“Triple hit” lymphomas: A retrospective cytology case series of an uncommon high grade B‐cell malignancy with C‐MYC, BCL‐2 and BCL‐6 rearrangements

Abstract

The Revised fourth Edition World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissues suggests novel categories, including "high grade B-cell lymphoma with MYC and BCL2 and BCL6 gene rearrangements." These diseases are known colloquially as "double hit" and "triple hit" lymphomas. The "first-hit" in these cases is the harboring of a MYC rearrangement. Concurrent derangements of BCL2 and BCL6 can be the "second-hit" or "third-hit." To our knowledge, this is the first report of "triple-hit" lymphomas in cytology specimens. The files of the Cleveland Clinic (January 2007 through December 2017) were searched for all "triple hit" lymphomas. Four cases met inclusion criteria (cytology slides in files and histologically confirmed "triple hit" lymphoma). All slides were reviewed. The mean age was 65 years, with a male predominance. All patients presented at advanced stage and showed progressive disease despite therapy. FISH studies (histologic sections) confirmed translocations of MYC (8q24), BCL2 (18q21) and BCL6 (3q27) in all patients. All cases were characterized by high cellularity, dispersed cells, presence of stripped nuclei, lymphoglandular bodies, apoptotic bodies, cytomegaly, nucleomegaly, nuclear envelope irregularities, macronucleoli (most often single), recognizable mitoses and presence of cytoplasmic vacuoles (variable). The WHO recommends that all large B-cell lymphomas be investigated using cytogenetic or molecular techniques. Concurrent inhibition of MYC and BCL2 is a potentially effective treatment strategy for triple hit lymphomas, and an expanding literature exists regarding predictive biomarkers and therapeutic regimens. It is our intention to raise awareness of this uncommon mature B-cell neoplasm within the cytodiagnostic community.

Cytological Diagnosis of Aggressive Small-Cell Lymphomas

“…The disease is often widespread at diagnosis, with multiple affected sites, including bone marrow and extranodal disease. HGBLs have variable morphology, with areas of overlap among DLBCL, BL, and ALL/LBL [1, 16, 17].…”

“…As with most other lymphomas, the diagnostic criteria are based on morphology and ancillary techniques that can be performed on cytologic material. Therefore, cytological diagnosis of HGBL is possible and has been reported [16].…”

Primary thyroid high‐grade B‐cell lymphoma with MYC and BCL2 rearrangements in Hashimoto's thyroiditis

“…Furthermore, MYC and BCL2 are not expressed by immunohistochemistry in up to 20% of double‐hit lymphomas 8 . The presence of apoptotic bodies, tingible body macrophages, cytomegaly, nucleomegaly, nuclear envelope irregularities, single macronucleoli, and cytoplasmic vacuoles on cytologic preparations can serve as helpful diagnostic clues in cases of double/triple hit lymphomas but the final diagnosis rests on the detection of MYC and BCL2 and/or BCL6 rearrangements by FISH or molecular testing 9 …”