Zamò, Alberto

The mature splenic B‐cell lymphomas are an enigmatic group of lymphoid neoplasms that have long caused significant difficulty for the practicing pathologist due to overlapping diagnostic features among entities and the decreasing availability of splenic tissue for assessment. While some entities have highly characteristic and specific clinicopathological features (e.g. hairy cell leukaemia), others are substantially more difficult to recognise (e.g. splenic diffuse red pulp lymphoma). At the same time, classification systems have been evolving, resulting in multiple changes to the boundaries among these entities and even the existence of some entities in their own right. Moreover, unbiased multi‐omic interrogation (whole genome/transcriptome sequencing, methylome) of the splenic B‐cell lymphomas over the past decade has given us significant insights into the underling biology of these neoplasms. We present a clinicopathological perspective on the historical, current and future state of the diagnosis and classification of splenic B‐cell lymphomas integrating multi‐omic data and highlighting areas of focus for the field in order to continue to strive to improve patient outcomes through accurate diagnosis.

Abstract Objectives The 2019 Society for Hematopathology and European Association for Haematopathology Workshop reviewed the spectrum of neoplastic, nonneoplastic, and borderline entities associated with reactive eosinophilia in tissue. Methods The workshop panel reviewed 46 cases covered in 2 workshop sessions. Results The 46 cases were presented with their consensus diagnoses during the workshop. Reactive eosinophilia in lymph nodes and other tissues may be accompanied by or be distinct from peripheral blood eosinophilia. Reactive etiologies included inflammatory disorders such as Kimura disease and IgG4-related disease, which may show overlapping pathologic features and reactions to infectious agents and hypersensitivity (covered in a separate review). Hodgkin, T-cell, and B-cell lymphomas and histiocytic neoplasms can result in reactive eosinophilia. The spectrum of these diseases is discussed and illustrated through representative cases. Conclusions Reactive eosinophilia in lymph nodes and tissues may be related to both nonneoplastic and neoplastic lymphoid proliferations and histiocytic and nonhematolymphoid processes. Understanding the differential diagnosis of reactive eosinophilia and the potential for overlapping clinical and pathologic findings is critical in reaching the correct diagnosis so that patients can be treated appropriately.

Abstract Richter syndrome represents the evolution of chronic lymphocytic leukemia into an aggressive tumor, most commonly diffuse large B-cell lymphoma. The lack of in vitro and in vivo models has severely hampered drug testing in a disease that is poorly responsive to common chemoimmunotherapeutic combinations as well as to novel kinase inhibitors. Here we report for the first time the establishment and genomic characterization of two patient-derived tumor xenograft (PDX) models of Richter syndrome, RS9737 and RS1316. Richter syndrome xenografts were genetically, morphologically, and phenotypically stable and similar to the corresponding primary tumor. RS9737 was characterized by biallelic inactivation of CDKN2A and TP53, monoallelic deletion of 11q23 (ATM), and mutations of BTK, KRAS, EGR2, and NOTCH1. RS1316 carried trisomy 12 and showed mutations in BTK, KRAS, MED12, and NOTCH2. RNA sequencing confirmed that in both cases >80% of the transcriptome was shared between primary tumor and PDX. In line with the mutational profile, pathway analyses revealed overactivation of the B-cell receptor, NFκB, and NOTCH pathways in both tumors, potentially providing novel tumor targets. In conclusion, these two novel models of Richter syndrome represent useful tools to study biology and response to therapies of this highly aggressive and still incurable tumor. Significance: Two patient-derived xenograft models of Richter syndrome represent the first ex vivo model to study biology of the disease and to test novel therapeutic strategies. Cancer Res; 78(13); 3413–20. ©2018 AACR.