The Post-transplant Lymphoproliferative Disorders-Metagenomic Shotgun Microbial Sequencing (PTLD-MSMS) Study Methods and Protocol.

Post-transplant lymphoproliferative disorders (PTLDs) remain a feared complication of transplantation, with significant morbidity and mortality. The oncogenic Epstein-Barr virus (EBV) is a key pathogenic driver in 50%-80% of cases. Numerous prognostic indices, comprising multiple clinical, epidemiological and tumor characteristics, including EBV tumor positivity, do not consistently associate with worse patient survival, suggesting a potential role for EBV genome variants in determining outcome.

Performance of , , and break-apart FISH in small biopsies with large B-cell lymphoma: a retrospective Cytopathology Hematopathology Interinstitutional Consortium study.

Introduction: Fluorescence hybridization (FISH) is an essential ancillary study used to identify clinically aggressive subsets of large B-cell lymphomas that have , or rearrangements. Small-volume biopsies such as fine needle aspiration biopsy (FNAB) and core needle biopsy (CNB) are increasingly used to diagnose lymphoma and obtain material for ancillary studies such as FISH. However, the performance of FISH in small biopsies has not been thoroughly evaluated or compared to surgical biopsies.

A pathologist-AI collaboration framework for enhancing diagnostic accuracies and efficiencies.

In pathology, the deployment of artificial intelligence (AI) in clinical settings is constrained by limitations in data collection and in model transparency and interpretability. Here we describe a digital pathology framework, nuclei.io, that incorporates active learning and human-in-the-loop real-time feedback for the rapid creation of diverse datasets and models.

Risk of Second Tumors and T-Cell Lymphoma after CAR T-Cell Therapy.

Background: The risk of second tumors after chimeric antigen receptor (CAR) T-cell therapy, especially the risk of T-cell neoplasms related to viral vector integration, is an emerging concern.

Methods: We reviewed our clinical experience with adoptive cellular CAR T-cell therapy at our institution since 2016 and ascertained the occurrence of second tumors. In one case of secondary T-cell lymphoma, a broad array of molecular, genetic, and cellular techniques were used to interrogate the tumor, the CAR T cells, and the normal hematopoietic cells in the patient.

Epstein-Barr virus-associated post-transplant lymphoproliferative disorders in pediatric transplantation: A prospective multicenter study in the United States.

Background: Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorders (PTLD) is the most common malignancy in children after transplant; however, difficulties for early detection may worsen the prognosis.

Methods: The prospective, multicenter, study enrolled 944 children (≤21 years of age). Of these, 872 received liver, heart, kidney, intestinal, or multivisceral transplants in seven US centers between 2014 and 2019 (NCT02182986).

p53 immunohistochemistry as an ancillary tool for rapid assessment of residual disease in TP53-mutated acute myeloid leukemia and myelodysplastic syndromes.

Objectives: Measurable residual disease flow cytometry (MRD-FC) and molecular studies are the most sensitive methods for detecting residual malignant populations after therapy for TP53-mutated acute myeloid leukemia and myelodysplastic neoplasms (TP53+ AML/MDS). However, their sensitivity is limited in suboptimal aspirates or when the immunophenotype of the neoplastic blasts overlaps with erythroids or normal maturing myeloid cells. In this study, we set out to determine if p53 immunohistochemistry (IHC) correlates with MRD-FC and next-generation sequencing (NGS) in the posttherapy setting and to determine the utility of p53 IHC to detect residual disease in the setting of negative or equivocal MRD-FC.

National pilot of entrustable professional activities in pathology residency training.

Entrustable professional activities (EPAs) are observable clinical skills and/or procedures that have been introduced into medical education at the student and resident levels in most specialties to determine readiness to advance into residency or independent practice, respectively. This publication describes the process and outcomes of a pilot study looking at the feasibility of using two anatomic pathology and two clinical pathology EPAs in pathology residency in 6 pathology residency programs that volunteered for the study. Faculty development on EPAs and their assessment was provided to pilot program faculty, and EPA assessment tools were developed and used by the pilot programs.

Leveraging faculty development to support validation of entrustable professional activities assessment tools in anatomic and clinical pathology training.

Entrustable professional activities (EPAs) are observable activities that define the practice of medicine and provide a framework of evaluation that has been incorporated into US medical school curricula in both undergraduate and graduate medical education. This manuscript describes the development of an entrustment scale and formative and summative evaluations for pathology EPAs, outlines a process for faculty development that was employed in a pilot study implementing two Anatomic Pathology and two Clinical Pathology EPAs in volunteer pathology residency programs, and provides initial validation data for the proposed pathology entrustment scales. Prior to implementation, faculty development was necessary to train faculty on the entrustment scale for each given activity.

The 5th edition of the World Health Organization Classification of mature lymphoid and stromal tumors - an overview and update.

The purpose of this review is to give an overview on the conceptual framework and major developments of the upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid tumours (WHO-HAEM5) and to highlight the most significant changes made in WHO-HAEM5 compared with the revised 4 edition (WHO-HAEM4R) of lymphoid and stromal neoplasms. The changes from the revised 4th edition include the reorganization of entities by means of a hierarchical system that is realized throughout the 5th edition of the WHO classification of tumors of all organ systems, a modification of nomenclature for some entities, the refinement of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities. For the first time, tumor-like lesions, mesenchymal lesions specific to lymph node and spleen, and germline predisposition syndromes associated with the lymphoid neoplasms are included in the classification.

Comparison of two immunohistochemical staining protocols for ALK demonstrates non-inferiority of a 5A4 clone-based protocol versus an ALK01 clone-based protocol for the diagnosis of ALK + anaplastic large cell lymphoma.

Detection of ALK rearrangement and/or expression of the ALK protein is an essential component in the evaluation of many neoplasms. Variability has been reported in the ability of different antibody clones to detect ALK expression. The ALK01 clone is commonly used to detect ALK expression in ALK-positive anaplastic large cell lymphoma (ALK + ALCL).

A personalized approach to lymphoproliferations in patients with inborn errors of immunity.

Biopsies from patients with inborn error of immunity (IEI) may pose a diagnostic challenge due to the abnormal anatomy of their lymphoid organs and the tendency for the development of lymphoproliferations in various organs, some of which may lead to the wrong impression of malignant lymphoma which may prompt aggressive unnecessary treatment. In this article we will review typical histologic findings in various IEI's described in the literature and discuss the appropriate approach to the diagnosis of lymphoproliferations in these patients by presenting illustrative cases.

Identification and confirmation via in situ hybridization of Merkel cell polyomavirus in rare cases of posttransplant cutaneous T-cell lymphoma.

Background: Viral infection is an oncogenic factor in many hematolymphoid malignancies. We sought to determine the diagnostic yield of aligning off-target reads incidentally obtained during targeted hematolymphoid next-generation sequencing to a large database of viral genomes to screen for viral sequences within tumor specimens.

Methods: Alignment of off-target reads to viral genomes was performed using magicBLAST.

Mutations in latent membrane protein 1 of Epstein-Barr virus are associated with increased risk of posttransplant lymphoproliferative disorder in children.

Epstein-Barr virus (EBV)-positive posttransplant lymphoproliferative disorder (PTLD) results in significant morbidity and mortality in pediatric transplant recipients. Identifying individuals at an increased risk of EBV-positive PTLD could influence clinical management of immunosuppression and other therapies, improving posttransplant outcomes. A 7-center prospective, observational clinical trial of 872 pediatric transplant recipients evaluated the presence of mutations at positions 212 and 366 of EBV latent membrane protein 1 (LMP1) as an indicator of risk of EBV-positive PTLD (clinical trials: NCT02182986).

Systemic Presentation of Somatic TET2 Mutated B-Cell Lymphoma in a Child With Kabuki Syndrome and a Germline KMT2D Variant.

Objectives: Kabuki syndrome (KS) is a rare congenital malformation syndrome associated with germline KMT2D mutations. Recurrent somatic mutations in KMT2D have frequently been observed in B-cell lymphoma, but limited studies are available that evaluate the genetic landscape of B-cell lymphomas in the setting of KS.

Methods: We describe a unique case of B-cell lymphoma that illustrates histologic features of pediatric-type follicular lymphoma (FL) in a young patient with KS and autoimmune disease who showed a systemic presentation of widespread lymphadenopathy and clonal lymphocytosis.

Trichodysplasia Spinulosa Polyomavirus Endothelial Infection, California, USA.

We describe 3 patients in California, USA, with trichodysplasia spinulosa polyomavirus (TSPyV) infection of endothelium after steroid administration. We detected TSPyV RNA in tissue specimens by in situ hybridization, which revealed localization to endothelial cells. These cases suggest that diseases associated with endothelial inflammation could be associated with TSPyV infection.

Histiocytic Sarcoma With CCND1 Gene Rearrangement Clonally Related and Transdifferentiated From Mantle Cell Lymphoma.

Objectives: Histiocytic neoplasms demonstrate shared gene translocations and clonal immunoglobulin gene rearrangements in cases of associated B-cell lymphomas. However, the evolution of these related disease processes remains largely uncertain, especially in the setting of a prior mantle cell lymphoma.

Methods: We describe a unique case of a histiocytic sarcoma that transdifferentiated from blastoid mantle cell lymphoma after extensive therapy.

Diagnostic Impact of Next-Generation Sequencing Panels for Lymphoproliferative Neoplasms on Small-Volume Biopsies.

Objectives: We investigated the feasibility and utility of next-generation sequencing (NGS)-based targeted somatic mutation panels and IG/TR gene rearrangement assays in the diagnosis of lymphoproliferative disorders (LPDs) in small-volume biopsies.

Materials: We performed a retrospective, single-institution review of all NGS assays requested over a 3-year period by hematopathologists for diagnostic purposes on small-volume biopsies.

Results: We identified 59 small-volume biopsies.

Machine Learning Predictability of Clinical Next Generation Sequencing for Hematologic Malignancies to Guide High-Value Precision Medicine.

Advancing diagnostic testing capabilities such as clinical next generation sequencing methods offer the potential to diagnose, risk stratify, and guide specialized treatment, but must be balanced against the escalating costs of healthcare to identify patient cases most likely to benefit from them. Heme-STAMP (Stanford Actionable Mutation Panel for Hematopoietic and Lymphoid Malignancies) is one such next generation sequencing test. Our objective is to assess how well Heme-STAMP pathological variants can be predicted given electronic health records data available at the time of test ordering.