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BACKGROUND In situ follicular neoplasia (ISFN) is a t(14;18)(q32;q21)+ precursor lesion of follicular lymphoma (FL), which in turn can transform into diffuse large B‑cell lymphoma (DLBCL). For DLBCL that arise de novo, no precursor lesion is known. Given the high frequency of the t(14;18) translocation in de novo DLBCL as well, we investigated whether they can also arise from ISFN without FL as an intermediate step. OBJECTIVES To investigate the clonal evolution of ISFN to DLBCL - transformed from FL and de novo. MATERIALS AND METHODS Identification of ISFN lesions in patients with DLBCL was performed by BCL2 staining of reactive lymphoid tissues. ISFN and DLBCL were subsequently analyzed by fluorescence in situ hybridization, clonality analyses, sequencing of the t(14;18) breakpoint, and targeted next-generation sequencing. RESULTS 10 cases with paired ISFN and DLBCL samples were identified, 6 of which were de novo DLBCL and 4 transformed from FL. 3 DLBCL carried MYC-rearrangements in addition to the t(14;18) and were classified as high-grade B‑cell lymphoma (HGBL). The clonal relationship of ISFN and DLBCL/HGBL was confirmed for all cases. CREBBP, KMT2D, EZH2, TNFRSF14, and BCL2 were the genes most frequently mutated, with the distribution of private and shared mutations pointing to 2 different scenarios of clonal evolution. In most cases, DLBCL/HGBL, ISFN, and, if also present, FL had evolved divergently from a common progenitor, whereas linear evolution was less frequent. CONCLUSION We show for the first time that t(14;18)+ DLBCL/HGBL can arise directly from ISFN without FL as an intermediate step and that during this progression, divergent evolution is common.

Background Multiple myeloma (MM) is one of the most common hematological neoplasms and accounts for approximately 1% of human cancers. Objectives Description of current diagnostics and classification of MM and related plasma cell neoplasms from the pathology viewpoint. Materials and methods Current knowledge regarding pathology and genetics of MM is summarized and tissue-based diagnostics following international consensus classifications and the current S3 guideline are described. Results MM and related neoplasms are composed of malignant plasma cells that secrete a monoclonal immunoglobulin, which is an important parameter of disease activity. MM shows a multistage development. Almost all cases are preceded by a clinically inapparent precursor lesion, monoclonal gammopathy of undetermined significance (MGUS), which can progress to smoldering myeloma with a higher tumor burden, but absence of organ damage. Systemic MM needs to be discerned from the localized forms, solitary osseous and primary extramedullary plasmacytoma. MM is genetically very heterogeneous and can be broadly subdivided into two cytogenetic groups, cases with primary IGH translocations and cases with hyperdiploidy. Intratumoral genetic heterogeneity is frequently pronounced and correlates with the size of focal lesions in imaging. Conclusions Diagnosis of plasma cell neoplasms is done according to the criteria of the International Myeloma Working Group (IWMG) and requires interdisciplinary evaluation of clinical, serological, pathological and radiological features. In addition to clinical parameters, molecular markers, especially cytogenetic aberrations, are of great prognostic relevance.

The pandemia of coronavirus disease 2019 (COVID-19) has caused more than 355,000 confirmed deaths worldwide. However, publications on postmortem findings are scarce. We present the pulmonary findings in four cases of fatal COVID-19 with a spectrum of lung pathology reflecting disease course and duration, invasive therapies, and laboratory features. Early disease is characterized by neutrophilic, exudative capillaritis with microthrombosis and high levels of IL-1beta and IL-6. Later stages are associated with diffuse alveolar damage and ongoing intravascular thrombosis in small to medium-sized pulmonary vessels, occasionally with areas of infarction equivalents, accompanied by laboratory features of disseminated intravascular coagulation. In late stages, organizing pneumonia with extensive intra-alveolar proliferation of fibroblasts and marked metaplasia of alveolar epithelium can be observed. Viral RNA is encountered in the lung, with virus particles in endothelial cells and pneumocytes. In many patients, multi-organ failure with severe liver damage sets in finally, possibly as consequence of an early-onset pro-inflammatory cytokine storm and/or thrombotic microangiopathy. Electronic supplementary material The online version of this article (10.1007/s00428-020-02881-x) contains supplementary material, which is available to authorized users.

Multiple myeloma (MM) is one of the most common hematological neoplasms and accounts for approximately 1% of human cancers.Description of current diagnostics and classification of MM and related plasma cell neoplasms from the pathology viewpoint.Current knowledge regarding pathology and genetics of MM is summarized and tissue-based diagnostics following international consensus classifications and the current S3 guideline are described.MM and related neoplasms are composed of malignant plasma cells that secrete a monoclonal immunoglobulin, which is an important parameter of disease activity. MM shows a multistage development. Almost all cases are preceded by a clinically inapparent precursor lesion, monoclonal gammopathy of undetermined significance (MGUS), which can progress to smoldering myeloma with a higher tumor burden, but absence of organ damage. Systemic MM needs to be discerned from the localized forms, solitary osseous and primary extramedullary plasmacytoma. MM is genetically very heterogeneous and can be broadly subdivided into two cytogenetic groups, cases with primary IGH translocations and cases with hyperdiploidy. Intratumoral genetic heterogeneity is frequently pronounced and correlates with the size of focal lesions in imaging.Diagnosis of plasma cell neoplasms is done according to the criteria of the International Myeloma Working Group (IWMG) and requires interdisciplinary evaluation of clinical, serological, pathological and radiological features. In addition to clinical parameters, molecular markers, especially cytogenetic aberrations, are of great prognostic relevance.HINTERGRUND: Das multiple Myelom (MM) ist eine der häufigsten hämatologischen Neoplasien und macht etwa 1 % aller Krebserkrankungen aus.Darstellung der aktuellen Diagnostik und Klassifikation des MM und verwandter Plasmazellneoplasien aus Sicht der Pathologie.Erläuterung des aktuellen Wissensstands zur Pathologie und Genetik des MM sowie Darstellung der gewebebasierten Diagnostik unter Berücksichtigung der internationalen Konsensusklassifikationen und der aktuellen S3-Leitlinie.Das MM und verwandte Neoplasien bestehen aus maligne entarteten Plasmazellen, die meist ein monoklonales Immunglobulin sezernieren, das einen wichtigen Parameter der Krankheitsaktivität darstellt. Das MM zeigt eine stadienhafte Entwicklung. Nahezu alle Fälle gehen aus einer klinisch inapparenten Vorläuferläsion, der monoklonalen Gammopathie unbestimmter Signifikanz (MGUS) hervor, an die sich ein sog. „smoldering“ Myelom anschließen kann. Vom MM müssen die lokalisierten Formen, das solitäre ossäre und das primäre extramedulläre Plasmozytom abgegrenzt werden. Das MM ist genetisch sehr heterogen und kann grob in 2 zytogenetische Gruppen unterteilt werden: Fälle mit primären IGH-Translokationen und Fälle mit Hyperdiploidie. Das Ausmaß der oft ausgeprägten intratumoralen genetischen Heterogenität korreliert mit der Größe fokaler Läsionen in der Bildgebung.Die Diagnose von Plasmazellneoplasien nach den Kriterien der International Myeloma Working Group (IMWG) erfolgt interdisziplinär unter Einbeziehung klinischer, serologischer, pathologischer und radiologischer Befunde. Neben konventionellen klinischen Parametern sind molekulare Marker, insbesondere zytogenetische Aberrationen von großer prognostischer Relevanz.

In situ follicular neoplasia (ISFN) is the earliest morphologically identifiable precursor of follicular lymphoma (FL). Although it is genetically less complex than FL and has low risk for progression, ISFN already harbors secondary genetic alterations, in addition to the defining t(14;18)(q32;q21) translocation. FL, in turn, frequently progresses to diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBL). By BCL2 staining of available reactive lymphoid tissue obtained at any time point in patients with aggressive B-cell lymphoma (BCL), we identified ten paired cases of ISFN and DLBCL/HGBL, including six de novo tumors and four tumors transformed from FL as an intermediate step, and investigated their clonal evolution using microdissection and next-generation sequencing. A clonal relationship between ISFN and aggressive BCL was established by immunoglobulin and/or BCL2 rearrangements and/or the demonstration of shared somatic mutations for all ten cases. Targeted sequencing revealed CREBBP, KMT2D, EZH2, TNFRSF14 and BCL2 as the genes most frequently mutated already in ISFN. Based on the distribution of private and shared mutations, two patterns of clonal evolution were evident. In most cases, the aggressive lymphoma, ISFN and, when present, FL revealed divergent evolution from a common progenitor, whereas linear evolution with sequential accumulation of mutations was less frequent. In conclusion, we demonstrate for the first time that t(14;18)+ aggressive BCL can arise from ISFN without clinically evident FL as an intermediate step and that during this progression, branched evolution is common.