Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma – Accelerated Phase
The first case in our series on lymphoid neoplasms
Sanam Loghavi, Kamran Mirza, Amy Wang, Sonali M. Smith | | Longer Read
67-year-old woman presented with bilateral neck swelling.
Multicompartmental lymphadenopathy above and below the diaphragm.
Complete blood count and differential (reference range)
Additional laboratory results
Lymph node morphology
Immunohistochemical characterization of neoplastic lymphoid cells
Examination of bone marrow showed extensive involvement by a small B cell neoplasm. Aberrant B cells represented 63 percent of all cells by flow cytometry and were positive for CD5, CD23, and CD200.
Fluorescence in situ hybridization performed on bone marrow
Positive for +12 and del(13q) in 41 percent and 2.2 percent of analyzed interphases, respectively. The TP53 locus was intact.
DNA sequencing studies performed on a bone marrow sample showed unmutated IGHV.
Next-generation sequencing performed on a bone marrow sample showed mutation involving NOTCH1 and BIRC3. TP53 was wild-type.
Chronic lymphocytic leukemia/small lymphocytic lymphoma with increased large cells and proliferation rate (25 percent) suggestive of accelerated phase.
The pathologist’s view
Routine cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) often present little diagnostic challenge. The histopathologic features of most CLL/SLL are typical: a proliferation of small, mature B-cells with irregularly condensed chromatin, dim CD20 expression, CD5 co-expression, light chain restriction, and no evidence of t(11;14). A histologic hallmark of CLL/SLL, particularly when it involves lymph nodes, is the formation of proliferation centers (PCs) characterized by nodular expansions of prolymphocytes and paraimmunoblasts admixed with small lymphocytes.
Richter transformation (RT) is often used synonomously with Richter syndrome, a term used to describe a setting in which a patient with CLL/SLL also develops diffuse large B cell lymphoma (DLBCL), most commonly as a result of histologic transformation of the underlying CLL/SLL to DLBCL. RT is also applicable when CLL/SLL transforms to aggressive lymphoid neoplasms such as Hodgkin lymphoma, plasmablastic lymphoma, or B lymphoblastic leukemia/lymphoma. Though histologic transformation occurs in patients with other types of low-grade B cell neoplasms, the term RT is used solely in the context of CLL/SLL (1).
Clinically, RT is suspected when patients with CLL/SLL develop sudden-onset B symptoms and present with rapid lymph node enlargement (often with radiologic evidence of increased metabolic uptake); it is often confirmed via tissue biopsy. From the pathologist’s perspective, clear-cut CLL/SLL and DLBCL pose little diagnostic challenge – but a grey zone, known as accelerated CLL/SLL or “CLL with expanded proliferation centers,” exists between the two. It is histologically described by the presence of proliferation centers (PC) broader than a 20x field (or 0.95 mm2) and a high proliferation rate (Ki-67 >40 percent or >2.4 mitoses/PC) (2). This phenomenon is histologically distinct from RT, which requires the presence of confluent sheets of large B cells in DLBCL-type transformation or Reed-Sternberg cells in Hodgkin-type transformation. The current case represents an example of CLL/SLL with expanded PCs, as shown by expanded, pale, nodular areas on low-power magnification and increased numbers of paraimmunoblasts within these areas on high-power magnification; however, confluent sheets of large cells are lacking.
Genotypically, a subset of CLL/SLL cases with confluent PCs have been shown to be associated with 17p- and +12 (3). The larger cells in these expanded PCs may express cyclin D1 or overexpress p53 and/or MYC without the associated gene alterations. In this context, cyclin D1 expression does not imply a diagnosis of mantle cell lymphoma (4,5). Nevertheless, performing these in addition to Ki-67 may help highlight the expanded PCs, as is seen in the current case (6). Weak nuclear p53 positivity in a large number of cells in this case is not a manifestation of TP53 alteration.
It is important to recognize and document accelerated-phase CLL/SLL because of the correlation with more aggressive clinical course. Despite application of criteria for accelerated phase, it is often difficult to decide where a case lies on the pathologic spectrum of CLL/SLL to DLBCL. Given the need to see a broad architectural landscape, tissue sampling is extremely important. Smaller core biopsies may miss areas of increased large cells, high mitotic rate, or even overt DLBCL, making excisional biopsies (when possible) the preferred sample type when RT is a clinical consideration.
The hematologist’s view
It is increasingly clear that many hematologic malignancies present along a spectrum reflecting progression from premalignant to malignant to accelerated/aggressive states. This is illustrated by chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL), where the spectrum begins with a monoclonal B cell lymphocytosis at one end and Richter transformation at the other. Despite attempts to “draw the line” with strict diagnostic criteria, there will always be grey areas that challenge an algorithmic approach to diagnosis and treatment.
Clinically, accelerated CLL/SLL is difficult to identify or predict because patients with standard versus accelerated CLL/SLL often present similarly with regard to B symptoms, disease bulk, functional status, or clinical stage. Only LDH and ZAP-70 levels are noted to be higher in accelerated CLL/SLL (2). In contrast, patients with Richter transformation are more symptomatic and have elevated LDH, lower performance status, and high uptake on PET scans.
Accelerated CLL/SLL with expanded or highly active proliferation centers behaves more aggressively than standard CLL/SLL and is associated with inferior survival (3). Although there is limited data, one report showed that median survival from the time of lymph node biopsy was 4.3, 34, and 76 months for Richter transformation, accelerated CLL/SLL, and non-accelerated CLL/SLL, respectively (2). However, this dataset precedes the current era of biologic agents’ use in CLL/SLL, so the survival discrepancies may not be accurate today.
The relative prognostic impact of cytogenetic and molecular factors in accelerated CLL/SLL is also unclear. This patient has trisomy 12 (a more favorable cytogenetic abnormality) but, more importantly, she does not have a TP53 mutation or 17p deletion. Sequencing revealed a NOTCH1 clonal mutation, found in about 20 percent of CLL/SLL patients, that predicts shorter overall survival (7); allelic frequency can potentially be tracked over time to determine the patient’s response to therapy. NOTCH1 mutations are associated with more aggressive disease and RT. The subclonal BIRC3 mutation has no clear prognostic value in her case.
In the era of novel targeted agents and immunotherapy, we have seen major paradigm shifts in CLL/SLL management over the past five years, with chemoimmunotherapy largely replaced by bruton tyrosine kinase (BTK) inhibitors, BCL2 inhibitors, and potent monoclonal antibodies against CD20. Are these agents and regimens equally effective in accelerated CLL? Should accelerated CLL be treated like RT or standard CLL? Given the poor prognosis relative to standard CLL/SLL, should treatment be initiated when patients are asymptomatic? Unfortunately, prospective studies on management of accelerated CLL/SLL are lacking, so it is often treated like standard CLL/SLL by default.
For this patient with a confirmed diagnosis of accelerated CLL/SLL, we recommend treatment initiation given the new adenopathy, elevated LDH, and overall high tumor burden with extensive marrow involvement. However, a period of very close observation is also reasonable, especially because we do not know whether early treatment impacts survival. Our preferred option is a limited-duration regimen of venetoclax plus obinutuzumab, which is associated with an 85 percent overall response rate (8) and 82 percent three-year progression free survival in standard CLL/SLL (7). Reflecting the lack of directly comparative data, continuous use of a BTK inhibitor is also reasonable. There is an ongoing study evaluating the role of a limited-duration triplet regimen (ibrutinib, venetoclax, obinutuzumab, NCT03701282), but it will be several years before results are available. Overall, this patient has a much more aggressive disease than standard CLL/SLL, but it is not RT, and our personal experience is that novel agents offer excellent disease control. Going forward, clearly defined parameters and treatment data for accelerated disease will be essential.
Read on to discover our other lymphoid cases...
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- RLMC Agbay et al., “Histologic transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma,” Am J Hematol, 91, 1036 (2016). PMID: 27414262.
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- SE Gibson et al., “Proliferation centres of chronic lymphocytic leukaemia/small lymphocytic lymphoma have enhanced expression of MYC protein, which does not result from rearrangement or gain of the MYC gene,” Br J Haematol, 175, 173 (2016). PMID: 26568397.
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- K Fischer et al., “Venetoclax and obinutuzumab in patients with CLL and coexisting conditions,” N Engl J Med, 380, 2225 (2019). PMID: 31166681.