With the advent of various new chemotherapeutic agents, the survival of patients with HCL has greatly improved; however, population-based studies have highlighted an increased risk of second malignancies on long term follow-up in such patients. Among these, Hodgkin lymphoma, non-Hodgkin lymphoma, and thyroid cancer are common second malignancies [2]. Occasionally, synchronous occurrences of HCL with other hematolymphoid neoplasms at the time of diagnosis have been reported [3456789101112]. Among these, B-cell lymphomas, followed by T-cell lymphomas and myeloid malignancies are common types. These second malignancies most frequently coexist with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), although only a few case studies have been reported.

Here, we report a case of HCL with a synchronous clone of CLL/SLL cells in peripheral blood and bone marrow in a patient with splenomegaly and pancytopenia.

The patient was 75-year-old male with history of generalized weakness, loss of weight and appetite along with early satiety, and abdominal distension over a 3-month period. On examination, there was sub-centimetric axillary and inguinal lymphadenopathy along with hepatosplenomegaly. Complete blood count (CBC) analysis revealed pancytopenia (hemoglobin, 6.4 g/dL; total leukocyte count, 4.1×10⁹/L; absolute neutrophil count, 0.94×10⁹/L; and platelet count, 60×10⁹/L). The peripheral blood smear had predominantly mature-appearing lymphocytes (77%). However, some of these cells (approximately 5%) had a moderate amount of cytoplasm with fine hairy circumferential projections (Fig. 1A). The aparticulate and hemodiluted bone marrow aspirate predominantly showed lymphocytes and a few (13%) “hairy” cells. Flow cytometric immunophenotyping of the bone marrow aspirate revealed two populations of CD19 bright positive cells. The larger population (approximately 36%) was positive for CD5, CD23, CD20, CD43, and CD200 along with weak lambda light chain restriction, and was negative for CD79b, CD10, and FMC-7, consistent with a phenotype of CLL/SLL. A smaller proportion (approximately 6%) of CD19 bright positive cells displayed positivity for CD20, CD11c, CD103, CD25 and lambda light chain restriction, indicative of a phenotype of HCL (Fig. 2). The trephine biopsy section had lymphoid infiltrates. The marrow spaces were hypercellular with extensive interstitial infiltration by characteristic “hairy” cells having abundant cytoplasm and distinct cell borders, giving them a “fried egg” appearance (Fig. 1B). In addition, there were multiple well-defined interstitial nodules of mature-appearing lymphoid cells. The characteristic pericellular distribution of fibrosis seen in HCL was identified in the interstitial infiltrates on reticulin stain. On immunohistochemistry, the two distinct populations were well characterized with the lymphoid nodules showing positivity for CD5 and CD23 (Fig. 1C, D) and the hairy cells showing positivity for CD20 and DBA.44 (Fig. 1E, F).

The diagnosis of a composite lymphoma-predominant HCL with a minor clone of CLL/SLL was made. The patient declined therapy.

HCL is an indolent B-cell neoplasm with a good prognosis due to the availability of effective therapeutic agents [2]. Although metachronous lymphomas and malignancies have been well characterized in HCL patients undergoing chemotherapy, synchronous hematolymphoid malignancies have rarely been reported as case reports. Among the synchronous hematolymphoid malignancies, CLL [341112], multiple myeloma [5], chronic myelogenous leukemia [6], peripheral T-cell lymphoma [7], large granular lymphocytic leukemia [8], Hodgkin lymphoma [9] and hepatosplenic T-cell lymphoma [10] have been reported. CLL has an unusual propensity for being one of the components for reasons that remain unclear.

To the best of our knowledge, only five cases of synchronous HCL with CLL/SLL have been reported. Giné et al. [3] reported two cases of synchronous and one case of metachronous CLL with HCL. This combination may in fact be rare, or is being missed, and therefore under-reported. The salient clinico-pathologic features of the reported cases are compared with the current case in Table 1.

All six cases occurred in elderly males, with mild to moderate splenomegaly and asymptomatic lymphadenopathy, bi-/pancytopenia, and a predominant HCL population in trephine biopsy. Four of the cases had relative lymphocytosis. Immunoglobulin heavy chain gene rearrangement studies at the time of diagnosis were performed in cases 2 and 5 and revealed two clonal bands, whereas for cases 1 and 4, this was performed post-chemotherapy and showed one and two bands, respectively. The presence of BRAF V600E and RB1 (L343fs^*6) mutations in distinct clonal populations of HCL and CLL, respectively, was demonstrated in case 5. Because of cytopenia/symptomatic organomegaly, cases 1 to 5 were initially treated with 2′-Deoxycoformycin (dCF)/2-Chlorodeoxyadenosine (2-CdA) chemotherapy regimen for the HCL component and showed a good clinical and hematological response, but the CLL/SLL clone was still detectable on flow cytometry/molecular studies. After completion of chemotherapy, case 3 showed progression in the form of severe anemia due to CLL infiltration in the bone marrow, and was then treated with rituximab, and became stable. Our patient did not opt for therapy.

In these cases, there was a predominant component of HCL, persistence of CLL/SLL component post-chemotherapy, and presence of either a single clone or two different clones giving rise to two distinct neoplastic populations. The clonal origin of these cells was established only in two cases and was not available in other cases at the point of diagnosis; hence, making it unclear as to whether the same or a different clone gave rise to two different neoplastic cell populations.

The favored cell of origin in HCL is the post-germinal center memory B-cell [13] whereas for CLL, this remains unclear. Germinal-center experienced cells or memory-like B cells generated in a T cell-independent reaction have been shown to be the initiating cells for CLL pathogenesis [14]. It can only be conjectured as to which came first, either HCL or CLL, and whether the CLL clone gave rise to HCL or vice-versa, as both can also arise from post-germinal center cells. Either one could have contributed to the occurrence of the other because of associated impaired immune surveillance in patients with lymphoid neoplasms [15]. Patients with two clones initially may show differential response to chemotherapy with the susceptible clone rendered undetectable and the less susceptible clone proliferating and dominating over time. This is unlikely in the pathogenesis of the index case since the patient was naïve to lymphoreductive therapy. Further studies would be helpful to elucidate the pathogenetic mechanisms of the evolution of these clonal neoplasms. CLL can be detected early, even without organomegaly and before the anemia and thrombocytopenia supervene due to lymphocytosis. Concurrent HCL with marrow fibrosis in this case may have contributed to the lack of absolute lymphocytosis.

To conclude, this case highlights a rare association of the two B cell lymphoid neoplasms detected from marrow infiltrates. This case adds to the existing pool of cases with synchronous HCL and CLL, highlights the power of flow cytometry in identifying them with certainty, and underlines the need for detection of as yet unknown pathways in the pathobiology of lymphoid neoplasms.