMV risk group:130 +/- 66 micromol/iter, control group: 126 +/- 37 micromol/ liter (P=0.56), proteinuria: CMV risk group: 0.02 +/- 0.02 g/mmol creatinine, control group: 0.02 +/- 0.02 g/mmol creatinine (P=1.0). CONCLUSION: CMV infection within 4 months posttransplant, as defined by a positive antigenemia assay was not found to be a risk factor for acute graft rejection or chronic graft dysfunction at 5 years.

Transplantation-associated malignancies: restriction of human herpes virus 8 to Kaposi's sarcoma.

BACKGROUND: The human herpes virus 8 (HHV8) has been detected in all forms of Kaposi's sarcoma. HHV8 was also reported to be present in epithelial skin tumors of patients after renal transplantation, raising the question of the clinical relevance of HHV8 in transplant-related tumors. METHODS: Using a highly sensitive nested polymerase chain reaction assay, we analyzed for the presence of HHV8-DNA in the tumor tissue of renal transplant recipients with Kaposi's sarcoma (n=2) and non-Hodgkin's lymphomas (n=6), and in 32 tumors from 10 patients with multiple epithelial skin tumors. RESULTS: HHV8-DNA was detected in both cases of Kaposi's sarcoma but not in either the non-Hodgkin's lymphomas or the epithelial skin tumors. CONCLUSIONS: Our data confirm the association of HHV8 with Kaposi's sarcoma but not with other transplant-related tumors. Further studies are needed to analyze the risk for transmission of HHV8 by the donor and the possible exclusion of HHV8-positive patients as organ donors.

Pulmonary cytomegalovirus infection in immunocompromised patients.

BACKGROUND: Cytomegalovirus (CMV) infection and CMV disease are frequent complications in immunocompromised patients. In this study, the incidence of pulmonary CMV infection was analyzed in different groups of immunocompromised patients and the diagnostic value of immunostaining with anti-CMV antibodies in BAL cells was evaluated in regard to the diagnosis of CMV pneumonitis. METHODS: Five hundred eighty consecutive BAL procedures were analyzed prospectively in 442 immunocompromised and 126 nonimmunocompromised control subjects. CMV culture in BAL fluid was performed by shell vial assay and immunostaining using three monoclonal anti-CMV antibodies. RESULTS: The incidence of culture results positive for CMV in the BAL fluid varied from 20 to 30% in HIV-positive patients, in patients following stem cell or renal transplantation, and in patients with autoimmune disease or lung fibrosis treated with immunosuppressive agents. CMV was cultured from 4.4% of BALs in patients treated with high-dose chemotherapy and from 2.4% of control subjects. CMV disease developed in 37 patients; in 18 of these patients, CMV pneumonitis was present. The results of CMV immunostaining were positive in a total of 22 BALs, all in patients with CMV disease. The sensitivity, specificity, and positive and negative predictive values of positive CMV immunostaining results for the diagnosis of CMV pneumonitis were 88.9%, 98.6%, 72.7%, and 99.5%, respectively. CONCLUSION: The incidence of pulmonary CMV infection is similar in different groups of immunocompromised patients except for patients following high-dose chemotherapy. CMV immunostaining in the BAL fluid is a very helpful method to diagnose CMV pneumonitis in these patients.

Celiac disease transmitted by allogeneic non-T cell-depleted bone marrow transplantation.

We observed the occurrence of celiac disease following allogeneic bone marrow transplantation in a patient transplanted for acute leukemia. The marrow donor was his HLA-identical sister, who had suffered from celiac disease since birth. The post-transplant period was characterized by recurrent episodes of diarrhea. Detailed workup showed atrophic intestinal mucosa on histology and anti-gliadin and anti-endomysium antibodies in the serum, features that were not present before transplantation. GVHD was absent at that time. The patient remains free of symptoms on gluten-free diet and slight immunosuppression. This case suggests transmission of celiac disease by bone marrow transplantation and supports the T cell concept in celiac disease.

A spectrum of histopathologic findings in autoimmune liver disease.

We retrospectively studied 42 liver biopsy specimens from 39 patients who met serologic and histologic criteria of autoimmune liver diseases. We found 10 cases of overlap syndrome (OLS), 10 autoimmune cholangitis (AIC), 10 primary biliary cirrhosis (PBC), and 9 autoimmune hepatitis (AIH) type 1. The following results were obtained: (1) Granulomas and biliary duct lesions were more prominent in PBC and AIC than in OLS and AIH. (2) Bile duct loss was not observed in AIH cases. (3) Features of hepatocellular damage such as piecemeal necrosis, spotty lobular necrosis, and confluent necrosis, were much more prevalent in OLS and AIH than in PBC and AIC. (4) HLA-DR antigen expression by hepatocytes was more frequent in AIH and OLS, whereas the expression of the same antigen by the bile duct epithelium was more frequent in PBC and AIC. We conclude there is a morphologic spectrum in autoimmune liver diseases, in which PBC forms one end of the spectrum, AIH the other, OLS the middle but closer clinically and histologically to AIH than to PBC, and AIC, which seems to be an antimitochondrial antibody-negative subtype of PBC.

Human herpes virus 8: a new virus discloses its face.

The human herpes virus 8 (HHV8) or Kaposi's sarcoma-associated herpes virus (KSHV) is present in all Kaposi's sarcoma, and the detection of the virus using polymerase chain reaction or in situ hybridization is a highly sensitive and specific diagnostic test for the diagnosis of this neoplasm. HHV8 is furthermore invariably present in primary effusion lymphoma (PEL) and has also been detected in patients with acquired immunodeficiency syndrome (AIDS)-associated multicentric Castleman's disease (MCD) as well as, to a lesser extent, in non-AIDS MCD. In contrast to Kaposi's sarcoma, in which the tumor cells show primarily latent HHV8 infection, a higher rate of lytically infected cells can be observed in MCD. Epidemiological surveys indicate that the seroprevalence for HHV8 parallels the risk of developing Kaposi's sarcoma--5-10% in the general population of the Western world but ranging up to 20-70% in homosexual human immunodeficiency virus (HIV)-infected patients, and the infection precedes the development of Kaposis's sarcoma. Finally, HHV8 has been reported in a number of other diseases, especially in multiple myeloma. However, the highly controversial role of HHV8 in these lesions has to be clarified. Based on the data available today, HHV8 can be assigned as a new human virus, associated with tumors.

Effect of buffered formalin on amplification of DNA from paraffin wax embedded small biopsies using real-time PCR.

BACKGROUND: The isolation of good quality DNA from routinely fixed and processed biopsy samples is crucial for the success of subsequent molecular analysis. AIMS: To compare the amount of beta actin DNA extracted from upper gastrointestinal tract biopsies fixed in buffered and unbuffered formalin. METHODS: Amounts of beta actin DNA extracted from forceps biopsies of the upper gastrointestinal tract fixed in unbuffered (n = 22) and buffered formalin (n = 16) were estimated by quantitative real-time polymerase chain reaction. RESULTS: The yield of beta actin DNA was significantly higher in biopsies fixed in buffered formalin than in those fixed in unbuffered formalin (median 2.8 x 10(4) and 5.3 x 10(2) DNA molecules, respectively; p < 0.005). Furthermore, fixation in buffered formalin led to a more reproducible DNA extraction, as indicated by the coefficient of variation (1.0 and 2.2, respectively). CONCLUSIONS: This study indicates that tissue samples should be fixed in buffered formalin to facilitate the use of molecular pathology analysis in routine biopsy material.

Detection and typing of hepatitis C RNA in liver biopsies and its relation to histopathology.

This paper describes the correlation of hepatitis C genotypes detected in liver tissue with histological grading (inflammatory activity) and staging (degree of fibrosis/cirrhosis). The viral genotype was analysed by type-specific polymerase chain reaction (PCR) and correlated with histology and age of patients. In 69 patients with chronic hepatitis C (HCV) infection, genotypes 1a and 1b were detected in 13 (18.8%) and 31 (44.9%) liver biopsies, respectively. Genotypes 2a and 2b were each detected once (1.5%) and 12 (17.4%) tissue samples showed a mixed infection with two genotypes. In 11 (15.9%) biopsies, no genotype could be established. The liver specimens were grouped according to the presence or absence of genotype 1b: group A consisted of specimens infected with genotypes 1a, 2a, and 2b (n = 16), Group B contained biopsies infected with genotype 1b (n = 42), and group C were biopsies with no detectable genotype (n = 11). Activity (grade) of chronic hepatitis was not different in these three groups. However, advanced fibrosis/cirrhosis was observed in 16 (38.1%) biopsies in group B (containing genotype 1b), compared with none in group A (P = 0.01). The mean age of patients in group B was significantly higher than that in group A (P = 0.038), and the mean age of patients with advanced fibrosis was higher than that of patients with low fibrosis scores within these two groups (P = 0.004). Stepwise logistic regression revealed an independent association of age and genotype 1b (group B) with advanced fibrosis/cirrhosis. These data indicate that patients infected with genotype 1b have an higher risk of developing cirrhosis than do patients with other genotypes.

Detection of herpesvirus-like DNA by nested PCR on archival skin biopsy specimens of various forms of Kaposi sarcoma.

AIMS: To detect herpesvirus-like DNA sequences, defining a new herpesvirus, human herpesvirus 8 (HHV8), in paraffin wax embedded skin biopsy specimens of the various forms of Kaposi sarcoma. METHODS: DNA was extracted from archival skin biopsy specimens of Kaposi sarcoma, other mesenchymal skin tumours and various inflammatory skin lesions of HIV seropositive and negative patients. HHV8 DNA was detected by using a nested PCR assay. Human beta-globin DNA served as an internal control. RESULTS: Twenty two samples of Kaposi sarcoma were analysed, comprising 12 of the endemic type, nine HIV associated and one transplantation related. HHV8 DNA was detected by nested PCR in all forms of Kaposi sarcoma. By contrast, no HHV8 DNA was detected in five mesenchymal skin tumours or nine biopsy specimens of unspecific inflammatory skin lesions of HIV seropositive and negative patients. CONCLUSIONS: Detection of HHV8 DNA in paraffin wax embedded tissue can be used to confirm a diagnosis of Kaposi sarcoma.