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The COVID-19 pandemic represents a so far unknown challenge for the medical community. Autopsies are important for studying this disease, but their safety was challenged at the beginning of the pandemic.To determine whether COVID-19 autopsies can be performed under existing legal conditions and which safety standards are required.The autopsy procedure undertaken in five institutions in Germany, Austria, and Switzerland is detailed with respect to legal and safety standards.In all institutions the autopsies were performed in technically feasible rooms. The personal equipment consisted of functional clothing including a disposable gown and apron, a surgical cap, eye protection, FFP‑3 masks, and two pairs of gloves. In four institutions, complete autopsies were performed; in one institution the ultrasound-guided biopsy within the postmortal imaging and biopsy program. The latter does not allow the appreciation of gross organ pathology; however, it is able to retrieve standardized biopsies for diagnostic and research purposes. Several scientific articles in highly ranked journals resulted from these autopsies and allowed deep insights into organ damage and conclusions to better understand the pathomechanisms. Viral RNA was frequently detectable in the COVID-19 deceased, but the issue of infectivity remains unresolved and it is questionable if Ct values are greater than 30.With appropriate safeguards, autopsies of people who have died from COVID-19 can be performed safely and are highly relevant to medical research.HINTERGRUND: Die COVID-19-Pandemie stellt die medizinische Fachwelt vor eine bislang ungekannte Herausforderung. Obduktionen sind für die Erforschung dieser neuen Krankheit wesentlich, ihre sichere Durchführbarkeit wurde aber anfangs infrage gestellt.Unter welchen rechtlichen Rahmenbedingungen und unter welchen Schutzmaßnahmen können COVID-19-Obduktionen durchgeführt werden?Das obduktionstechnische Vorgehen in 5 Zentren in Deutschland, Österreich und der Schweiz wird unter Berücksichtigung der jeweiligen rechtlichen Grundlagen und der ergriffenen Schutzmaßnahmen dargestellt.In allen Institutionen konnten die Obduktionen in technisch geeigneten Räumen sicher durchgeführt werden. Die persönliche Schutzausrüstung umfasste Augenschutz, Mund-Nasen-Masken (mindestens FFP2), Kopfhauben, Funktionskleidung, Mäntel, Schürzen und 2 Paar Handschuhe. In 4 Instituten wurden die Leichen nach unterschiedlichen Techniken eröffnet. In einem Institut wurde ein minimal-invasives Verfahren, die postmortale ultraschallunterstützte Gewebeentnahme im Rahmen des „postmortal imaging and biopsy programs“, durchgeführt. Letztere gibt zwar keine makroskopischen Einblicke in die inneren Organe, ermöglicht aber eine standardisierte bioptische Gewinnung von Gewebe für Diagnostik und Forschung. Aus den Obduktionen resultierten mehrere Arbeiten in hochrangigen Journalen, die profunde Einblicke in die Organveränderungen ermöglichten und wesentliche Schlüsse auf die Pathomechanismen zuließen. Virus-RNA konnte häufig in COVID-19-Verstorbenen nachgewiesen werden. Vereinzelt gelang auch die Anzüchtung der Viren. Die Frage nach der postmortalen Infektiosität bleibt aber unklar und bei Ct-Werten über 30 umstritten.Unter Beachtung geeigneter Schutzmaßnahmen sind Obduktionen von COVID-19-Verstorbenen sicher durchführbar und für die medizinische Forschung hoch relevant.

Zusammenfassung Hintergrund COVID-19 wird als systemische Erkrankung eingestuft. Ein schwerer Verlauf mit tödlichem Ausgang ist möglich und unvorhersehbar. Fragestellung Welche Organsysteme sind primär betroffen? Welche Organveränderungen prädisponieren für einen ungünstigen Verlauf? Welche Organschädigungen finden sich bei letalem Ausgang? Material und Methode Daten aus publizierten Obduktionsstudien (davon 28 eigene publizierte Fälle) in Hinblick auf Organschädigung und mögliche Todesursachen. Ergebnisse Die schwersten Veränderungen finden sich in den Lungen in Form eines diffusen Alveolarschadens als akutes Atemnotsyndrom des Erwachsenen (ARDS), zum Teil bereits mit Fibrose. Thrombosen in kleinen bis mittelgroßen Pulmonalarterien sind mit Lungeninfarkten vergesellschaftet. Häufige Komplikationen sind bakterielle Bronchopneumonien, seltener Pilzpneumonien. Pulmonale Thromboembolien finden sich in 20–30 % der tödlichen Verläufe, auch bei Fehlen einer tiefen Beinvenenthrombose. Eine intestinale Beteiligung von COVID-19 kann mit ischämischer Schädigung des Darmes einhergehen, in erster Linie bedingt durch Schock oder lokale Thrombose. Die Nieren zeigen eine akute Tubulusschädigung als Ausdruck eines akuten Nierenversagens, Lymphknoten und Milz einen Schwund der Lymphozyten, die Nebennierenrinde eine Hyperplasie. In der Leber finden sich häufig eine Steatose, Leberzellnekrosen, ein portales Entzündungsinfiltrat und eine Proliferation der Kupffer-Zellen. Häufige Grunderkrankungen sind in den Autopsiekollektiven arterieller Hypertonus mit hypertensiver und ischämischer Kardiomyopathie und Diabetes mellitus. In großen bevölkerungsbasierten Studien ergibt sich aber für Hypertoniker im Gegensatz zu Diabetikern kein erhöhtes Mortalitätsrisiko. Schlussfolgerungen Pulmonale Kreislaufstörungen mit arteriellen Thrombosen, Infarkten und Pneumonien sind wesentliche und oft letale Komplikationen des ARDS bei COVID-19. Die Erkenntnisse aus Obduktionsstudien haben Therapie und Prophylaxe beeinflusst.

The recent outbreak of coronavirus disease 2019 (COVID‐19), caused by the Severe Acute Respiratory Syndrome Coronavirus‐2 (SARS‐CoV‐2) has resulted in a world‐wide pandemic. Disseminated lung injury with the development of acute respiratory distress syndrome (ARDS) is the main cause of mortality in COVID‐19. Although liver failure does not seem to occur in the absence of pre‐existing liver disease, hepatic involvement in COVID‐19 may correlate with overall disease severity and serve as a prognostic factor for the development of ARDS. The spectrum of liver injury in COVID‐19 may range from direct infection by SARS‐CoV‐2, indirect involvement by systemic inflammation, hypoxic changes, iatrogenic causes such as drugs and ventilation to exacerbation of underlying liver disease. This concise review discusses the potential pathophysiological mechanisms for SARS‐CoV‐2 hepatic tropism as well as acute and possibly long‐term liver injury in COVID‐19.

Coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become pandemic, with substantial mortality.To evaluate the pathologic changes of organ systems and the clinicopathologic basis for severe and fatal outcomes.Prospective autopsy study.Single pathology department.11 deceased patients with COVID-19 (10 of whom were selected at random for autopsy).Systematic macroscopic, histopathologic, and viral analysis (SARS-CoV-2 on real-time polymerase chain reaction assay), with correlation of pathologic and clinical features, including comorbidities, comedication, and laboratory values.Patients' age ranged from 66 to 91 years (mean, 80.5 years; 8 men, 3 women). Ten of the 11 patients received prophylactic anticoagulant therapy; venous thromboembolism was not clinically suspected antemortem in any of the patients. Both lungs showed various stages of diffuse alveolar damage (DAD), including edema, hyaline membranes, and proliferation of pneumocytes and fibroblasts. Thrombosis of small and mid-sized pulmonary arteries was found in various degrees in all 11 patients and was associated with infarction in 8 patients and bronchopneumonia in 6 patients. Kupffer cell proliferation was seen in all patients, and chronic hepatic congestion in 8 patients. Other changes in the liver included hepatic steatosis, portal fibrosis, lymphocytic infiltrates and ductular proliferation, lobular cholestasis, and acute liver cell necrosis, together with central vein thrombosis. Additional frequent findings included renal proximal tubular injury, focal pancreatitis, adrenocortical hyperplasia, and lymphocyte depletion of spleen and lymph nodes. Viral RNA was detectable in pharyngeal, bronchial, and colonic mucosa but not bile.The sample was small.COVID-19 predominantly involves the lungs, causing DAD and leading to acute respiratory insufficiency. Death may be caused by the thrombosis observed in segmental and subsegmental pulmonary arterial vessels despite the use of prophylactic anticoagulation. Studies are needed to further understand the thrombotic complications of COVID-19, together with the roles for strict thrombosis prophylaxis, laboratory and imaging studies, and early anticoagulant therapy for suspected pulmonary arterial thrombosis or thromboembolism.None.

The persistence of SARS-CoV-2 after death of infected individuals is unclear. The aim of this study was to investigate the presence of SARS-CoV-2 RNA in different organs in correlation with tissue damage and post-mortem viral dynamics in COVID-19 deceased. Twenty-eight patients (17 males, 11 females; age 66–96 years; mean 82.9, median 82.5 years) diagnosed with COVID-19 were studied. Swabs were taken post-mortem during autopsy (N = 19) from the throat, both lungs, intestine, gallbladder, and brain or without autopsy (N = 9) only from the throat. Selective amplification of target nucleic acid from the samples was achieved by using primers for ORF1a/b non-structural region and the structural protein envelope E-gene of the virus. The results of 125 post-mortem and 47 ante-mortem swabs were presented as cycle threshold (Ct) values and categorized as strong, moderate, and weak. Viral RNA was detected more frequently in the lungs and throat than in the intestine. Blood, bile, and the brain were negative. Consecutive throat swabs were positive up to 128 h after death without significant increase of Ct values. All lungs showed diffuse alveolar damage, thrombosis, and infarction and less frequently bronchopneumonia irrespective of Ct values. In 30% the intestine revealed focal ischemic changes. Nucleocapsid protein of SARS-CoV-2 was detected by immunohistochemistry in bronchial and intestinal epithelium, bronchial glands, and pneumocytes. In conclusion, viral RNA is still present several days after death, most frequently in the respiratory tract and associated with severe and fatal organ damage. Potential infectivity cannot be ruled out post-mortem. Electronic supplementary material The online version of this article (10.1007/s00428-020-02903-8) contains supplementary material, which is available to authorized users.

ZusammenfassungDie Möglichkeit einer Tumorerkrankung auf Basis eines familiären Tumorprädispositionssyndroms muss bei jeder Krebsdiagnose in Betracht gezogen werden. Die Erfassung erkrankter „Index“-PatientInnen ist entscheidend für die Ermittlung des Risikos für Neu- oder Wiedererkrankungen bei den Betroffenen wie auch für das Auftreten von Tumoren bei bisher gesunden Verwandten. Die Erfassung von PatientInnen mit familiärer Tumorprädisposition erlaubt es, Betroffene in Vorsorgeprogramme zur Senkung von Morbidität und Letalität aufzunehmen. Für das erbliche Brust- und Eierstockkrebssyndrom besteht in Österreich ein breites Bewusstsein. Dadurch wird eine zufriedenstellende Erfassung der PatientInnen erreicht. Das ist für das Lynch-Syndrom, welches bei 2–3 % aller Kolorektal- und Endometriumkarzinome vorliegt, leider nicht der Fall. Um die Identifizierung von Lynch-Syndrom-PatientInnen zu verbessern, empfiehlt die Österreichische Arbeitsgemeinschaft Pathologie-Humangenetik (die Österreichische Arbeitsgemeinschaft Pathologie-Humangenetik setzt sich aus jeweils fünf Delegierten der Österreichischen Gesellschaft für Klinische Pathologie und Molekularpathologie und der Österreichischen Gesellschaft für Humangenetik zusammen) in diesem Konsensus-Statement eine diagnostische Strategie, die möglichst alle Lynch-Syndrom-assoziierten Kolorektal- und Endometriumkarzinome im Rahmen der pathologischen Tumorbeurteilung erfasst. Durch eine darauf basierende systematische Zuweisung von PatientInnen mit Verdacht auf Lynch-Syndrom an ein Zentrum für medizinische Genetik zur genetischen Beratung und weiterführenden genetischen Diagnostik wird sichergestellt, dass auch Familienangehörige mit Lynch-Syndrom erfasst werden.

Papillary lesions of the breast represent a heterogeneous group of lesions including benign papillomas, papillomas with focal epithelial atypia, fully fledged ductal carcinoma in situ (DCIS) or lobular neoplasia, papillary DCIS, encapsulated papillary carcinomas without or with invasion, solid papillary carcinomas, and invasive papillary carcinomas. A micropapillary pattern characterized by lack of fibrous stalks within the papillae is observed in micropapillary DCIS and invasive micropapillary carcinoma. In addition, a variety of other rare breast lesions reveals a papillary architecture such as tall cell carcinoma with reversed polarity (TCCRP) and mucinous cystadenocarcinoma, adenomyoepithelioma, and secretory carcinoma. In addition, benign lesions such as usual ductal hyperplasia, apocrine metaplasia, gynecomastia, and juvenile papillomatosis may show a papillary or micropapillary architecture. Fragments of a benign papilloma in a breast biopsy are considered a lesion of uncertain malignant potential (B3 in the European classification) and excision is mostly recommended. Although the knowledge about molecular pathology of papillary breast lesions has increased, there is not sufficient evidence for diagnostically useful molecular features, yet. The aim of this review is to provide an update on papillary and micropapillary lesions with emphasis on problematic areas for daily diagnostic work including biopsies. ispartof: VIRCHOWS ARCHIV vol:480 issue:1 pages:65-84 ispartof: location:Germany status: published

Background The purpose of this study was to assess the concordance of real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) detection of ESR1, PGR, ERBB2, and MKi67 messenger RNA (mRNA) in breast cancer tissues with central immunohistochemistry (IHC) in women treated within the prospective, randomized Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 6. Patients and methods We evaluated ESR1, PGR, ERBB2, and MKi67 mRNA expression by Xpert® Breast Cancer STRAT4 (enables cartridge-based RT-qPCR detection of mRNA in formalin-fixed paraffin-embedded tissues) and estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki67 protein expression by IHC [in situ hybridization (ISH) for HER2 IHC 2+] in 1115 surgical formalin-fixed paraffin-embedded specimens from patients of ABCSG Trial 6. Overall percent agreement (concordance), positive percent agreement (sensitivity), and negative percent agreement (specificity) between STRAT4 and IHC were determined for each marker. The primary objective of the study was concordance between STRAT4 mRNA measurements of ESR1, PGR, ERBB2, and MKi67 with central reference laboratory IHC (and ISH for HER2 IHC 2+ cases). Time to distant recurrence was analyzed by Cox models. Results All performance targets for ER, PR, and Ki67 were met. For HER2, the negative percent agreement target but not the positive percent agreement target was met. Concordance between STRAT4 and IHC was 98.9% for ER, 89.9% for PR, 98.2% for HER2, and 84.8% for Ki67 (excluding intermediate IHC 10%-20% staining). In univariable and multivariable Cox regression analyses, all four biomarkers tested by either STRAT4 RT-qPCR or by central IHC (ISH) had a comparable time to distant recurrence indicating similar prognostic value. Conclusions With the exception of HER2, we demonstrate high concordance between centrally assessed IHC and mRNA measurements of ER, PR, and Ki67 as well as a high correlation of the two methods with clinical outcome. Thus, mRNA-based assessment by STRAT4 is a promising new tool for diagnostic and therapeutic decisions in breast cancer., Highlights • Immunohistochemistry is the clinical gold standard for assessing ER, PR, HER2, and Ki67 expression in breast cancer. • RNA expression assays provide an alternative approach to measuring these biomarkers. • We demonstrate high concordance of STRAT4 mRNA detection in comparison to central immunohistochemistry. • The STRAT4 assay is a promising new tool which can be carried out in

Primary and metastatic cardiac sarcomas represent rare neoplasms with a variable clinical course. We present a rare case of an 84-year-old man with a cardiac pacemaker and heart osteosarcoma, hepatocellular and prostatic carcinoma, who was admitted with suspected symptoms of infective endocarditis. Findings of cardiac osteosarcoma in a patient with a pacemaker and three malignancies have not been reported before in the literature. J Med Cases. 2019;10(8):234-240 doi: https://doi.org/10.14740/jmc3333

Most ovarian carcinomas (OC) are characterized by poor prognosis, particularly the most frequent type high-grade serous carcinoma. Besides PARP inhibitors, target-based therapeutic strategies are not well established. We asked the question which other therapeutic targets could be of potential value and, therefore, analyzed a large cohort of OC for several predictive factors. Two hundred eighty-eight (288) cases of OC including the major histological types were analyzed by immunohistochemistry for PD-L1HER2, ALK, and the mismatch repair (MMR) proteins MLH1, PMS2, MSH2, and MSH6. HER2 amplification and ALK/EML4 fusion were assessed by fluorescence in situ hybridization. The most frequent finding was PD-L1 expression ≥ 1% in 19.5% of the cases, which correlated with a significantly better overall survival in multivariate analysis (p < 0.001). HER2 amplification was detected in 11 cases (4%), all high-grade serous carcinomas. Amplification of HER2 did not correlate with patients' survival. ALK/EML4 fusion was found in two cases (0.74%): one high-grade serous and one endometrioid carcinoma. MMR deficiency was only present in one case of stage IV high-grade serous carcinoma. Subsets of high-grade serous carcinomas show PD-L1 expression and HER2 amplification, respectively, and, therefore, could qualify for immune checkpoint inhibitor therapy or anti HER2 therapy. PD-L1 is also of prognostic impact. ALK/EML4 fusion is very rare in OC and not a putative therapeutic target.

Die WHO-Klassifikation 2014 unterscheidet 2 Vorlauferlasionen fur das endometrioide Endometriumkarzinom: die Endometriumhyperplasie ohne Atypien (EH) und die atypische Endometriumhyperplasie/endometrioide intraepitheliale Neoplasie (AEH/EIN). Die AEH/EIN ist durch dicht liegende Drusen mit atypischem Epithel charakterisiert, zwischen denen das Stroma deutlich reduziert ist. Die zellularen Atypien sind durch Verlust der Polaritat mit Ausbildung runder bis ovaler Zellkerne mit deutlichen Nukleolen charakterisiert. Der Vergleich mit quasi normalen Drusen der Umgebung erleichtert das Erkennen der Atypien. Die AEH/EIN kann sekretorische und muzinose Veranderungen sowie eine Plattenepithelmetaplasie enthalten. Epitheliale Metaplasien konnen sowohl in benignen Lasionen als auch in Karzinomen des Endometriums vorkommen. In etwa zwei Drittel der AEH/EIN kommt es zu einem Verlust der Immunreaktivitat fur PTEN und/oder PAX2. Die Differenzialdiagnose zum invasiven, gut differenzierten endometrioiden Karzinom basiert auf einem konfluenten Wachstumsmuster mit Ausbildung labyrinthartiger oder kribroser Strukturen. Differenzialdiagnostisch spielen hyperplastische Polypen und papillare Proliferationen eine Rolle, andererseits kann eine AEH/EIN auch in Polypen vorkommen. Eine Therapie einer AEH/EIN mit Gestagenen ist nicht evidenzbasiert, fuhrt aber haufig zu deren Ruckbildung. Das serose intraepitheliale Karzinom (SEIC) ist durch hochgradige zellulare Atypien und Polymorphie, Ablosen von Zellen, ein mutationspezifisches immunhistchemisches Farbemuster fur P53 und einen erhohten Ki67 Farbeindex charakterisiert. Obwohl es Vorlaufer des serosen Karzinoms ist, wird das SEIC biologisch als nichtinvasives seroses Karzinom betrachtet, da es bereits mit extrauterinen Metastasen einhergehen kann.

Biliary tract cancer (BTC) represents a malignant tumor of the biliary tract including cholangiocarcinoma (CCA) and the carcinoma of the gallbladder (GBC) with a 5-year survival rate between 5 and 18% due to late diagnosis and rapid disease progression. Chronic inflammation is one of the main risk factors for CCA and GBC in particular. IL-6, as a mediator of inflammation, can act through a membrane-bound receptor alpha-chain (mIL-6R, "IL-6 classic signaling") or via soluble forms (sIL-6R, "IL-6 trans-signaling"). However, little is known about the impact on cellular responses of IL-6 trans-signaling on BTC. We analyzed primary tumors as whole sections and as tissue microarrays, and also searched The Cancer Genome Atlas database. Compared to non-neoplastic, non-inflamed gallbladder tissue, IL-6Rα was downregulated in GBC, and this correlated with the patients' overall survival. Furthermore, different CCA cell lines and compounds for activation (IL-6 and Hyper-IL-6) or inhibition (Tocilizumab and sgp130Fc) of IL-6 classic signaling and trans-signaling were used to determine their effects on cellular processes between the two modes of IL-6 signaling. Inhibition of IL-6 trans-signaling by sgp130Fc reduced CCA cell line viability and apoptosis, whereas migration and proliferation were increased. We conclude that IL-6Rα expression is a good prognostic marker for GBC, and that the blocking of IL-6 trans-signaling and activation of IL-6 classic signaling have tumor promoting activity. These findings warrant the exclusion of patients with GBC or other malignancies associated with bile metabolism from IL-6R inhibitor therapy.

Fur epitheliale Ovarialtumoren gibt es diagnostische Probleme von unterschiedlicher praktischer Relevanz. Bei der Abgrenzung der Borderlinetumoren/atypisch proliferierten Tumoren von Zystadenomen wird eine Ausdehnung der atypischen Epithelproliferation von 10 % empfohlen. Die mikropapillare Variante des serosen Borderlinetumors ist haufiger mit invasivem Wachstum und einem hoheren Stadium vergesellschaftet als konventionelle Borderlinetumoren. Extraaovarielle Lasionen sind prognostisch wichtig, da sie ein hoheres Stadium nach sich ziehen. Die rezente WHO-Klassifikation 2014 empfiehlt invasive Implantate als low-grade serose Karzinome zu bezeichnen und den Begriff Implantat fur nichtinvasive Lasionen zu verwenden. Bei low-grade serosen Karzinomen sind unregelmasig verteilte Tumorzellnester in spaltformigen Hohlraumen die haufigste Form invasiven Wachstums. Bei muzinosen und endometrioiden Karzinomen uberwiegt hingegen ein konfluentes Wachstumsmuster, ein nodulares Wachstumsmuster ist verdachtig auf Metastasen. Fur die differenzialdiagnostische Abgrenzung gegenuber Metastasen sind klinische Informationen und Immunhistochemie hilfreich. Die Unterscheidung zwischen low-grade und high-grade serosen Karzinomen basiert auf dem Grad der Kernpolymorphie und dem Mitosegehalt. Seromuzinose Tumoren ersetzen die endozervikalen muzinosen Tumoren und ahneln histologisch und klinisch serosen und endometrioiden Tumoren. Endometrioide Tumoren mit fibromatosem Stroma mussen speziell gegenuber Tumoren mit Sertoli-Zell-Differenzierung und neuroendokrinen Tumoren abgegrenzt werden. Fur die Differenzialdiagnose epithelialer Ovarialtumoren, speziell der Karzinome, empfiehlt sich der gezielte Einsatz eines Panels immunhistochemischer Marker unter Berucksichtigung der Histomorphologie.

Benign leiomyomas are the most frequent mesenchymal tumors of the uterus. In contrast, uterine sarcomas are very rare. Leiomyosarcomas are the most frequent sarcomas followed by endometrial stromal sarcomas (ESS). Leiomyosarcomas are characterized by marked nuclear atypia and high mitotic count and may also show tumor cell necrosis and myometrial and vascular invasion. For cases of diagnostic uncertainty, the category of smooth muscle tumor of uncertain malignant potential (STUMP) may be considered but should be rarely used. Besides low-grade ESS and stromal nodules, a category of high-grade ESS was reconsidered by the WHO in 2014. High-grade ESS are characterized by fibromyxoid and round cell histology, myoinvasive growth, and immunoreactivity for cyclin D1 and BCOR and distinct gene fusions involving YWHAE and BCOR, respectively. The very rare undifferentiated uterine sarcomas need to be redefined due to overlap with high-grade ESS. Uterine tumors resembling ovarian sex cord tumors (UTROSCT) rarely behave malignant, but need to be distinguished from endometrial carcinomas. Mixed epithelial and mesenchymal tumors of the uterus are rare with carcinosarcomas occurring more frequently than adenosarcomas. For prognosis of adenosarcomas the recognition of sarcomatous overgrowth is crucial. Carcinosarcomas are histologically heterogeneous although genetically clonal; biologically they are considered as undifferentiated carcinomas. There will be an increasing importance of molecular pathology for the classification of rare and unusual mesenchymal uterine tumors.

Summary The first German interdisciplinary S3-guideline on the diagnosis, therapy and follow-up of patients with endometrial cancer was published in April 2018. Funded by German Cancer Aid as part of an Oncology Guidelines Program, the lead coordinators of the guideline were the German Society of Gynecology and Obstetrics (DGGG) and the Gynecological Oncology Working Group (AGO) of the German Cancer Society (DKG). Purpose Using evidence-based, risk-adapted therapy to treat low-risk women with endometrial cancer avoids unnecessarily radical surgery and non-useful adjuvant radiotherapy and/or chemotherapy. This can significantly reduce therapy-induced morbidity and improve the patientʼs quality of life as well as avoiding unnecessary costs. For women with endometrial cancer and a high risk of recurrence, the guideline defines the optimal extent of surgical radicality together with the appropriate chemotherapy and/or adjuvant radiotherapy if required. An evidence-based optimal use of different therapeutic modalities should improve the survival rates and quality of life of these patients. This S3-guideline on endometrial cancer is intended as a basis for certified gynecological cancer centers. The aim is that the quality indicators established in this guideline will be incorporated in the certification processes of these centers. Methods The guideline was compiled in accordance with the requirements for S3-level guidelines. This includes, in the first instance, the adaptation of source guidelines selected using the DELBI instrument for appraising guidelines. Other consulted sources included reviews of evidence, which were compiled from literature selected during systematic searches of literature databases using the PICO scheme. In addition, an external biostatistics institute was commissioned to carry out a systematic search and assessment of the literature for one part of the guideline. Identified materials were used by the interdisciplinary working groups to develop suggestions for Recommendations and Statements, which were then subsequently modified during structured consensus conferences and/or additionally amended online using the DELPHI method, with consent between members achieved online. The guideline report is freely available online. Recommendations Part 2 of this short version of the guideline presents recommendations for the therapy of endometrial cancer including precancers and early endometrial cancer as well as recommendations on palliative medicine, psycho-oncology, rehabilitation, patient information and healthcare facilities to treat endometrial cancer. The management of precancers of early endometrial precancerous conditions including fertility-preserving strategies is presented. The concept used for surgical primary therapy of endometrial cancer is described. Radiotherapy and adjuvant medical therapy to treat endometrial cancer and uterine carcinosarcomas are described. Recommendations are given for the follow-up care of endometrial cancer, recurrence and metastasis. Palliative medicine, psycho-oncology including psychosocial care, and patient information and rehabilitation are presented. Finally, the care algorithm and quality assurance steps for the diagnosis, therapy and follow-up of patients with endometrial cancer are outlined.

Background: The prognostic performance of the residual cancer burden (RCB) score is a promising tool for breast cancer patients undergoing neoadjuvant therapy. We independently evaluated the prognostic value of RCB scores in an extended validation cohort. Additionally, we analyzed the association between chemotherapy dose reduction and RCB scores. Methods: In this extended validation study, 367 breast cancer patients with available RCB scores were followed up for recurrence-free survival (RFS), distant disease-free survival (DDFS), and overall survival (OS). We also computed standardized cumulative doses of anthracyclines and taxanes (A/Ts) to investigate a potential interaction between neoadjuvant chemotherapy dose reduction and RCB scores. Results: Higher RCB scores were consistently associated with adverse clinical outcomes across different molecular subtypes (HR for RFS = 1.60, 95% CI 1.33–1.93, p &lt, 0.0001, HR for DDFS = 1.70, 95% CI 1.39–2.05, p &lt, HR for OS = 1.67, 95% CI 1.34–2.08, p &lt, 0.0001). The adverse impact prevailed throughout 5 years of follow-up, with a peak for relapse risk between 1–2 years after surgery. Clinical outcomes of patients with RCB class 1 did not differ substantially at 5 years compared to RCB class 0. A total of 180 patients (49.1%) underwent dose reduction of neoadjuvant A/T chemotherapy. We observed a statistically significant interaction between dose reduction and higher RCB scores (interaction p-value = 0.042). Conclusion: Our results confirm RCB score as a prognostic marker for RFS, DDFS, and OS independent of the molecular subtype. Importantly, we show that lower doses of cumulative neoadjuvant A/T were associated with higher RCB scores in patients who required a dose reduction.

To review the scientific evidence related to predictive biomarkers in cervical adenocarcinoma (ADC). The authors reviewed the literature regarding predictive biomarkers in cervical ADC. There were several limitations: (1) there is an overlap between predictive and prognostic biomarkers, as the vast majority of patients are treated with anticancer strategies; (2) in many studies and clinical trials, cervical ADC patients are included in a large series of patients predominantly composed of cervical squamous cell carcinomas; and (3) in most of the studies, and clinical trials, there is no distinction between human papillomavirus (HPV)-associated and HPV-independent cervical ADCs, or between various histologic subtypes. Results obtained from a small group of studies confirm that cervical ADCs exhibit distinct molecular features as compared with squamous carcinomas, and that there are different molecular features between different types of cervical ADCs. Promising areas of interest include ERBB2 (HER2) mutations and PD-L1 expression as predictive biomarkers for anti-HER2 treatment and immunotherapy, respectively. To date, no definitive data can be obtained from the literature regarding predictive biomarkers for cervical ADC. Clinical trials specifically designed for endocervical ADC patients are required to elucidate the predictive value of HER2 mutations and PD-L1 expression. The distinction between HPV-associated and HPV-independent cervical ADCs as well as early involvement of pathologists in the design of future clinical trials are needed to identify new predictive biomarkers in cervical ADC.

A European consensus conference on endometrial carcinoma was held in 2014 to produce multidisciplinary evidence-based guidelines on selected questions. Given the large body of literature on the management of endometrial carcinoma published since 2014, the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy & Oncology (ESTRO) and the European Society of Pathology (ESP) jointly decided to update these evidence-based guidelines and to cover new topics in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide. ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of endometrial carcinoma (27 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2014, identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 191 independent international practitioners in cancer care delivery and patient representatives. The guidelines comprehensively cover endometrial carcinoma staging, definition of prognostic risk groups integrating molecular markers, pre- and intra-operative work-up, fertility preservation, management for early, advanced, metastatic, and recurrent disease and palliative treatment. Principles of radiotherapy and pathological evaluation are also defined.

Autopsies on COVID-19 have provided deep insights into a novel disease with unpredictable and potentially fatal outcome. A standardized autopsy procedure preferably with an in-situ technique and systematic tissue processing is important. Strict safety measures include personal protective equipment with a standardized protocol for dressing and undressing, usage of FFP-3 masks and minimization of aerosol production. The use of an airborne infection isolation (AIIR) room is preferred. Viral RNA analysis using swabs from throat, both lungs and other organs provides information on cross-organ viral dynamics. To correctly determine the full extent of pathological organ changes an adequate processing procedure is of the utmost importance. Systematic dissection and processing of the lungs revealed pulmonary infarction caused by thrombosis and thromboembolism and bacterial bronchopneumonia as the most frequent cause of death. Fungal pneumonia (aspergillus) was found in one case. The quality of the tissue was sufficient for histopathological and immunohistochemistry analyses in all cases. Viral RNA from throat or lung swabs was detectable post mortem in 89 % of the cases and could also be detected from paraffin-embedded tissue by real-time PCR. Complete COVID-19 autopsies including extensive histopathological studies and viral RNA analysis require approximately three times more human and technical resources and time compared to standard non-COVID autopsies. Autopsies on COVID-19 are feasible, present a manageable risk, while following a strict protocol, and provide novel insights into disease pathogenesis and the clinician with important feedback.

We addressed a significant unknown feature of circulating tumor DNA (ctDNA), i.e., how ctDNA levels change during chemotherapy, by serially monitoring ctDNA in patients with colorectal cancer during the 48-h application of FOLFOX. Surprisingly, we did not observe a spike in ctDNA as a sign of a responsive tumor, but instead ctDNA levels initially decreased and remained low in patients with stable disease or partial response. Our observations reveal further insights into cell destruction during chemotherapy with important implications for the management of patients.

Tumors have evolved mechanisms to escape anti-tumor immunosurveillance. They limit humoral and cellular immune activities in the stroma and render tumors resistant to immunotherapy. Sensitizing tumor cells to immune attack is an important strategy to revert immunosuppression. However, the underlying mechanisms of immune escape are still poorly understood. Here we discover Indoleamine-2,3-dioxygenase-1 (IDO1)+ Paneth cells in the stem cell niche of intestinal crypts and tumors, which promoted immune escape of colorectal cancer (CRC). Ido1 expression in Paneth cells was strictly Stat1 dependent. Loss of IDO1+ Paneth cells in murine intestinal adenomas with tumor cell-specific Stat1 deletion had profound effects on the intratumoral immune cell composition. Patient samples and TCGA expression data suggested corresponding cells in human colorectal tumors. Thus, our data uncovered an immune escape mechanism of CRC and identify IDO1+ Paneth cells as a target for immunotherapy., Pflügler, Svinka et al. identify a subset of Paneth cells in mouse intestinal crypts and tumors, which express the immune checkpoint molecule Ido1 in a Stat1-dependent manner and promote tumor growth. Gene expression data from human colorectal cancer (CRC) suggest that a similar population is present in human cancer and opens the door for further studies of immune escape mechanisms in CRC.

The data presented here is related to the research article entitled “FERTILITY-SPARING SURGERY AND REPRODUCTIVE-OUTCOMES IN PATIENTS WITH BORDERLINE OVARIAN TUMORS” by Plett et al. in Journal of Gynecologic Oncology [1] and is analysed and discussed in detail. 18 Patients with Recurrent Borderline Ovarian Tumors (BOT) were identified and listed in Table 1. All patients underwent treatment for primary BOT either per radical surgery (RS) or fertility sparing surgery (FSS) by the same team in Horst Schmidt Klinik (HSK) in Wiesbaden and the Department of Gynecology and Gynecologic Oncology at Kliniken Essen-Mitte between January 2000 and December 2018 and were followed up closely. Details on patients` and surgical characteristics are given as well as management of character of recurrent disease. In Table 2 important publications from the last 20 years are listed in order to visualize better the oncologic outcomes (invasive and non-invasive relapses) and calculated risks of recurrence with the purpose to understand better the important findings of the related article cited above.

Background Bevacizumab, a monoclonal antibody against soluble VEGFA, is an approved and commonly administered anti-angiogenic drug in patients with metastasized colorectal cancer (mCRC). The survival benefit of anti-VEGF therapy in mCRC patients is limited to a few months, and acquired resistance mechanisms are largely unknown. Here, we employed whole-genome sequencing of plasma DNA to evaluate the tumor genome of patients undergoing treatment with bevacizumab to determine novel aberrations associated with resistance. Methods Using longitudinal plasma analyses, we studied the evolution of tumor genomes in a mCRC cohort (n = 150) and conducted analyses of CRC cases from The Cancer Genome Atlas (TCGA) database (n = 619) to identify associations between genomic aberrations and clinical features. We employed whole-genome sequencing to identify the most frequently occurring focal somatic copy number alterations (SCNAs). Using the TCGA data as a comparative and supporting dataset, we defined the minimally amplified overlapping region and studied the mechanistic consequences of copy number gain of the involved genes in this segment. In addition, we established an in vitro cell model and conducted downstream gene expression and cell viability assays to confirm our findings from the patient dataset. Results We observed a recurrent focal amplification (8.7% of cases) on chromosome 13q12.2. Analysis of CRC cases from the TCGA database suggested that this amplicon is associated with more advanced stages. We confirmed that this 13q12.2 amplicon frequently emerges later during the clinical course of disease. After defining the minimally amplified region, we observed that the amplification and expression of one gene, POLR1D, impacted cell proliferation and resulted in upregulation of VEGFA, an important regulator of angiogenesis which has been implicated in the resistance to bevacizumab treatment. In fact, in several patients, we observed the emergence of this 13q12.2 amplicon under bevacizumab treatment, which was invariably associated with therapy resistance. Conclusions Non-invasive analyses of cell-free DNA from patients undergoing treatment with bevacizumab enabled the tracking of evolving tumor genomes and helped identify a recurrent focal SCNA of clinical relevance. Here, we describe a novel resistance mechanism against a widely applied treatment in patients with mCRC which will impact the clinical management of patients.

Purpose: To assess the predictive value of molecular breast cancer subtypes in premenopausal patients with hormone receptor–positive early breast cancer who received adjuvant endocrine treatment or chemotherapy. Experimental Design: Molecular breast cancer subtypes were centrally assessed on whole tumor sections by IHC in patients of the Austrian Breast and Colorectal Cancer Study Group Trial 5 who had received either 5 years of tamoxifen/3 years of goserelin or six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF). Luminal A disease was defined as Ki67 Results: 185 (38%), 244 (50%), and 59 (12%) of 488 tumors were classified as luminal A, luminal B/HER2-negative and luminal B/HER2-positive, respectively. Luminal B subtypes were associated with poor outcome. Patients with luminal B tumors had a significantly shorter RFS [adjusted HR for recurrence: 2.22; 95% confidence interval (CI), 1.41–3.49; P = 0.001] and OS (adjusted HR for death: 3.51; 95% CI, 1.80–6.87; P < 0.001). No interaction between molecular subtypes and treatment was observed (test for interaction: P = 0.84 for RFS; P = 0.69 for OS). Conclusions: Determination of molecular subtypes by IHC is an independent prognostic factor for recurrence and death in premenopausal women with early-stage, hormone receptor–positive breast cancer but is not predictive for outcome of adjuvant treatment with tamoxifen/goserelin or CMF. See related commentary by Hunter et al., p. 5543

Introduction: The main differential diagnoses of secondary hyperthyroidism include thyrotropin-secreting neuroendocrine pituitary tumors (TSH-PitNETs) and resistance to thyroid hormone. As a rare cause of secondary hyperthyroidism, ectopic thyrotropin-producing neuroendocrine pituitary tumors must also be considered. Case Presentation: A 48-year-old female patient with overt hyperthyroidism and elevated thyrotropin was admitted to the endocrine outpatient clinic of a secondary care hospital in March 2018. The patient had an inconspicuous pituitary MRI and F18-F-DOPA PET-CT, but showed a tumor mass located at the pharyngeal roof. Most biochemical tests and an increased tracer uptake of the pharyngeal mass in a Ga68-DOTANOC PET-CT argued for the presence of an ectopic TSH-PitNET. After treatment with octreotide over 5 days and a consecutive normalization of free thyroxine and free triiodothyronine, the tumor was endoscopically resected. Histologically, the mass consisted of small partially spindle, partially polygonal monomorphic to mildly pleomorphic cells with immunoreactivity for thyrotropin and luteinizing hormone. Postoperatively, the patient required intermittent levothyroxine therapy. Discussion and Conclusions: Ectopic TSH-PitNETs represent an extremely rare cause for secondary hyperthyroidism. While the diagnostic process may be complicated by negative imaging studies of the pituitary gland, family history, biochemical tests, and functional imaging using gallium-labelled somatostatin analogues may be helpful in establishing the diagnosis.

Background: COVID-19 caused by the novel SARS-CoV-2 has rapidly become pandemic and has an estimated mortality rate of 3·4% of infected individuals However, th

Response evaluation of cancer therapeutics relies on the assessment of the change in tumor burden, which is performed in accordance with defined criteria every 8-12 weeks. However, predictive factors for response are not available for the majority of patients with advanced stage colorectal cancer. Here we show that measurement of circulating tumor DNA (ctDNA) levels during one of the most commonly administered drug regimens, i.e. FOLFOX, allows an early, real-time assessment of treatment response. During the 48-hour FOLFOX application, we serially assessed plasma DNA and observed that ctDNA levels initially decreased during the first 23 hours. In patients with stable disease or partial response, ctDNA levels remained low, whereas in patients with progressive disease, ctDNA levels increased at the end of the treatment cycle, predicting clinical and radiologic response correctly. Hence, ctDNA monitoring during treatment may contribute to an early outcome prediction with significant implications for the management of patients.

Im April 2018 erschien die erste deutsche interdisziplinare S3-Leitlinie fur die Diagnostik, Therapie und Nachsorge der Patientinnen mit Endometriumkarzinom. Dieser Beitrag ist die Zusammenfassung des Kap. 4: „Diagnose, Fruherkennung, Bildgebung und Pathologie“ mit dem Ziel, dem Leser eine Kurzfassung an die Hand zu geben. Dargestellt sind die Empfehlungen zur Diagnose und Fruherkennung von Endometriumkarzinomen, ferner die Indikationen zur Bildergebung und die Anforderungen fur die pathologische Aufarbeitung.

Background Mutations in BRCA1 and BRCA2 are associated with better survival in ovarian cancer (OC) patients due to a better response to platinum-based chemotherapy. However, the impact of the BRCA1/2 mRNA-expression is not well characterized in OC. Patients and methods We investigated BRCA1/2 mRNA-expression in 12 non-neoplastic fallopian tubes and 201 epithelial OCs in relation to their clinical characteristics. Results We found higher BRCA1/2 mRNA-expression in OCs compared to controls (P = 0.011, P

Background Borderline ovarian tumors (BOT) are considered a biological category with increased epithelial proliferation and cellular atypia in the absence of invasive growth. Since BOT occur often in young patients fertility sparing surgery (FSS) is an important issue. With this study we aimed to evaluate risk factors for relapses and fertility of patients after FSS. Methods Patients diagnosed with BOT and treated between 2000 and 2018 were included. External pathological review was done in all patients. FSS was performed after individual discussion and a complete surgical staging according to FIGO, without lymphadenectomy and with a waiver for preservation of uterus and one ovary. Results Among 352 Patients 80.2% had FIGO I and 63.9% had a serous BOT. Eighteen patients (5.1%) relapsed and 4 cases of malignant transformation were reported (1.1%). One patient of the latter died, all others have no evidence of disease. The overall recurrence-rate was 1.1% in FIGO-Stage I and 25.5% in FIGO III-IV (HR = 27; 95%-CI 7.7–95; p ≤.001). 95 patients underwent FSS. Thirteen (13.7%) of these patients relapsed, all as BOT. In multivariate analysis FIGO stages II-IV (HR = 27; 95%-CI: 8.1–102; p ≤.001) and FSS (HR = 12; 95%-CI: 2.9–47; p = .001) remained significant risk factors for recurrent disease. Pregnancy rate among forty-one patients attempting to conceive was 82.9%. 29 patients experienced at least one life-birth, in total 38 life-births were reported. Conclusion FSS in stage I is a safe procedure and life-birth-rates after FSS are high. More advanced FIGO stages have to be discussed individually and relapse rates have to be weighed against FSS. A central review of pathology, as we performed routinely, is mandatory and may have contributed to our low rate of invasive relapses.

// Verena Wieser 1 , Inge Gaugg 1 , Martina Fleischer 1 , Giridhar Shivalingaiah 2, 5 , Soeren Wenzel 2 , Susanne Sprung 3 , Sigurd F. Lax 4 , Alain G. Zeimet 1 , Heidelinde Fiegl 1 and Christian Marth 1 1 Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck 6020, Austria 2 Division of Human Genetics, Medical University of Innsbruck, Innsbruck 6020, Austria 3 Institute of Pathology, Medical University of Innsbruck, Innsbruck 6020, Austria 4 Department of Pathology, Hospital Graz Sud-West, Academic Teaching Hospital of the Medical University Graz, Graz 8020, Austria 5 Present address: Division Biological Chemistry, Biocenter, Innsbruck, Medical University of Innsbruck, Innsbruck 6020, Austria Correspondence to: Heidelinde Fiegl, email: Heidelinde.Fiegl@i-med.ac.at Keywords: ovarian cancer; PD-1; PD-L1; IFNγ; BRCA1/2 Received: July 31, 2017 Accepted: February 27, 2018 Published: April 03, 2018 ABSTRACT Checkpoint molecules such as programmed cell death protein-1 (PD-1) and its ligand PD-L1 are critically required for tumor immune escape. The objective of this study was to investigate tumoral PD-1 and PD-L1 mRNA-expression in a cohort of ovarian cancer (OC) patients in relation to tumor mutations. We analyzed mRNA expression of PD-1 , PD-L1 and IFNG by quantitative real-time PCR in tissue of 170 patients with low grade-serous (LGSOC), high-grade serous (HGSOC), endometrioid and clear cell OC compared to 28 non-diseased tissues (ovaries and fallopian tubes) in relation to tumor protein 53 ( TP53 ) and breast cancer gene 1/2 ( BRCA1/2 ) mutation status. TP53 -mutated OC strongly expressed PD-L1 compared to TP53 wild-type OC ( p = 0.028) and BRCA1/2 -mutated OC increasingly expressed PD-1 ( p = 0.024) and PD-L1 ( p = 0.012) compared to BRCA1/2 wild-type OC. For the first time in human, we noted a strong correlation between tumoral IFNG and PD-1 or PD-L1 mRNA-expression, respectively ( p < 0.001). OC tissue increasingly expressed PD-1 compared to healthy controls (vs. ovaries: p < 0.001; vs. tubes: p = 0.018). PD-1 and PD-L1 mRNA-expression increased with higher tumor grade ( p = 0.008 and p = 0.027, respectively) and younger age (< median age, p = 0.001). Finally, in the major subgroup of our cohort, FIGO stage III/IV HGSOC, high PD-1 and PD-L1 mRNA-expression was associated with reduced progression-free ( p = 0.024) and overall survival ( p = 0.049) but only in the univariate analysis. Our study suggests that in OC PD-1 / PD-L1 mRNA-expression is controlled by IFNγ and affected by TP53 and BRCA1/2 mutations. We suggest that these mutations might serve as potential predictive factors that guide anti- PD1 / PD-L1 immunotherapy.

A 48-year old patient with known xeroderma pigmentosum was referred to our skin cancer unit because of the recent development of histopathologically verified squamous cell carcinoma (SCC) lymph node metastasis on her left supraclavicular region. A whole body PET-CT showed additional abdominal and inguinal lymph node metastases. Her medical history included, in addition to several minimal surgeries of early forms of keratinocyte skin cancer, a poorly differentiated cutaneous SCC (cSCC) with invasion into the lymphatic vessels on her left tight, which was treated with wide surgical excision 5 years before.

ObjectiveIn cancer patients, the pathology report serves as an important basis for treatment. Therefore, a correct cancer diagnosis is crucial, and diagnostic discrepancies may be of clinical relevance. It was the aim of this study to perform a specialized histopathology review and to investigate potential clinical implications of expert second opinion pathology in endometrial cancer.MethodsPatients treated for endometrial carcinoma at the Tübingen University Women's hospital between 2003 and 2013 were identified. Original pathology reports were reviewed, and contributing pathologists were asked to submit original slides and paraffin blocks. Case review was subsequently performed by 3 pathologists specialized in gynecological pathology who were blinded for clinical information. For histological typing, the World Health Organization 2014 classification was used, grading and staging were performed according to International Federation of Gynecology and Obstetrics 2009. Risk assignment was performed based on the 2013 European Society for Medical Oncology clinical practice guidelines.ResultsIn 565 of 745 cases, which had originally been diagnosed as endometrial carcinoma, archival histological slides and blocks were available. In 55 (9.7%) of 565 cases, a major diagnostic discrepancy of potential clinical relevance was found after expert review. In 38 of these 55 cases, the diagnostic discrepancy was related to tumor type (n = 24), grade (n = 10) or myoinvasion (n = 4). In 17 cases, the diagnosis of endometrial carcinoma could not be confirmed (atypical hyperplasia, n = 10; endometrial carcinosarcoma, n = 4; neuroendocrine carcinoma, n = 1; leiomyosarcoma, n = 1; atypical polypoid adenomyoma, n = 1). Minor discrepancies not changing risk classification were also noted in 214 (37.9%) of 565, most frequently for grade within the low-grade (G1/G2) category (n = 184).ConclusionsA retrospective gynecopathological case review was shown to reveal limited but significant discrepancies in histological diagnoses as well as typing and grading of endometrial carcinomas, some directly impacting clinical management. Second opinion pathology therefore not only helps to improve the quality of translational research study cohorts but might also help to optimize patient care in difficult cases.

// Sonja M. Kessler 1, 2, * , Eva Lederer 1, * , Stephan Laggai 2 , Nicole Golob-Schwarzl 1, 3 , Kevan Hosseini 2 , Johannes Petzold 1 , Caroline Schweiger 1 , Robert Reihs 1 , Marlen Keil 4 , Jens Hoffmann 4 , Christian Mayr 5 , Tobias Kiesslich 5 , Martin Pichler 6, 7, 8 , Kyung Sik Kim 9 , Hyungjin Rhee 10 , Young Nyun Park 11 , Sigurd Lax 12 , Peter Obrist 13 , Alexandra K. Kiemer 2 and Johannes Haybaeck 1, 14 1 Institute of Pathology, Medical University of Graz, Graz, Austria 2 Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrucken, Germany 3 Center for Biomarker Research in Medicine, Graz, Austria 4 Experimental Pharmacology and Oncology Berlin-Buch GmbH, Berlin, Germany 5 Laboratory for Tumor Biology and Experimental Therapies, Institute of Physiology and Pathophysiology, Department of Internal Medicine I, Paracelsus Medical University, Salzburg, Austria 6 Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria 7 Research Unit for Non-coding RNAs and Genome Editing in Cancer, Medical University of Graz, Graz, Austria 8 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, USA 9 Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea 10 Department of Radiology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea 11 Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea 12 Department of Pathology, General Hospital Graz Sued-West, Graz, Austria 13 Laboratory of Pathology, Dr. Obrist and Dr. Brunhuber OG, Zams, Austria 14 Department of Pathology, Medical Faculty, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany * These authors contributed equally to this work Correspondence to: Johannes Haybaeck, email: johannes.haybaeck@med.ovgu.de Keywords: IGF2BP2/IMP2/p62, IGF2BP3/IMP3, IGF2BP1/IMP1, NADPH oxidase, gallbladder carcinoma Received: January 04, 2017 Accepted: September 04, 2017 Published: September 21, 2017 ABSTRACT Overexpression of the oncofetal insulin-like growth factor 2 mRNA-binding protein 2 (IMP2/IGF2BP2) has been described in different cancer types. Gallbladder carcinoma (GBC) is a rare but highly aggressive cancer entity with late clinical detection and poor prognosis. The aim of this study was to investigate the role of IMP2 in human GBC. Tissue microarrays (TMAs) of an international multi-center GBC sample collection from n = 483 patients were analyzed by immunohistochemistry. IMP2 immunoreactivity was found in 74.3% of the tumor samples on TMA, of which 14.0% showed strong and 86.0% low staining intensity. 72.4% of the tumor samples were IMP1 positive, but IMP1 showed lower expression in tumor tissue compared to control tissues. IMP3 immunoreactivity was observed in 92.7% of all tumors, of which 53.6% revealed strong IMP3 expression. Kaplan-Meier analysis linked high IMP2 expression to shorter survival time ( p = 0.033), whereas neither IMP1 nor IMP3 expression was linked to a decreased survival time. Eight different human biliary tract cancer (BTC) cell lines were evaluated for tumor growth kinetics in mouse xenografts. Cell lines with high IMP2 expression levels showed the fastest increase in tumor volumes in murine xenografts. Furthermore, IMP2 expression in these cells correlated with the generation of reactive oxygen species (ROS) and RAC1 expression in BTC cells, suggesting RAC1-induced ROS generation as a potential mechanism of IMP2-promoted progression of GBC. In conclusion, IMP2 is frequently overexpressed in GBC and significantly associated with poor prognosis and growth rates in vivo . IMP2 might therefore represent a new target for the treatment of advanced GBC.

In the 2014 WHO classification, squamous cell precursor lesions are classified as low-grade and high-grade intraepithelial lesions. LSIL corresponds to CIN1, HSIL includes CIN2 and CIN3. Only adenocarcinoma in situ (AIS) is accepted as precursor of adenocarcinoma and includes the stratified mucin-producing intraepithelial lesion (SMILE). Although relatively rare, adenocarcinoma and squamous cell carcinoma can be mixed with a poorly differentiated neuroendocrine carcinoma. Most cervical adenocarcinomas are low grade and of endocervical type. Mucinous carcinomas show marked intra- and extracellular mucin production. Almost all squamous cell carcinomas, the vast majority of adenocarcinomas, and many rare carcinoma types are HPV related. For low grade endocervical adenocarcinomas, the pattern-based classification according to Silva should be reported. Neuroendocrine tumors are rare and are classified into low-grade and high-grade, whereby the term carcinoid is still used.

Die WHO-Klassifikation von 2014 nimmt eine Unterteilung in verschiedene Subtypen des muzinosen Adenokarzinoms vor. Kurzlich beschrieben wurde der gastrische Subtyp, der keine Assoziation zu einer High-risk-HPV-Infektion (humane Papillomviren) zeigt, prognostisch ungunstig ist sowie bevorzugt bei Asiatinnen auftritt und beim Peutz-Jeghers-Syndrom vorkommen kann. Mittelfristig ist zu erwarten, dass sich beim Adenokarzinom der Cervix uteri ein auf verschiedenen Invasionsmustern beruhendes Grading etabliert. Die tiefe Stromainfiltration makroinvasiver Karzinome ist definiert als eine Infiltration von >66 % des zervikalen Stromas. Zukunftig konnte eine maximale Tumorgrose von 2 cm ein Parameter zur Planung einer eingeschrankt-radikalen Operation sein. Parameter des histopathologischen Befundberichts, die relevant fur die Prognoseabschatzung und Auswahl der adjuvanten Therapie sind und als Qualitatsindikatoren im Rahmen von Zertifizierungen dienen, werden beschrieben. Der histologische Typ Adenokarzinom hat fur sich allein genommen keine pradiktive bzw. prognostische Bedeutung bei Patientinnen mit primar operativer Therapie, einer neoadjuvanten Chemotherapie, einer kombinierten Radiochemotherapie bzw. dem Einsatz von Angiogeneseinhibitoren. Molekulare Parameter und Biomarker besitzen derzeit keine Relevanz.

Die Metastasierung von Malignomen des Uterus kann lymphogen, hamatogen oder per continuitatem erfolgen. Karzinome des Corpus und der Cervix uteri metastasieren lymphogen in die pelvinen und paraaortalen Lymphknoten. Beim Endometriumkarzinom sind die Tiefe der Myometriuminvasion, das Auftreten von Lymphgefaseinbruchen („lymphovascular space involvement“, LVSI) und ein sogenanntes Microcystic-elongated-fragmented(MELF)-Muster pradiktiv fur das Auftreten von Lymphknotenmetastasen. Eine Sentinellymphknotenbiopsie ist fur das klinische Stadium I des Endometriumkarzinoms und fruhe Stadien des Zervixkarzinoms moglich, aber noch nicht Routine. LVSI ist auch pradiktiv fur das Auftreten von Fernmetastasen. Die hamatogene Ausbreitung des Endometriumkarzinoms hangt vom histologischen Typ ab. Endometrioide und klarzellige Karzinome metastasieren in Lungen, Knochen, Leber und Gehirn und manifestieren sich selten als klinisch unauffallige solitare Metastasen. Serose Karzinome zeigen hingegen typischerweise eine ausgedehnte peritoneale Metastasierung. Die Uberexpression von p53, p16 und L1CAM scheint pradiktiv fur einen ungunstigen Verlauf, geht aber gleichzeitig mit dem prognostisch ungunstigen serosen Tumortyp einher. Die lymphogene Metastasierung der Plattenepithelkarzinome der Cervix uteri hangt stark vom Tumorvolumen ab und ist daher in mikroinvasiven Karzinomen gering. Fernmetastasen treten bevorzugt in Lungen, Leber, Knochen und Gehirn auf. In den gut differenzierten Adenokarzinomen der Zervix beeinflusst das Infiltrationsmuster des Tumors unabhangig von Tumorgrose und Invasionstiefe das Auftreten von Lymphknotenmetastasen. Mesenchymale Uterustumoren metastasieren bevorzugt hamatogen, Karzinosarkome dagegen lymphogen und hamatogen, die Lymphknotenmetastasen konnen einen rein epithelialen Phanotyp aufweisen.

Endometritis is nowadays rare in developed countries and typically shows a subclinical or mild course; therefore, there are probably more cases of endometritis than diagnosed but they lack clinical relevance. In the fertile period of life it can be the reason for vaginal bleeding and infertility. The most common causes for non-specific endometritis are residual placental tissue after abortion or childbirth, intrauterine interventions, lesions within the uterine cavity, such as endometrial polyps, endometrial hyperplasia and neoplasms, intrauterine devices (IUD) and cervical stenosis. The histological detection of plasma cells in the endometrial stroma is required for the diagnosis of chronic endometritis. These can be detected immunohistochemically using anti-CD138 antibodies, which should be carried out particularly in cases of infertility with only slight inflammatory symptoms and few plasma cells. The use of an IUD containing progestin is frequently associated with an asymptomatic lymphoplasmacytic infiltration. After curettage or endometrial biopsy, an eosinophilic xanthogranulomatous or granulomatous endometritis and also a foreign body granuloma reaction can occur. Specific forms of endometritis, such as caused by tuberculosis, sarcoidosis, mycoplasma and herpes are very rare. Cytomegalovirus endometritis is associated with immunosuppression. Endometritis caused by infections with Chlamydia trachomatis is characterized by an extensive lymphoplasmacytic infiltration. The differential diagnoses of chronic endometritis include the very rare malignant lymphoma, which is usually characterized by a relatively monotonous cell infiltration.

Background and Purpose Tumour cell migration and adhesion constitute essential features of metastasis. G-protein coupled receptor 55 (GPR55), a lysophospholipid receptor, has been shown to play an important role in carcinogenesis. Here, we investigated the involvement of GPR55 in migration and metastasis of colon cancer cells. Experimental Approach Adhesion and migration assays using the highly metastatic colon cancer cell line HCT116 and an in vivo assay of liver metastasis were performed. The GPR55 antagonist CID16020046, cannabidiol, a putative GPR55 antagonist and GPR55 siRNA were used to block GPR55 activity in HCT116 colon cancer cells. Key Results HCT116 cells showed a significant decrease in adhesion to endothelial cells and in migration after blockade with CID16020046 or cannabidiol. The inhibitory effects of CID16020046 or cannabidiol were averted by GPR55 siRNA knock down in cancer cells. The integrity of endothelial cell monolayers was increased after pretreatment of HCT116 cells with the antagonists or after GPR55 siRNA knockdown while pretreatment with lysophosphatidylinositol (LPI), the endogenous ligand of GPR55, decreased integrity of the monolayers. LPI also induced migration in GPR55 overexpressing HCT116 cells that was blocked by GPR55 antagonists. In a mouse model of metastasis, the arrest of HCT116 cancer cells in the liver was reduced after treatment with CID16020046 or cannabidiol. Increased levels of LPI (18:0) were found in colon cancer patients when compared with healthy individuals. Conclusions and Implications GPR55 is involved in the migratory behaviour of colon carcinoma cells and may serve as a pharmacological target for the prevention of metastasis. © 2015 The British Pharmacological Society

Background: In recent years, various efforts have been made to identify biomarkers in metastatic colorectal cancer patients (mCRC), all with the goal of improving patients' outcomes, including maximizing therapeutic response and minimizing exposure to ineffective treatments. Nevertheless, there is still no valid biomarker for the early assessment of therapeutic efficacy in the patient management strategy. To address this issue, we aimed to describe the predictive value of circulating tumor DNA (ctDNA) on the efficacy of FOLFOX treatment in mCRC patients. Patients and methods: A total of 11 patients with mCRC receiving FOLFOX therapy were included in this study. During the 48-hour FOLFOX cycle, we performed serial liquid biopsy-based ctDNA analysis before treatment start (T1) and at eight further time points (T2-T9). Among the 11 patients tested, all patients had detectable variants identified by either tumor tissue genotyping or baseline sample ctDNA sequencing for longitudinal analysis. We assessed genome-wide somatic copy number alterations (SCNAs) and highly sensitive sequencing approaches were utilized to monitor changes in the ctDNA mutant allele frequencies (mAFs) between baseline and on-treatment samples. Results: We were able to clearly assess different mAF patterns across patients with either stable disease, partial response or progressive disease. However, we invariably observed an early and deep ctDNA mAF decrease in all patients, as comparing the baseline (T1) mAF levels with the mAFs at all time points revealed that the most significant ctDNA drop was 23 hours after treatment start, i.e. at time point T5 (p Conclusion: Our observations clearly demonstrated for the first time that ctDNA dynamics allow real-time, individualized evaluation of treatment response using two early time points, i.e. at T5 and T9. Therefore, our data suggest that sequential ctDNA analysis can contribute to an improved patient treatment strategy. Nevertheless, further studies are clearly required to validate this promising early on-treatment indicator of therapeutic efficacy for CRC patients. Citation Format: Tina Moser, Julie Waldispuehl-Geigl, Jelena Belic, Samantha Perakis, Sabrina Weber, Qing Zhou, Heinz Sill, Sigurd Lax, Karl Kashofer, Gerald Hoefler, Helmut Schoellnast, Thomas Bauernhofer, Ellen Heitzer, Jochen B. Geigl, Michael R. Speicher. Early circulating tumor DNA dynamics as a real-time predictor of FOLFOX efficacy in advanced colorectal cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4295.

BackgroundDespite significant advances in the screening, detection, and treatment of preinvasive cervical lesions, invasive cervical cancer is the fifth most common cancer in European women. There are large disparities in Europe and worldwide in the incidence, management, and mortality of cervical cancer.ObjectiveThe European Society of Gynaecological Oncology (ESGO), the European Society for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) jointly develop clinically relevant and evidence-based guidelines in order to improve the quality of care for women with cervical cancer across Europe and worldwide.MethodsThe ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of cervical cancer (23 experts across Europe). To ensure that the guidelines are evidence based, the current literature identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 159 international reviewers, selected through ESGO/ESTRO/ESP and including patient representatives.ResultsThe guidelines cover comprehensively staging, management, and follow-up for patients with cervical cancer. Management includes fertility sparing treatment; stage T1a, T1b1/T2a1, clinically occult cervical cancer diagnosed after simple hysterectomy; early and locally advanced cervical cancer; primary distant metastatic disease; cervical cancer in pregnancy; and recurrent disease. Principles of radiotherapy and pathological evaluation are defined.

The European Society of Gynaecological Oncology (ESGO), the European Society for Radiotherapy & Oncology (ESTRO) and the European Society of Pathology (ESP) nominated an international multidisciplinary development group consisting of practicing clinicians who have demonstrated leadership and expertise in cervical cancer to produce evidence-based guidelines regarding all aspects of the management of patients with this disease. Herein, we provide a detailed analysis of the pathological reporting of cervical carcinoma specimens, focusing on practical aspects of specimen sampling and on the core pathological data which are critical for patient management.

In this issue of Virchows Archiv, there is a comprehensive review article on the most recent advances in our understanding of the pathologic and molecular features of endometrial stromal tumors [1]. The review is written by a team and a senior author, with considerable experience in the field. The manuscript describes the changes made since the first classification based on the number of mitotic figures to the current approach based on the resemblance to normal endometrial stroma of the proliferative phase.

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