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From the very beginning, special attention regarding severe acute respiratory syndrome-coronavirus‑2 (SARS-CoV-2) and the resulting coronavirus disease-2019 (COVID-19) has been paid to pregnant women.In this review, after a short introduction into the immunodefensive role of the placenta and viral infections in general, we describe the morphological changes of the placenta in SARS-CoV-2-infected pregnant women based on our own and other published studies, draw comparisons to the SARS epidemic, and discuss the question of vertical transmission of SARS-CoV‑2 from the mother to the neonate.The most common pathological findings of the placenta in SARS-CoV‑2 infection are signs of maternal and fetal malperfusion as well as potentially immunologically and/or thromboinflammation-mediated findings. These manifest as infarcts and decidual vasculopathy as well as thrombi in the fetal circulation and avascular villi. In some cases, there is also an inflammatory reaction with villitis, intervillositis, and fetal vasculitis. In addition, it has been shown that SARS-CoV‑2 can directly infect the placenta, so vertical transmission is possible.There is no COVID-19 specific pattern of placental alterations, although the detection of fetal thrombovasculitis, villitis, and intervillositis as well as fetal and maternal malperfusion could be best interpreted as the signature of SARS-CoV‑2 infection - considering the known pathophysiology of COVID-19 regarding other organs (inflammatory reaction and [micro]angiopathy). Detection of viral RNA in the fetal placental tissue and the umbilical cord indicates SARS-CoV‑2 vertical transmission.Ein besonderes Augenmerk bei der durch das Severe-acute-respiratory-syndrome-Coronavirus‑2 (SARS-CoV-2) hervorgerufenen Coronaviruskrankheit 2019 (COVID-19) wurde von Beginn an auf die Gruppe der Schwangeren gelegt.Nach einer Einführung zur Immunabwehr der Plazenta und viralen plazentaren Infektionen, beschreiben wir die morphologischen Veränderungen der Plazenta bei SARS-CoV-2-Infektion der Mutter, ziehen Vergleiche zur SARS-Epidemie und diskutieren die Frage der vertikalen Transmission von SARS-CoV‑2 von der Mutter auf das Neugeborene.Die häufigsten pathologischen Befunde der Plazenta bestehen in Zeichen der maternalen und auch fetalen Malperfusion sowie immunologisch bzw. thromboinflammatorisch vermittelten Veränderungen. Es finden sich Infarkte, deziduale Vaskulopathie sowie Thromben im fetalen Kreislauf und Vermehrung avaskulärer Villi. Daneben zeigen sich in einigen Fällen Entzündungsreaktionen mit Villitis und Intervillositis sowie eine Vaskulitis fetaler Gefäße. Zudem konnte der Nachweis erbracht werden, dass SARS-CoV‑2 die Plazenta direkt infizieren kann. Somit ist auch eine vertikale Transmission möglich.Ein COVID-19-spezifisches Schädigungsmuster der Plazenta liegt bislang nicht vor, obwohl der Nachweis von fetaler Thrombovaskulitis, Villitis und Intervillositis sowie einer fetalen und maternalen Malperfusion in Analogie zu der bereits bekannten allgemeinen Pathophysiologie von COVID-19 (Entzündungsreaktion und Mikrozirkulationsstörung) interpretiert werden könnte. Der Nachweis viraler RNA in den fetalen Kompartimenten der Plazenta/der Nabelschnur zeugt von der vertikalen SARS-CoV‑2 Transmission.

SMARCA4-deficient thoracic sarcoma is a newly described entity of thoracic sarcomas with a poor prognosis, defined by poorly differentiated epithelioid to rhabdoid histomorphology and SMARCA4 gene inactivation. We present a case of a SMARCA4-deficient thoracic sarcoma in a 41-year-old male with a smoking history who presented with an upper anterior mediastinal mass, after seeking medical evaluation for increasing thoracic pain, odynophagia, and dizziness. The biopsy confirmed a large cell tumor with an epithelioid to rhabdoid histomorphology, positive for EMA, CD99, vimentin, TLE1, INI1, PAS-positive cytoplasmic granules, and PD-L1 (100% of tumor cells). High TMB and HRD scores were displayed in the tumor. The histology and immunophenotype of the mass were in line with the diagnosis of SMARCA4-deficient thoracic sarcoma. In the course of his treatment, the patient showcased a partial response to pembrolizumab and the combination of pembrolizumab and ipilimumab. This case report highlights the importance of recognizing SMARCA4-deficient thoracic sarcoma as an individual entity and supports the importance of checkpoint inhibition therapy for SMARCA4-deficient thoracic sarcomas, particularly in cases with a high TMB and PD-L1 expression.

INTRODUCTION CD56 is aberrantly expressed in myeloid neoplasms including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Considering the adhesion effects of CD56, blast quantification in bone marrow might depend on the technique used to obtain respective diagnostic specimens. Therefore, the objective of our study was to investigate the impact of CD56-expression on blast counts in myeloid neoplasms comparing bone marrow aspirates to biopsies. METHODS We retrospectively analyzed 75 patients diagnosed with MDS and AML. We compared patients with (n = 36) and without (n = 39) CD56-expression by flow cytometry with respect to their blast quantities assessed on bone marrow aspirates versus biopsies. RESULTS The frequency of CD56-expression on blasts correlated with higher blast counts on biopsies vs. aspirate smears (rs = 0.52; P = .001). This difference in blast counts was only significant in the CD56 high expressing subgroup (median 68%, 5.5%-95% in biopsy compared to median 32.5%, 1.5%-90% in aspirate; P

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.

The lung is the main affected organ in severe coronavirus disease 2019 (COVID-19) caused by the novel coronavirus SARS-CoV-2, and lung damage is the leading cause of death in the vast majority of patients. Mainly based on results obtained by autopsies, the seminal features of fatal COVID-19 have been described by many groups worldwide. Early changes encompass edema, epithelial damage, and capillaritis/endothelialitis, frequently combined with microthrombosis. Subsequently, patients with manifest respiratory insufficiency exhibit exudative diffuse alveolar damage (DAD) with hyaline membrane formation and pneumocyte type 2 hyperplasia, variably complicated by superinfection, which may progress to organizing/fibrotic stage DAD. These features, however, are not specific for COVID-19 and can be found in other disorders including viral infections. Clinically, the early disease stage of severe COVID-19 is characterized by high viral load, lymphopenia, massive secretion of pro-inflammatory cytokines and hypercoagulability, documented by elevated D-dimers and an increased frequency of thrombotic and thromboembolic events, whereas virus loads and cytokine levels tend to decrease in late disease stages, when tissue repair including angiogenesis prevails. The present review describes the spectrum of lung pathology based on the current literature and the authors’ personal experience derived from clinical autopsies, and tries to summarize our current understanding and open questions of the pathophysiology of severe pulmonary COVID-19.

Objectives The 2019 Workshop of the Society for Hematopathology/European Association for Haematopathology received and reviewed cases covering the spectrum of mastocytosis and related diseases, including morphologic mimics, focusing on recent updates and relevant findings for pathologists. Methods The workshop panel reviewed 99 cases of cutaneous and systemic mastocytosis (SM) and SM and associated hematologic neoplasms (SM-AHN). Results Despite a common theme of KIT mutation (particularly D816V), mastocytosis is a heterogeneous neoplasm with a wide variety of presentations. This spectrum, including rare subtypes and extramedullary organ involvement, is discussed and illustrated by representative cases. Conclusions In the age of targeted treatment aimed at KIT, the accurate diagnosis and classification of mastocytosis has major implications for therapy and further interventions. Understanding the clinical, pathologic, and genetic findings of mastocytosis is crucial for selecting the proper tests to perform and subsequent arrival at a correct diagnosis in this rare disease.

In contrast to other tumour entities such as lung carcinoma, melanoma or gynaecological and gastrointestinal tumours, the routine application of mutation analyses using high-throughput sequencing via next-generation sequencing (NGS) has not yet been widely established in haematopathology, especially not in lymphomas.Here we describe our experience with the use and routine implementation of a lymphoma NGS panel primarily developed for research purposes.In addition to a discussion of the steps necessary for transferring such a panel into the routine framework of an accredited institute, we show by the comprehensive workup of 80 investigations and the presentation of several case studies how the panel was able to guide us to the correct diagnosis and how it also provided clinicians with indications for possible tailored therapy options.Even if NGS does not (yet) have to be routinely applied in lymphoma diagnostics for every case, a respectively dedicated NGS panel offers the advantage of having an additional option in the case of difficult differential diagnostic considerations or uncertainties as well as at the request of the treating oncologist to identify potential targets for tailored treatment of the patients.

Introduction: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread around the world. While the first case was recorded in Hubei in December 2019, the extent of early community spread in Central Europe before this period is unknown. A high proportion of asymptomatic cases and undocumented infections, high transmissibility, and phylogenetic genomic diversity have engendered the controversial possibility of early international community spread of SARS-CoV-2 before its emergence in China. Methods: To assess the early presence of lethal COVID-19 in Switzerland, we retrospectively performed an analysis of deaths at University Hospital Basel between October 2019 and February 2020 (n = 310), comparing the incidence of clinical causes of death with March 2020 (n = 72), the month during which the first lethal COVID-19 cases in Basel were reported. Trends of COVID-19-suggestive sequelae, such as bronchopneumonia with organization, acute respiratory distress syndrome (ARDS), or pulmonary embolisms (PE) were evaluated. In cases where autopsy was performed (n = 71), analogous analyses were conducted on the cause of death and pulmonary histological findings. Eight cases with a COVID-19-suggestive clinical history and histopathology between October 2019 and February 2020, and 3 cases before October 2019, were selected for SARS-CoV-2 RT-PCR. Results: A statistically significant rise in pulmonary causes of death was observed in March 2020 (p = 0.03), consistent with the reported emergence of lethal COVID-19 in Switzerland. A rise in lethal bronchopneumonia was observed between December 2019 and January 2020, which was likely seasonal. The incidence of lethal ARDS and PE was uniformly low between October 2019 and February 2020. All autopsy cases analyzed by means of SARS-CoV-2 RT-PCR yielded negative results. Conclusion: Our data suggest the absence of early lethal community spread of COVID-19 in Basel before its initial reported emergence in Switzerland in March 2020.

Coronavirus Disease 19 (COVID-19) is a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has grown to a worldwide pandemic with substantial mortality. Immune mediated damage has been proposed as a pathogenic factor, but immune responses in lungs of COVID-19 patients remain poorly characterized. Here we show transcriptomic, histologic and cellular profiles of post mortem COVID-19 (n = 34 tissues from 16 patients) and normal lung tissues (n = 9 tissues from 6 patients). Two distinct immunopathological reaction patterns of lethal COVID-19 are identified. One pattern shows high local expression of interferon stimulated genes (ISGhigh) and cytokines, high viral loads and limited pulmonary damage, the other pattern shows severely damaged lungs, low ISGs (ISGlow), low viral loads and abundant infiltrating activated CD8+ T cells and macrophages. ISGhigh patients die significantly earlier after hospitalization than ISGlow patients. Our study may point to distinct stages of progression of COVID-19 lung disease and highlights the need for peripheral blood biomarkers that inform about patient lung status and guide treatment., The immunopathological features of SARS-CoV-2 infection in the lungs remain unclear. Here, the authors provide a comprehensive characterization of post mortem lung tissues of COVID-19 patients and find two distinct patterns characterized by differential expression of interferon stimulated genes (ISGs), which correlate to viral loads, cytokines, lung damage and time of hospitalization, suggesting ISG profiles to mark disease progression

Since the outbreak of coronavirus disease 2019 (COVID-19), there has been a debate whether pregnant women are at a specific risk for COVID-19 and whether it might be vertically transmittable through the placenta. We present a series of five placentas of SARS coronavirus 2 (SARS-CoV-2)-positive women who had been diagnosed with mild symptoms of COVID-19 or had been asymptomatic before birth. We provide a detailed histopathologic description of morphological changes accompanied by an analysis of presence of SARS-CoV-2 in the placental tissue. All placentas were term deliveries (40th and 41st gestational weeks). One SARS-CoV-2-positive patient presented with cough and dyspnoea. This placenta showed prominent lymphohistiocytic villitis and intervillositis and signs of maternal and foetal malperfusion. Viral RNA was present in both placenta tissue and the umbilical cord and could be visualized by in situ hybridization in the decidua. SARS-CoV-2 tests were negative at the time of delivery of 3/5 women, and their placentas did not show increased inflammatory infiltrates. Signs of maternal and/or foetal malperfusion were present in 100% and 40% of cases, respectively. There was no transplacental transmission to the infants. In our cohort, we can document different time points regarding SARS-CoV-2 infection. In acute COVID-19, prominent lymphohistiocytic villitis may occur and might potentially be attributable to SARS-CoV-2 infection of the placenta. Furthermore, there are histopathological signs of maternal and foetal malperfusion, which might have a relationship to an altered coagulative or microangiopathic state induced by SARS-CoV-2, yet this cannot be proven considering a plethora of confounding factors.

BackgroundThe world is currently witnessing a major devastating pandemic of Coronavirus disease-2019 (COVID-19). This disease is caused by a novel coronavirus named Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). It primarily affects the respiratory tract and particularly the lungs. The virus enters the cell by attaching its spike-like surface projections to the angiotensin-converting enzyme-2 (ACE-2) expressed in various tissues. Though the majority of symptomatic patients have mild flu-like symptoms, a significant minority develop severe lung injury with acute respiratory distress syndrome (ARDS), leading to considerable morbidity and mortality. Elderly patients with previous cardiovascular comorbidities are particularly susceptible to severe clinical manifestations.BodyCurrently, our limited knowledge of the pathologic findings is based on post-mortem biopsies, a few limited autopsies, and very few complete autopsies. From these reports, we know that the virus can be found in various organs but the most striking tissue damage involves the lungs resulting almost always in diffuse alveolar damage with interstitial edema, capillary congestion, and occasional interstitial lymphocytosis, causing hypoxia, multiorgan failure, and death. A few pathology studies have also reported intravascular microthrombi and pulmonary thrombembolism. Although the clinical presentation of this disease is fairly well characterized, knowledge of the pathologic aspects remains comparatively limited.ConclusionIn this review, we discuss clinical, pathologic, and genomic features of COVID-19, review current hypotheses regarding the pathogenesis, and briefly discuss the clinical characteristics. We also compare the salient features of COVID-19 with other coronavirus-related illnesses that have posed significant public health issues in the past, including SARS and the Middle East Respiratory Syndrome (MERS).

Acquired aplastic anemia and severe congenital neutropenia (SCN) are bone marrow (BM) failure syndromes of different origin, however, they share a common risk for secondary leukemic transformation. Here, we present a patient with severe aplastic anemia (SAA) evolving to secondary chronic neutrophilic leukemia (CNL; SAA-CNL). We show that SAA-CNL shares multiple somatic driver mutations in CSF3R, RUNX1, and EZH2/SUZ12 with cases of SCN that transformed to myelodysplastic syndrome or acute myeloid leukemia (AML). This molecular connection between SAA-CNL and SCN progressing to AML (SCN-AML) prompted us to perform a comparative transcriptome analysis on nonleukemic CD34high hematopoietic stem and progenitor cells, which showed transcriptional profiles that resemble indicative of interferon-driven proinflammatory responses. These findings provide further insights in the mechanisms underlying leukemic transformation in BM failure syndromes.

Background: The incidence and the outcomes of pulmonary embolism (PE) missed during emergency department (ED) workup are largely unknown. Objectives: To describe the frequency, demographics, and outcomes of patients with delayed diagnosis of PE. Methods: We retrospectively compared patients diagnosed with PE during ED workup (early diagnosis) with patients diagnosed with PE thereafter (delayed diagnosis). Electronic health records (EHR) of 123,560 consecutive patients who attended a tertiary hospital ED were screened. Data were matched with radiology and pathology results from the EHR. Results: Of 1,119 patients presenting to the ED with early workup for PE, PE was diagnosed in 182 patients (80.5%) as early diagnosis. Delayed diagnosis was established in 44 cases (19.5%) using radiology and/or autopsy data. Median age of patients with early diagnosis was significantly lower as compared to delayed diagnosis (67 vs. 77.5 years). Main symptoms were dyspnea (109 patients [59.9%] in early, 20 patients [45.5%] in delayed diagnosis), chest pain (90 patients [49.5%] in early, 8 patients [18.2%] in delayed diagnosis), and nonspecific complaints (16 patients [8.8%] in early, 13 patients [29.5%] in delayed diagnosis). In-hospital mortality was 1.6% in early diagnosis and 43.2% in delayed diagnosis. Conclusions: Delayed diagnosis of PE carries a worse prognosis than early diagnosis. This discrepancy may arise from either delayed therapy, confounding variables (e.g., older age), or both. Possible reasons for delayed diagnoses are nonspecific presentations and symptoms overlapping with preexisting conditions.

Background: Coronavirus disease 2019 (COVID-19) is associated with a hypercoagulable state that increases the risk for thrombosis, hospitalization, and mortality. Limited data exist informing the relationship between outpatient anticoagulation therapy 90 days prior to diagnosis and risk for COVID-19 related hospitalization and mortality. Methods: This is a prospective cohort study from March 4th and August 27th, 2020 among 12 hospitals and 60 clinics. We evaluated all patients over the age of 18 diagnosed with COVID-19 for a total of 6,195 consecutive patients. Objectives: We investigated the relationship between 90-day anticoagulation therapy among outpatients prior to COVID-19 diagnosis (OPAC) therapy and the risk for 45 days hospitalization, and mortality as well as the relationship between inpatient prophylactic, escalated prophylactic, or therapeutic anticoagulation (IPAC) therapy and 45 days mortality risk. Results: 598 were immediately hospitalized, and 5,597 were initially treated as outpatients. The case fatality rate was 2.8% (n=175 deaths) and 13% for the overall 45 days mortality and inpatient mortality respectively. Among 5,597 COVID-19 patients initially treated as outpatients, 160 (2.9%) were on anticoagulation, and 331 were hospitalized (5.9%). In a multivariable analysis, OPAC use was associated with a 43% reduction in risk for hospital admission, HR (95%CI)=0.57 (0.38, 0.86), p=0.007, but was not associated with mortality, HR (95%CI)=0.88 (0.50, 1.52), p=0.64. In comparison to inpatients who continued anticoagulation therapy upon admission, inpatients who never initiated anticoagulation (before or after hospitalization) realized increased mortality risk, HR (95%CI)=2.26 (1.17, 4.37), p=0.015, while inpatients who initiated anticoagulation upon admission realized no increased risk for mortality HR(95%CI)=1.27(0.75,2.14), p=0.38. Conclusion: Outpatients with COVID-19 using anticoagulation experienced a 43% reduced risk of hospitalization, and initiation of anticoagulation among inpatients was not associated with increased mortality risk. Funding Statement: No specific grant funding was obtained for this study. Declaration of Interests: Dr. Tignanelli is a principal investigator on randomized trials for Covid-19, but not related to anticoagulation. Dr. Haslbauer and Dr. Tzankov received funding support from the Botnar Research Centre for Child Health for all their COVID-19 related research. The remaining authors have nothing to disclose. Ethics Approval Statement: This study was approved by the University of Minnesota’s institutional review board (IRB).

The COVID-19 pandemic, caused by the viral pathogen SARS-CoV-2, has taken the lives of millions of individuals around the world. Obesity is associated with adverse COVID-19 outcomes, but the underlying mechanism is unknown. In this report, we demonstrate that human adipose tissue from multiple depots is permissive to SARS-CoV-2 infection and that infection elicits an inflammatory response, including the secretion of known inflammatory mediators of severe COVID-19. We identify two cellular targets of SARS-CoV-2 infection in adipose tissue: mature adipocytes and adipose tissue macrophages. Adipose tissue macrophage infection is largely restricted to a highly inflammatory subpopulation of macrophages, present at baseline, that is further activated in response to SARS-CoV-2 infection. Preadipocytes, while not infected, adopt a proinflammatory phenotype. We further demonstrate that SARS-CoV-2 RNA is detectable in adipocytes in COVID-19 autopsy cases and is associated with an inflammatory infiltrate. Collectively, our findings indicate that adipose tissue supports SARS-CoV-2 infection and pathogenic inflammation and may explain the link between obesity and severe COVID-19.One sentence summaryOur work provides the first in vivo evidence of SARS-CoV-2 infection in human adipose tissue and describes the associated inflammation.

Risk stratification of COVID‐19 patients is essential for pandemic management. Changes in the cell fitness marker, hFwe‐Lose, can precede the host immune response to infection, potentially making such a biomarker an earlier triage tool. Here, we evaluate whether hFwe‐Lose gene expression can outperform conventional methods in predicting outcomes (e.g., death and hospitalization) in COVID‐19 patients. We performed a post‐mortem examination of infected lung tissue in deceased COVID‐19 patients to determine hFwe‐Lose’s biological role in acute lung injury. We then performed an observational study (n = 283) to evaluate whether hFwe‐Lose expression (in nasopharyngeal samples) could accurately predict hospitalization or death in COVID‐19 patients. In COVID‐19 patients with acute lung injury, hFwe‐Lose is highly expressed in the lower respiratory tract and is co‐localized to areas of cell death. In patients presenting in the early phase of COVID‐19 illness, hFwe‐Lose expression accurately predicts subsequent hospitalization or death with positive predictive values of 87.8–100% and a negative predictive value of 64.1–93.2%. hFwe‐Lose outperforms conventional inflammatory biomarkers and patient age and comorbidities, with an area under the receiver operating characteristic curve (AUROC) 0.93–0.97 in predicting hospitalization/death. Specifically, this is significantly higher than the prognostic value of combining biomarkers (serum ferritin, D‐dimer, C‐reactive protein, and neutrophil–lymphocyte ratio), patient age and comorbidities (AUROC of 0.67–0.92). The cell fitness marker, hFwe‐Lose, accurately predicts outcomes in COVID‐19 patients. This finding demonstrates how tissue fitness pathways dictate the response to infection and disease and their utility in managing the current COVID‐19 pandemic., A post‐mortem examination of COVID‐19 infected lung tissues and an observational study were performed in order to evaluate whether expression of cell fitness marker hFwe‐Lose in patient's nasopharyngeal swabs could predict hospitalization or death from COVID‐19.

Zusammenfassung: Neben den wesentlich häufigeren Lymphomen können auch Neoplasien der dendritischen und anderer, sog. "akzessorischer" Zellen primär im Lymphknoten entstehen. Dazu gehören histiozytäre Sarkome, follikuläre dendritische Sarkome, interdigitierende dendritische Sarkome, fibroblastäre Retikulumzelltumoren/zytokeratinpositive Interstitialzellneoplasien sowie schließlich Neoplasien indeterminierter dendritischer Zellen. Allen diesen Tumoren ist gemeinsam, dass sie - primär wegen ihrer Seltenheit - eine sehr schwierige Differenzialdiagnose darstellen. Durch eine sorgfältige Analyse gelingen aber die Abgrenzung zu anderen Sarkomen, sarkomatoiden Karzinomen, Lymphomen und Melanomen sowie dann eine exakte Klassifikation der entsprechenden Läsionen. Pathogenetisch ist die gehäufte Assoziation dieser Tumoren mit Lymphomen und Leukämien sowie der Nachweis identischer klonaler Antigenrezeptor-Rearrangements und/oder der Nachweis rekurrierender genetischer Aberrationen in beiden histologisch unterschiedlichen Tumoren interessant. Dies weist auf eine gemeinsame Vorläuferzelle bzw. zumindest auf einen gemeinsamen Ursprung hin.

Understanding viral tropism is an essential step toward reducing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, decreasing mortality from coronavirus disease 2019 (COVID-19) and limiting opportunities for mutant strains to arise. Currently, little is known about the extent to which distinct tissue sites in the human head and neck region and proximal respiratory tract selectively permit SARS-CoV-2 infection and replication. In this translational study, we discover key variabilities in expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), essential SARS-CoV-2 entry factors, among the mucosal tissues of the human proximal airways. We show that SARS-CoV-2 infection is present in all examined head and neck tissues, with a notable tropism for the nasal cavity and tracheal mucosa. Finally, we uncover an association between smoking and higher SARS-CoV-2 viral infection in the human proximal airway, which may explain the increased susceptibility of smokers to developing severe COVID-19. This is at least partially explained by differences in interferon (IFN)-β1 levels between smokers and non-smokers., Graphical Abstract, Nakayama et al. discover key variabilities in expression of SARS-CoV-2 entry factors among human head and neck mucosal tissues. They demonstrate that SARS-CoV-2 preferentially infects the nasal cavity and trachea. They uncover an association between smoking and higher SARS-CoV-2 in the human proximal airway, in part because of differences in IFN-β1 expression.

In this review, we discuss spatiotemporal kinetics and inflammatory signatures of innate immune cells specifically found in response to SARS-CoV-2 compared to influenza virus infection. Importantly, we cover the current understanding on the mechanisms by which SARS-CoV-2 may fail to engage a coordinated type I response and instead may lead to exaggerated inflammation and death. This knowledge is central for the understanding of available data on specialized pro-resolving lipid mediators in severe SARS-CoV-2 infection pointing toward inhibited E-series resolvin synthesis in severe cases. By investigating a publicly available RNA-seq database of bronchoalveolar lavage cells from patients affected by COVID-19, we moreover offer insights into the regulation of key enzymes involved in lipid mediator synthesis, critically complementing the current knowledge about the mediator lipidome in severely affected patients. This review finally discusses different potential approaches to sustain the synthesis of 3-PUFA-derived pro-resolving lipid mediators, including resolvins and lipoxins, which may critically aid in the prevention of acute lung injury and death from COVID-19.

We report on an impressive case of a previously healthy 47-year-old female Caucasian SARS-CoV-2 positive patient who died within 48 h after initial cardiac symptoms. Autopsy revealed necrotizing myocarditis and extensive microthrombosis as the cause of death. The interesting feature of this case is the combination of both myocarditis and extensive localized microthrombosis of cardiac capillaries. Microthrombosis was not present in other organs, and the patient did not show typical features of diffuse alveolar damage in the lungs. Taken together, our morphologic findings illustrate the angiocentric, microangiopathic, thromboinflammatory disease with significant thrombotic diathesis prevalent in COVID-19, which has been previously described in the literature, likely warranting thromboprophylaxis even in oligosymptomatic circumstances. This case also delineates several potential etiologies for microthrombosis, i.e., inflammatory reactions and primary hypercoagulative states. Further systematic analyses on risk stratification for receipt of prophylactic anticoagulation in COVID-19 are urgently required.

Clinical characterization of COVID-19 (Corona Virus Disease 2019) is being performed worldwide to gain insights into the pathogenesis and course of the disease. Little is known regarding morphological findings, which are essential to understanding the unique features and pathomechanisms of the disease, from which one can identify possible new treatments. It has been shown that diffuse alveolar damage, signifying acute respiratory distress syndrome, is present together with atypical multinucleated cells in reported cases of the disease by Tian et al. (J Thorac Oncol 15:700–704, 2020). Macroscopic morphological findings in COVID-19 remain elusive to this day. Here, we report the case of the first German to die due to COVID-19. A detailed examination consisting of full-body computed tomography, autopsy, histology assessment, and viral assessment has been performed. The lungs of the deceased contained high concentrations of SARS-CoV-2 RNA and displayed the typical radiological signatures of COVID-19. Furthermore, a morphological pattern was found displaying hyperaemic areas interspersed by normally perfused areas affecting the whole lung. We also report a finding suggestive of micro-thrombotic events in the lung, which is compatible with the recently described coagulation changes and increased incidence of pulmonary artery embolisms seen in COVID-19 patients as reported by Wichmann et al. (Ann Intern Med, 2020). A broader study is needed to confirm these findings. Electronic supplementary material The online version of this article (10.1007/s00428-020-02872-y) contains supplementary material, which is available to authorized users.

Background Traumatic ulcerative granuloma with stromal eosinophilia (TUGSE) is a rare self-limiting condition of the oral mucosa. The lesion manifests as an isolated ulcer that can be either asymptomatic or associated with mild to severe pain, and in most cases, it affects the tongue. TUGSE lesions may mimic malignancy such as squamous cell carcinoma, CD30 positive lymphoproliferative disorder, or infectious diseases such as primary syphilis, tuberculosis, or Epstein-Barr virus mucocutaneous ulcer. Histologically dominating cells are lymphocytes, histiocytes, and eosinophils. Case presentation We describe a TUGSE case of a patient with a solitary ulcer on the lower left retromolar buccal plane. Upon presentation, the patient reported a swelling on the buccal mucosa of the left lower jaw since 1 year with rapid growth over the last days and mild pain while chewing. The diameter of the intraoral lesion on the lower left retromolar buccal plane was approximately 4 × 3 cm; the lesion presented as indurated base with a central superficial ulceration of 2 × 1 cm, indicative for a malignant process. Histologically, the ulceration showed an expanding, infiltrative, and vaguely granulomatous morphology, involving the superficial mucosa and the fatty tissue, and extended between the deep striated muscle fibers. The lesion was rich in lymphocytes, histiocytes, and eosionophils intermingled with activated T-blasts without phenotypic abnormalities. TUGSE was then diagnosed based on the phenotype (especially the lacking expression of CD30, the retained T-cell phenotype, and the absence of Epstein-Barr virus), the clinical presentation, and the morphology. Twenty-six months after diagnosis, no recurrence of the ulceration was seen. Conclusions As TUGSE may mimic malignancy or infectious diseases, biopsy is mandatory and should be combined with thorough clinical examination. A screening for infectious diseases (mainly syphilis, Epstein-Barr virus, and HIV infections) must be performed routinely. In most cases, the lesions resolve spontaneously, obviating the need of further actions other than clinical follow-up. The pathogenesis of TUGSE lesions is still under debate, although local traumatic events and a locotypic immune response have been suggested to be major contributing factors.

Context.— Angioimmunoblastic T-cell lymphomas originate from T follicular helper cells and express respective markers (BCL6, CD10, CXCL13, ICOS, and PD-1). Although commonly present, bone marrow involvement by angioimmunoblastic T-cell lymphoma can be diagnostically challenging. Additionally, only little is known about the distribution of T follicular helper cells in healthy and reactively changed bone marrows or in samples affected by other lymphomas. Objective.— To establish a diagnostic approach to reliably identify bone marrow infiltration of angioimmunoblastic T-cell lymphoma. Design.— We analyzed the morphologic infiltration pattern and the expression of T follicular helper-cell markers in 42 matched paired lymph node and bone marrow samples and applied comparative clonality testing. Furthermore, we studied the expression of BCL6 and PD-1 in a control cohort of healthy, reactively changed, and otherwise affected bone marrows. Results.— We identified 3 different bone marrow infiltration patterns correlating with overall survival (interstitial/micronodular infiltration with or without eosinophilia and diffuse infiltration with eosinophilia). The matched pairs showed a consistent (co)expression of PD-1 and BCL6 with a generally weaker expression in the bone marrow than in the lymph nodes. Comparative clonality testing was helpful in only a minority of cases. Infiltrates of the most important differential diagnoses contained either PD-1– or BCL6-positive tumor-infiltrating cells, but no coexpressing cells. Conclusions.— Bone marrow infiltration by angioimmunoblastic T-cell lymphoma displays 3 different patterns that correlate with prognosis. BCL6 and PD-1 can be reliably used to identify lymphoma infiltrates and to help rule out several differential diagnoses. Comparative clonality testing rarely provides additional value and cannot replace morphologic and phenotypic analyses.

This short review aims at summarizing the current standards of lymphoma diagnostics and some novelties in the recent WHO classification. The importance of close collaboration between clinicians and pathologists to render the correct diagnosis and to find the most appropriate treatment for each individual patient is highlighted. In lymphomas, the diagnostic evaluation of histopathology, immune phenotype and genetics are puzzle pieces that have to be put into a broader context with the help of the information given by the clinical colleagues, such as patient’s age and sex, location of the lesion, previous medical history and medication. An excision of the affected lymph node is always preferable to fine needle biopsies, as—in many instances—only the evaluation of the whole specimen allows for reliable diagnosis, grading and additional investigations. The new WHO classification entailed many changes in the category of diffuse large B‑cell lymphoma and high-grade B‑cell lymphoma. The obligatory specification of the cell of origin in diffuse large B‑cell lymphoma is obtained via additional immunohistochemical stainings. The identification of high-grade B‑cell lymphomas with genetic double/triple hits, requiring a more aggressive management, can only be achieved by the detection of chromosomal translocations (MYC, BCL2 and/or BCL6). Significant changes in the classification of T‑cell lymphomas have occurred due to the recognition of the follicular T‑helper cell origin in some instances, and sharpening diagnostic borders of intestinal T‑cell- and Epstein-Barr-virus-associated proliferations. Finally, the discovery of disease-defining and/or prognostically relevant mutations makes the introduction of proper routine molecular testing mandatory.

The 13th workshop of the European Bone Marrow Working Group in Utrecht, The Netherlands, was devoted to studying myelodysplastic syndromes (MDS) and their boundaries. The panel received 44 cases submitted to the 3 invited categories, which included: reactive cytopenias with dysplasia, idiopathic cytopenia of undetermined significance, clonal haematopoiesis of indeterminate potential, idiopathic dysplasia of uncertain significance and overt MDS. For this summary, we have selected 17 cases that highlight difficulties in separating true MDS from other causes of cytopenia and the intricate relationship between clonal haematopoiesis and true MDS. In addition, cases of overt MDS with challenging features were also selected. All cases were stained for p53 expression. Using instructive submitted cases we discuss the following: (1) cytopenia with clonal haematopoiesis not fulfilling MDS criteria, (2) cytopenia and/or dysplasia with germline mutations and/or familial history suggesting an underlying gene defect, (3) MDS based on a recurrent chromosomal abnormality and (4) overt MDS with diagnostic difficulties due to concurrent treatment or disease. The lively discussion in the open forum of the workshop illustrated the need for better integrative understanding of the evolution of acquired genetic abnormalities in haematopoiesis, and the challenge of diagnosing true MDS in cytopenic patients with genetic abnormalities, either germline or acquired.

Acute graft-versus-host disease (aGvHD) remains a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Prophylaxis with cyclosporine A (CsA) is the backbone of GvHD prevention. In a retrospective analysis of patients treated with allo-HSCT, we correlated CsA levels on the day of transplantation (day 0) and on day + 10 with the incidence of acute and chronic GvHD. We assessed 660 patients with either AML n = 248, lymphoma/myeloma n = 127, MDS/MPN n = 124, ALL n = 79, CLL n = 36, CML n = 23, or bone marrow failure n = 22. In patients with clinically relevant aGvHD grade ≥ 2, mean CsA levels was lower on day 0 and day + 10 (142 ± 88 μg/L and 183 ± 64 μg/L, respectively) compared to patients without aGvHD (156 ± 81 μg/L and 207 ± 67 μg/L, respectively; day 0: p = 0.003; day + 10: p = 7.57 × 10−9). In patients with CsA level 200 μg/L [(234/356 (66%) versus 91/248 (37%); p = 1.34 × 10−12]. In patients with cGvHD, there was no significant difference between CsA levels 200 μg/L (96/233; p = 0.312). The optimal CsA cutoff level for the prevention (i.e., roughly 50% incidence reduction) of aGvHD was > 201 μg/L at day 0 and > 195 μg/L at day + 10. In a competing risk analysis, time to aGvHD grade ≥ 2 (using death of other causes as competing risk) was associated with CsA levels > 200 μg/L on day 0 and on day 10, unrelated donors, myeloablative conditioning (MAC), and for the diagnosis lymphoma/myeloma. Our data support close monitoring with active adjustments of CsA dosing to maintain therapeutic CsA levels above 195 μg/L in the first 10 days of allo-HCST to reduce aGvHD.

This translational study aimed at gaining insight into the effects of lenalidomide in acute myeloid leukemia (AML). Forty-one AML patients aged 66 or older of the Swiss cohort of the HOVON-103 AML/SAKK30/10 study were included. After randomization, they received standard induction chemotherapy with or without lenalidomide. Bone marrow biopsies at diagnosis and before the 2nd induction cycle were obtained to assess the therapeutic impact on leukemic blasts and microenvironment. Increased bone marrow angiogenesis, as assessed by microvessel density (MVD), was found at AML diagnosis and differed significantly between the WHO categories. Morphological analysis revealed a higher initial MVD in AML with myelodysplasia-related changes (AML-MRC) and a more substantial decrease of microvascularization after lenalidomide exposure. A slight increase of T-bet-positive TH1-equivalents was identifiable under lenalidomide. In the subgroup of patients with AML-MRC, the progression-free survival differed between the two treatment regimens, showing a potential but not significant benefit of lenalidomide. We found no correlation between the cereblon genotype (the target of lenalidomide) and treatment response or prognosis. In conclusion, addition of lenalidomide may be beneficial to elderly patients suffering from AML-MRC, where it leads to a reduction of microvascularization and, probably, to an intensified specific T cell-driven anti-leukemic response. Supplementary Information The online version contains supplementary material available at 10.1007/s00277-021-04467-2.

The effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the pathophysiology of the placenta and its impact on pregnancy outcome has not yet been fully elucidated. Here, we present a comprehensive clinical, morphological, and molecular analysis of placental tissues from pregnant women with and without SARS-CoV-2 infection. SARS-CoV-2 could be detected in half of placental tissues from SARS-CoV-2-positive women. The presence of the virus was not associated with any distinctive pathological, maternal, or neonatal outcome features. SARS-CoV-2 tissue load was low in all but one patient who exhibited severe placental damage leading to neonatal neurological manifestations. The placental transcriptional response induced by high viral load of SARS-CoV-2 showed an immunopathology phenotype similar to autopsy lung tissues from patients with severe coronavirus disease 2019. This finding contrasted with the lack of inflammatory response in placental tissues from SARS-CoV-2-positive women with low viral tissue load and from SARS-CoV-2-negative women. Importantly, no evidence of vertical transmission of SARS-CoV-2 was found in any newborns, suggesting that the placenta may be an effective maternal-neonatal barrier against the virus even in the presence of severe infection. Our observations suggest that severe placental damage induced by the virus may be detrimental for the neonate independently of vertical transmission.

While coronavirus disease 2019 (COVID‐19) primarily affects the respiratory tract, pathophysiological changes of the cardiovascular system remain to be elucidated. We performed a retrospective cardiopathological analysis of the heart and vasculature from 23 autopsies of COVID‐19 patients, comparing the findings with control tissue. Myocardium from autopsies of COVID‐19 patients was categorised into severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) positive (n = 14) or negative (n = 9) based on the presence of viral RNA as determined by reverse transcriptase polymerase chain reaction (RT‐PCR). Control tissue was selected from autopsies without COVID‐19 (n = 10) with similar clinical sequelae. Histological characteristics were scored by ordinal and/or categorical grading. Five RT‐PCR‐positive cases underwent in situ hybridisation (ISH) for SARS‐CoV‐2. Patients with lethal COVID‐19 infection were mostly male (78%) and had a high incidence of hypertension (91%), coronary artery disease (61%), and diabetes mellitus (48%). Patients with positive myocardial RT‐PCR died earlier after hospital admission (5 versus 12 days, p

Complications affecting the lung are hallmarks of severe coronavirus disease 2019 (COVID-19). While there is evidence for autoimmunity in severe COVID-19, the exact mechanisms remain unknown. Here, we established a prospective observational cohort to study lung specific autoantibodies (auto-Abs). Incubation of plasma from severe COVID-19 patients with healthy human lung tissue revealed the presence of IgA antibodies binding to surfactant-producing pneumocytes. Enzyme-linked immunosorbent assays (ELISA) and protein pull-downs using porcine surfactant confirmed the presence of auto-Abs binding to surfactant proteins in severe COVID-19 patients. Mass spectrometry and ELISAs with recombinant proteins identified IgA auto-Abs that target human surfactant proteins B and C. In line with these findings, lungs of deceased COVID-19 patients showed reduced pulmonary surfactant. Our data suggest that IgA-driven autoimmunity against surfactant may result in disease progression of COVID-19.

The authors present the case of a 58-year-old man with the unique combination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and, later on, haemophagocytic lymphohistiocytosis admitted to the intensive care unit. During his ICU stay the patient developed a variety of complications including acute respiratory distress syndrome, pulmonary embolism, right heart failure and suspected HLH leading to multiorgan failure and death. Despite the proven diagnosis of haemophagocytic lymphohistiocytosis, the excessively high ferritin levels of the patient did not seem fully explained by this diagnosis. Therefore, the authors want to highlight different causes of hyperferritinaemia in critically ill patients and underline the importance of differential diagnoses when interpreting continuously rising ferritin levels.

Plasmablastic lymphoma (PBL) represents a rare and aggressive lymphoma subtype frequently associated with immunosuppression. Clinically, patients with PBL are characterized by poor outcome. The current understanding of the molecular pathogenesis is limited. A hallmark of PBL represents its plasmacytic differentiation with loss of B-cell markers and, in 60% of cases, its association with Epstein-Barr virus (EBV). Roughly 50% of PBLs harbor a MYC translocation. Here, we provide a comprehensive integrated genomic analysis using whole exome sequencing (WES) and genome-wide copy number determination in a large cohort of 96 primary PBL samples. We identify alterations activating the RAS-RAF, JAK-STAT, and NOTCH pathways as well as frequent high-level amplifications in MCL1 and IRF4. The functional impact of these alterations is assessed using an unbiased shRNA screen in a PBL model. These analyses identify the IRF4 and JAK-STAT pathways as promising molecular targets to improve outcome of PBL patients., Plasmablastic lymphoma (PBL) is an aggressive lymphoma subtype characterized by poor prognosis but the molecular knowledge of the disease is limited. Here, the authors perform whole exome sequencing and copy number determination of primary samples highlighting IRF4 and JAK-STAT pathways as therapeutic targets for PBL.

Background. Neuroendocrine tumors (NETs) are a rare entity and are most commonly found in the gastroenteropancreatic tract. The clinical outcome depends on the potential resectability, grade, and stage. Here, we report a case of a tumor debulking in a metastatic NET of the pancreas. A 25-year-old woman with stable metastatic NET of the pancreas G2 T4N1M1 (hepatic, extrahepatic) already underwent several therapies. Case Presentation. A 25-year-old woman with stable metastatic NET of the pancreas G2 T4N1M1 (hepatic, extrahepatic) already underwent several pharmaceutical therapies. Due to the young age, the G2 characteristic, and the stable liver disease, the decision for debulking was made. Based on a 3D CT scan, an embolization was successfully performed directly prior to a pylorus-preserving pancreatic head resection, advanced interaortocaval lymph node dissection, and an atypical liver resection within segment VI. Histological workup revealed a stage pT3, G2, pN1 (29/34), pM1c (hepatic and extrahepatic), L1, V0, Pn0 with complete surgical resection of the primary tumor (180 mm). The excision of the liver segment V showed a completely resected metastasis. Conclusions. In this patient, extensive surgery of a pancreatic NET with the aim of a prolonged progression-free survival was performed. Close cooperation between different disciplines is absolutely mandatory. Modern imaging allowed a precise therapy plan to be worked out.

Diffuse large B-cell lymphoma (DLBCL) is the major type of aggressive B-cell lymphoma. High-grade B-cell lymphoma (HGBCL) with MYC/BCL2 double-hit (DH) represents a distinct entity with dismal prognosis after standard immunochemotherapy in the current WHO lymphoma classification. However, whether TP53 mutation synergizes with MYC abnormalities (MYC rearrangement and/or Myc protein overexpression) contributing to HGBCL-like biology and prognosis is not well investigated. In this study, patients with DLBCL with MYC/TP53 abnormalities demonstrated poor clinical outcome, high-grade morphology, and distinct gene expression signatures. To identify more effective therapies for this distinctive DLBCL subset, novel MYOTP53/BCI.-2-targeted agents were investigated in DLBCI. cells with MYC/TP53 dual alterations or HGBCL-MYC/BCL2-DH. A BET inhibitor INCB057643 effectively inhibited cell viability and induced apoptosis in DLBCL/HGBCL cells regardless of MYC/BCL2/TP53 status. Combining LNCB057643 with a MDM2-p53 inhibitor DS3032b significantly enhanced the cytotoxic effects in HGBCL-DH without TP53 mutation, while combining with the BCL-2 inhibitor venetoclax displayed potent therapeutic synergy in DLBCL/HGBCL cells with and without concurrent TP53 mutation. Reverse-phase protein arrays revealed the synergistic molecular actions by INICB057643, DS3032b and venetoclax to induce cellcycle arrest and apoptosis and to inhibit A KT/MEK/ERK/mTOR pathways, as well as potential drug resistance mechanisms mediated by upregulation of Mcl-1 and RAS/RAF/MEK/ERK pathways. In summary, these findings support subclassification of DLBCL/HGBCL with dual MYC/1153 alterations, which demonstrates distinct pathobiologic features and dismal survival with standard therapy, therefore requiring additional targeted therapies. Diffuse large B-cell lymphoma (DLBCL) is the major type of aggressive B-cell lymphoma. High-grade B-cell lymphoma (HGBCL) with MYC/BCL2 double-hit (DH) represents a distinct entity with dismal prognosis after standard immunochemotherapy in the current WHO lymphoma classification. However, whether TP53 mutation synergizes with MYC abnormalities (MYC rearrangement and/or Myc protein overexpression) contributing to HGBCL-like biology and prognosis is not well investigated. In this study, patients with DLBCL with MYC/TP53 abnormalities demonstrated poor clinical outcome, high-grade morphology, and distinct gene expression signatures. To identify more effective therapies for this distinctive DLBCL subset, novel MYC/TP53/BCL-2–targeted agents were investigated in DLBCL cells with MYC/TP53 dual alterations or HGBCL-MYC/BCL2-DH. A BET inhibitor INCB057643 effectively inhibited cell viability and induced apoptosis in DLBCL/HGBCL cells regardless of MYC/ BCL2/TP53 status. Combining INCB057643 with a MDM2-p53 inhibitor DS3032b significantly enhanced the cytotoxic effects in HGBCL-DH without TP53 mutation, while combining with the BCL-2 inhibitor venetoclax displayed potent therapeutic synergy in DLBCL/HGBCL cells with and without concurrent TP53 mutation. Reverse-phase protein arrays revealed the synergistic molecular actions by INCB057643, DS3032b and venetoclax to induce cell-cycle arrest and apoptosis and to inhibit AKT/MEK/ERK/mTOR pathways, as well as potential drug resistance mechanisms mediated by upregulation of Mcl-1 and RAS/RAF/MEK/ERK pathways. In summary, these findings support subclassification of DLBCL/HGBCL with dual MYC/TP53 alterations, which demonstrates distinct pathobiologic features and dismal survival with standard therapy, therefore requiring additional targeted therapies. Implications: The clinical and pharmacologic studies suggest recognizing DLBCL with concomitant TP53 mutation and MYC abnormalities as a distinctive entity necessary for precision oncology practice.

An excess formation of neutrophil extracellular traps (NETs), previously shown to be strongly associated with cytokine storm and acute respiratory distress syndrome (ARDS) with prevalent endothelial dysfunction and thrombosis, has been postulated to be a central factor influencing the pathophysiology and clinical presentation of severe COVID-19. A growing number of serological and morphological evidence has added to this assumption, also in regard to potential treatment options. In this study, we used immunohistochemistry and histochemistry to trace NETs and their molecular markers in autopsy lung tissue from seven COVID-19 patients. Quantification of key immunomorphological features enabled comparison with non-COVID-19 diffuse alveolar damage. Our results strengthen and extend recent findings, confirming that NETs are abundantly present in seriously damaged COVID-19 lung tissue, especially in association with microthrombi of the alveolar capillaries. In addition, we provide evidence that low-density neutrophils (LDNs), which are especially prone to NETosis, contribute substantially to COVID-19-associated lung damage in general and vascular blockages in particular.

The coronavirus SARS-CoV-2 is the causative agent of the ongoing severe acute respiratory disease pandemic COVID-19. Tissue and cellular tropism is one key to understanding the pathogenesis of SARS-CoV-2. We investigate the expression and subcellular localization of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), within the upper (nasal) and lower (pulmonary) respiratory tracts of human donors using a diverse panel of banked tissues. Here, we report our discovery that the ACE2 receptor protein robustly localizes within the motile cilia of airway epithelial cells, which likely represents the initial or early subcellular site of SARS-CoV-2 viral entry during host respiratory transmission. We further determine whether ciliary ACE2 expression in the upper airway is influenced by patient demographics, clinical characteristics, comorbidities, or medication use, and show the first mechanistic evidence that the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) does not increase susceptibility to SARS-CoV-2 infection through enhancing the expression of ciliary ACE2 receptor. These findings are crucial to our understanding of the transmission of SARS-CoV-2 for prevention and control of this virulent pathogen., Understanding how SARS-CoV-2 gains initial entry into the human body is a key step towards the development of prophylaxes and therapeutics for COVID-19. Here, the authors show that ACE2, the receptor for SARS-CoV-2, is abundantly expressed in the motile cilia of the human nasal and respiratory tract and is not affected by the use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers.

The XPO1 inhibitor selinexor was recently approved in relapsed/refractory DLBCL patients but only demonstrated modest anti-DLBCL efficacy, prompting us to investigate the prognostic effect of XPO1 in DLBCL patients and the rational combination therapies in high-risk DLBCL. High XPO1 expression (XPO1high) showed significant adverse prognostic impact in 544 studied DLBCL patients, especially in those with BCL2 overexpression. Therapeutic study in 30 DLBCL cell lines with various molecular and genetic background found robust cytotoxicity of selinexor, especially in cells with BCL2-rearranged (BCL2-R+) DLBCL or high-grade B-cell lymphoma with MYC/BCL2 double-hit (HGBCL-DH). However, expression of mutant (Mut) p53 significantly reduced the cytotoxicity of selinexor in overall cell lines and the BCL2-R and HGBCL-DH subsets, consistent with the favorable impact of XPO1high observed in Mut-p53-expressing patients. The therapeutic effect of selinexor in HGBCL-DH cells was significantly enhanced when combined with a BET inhibitor INCB057643, overcoming the drug resistance in Mut-p53-expressing cells. Collectively, these data suggest that XPO1 worsens the survival of DLBCL patients with unfavorable prognostic factors such as BCL2 overexpression and double-hit, in line with the higher efficacy of selinexor demonstrated in BCL2-R+ DLBCL and HGBCL-DH cell lines. Expression of Mut-p53 confers resistance to selinexor treatment, which can be overcome by combined INCB057643 treatment in HGBCL-DH cells. This study provides insight into the XPO1 significance and selinexor efficacy in DLBCL, important for developing combination therapy for relapsed/refractory DLBCL and HGBCL-DH.

Aims Plasmablastic lymphoma (PBL) is a rare aggressive B-cell lymphoma that frequently arises at extranodal sites in the setting of immunosuppression. The diagnosis of PBL is complex, owing to a frequent solid or cohesive growth pattern, and an often unusual immunophenotype. Several case reports have described cytokeratin (CK) expression in PBL, introducing a diagnostic pitfall. The aim of this study was to determine the frequency of CK expression in PBL in the largest series available to date. Methods and results By using immunohistochemistry in a cohort of 72 PBLs, we identified CK8/18 positivity in 11 of 72 cases (15%) and AE1/3 positivity in six of 65 cases (9%), clearly contrasting with a control series of non-PBL aggressive B-cell lymphomas (one of 96 diffuse large B-cell lymphomas), as well as with data in the literature describing only occasional CK expression in haematological neoplasms. Conclusions Our data indicate CK expression in a substantial number (15%) of PBLs. In view of the particular morphological features of PBL and its frequent negativity for the common leukocyte antigen and B-cell markers, this feature represents a pitfall in the routine diagnostic work-up of PBL, and requires more extensive immunohistochemical and molecular characterisation of cases entering the differential diagnosis.

Although primarily targeting the respiratory system, coronavirus disease 2019 (COVID-19) affects the CNS in up to 80% of patients.[1][1] Yet, findings on COVID-19 neuropathology have been conflicting: autopsy reports range from inflammatory CNS syndromes, cerebrovascular events,[1][1] and

For more than half a year, the world is grappling with coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). A long-time neglected part of the work of surgical pathologists, autopsy has thus again shifted into the spotlight as an indispensable tool to analyse new diseases systematically and comprehensively [1]. Tissue-based analysis of samples collected at autopsies of COVID-19 patients has contributed significantly to understanding this novel disease [2, 3], outlining its main adverse features, and thus helping to focus on potential life-saving therapeutic approaches, for example, improving the rheological properties of the blood or endothelial fitness in face of the microthromboses detected at autopsies (Fig. 1) [4]. Autopsy could also help to define high-risk patient cohorts and contribute to answering the question whether patients tested positive for SARS-CoV-2 and/or displaying symptoms of COVID-19 were dying with or of the disease [2, 5]. COVID-19 has led to an unprecedented flood of publications and theories related to the disease leading to controversies and uncertainties regarding many aspects, ranging from the occurrence of endothelialitis [6, 7] and the question of virally induced acute kidney injury [8] or encephalitis [9] to the visualisation of SARS-CoV-2 by electron microscopy [7]. To resolve these open issues, comprehensive and in-depth studies and larger meta-analyses will be needed, to which currently Pathobiology is contributing a dedicated fascicle. In this special issue of Pathobiology, a wide spectrum of research performed by surgical pathologists from Europe and the USA has been collected in an effort to get a better understanding of the pathophysiology of CO­VID-19 and help to tackle the issues mentioned above. A large autopsy study of 32 cases by Salvatore et al. [10] from the New York, one of the epicentres of the pandemic, showed the diversity of pathologic findings: besides diffuse alveolar damage, this cohort confirmed the increased frequency thromboembolisms in multiple organ systems. Furthermore, thanks to the diligent work-up of the cases, distinct histopathological patterns in lymph nodes and the liver were observed. Analysis of the patient collective reinforces the link between comorbid disease and lethal COVID-19. A smaller case series from Poland by Chmielik et al. [11] shows similar variegated pathology findings of COVID-19 and, importantly, that previously healthy individuals can succumb to this disease. The latter observation particularly highlights the importance to perform autopsies and collect material for further in-depth investigations such as whole-genome sequencing which would identify specific risk factors in younger individuals without obvious risk factors. Thanks to these post-mortem analyses, we now acknowledge that COVID-19 is a systemic angiocentric disease (Fig. 2) primarily involving the lungs [3] with an additional major impact on coagulation and other organ functions. Wool and Miller [12] review the current state of knowledge regarding COVID-19 and alterations of platelets and coagulation. They show a positive correlation between elevated D-dimers and mortality and a prominence of thrombembolisms and microvascular thrombotic disorders in COVID-19 patients. However, they also raise the question whether coagulopathies seen in COVID-19 should rather be seen in the context of generalized inflammatory response and not as being a unique specific feature. Indeed, a report of an autopsy series focusing on liver pathology by Schmit et al. [13] from Belgium showed that liver findings are primarily to be interpreted as secondary changes due to hypoxia or drug toxicity, in line with neuropathological data on COVID-19, which is likely a correlate of critical illness-related encephalopathy and thus not a result of virally induced damage [9]. A case report by Showers et al. [14] on a woman suffering from COVID-19 and concomitant complement-mediated coagulopathy and transient antiphospholipid antibody positivity points, along with other recent observations [15, 16], towards a possible link between CO­VID-19 and the generation of such antibodies with subsequent thromboembolic events. Importantly, this may explain the fact that despite adequate thromboprophylaxis, COVID-19 is still associated with a high rate of venous and arterial thromboembolic events. Two contributions from Switzerland include a characterization of the morphology of placentas of women infected with SARS-CoV-2 and a retrospective analysis of autopsies performed before the outbreak of CO­VID-19 aiming to elucidate whether SARS-CoV-2 had reached Basel before the country's first case in late February 2020 [17, 18]. The placenta study revealed that in gravid women with manifest COVID-19, there are signs of lymphohistiocytic inflammation as well as presence of SARS-CoV-2 in the decidua and in decidualized endometrium, another piece of evidence which points to pregnant women as a risk group for serious disease [19]. On the other hand, asymptomatic women tested SARS-CoV-2 positively before or at the time of birth only showed mild placental changes. Haslbauer et al. [18] found no evidence of SARS-CoV-2-infection before the officially declared first case in Switzerland by retrospectively analysing collected pulmonary tissues of patients who have died between 2019 and February 2020 with symptoms resembling COVID-19 or displaying histopathological changes commonly observable in lethal COVID-19. In order to perform autopsies of COVID-19 patients and to analyse potentially highly contagious tissue, a special equipment is required in pathology laboratories. Loibner et al. [20] give an overview on biosafety requirements according to different international standards and provide insights into the design and technical equipment of the biosafety level-3 laboratory at the Medical University of Graz that is specifically designed for autopsies involving highly pathogenic agents or other unknown pathogens. The economic impact of the current pandemic has reached pathology laboratories. De Pelsemaeker et al. [21] were able to show in a retrospective analysis that the overall amount of specimens in both surgical pathology and cytopathology significantly decreased in Belgium. This was especially related to a reduction of samples related to cancer screening. This diagnostic delay in diagnoses of malignancies points towards another potential severe consequence of COVID-19, in particular with patients suffering from highly aggressive tumours [22, 23, 24]. Taken together, we hope the reader of this special issue of Pathobiology can benefit from the collected high-quality contributions bearing new insights in pathologies encountered in COVID-19 as well as getting information on the impact of the pandemic on global healthcare challenges. The close collaboration of medical specialists in the learning process around COVID-19 and other unknown disease is mandatory. No single expertise will be able to “solve” the riddle. A virus is nothing without the host and its reactions. So the understanding of any viral disease will go along with the fine analysis of the hosts' tissue and immunological reaction. We have to foster the interdisciplinary work-up of COVID with the histopathological work-up as an incontournable starting point. Conflict of Interest Statement The authors declare to have no competing interests. Funding Sources This work is supported by the Botnar Research Centre for Child Health, BRCCH. Author Contributions Both T.M. and A.T. designed and wrote the editorial. A.T. provided the figures.

Introduction: In December 2019, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic broke out. The virus rapidly spread globally, resulting in a major world public-health crisis. The major disease manifestation occurs in the respiratory tract. However, further studies documented other systemic involvement. This study investigates histopathologic eye changes in postmortem material of coronavirus disease 2019 (COVID-19) patients. Methods: Sections of formalin-fixed, paraffin-embedded eyes from 5 patients (10 eyes) who died of COVID-19 at the University Hospital in Basel were included. Gross examination and histological evaluation were performed by 3 independent ophthalmopathologists. Immunohistochemical staining was performed using antibodies against fibrin, cleaved caspase 3, and ACE-2. Five enucleated eyes of patients not infected with SARS-CoV-2 served as control group. All cases have been studied for presence of SARS-CoV-2 RNA by means of reverse transcription PCR and RNA in situ hybridization (ISH). The choroidal vessels of one case were analyzed with electron microscope. Results: Ophthalmopathologically, 8 eyes from 4 patients displayed swollen endothelial cells in congested choroidal vessels. No further evidence of specific eye involvement of SARS-CoV-2 was found in any of the patients. In the 8 eyes with evidence of changes due to SARS-CoV-2, immunohistochemical staining demonstrated fibrin microthrombi, apoptotic changes of endothelial and inflammatory cells. In control eyes, ACE-2 was detectable in the conjunctiva, cornea, retina, and choroidea and displayed significantly lower amounts of stained cells as in COVID-19 eyes. SARS-CoV-2 RNA was detectable in both bulbi of 2/5 patients, yet ISH failed to visualize viruses. Electron microscopy showed no significant results due to the artifacts. Discussion/Conclusion: As already described in other organs of COVID-19 patients, the ophthalmological examination revealed-microthrombi, that is, hypercoagulation and vasculopathy most probably due to endothelial damage. A possible viral spread to the endothelial cells via ACE-2 provides one pathophysiological explanation. The expression of ACE-2 receptors in the conjunctiva hints toward its susceptibility to infection. To what extend eyes, function is disrupted by SARS-CoV-2 is subject to further studies, especially in the clinic.