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Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive diseases associated with poor outcomes. Recent progress in understanding of the biology and pathogenesis based on molecular profiling and next-generation sequencing has led to the introduction of new provisional entities in the World Health Organization (WHO) classification system of 2017 and to the emergence of new drugs.1 Previous Belgian guidelines were published in 2013.2 This review will discuss the diagnosis, work-up and treatment of PTCL including these advances as well as the limitation of the availability of drugs according to the Belgian reimbursement rules.

Post-transplant lymphoproliferative disorder (PTLD) is a complication of organ transplantation classified according to the WHO as nondestructive, polymorphic, monomorphic, and classic Hodgkin Lymphoma subtypes. In this retrospective study, we investigated the potential of semi-quantitative 2-[F]fluoro-2-deoxy-D-glucose ([F]FDG) PET/computed tomography (CT)-based parameters to differentiate between the PTLD morphological subtypes. 96 patients with histopathologically confirmed PTLD and baseline [F]FDG PET/CT between 2009 and 2019 were included. Extracted semi-quantitative measurements included: Maximum, peak, and mean standardized uptake value (SUV, SUV, and SUV). Median SUVs were highest for monomorphic PTLD followed by polymorphic and nondestructive subtypes. The median SUV at the biopsy site was significantly higher in monomorphic PTLD (17.8, interquartile range (IQR):16) than in polymorphic subtypes (9.8, IQR:13.4) and nondestructive (4.1, IQR:6.1) ( = 0.04 and ≤ 0.01, respectively). An SUV ≥ 24.8 was always indicative of a monomorphic PTLD in our dataset. Nevertheless, there was a considerable overlap in SUV across the different morphologies. The median SUV at the biopsy site was significantly higher in monomorphic PTLD than polymorphic and nondestructive subtypes. However, due to significant SUV overlap across the different subtypes, these values may only serve as an indication of PTLD morphology, and SUV-based parameters cannot replace histopathological classification.

A 53-year-old patient with acute kidney injury A 53-year-old patient was admitted with acute kidney injury and hypercalcemia. Further investigation with PET-CT revealed a strong FDG-uptake in the spleen and minor uptake in some mediastinal lymph nodes. EBUS-FNA of a mediastinal lymph node was unrevealing. Other examinations could not differentiate reliably between lymphoma and sarcoidosis. A diagnostic splenectomy was necessary to make a definitive diagnosis. ispartof: Tijdschrift voor Geneeskunde vol:74 issue:12 pages:886-889 status: published

Anaplastic large-cell lymphomas (ALCLs) are a group of clinically and biologically heterogeneous diseases including the ALK(+) and ALK(-) systemic forms. Whereas ALK(+) ALCLs are molecularly characterized and can be readily diagnosed, specific immunophenotypic or genetic features to define ALK(-) ALCL are missing, and their distinction from other T-cell non-Hodgkin lymphomas (T-NHLs) remains controversial. In the present study, we undertook a transcriptional profiling meta-analysis of 309 cases, including ALCL and other primary T-NHL samples. Pathway discovery and prediction analyses defined a minimum set of genes capable of recognizing ALK(-) ALCL. Application of quantitative RT-PCR in independent datasets from cryopreserved and formalin-fixed paraffin-embedded samples validated a 3-gene model (TNFRSF8, BATF3, and TMOD1) able to successfully separate ALK(-) ALCL from peripheral T-cell lymphoma not otherwise specified, with overall accuracy near 97%. In conclusion, our data justify the possibility of translating quantitative RT-PCR protocols to routine clinical settings as a new approach to objectively dissect T-NHL and to select more appropriate therapeutic protocols. (Blood. 2012;120(6):1274-1281) Anaplastic large-cell lymphomas (ALCLs) are a group of clinically andbiologically heterogeneous diseases including the ALK(+) and ALK(-) systemicforms. Whereas ALK(+) ALCLs are molecularly characterized and can be readilydiagnosed, specific immunophenotypic or genetic features to define ALK(-) ALCLare missing, and their distinction from other T-cell non-Hodgkin lymphomas(T-NHLs) remains controversial. In the present study, we undertook atranscriptional profiling meta-analysis of 309 cases, including ALCL and otherprimary T-NHL samples. Pathway discovery and prediction analyses defined aminimum set of genes capable of recognizing ALK(-) ALCL. Application ofquantitative RT-PCR in independent datasets from cryopreserved and formalin-fixedparaffin-embedded samples validated a 3-gene model (TNFRSF8, BATF3, and TMOD1)able to successfully separate ALK(-) ALCL from peripheral T-cell lymphoma nototherwise specified, with overall accuracy near 97%. In conclusion, our datajustify the possibility of translating quantitative RT-PCR protocols to routineclinical settings as a new approach to objectively dissect T-NHL and to selectmore appropriate therapeutic protocols

Introduction/ Background The whole slide imaging (WSI) market has developed enormously in the recent years. This evolution has made the selection and the implementation of digital pathology more complicated. Based on a validation process, we developed recommendations that need to be taken into account when implementing whole slide imaging. In addition to selecting the right hardware, one should also focus on laboratory organization, integration, training and handling. Aims The aim is to integrate WSI as efficiently as possible in a standardized process. This should lead to a user friendly workflow for pathologists and must ensure the quality of the diagnosis. Methods We organized on-site demonstrations to test several available WSI systems with a fixed set of histology slides. We evaluated scanning quality, measured the scanning time, the amount of data produced and made a simulation of a routine workflow. We developed a to-be workflow beginning with the scanning process until the final diagnosis of the pathologist. The workflow focused on the integration of the system into the laboratory information system. We standardized the technical laboratory processes to increase the quality of the slides and the efficiency of WSI. The standardization included good labeling, adequate quality, standardized location and correct number of sections on the slide. We introduced a continuous workflow to reduce batch size and to decrease the turn-around-time. The pathologists were only allowed to work with WSI after training in order to manipulate the images as efficiently as possible. Finally we validated the system according to CAP guidelines for WSI for diagnostic purpose in pathology. Results It is very important to determine what the purpose of WSI implementation in the lab is. The different systems show large variations between them and not every set up will fit in the specific workflow of each lab. The workflow simulation gave us an idea of the scanning turn-around-time and made it possible to estimate the amount of scanners that would be necessary in daily routine. Another focus point is the total integration of WSI to find a synergy between the hardware, workflow and the way the system can be integrated into the IT infrastructure of the lab. Beside the bidirectional communication with the laboratory information system, data storage organization and its influence on the lab’s productivity is also very important. Organizing the laboratory with a standardized continuous workflow will reduce the amount of data, increase speed and lower the amount of rescans. To prevent that WSI is used inefficiently, it is crucial to train the pathologists before they start using it. A lack of training will lead to a dislike of WSI due to poor knowledge of the available applications. The pathologists are indicating that it’s crucial to have the correct hardware to manipulate the image in order to ensure diagnostic speed and to lower the threshold towards WSI. We may conclude that choosing and implementing the correct WSI solution needs a systematic approach to succeed on the long term. Defining and optimizing the workflow before implementing whole slide imaging is crucial. Hardware, workflow and IT infrastructure should match to ensure productivity. Training of the pathologists is decisive in order to ensure efficient use., Diagnostic Pathology, Vol 1 No 8 (2016): 13. European Congress on Digital Pathology

We examined the brains of 266 patients with prion disease (PrionD) and found that 46 patients (17%) had Alzheimer disease (AD)-like changes. To explore potential mechanistic links between PrionD and AD, we exposed human brain aggregates (BrnAggs) to a brain homogenate from a patient with sporadic Creutzfeldt-Jakob disease and found that neurons in human BrnAggs produced many β-amyloid (Aβ; Aβ42) inclusions, whereas uninfected control-exposed human BrnAggs did not. Western blot analysis of 20 pooled Creutzfeldt-Jakob disease-infected BrnAggs verified Aβ42 levels higher than those in controls. We next examined the CA1 region of the hippocampus from 14 patients with PrionD and found that 5 patients had low levels of scrapie-associated prion protein (PrP), many Aβ42 intraneuronal inclusions, low apolipoprotein E-4 (APOE-4), and no significant nerve cell loss. Seven patients had high levels of PrP, low Aβ42, high APOE-4, and 40% nerve cell loss, suggesting that APOE-4 and PrP together cause neuron loss in PrionD. There were also increased levels of hyperphosphorylated tau protein (Hτ) and Hτ-positive neuropil threads and neuron bodies in both PrionD and AD groups. The brains of 6 age-matched control patients without dementia did not contain Aβ42 deposits; however, there were rare Hτ-positive threads in 5 controls, and 2 controls had few Hτ-positive nerve cell bodies. We conclude that PrionD may trigger biochemical changes similar to those triggered by AD and suggest that PrionD is a disease involving PrP, Aβ42, APOE-4, and abnormal tau.

Abundant macrophage infiltration in tumors often correlates with a poor prognosis. T cell/histiocyte rich large B cell lymphoma (THRLBCL) is a distinct aggressive B cell lymphoma entity showing a high macrophage content. To further elucidate the role of tumor-associated macrophages in THRLBCL, we performed gene expression profiling of microdissected histiocyte subsets of THRLBCL, nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), Piringer lymphadenitis, sarcoidosis, nonspecific lymphadenitis and monocytes from peripheral blood. In a supervised principal component analysis, histiocytes from THRLBCL were most closely related to epithelioid cells from NLPHL, with both types of cells expressing genes related to proinflammatory and regulatory macrophage activity. Moreover, histiocytes from THRLBCL strongly expressed metal-binding proteins like MT2A, by which histiocytes of THRLBCL can be distinguished from the other histiocyte subsets investigated. Interestingly, the validation at the protein level showed a strong expression of TXN, CXCL9, MT2A and SOD2 not only in macrophages of THRLBCL but also in the tumor cells of NLPHL and classical Hodgkin lymphoma (cHL). Overall, the present findings indicate that macrophages in the microenvironment of THRLBCL have acquired a distinct gene expression pattern that is characterized by a mixed M1/M2 phenotype and a strong expression of several metal binding proteins. The microenvironments in NLPHL and THRLBCL appear to have a similar influence on the macrophage phenotype. The high expression of metal binding proteins in histiocytes of THRLBCL may be diagnostically useful, but a potential pathophysiological role remains to be identified.

Posttransplant lymphoproliferative disorder (PTLD) is a potentially fatal disease that arises in 2%–10% of solid organ and hematopoietic stem cell transplants and is most frequently of B-cell origin. This very heterogeneous disorder ranges from benign lymphoproliferations to malignant lymphomas, and despite the clear association with Epstein-Barr Virus (EBV) infection, its etiology is still obscure. Although a number of risk factors have been identified (EBV serostatus, graft type, and immunosuppressive regimen), it is currently not possible to predict which transplant patient will eventually develop PTLD. Genetic studies have linked translocations (involving C-MYC, IGH, BCL-2), various copy number variations, DNA mutations (PIM1, PAX5, C-MYC, RhoH/TTF), and polymorphisms in both the host (IFN-gamma, IL-10, TGF-beta, HLA) and the EBV genome to B-cell PTLD development. Furthermore, the tumor microenvironment seems to play an important role in the course of disease representing a local niche that can allow antitumor immune responses even in an immunocompromised host. Taken together, B-cell PTLD pathogenesis is very complex due to the interplay of many different (patient-dependent) factors and requires thorough molecular analysis for the development of novel tailored therapies. This review aims at giving a global overview of the currently known parameters that contribute to the development of B-cell PTLD.

BACKGROUND: Lymphadenopathy (LA) imposes a diagnostic challenge in internal medicine. Exclusion of malignancy is the primary concern. METHODS: A retrospective case series, including 40 adult patients from the general internal medicine department who underwent lymph node biopsy (LNB) at a single university hospital. Demographics, clinical data and histopathological diagnoses were registered. By means of the latest medical record, we obtained a final diagnosis for each patient and subsequently searched for variables correlated with malignancy. Follow-up was at least one year in 95% of cases. RESULTS: The prevalence of malignancy was 58%. Older age (p = 0.02) was significantly correlated with malignancy. The presence of painful lymphadenopathy at clinical examination (p = 0.02) was significantly associated with a benign outcome. No single or combination of baseline variables satisfactorily excluded malignancy. Histopathological analysis correctly predicted malignancy in 93% of cases. In two cases, an initial diagnosis of benign non-specific lymphadenopathy was reversed to non-Hodgkin lymphoma. In one case the pathological diagnosis was inconclusive. CONCLUSION: Rather than following a universal algorithm to determine the need for LNB in patients with LA, we call for individualized decision-making in each case, carefully appreciating all available information. Additionally, one should keep in mind that false-negative results occur due to sampling errors. Therefore, a minimal number of cases should end with a final diagnosis of benign non-specific lymphadenopathy. Intensive, multidisciplinary cooperation with surgeon and pathologist is needed. Moreover, clinical follow-up should be at least one year.

The receptor tyrosine kinases (RTKs) play a critical role, controlling cell proliferation, survival, and differentiation of normal cells. Their pivotal function has been firmly established in the pathogenesis of many cancers as well. The anaplastic lymphoma kinase (ALK), a transmembrane RTK, originally identified in the nucleophosmin (NPM)–ALK chimera of anaplastic large cell lymphoma, has emerged as a novel tumorigenic player in several human cancers. In this review, we describe the expression of the ALK–RTK, its related fusion proteins, and their molecular mechanisms of activation. Novel tailored strategies are briefly illustrated for the treatment of ALK-positive neoplasms.