Key points

Introduction

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL) in United States and worldwide, and approximately two-thirds of newly diagnosed patients can be expected to be cured using modern therapies. Over the last decade, a particularly high-risk entity within DLBCL has been identified, characterized molecularly by carrying translocations of the MYC proto-oncogene along with BCL2, or less commonly BCL6, or both. Presence of a MYC translocation in concert with either BCL2 or BCL6 is now known as a double-hit lymphoma (DHL), or as a triple-hit lymphoma (THL) if all 3 rearrangements are present. More recently, an adverse prognosis in DLBCL has also been attributed to dual immunohistochemical expression of both MYC and BCL2. Such cases of dual expression of MYC/BCL2 in the absence of dual genomic translocations should not be considered cases of DHL, but rather double-expressing lymphomas (DELs), which constitute a distinct phenotypic entity and have unique considerations in terms of prognosis and therapy. DHL and THL follow a highly aggressive natural history with disappointing responses to standard chemoimmunotherapy platforms, and a poor overall prognosis. The literature guiding understanding of these high-grade lymphomas is almost entirely retrospective in nature, and therefore limited by the biases inherent in such analyses. That said, recent large retrospective series have contributed to the current prognostication and therapeutic selection.

Introduction

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL) in United States and worldwide, and approximately two-thirds of newly diagnosed patients can be expected to be cured using modern therapies. Over the last decade, a particularly high-risk entity within DLBCL has been identified, characterized molecularly by carrying translocations of the MYC proto-oncogene along with BCL2, or less commonly BCL6, or both. Presence of a MYC translocation in concert with either BCL2 or BCL6 is now known as a double-hit lymphoma (DHL), or as a triple-hit lymphoma (THL) if all 3 rearrangements are present. More recently, an adverse prognosis in DLBCL has also been attributed to dual immunohistochemical expression of both MYC and BCL2. Such cases of dual expression of MYC/BCL2 in the absence of dual genomic translocations should not be considered cases of DHL, but rather double-expressing lymphomas (DELs), which constitute a distinct phenotypic entity and have unique considerations in terms of prognosis and therapy. DHL and THL follow a highly aggressive natural history with disappointing responses to standard chemoimmunotherapy platforms, and a poor overall prognosis. The literature guiding understanding of these high-grade lymphomas is almost entirely retrospective in nature, and therefore limited by the biases inherent in such analyses. That said, recent large retrospective series have contributed to the current prognostication and therapeutic selection.

Diagnosis of double-hit lymphoma

DHLs constitute an uncommon but high-risk subset within DLBCL. It is estimated that approximately 5% to 10% of DLBCLs will be characterized by double-hit cytogenetics. In addition to MYC, the most common additional translocation is BCL2 in approximately 85% of DHL cases, with a minority having a BCL6 translocation, or both (THL). It is important to recognize that karyotyping shows that these discrete chromosomal rearrangements occur in the broader context of a complex karyotype in virtually all cases, speaking to overall genomic instability. The majority of DHLs presents as a de novo DLBCL, while others will have their disease transform out of a low-grade follicular lymphoma. In 2008, the World Health Organization (WHO) created a provisional diagnostic category known as B-cell lymphoma unclassifiable with features intermediate between DLBCL and Burkitt lymphoma (BCLu). Cases in this category may have more aggressive morphologic features than a typical case of DLBCL, such as a high proliferation index and starry sky appearance, but are lacking in strict features diagnostic of Burkitt lymphoma such as having more pleomorphic morphology, immunohistochemical expression of BCL2, or presence of a complex karyotype. Though DHLs represent a distinct minority of DLBCLs as a whole, both retrospective and prospective cohorts suggest that DHL constitutes 50% to 75% of cases classified within the BCLu category. Increasingly, the identification of double-hit cytogenetics within a case of DLBCL has prompted hematopathologists to sign out these cases as BCLu rather than grouping them in with traditional DLBCLs, leading to a migration of DHLs out of the traditional DLBCL diagnostic category and into the provisional diagnosis of BCLu. Most recently, however, the WHO has issued a revision of the classification of lymphoid tumors and has eliminated the BCLu category. In recognition of the unique characteristics of DHL, these cases now have a distinct classification known as high-grade B-cell lymphoma (HGBCL), with MYC and BCL2 and/or BCL6 translocations. DEL will still largely be included in the traditional DLBCL, not otherwise specified (NOS) category, although cases with blastoid morphology or other highly aggressive histologic features will be included in a new category of HGBCL, NOS.

DLBCL is commonly subclassified based on cell of origin (COO) as either germinal center B-cell like (GCB) or activated B-cell like (ABC). Though this classification is defined by gene expression profiling (GEP), immunohistochemical correlates are commonly employed as imperfect surrogates for GEP, which can classify cases as either GCB or non-GCB. Nearly all true DHLs will be classified as GCB DLBCL, making them a particularly high-risk subset within the DLBCL COO category typically associated with the more favorable prognosis. Similarly, nearly all cases of DHL will also have immunohistochemical expression of MYC and BCL-2 at the protein level, most commonly defined as MYC expression of at least 40% of cells, and BCL-2 expression in at least 70% of cells. As noted previously, however, most cases with dual MYC/BCL2 immunohistochemical expression will not have true double-hit cytogenetics. In fact, these DEL cases are usually classified as ABC or non-GCB DLBCL. An additional pathologic feature identified in nearly all retrospective analyses in DHL is a high Ki-67 proliferation index with a median typically reported in the 80% to 90% range, and often approaching 100%. A controversial diagnostic question is whether all newly diagnosed cases of aggressive B-cell lymphoma should be evaluated with fluorescence in situ hybridization (FISH) for MYC, BCL2, and BCL6. Among all newly diagnosed lymphomas characterized morphologically and immunohistochemically as BCLu (or HGBCL using the revised 2016 classification), it would be prudent to perform FISH given the high prevalence of double-hit cytogenetics within this cohort. Among DLBCLs, however, the extensive testing of all patients may not be justified given that only a minority will be DHL, and it adds significant cost. Although no single pathologic correlate exists that perfectly predicts for double-hit cytogenetics, it is clear that there is an overall pathologic pattern that tracks with a diagnosis of DHL. As noted, DHL in DLBCL is enriched for GCB cell of origin, MYC and BCL-2 immunohistochemical expression, and proliferation index greater than 80%, although none of these features alone constitutes a definitive rule-in or rule-out test. It is a safe assertion, however, that a newly diagnosed DLBCL with none of these aforementioned features would have an extremely low risk of being a true DHL, and therefore may not justify the additional expense of FISH analysis in this subset of patients.

Clinical features and prognosis in double-hit lymphoma

Clinical features of DHL are summarized in Table 1 . DHL is predominantly a disease of older adults, with a median age in the 60s, although it can occur in both young adults and in the very elderly. The majority of patients will present with advanced stage disease, involvement of extranodal locations, significantly elevated lactate dehydrogenase (LDH), and high-intermediate or high-risk international prognostic index (IPI) score. Among extranodal locations, a high proportion of patients will have involvement of the bone marrow at the time of diagnosis, and this may involve a circulating leukemic phase in the peripheral blood, a finding that is rarely seen in typical DLBCL. Central nervous system (CNS) involvement at diagnosis, or subsequently at relapse, is also increased in DHL relative to other DLBCLs.

Table 1

Clinical and pathologic features of double-hit lymphoma in contemporary series

Series	n	Prior iNHL	GCB (IHC)	DLBCL Morphology	Median Age	Stage III-IV	IPI >1	t-BCL2	t-BCL6	THL	Elevated LDH	>1 EN Site	CNS Involved	Marrow Involved	Leukemic Disease
Abramson et al, 2012	37	27%	NR	38%	63	86%	86%	87%	11%	3%	89%	54%	16%	43%	24%
Copie-Bergman et al, 2015	32	NR	81%	90%	63	84%	84%	NR	NR	NR	75%	56%	NR	30%	NR
Oki et al, 2014	129	11%	93%	65%	62	84%	87%	84%	12%	11%	69%	49%	10%	42%	12%
Petrich et al, 2014	311	22%	87%	50%	60	81%	NR	87%	5%	8%	76%	28%	11%	44%	NR (22% elevated WBC)

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