Hairy Cell Leukemia Following a Diagnosis of Breast Cancer: Is There a Relationship?

Joshua D. Rosenberg, MD, and Alan Saven, MD

Clinical Advances in Hematology & Oncology

July 2013, Volume 11, Issue 7



Hairy Cell Leukemia Following a Diagnosis of Breast Cancer: Is There a Relationship?

Joshua D. Rosenberg, MD, and Alan Saven, MD

Division of Hematology and Oncology, Scripps Clinic, La Jolla, California

Hairy cell leukemia (HCL) is a rare, indolent, B-cell lymphoproliferative disorder that is characterized by pancytopenia, absolute monocytopenia, splenomegaly, and recurrent infections. Bouroncle1 first described this clinical entity, which she termed leukemic reticuloendotheliosis, in 1958. Schrek and associates2 further defined the morphology of HCL by describing abnormal mononuclear cells with their elongated, thin cytoplasmic projections, which they termed hairy cells. There is a strong male predominance of 3.44 to 1.3 Jewish men have a significantly increased risk of HCL compared to Protestant men, although no increased risk was seen for Jewish women.4 More recently, whole-exome gene sequencing has identified the BRAF V600E mutation in most HCL patients, suggesting disease-specific oncogene dependence.5

HCL remains a largely incurable, though highly treatable, disease.6 Generally, treatment is started in symptomatic patients or those with significant cytopenias, including hemoglobin less than 10 g/dL, platelet count less than 100 × 109/L, and/or neutrophils less than 1.0 × 109/L. 7 Splenectomy was the treatment of choice until the mid 1980s. Quesada and colleagues were the first to describe responses induced by interferon α in HCL patients, although further studies revealed a disappointingly low incidence of complete response, as well as a brief response duration.8,9 Subsequently, 2 nucleoside analogues, 2’-deoxycoformycin (pentostatin) and 2-chlorodeoxyadenosine (cladribine), were both found to induce long-lasting complete remissions in the majority of HCL patients.9-11

Mikler and coworkers report the diagnosis of HCL in a 65-year-old woman more than 2 decades after an initial diagnosis of invasive breast cancer.12 She was originally treated with 2 anti-metabolites and an alkylator, followed by a platinum and taxane at disease recurrence approximately 2 years predating her HCL diagnosis. The risk of second malignancies in patients with HCL has been published with widely varying results. The majority of studies have focused on second malignancies following the diagnosis of HCL. Au and associates reported on second cancers in as many as 31% of HCL patients followed for 20 years in British Columbia.13

Three reports11,13,14 have suggested an increased incidence of second malignancy, while 2 other studies do not corroborate these findings.15,16 Risk factors for developing a second malignancy following the diagnosis of HCL are thought to include a lower median age at diagnosis, coupled with longer survival rates with contemporary treatment.4 The oncogenic effect of systemic therapy has been questioned as well.17 Chronic lymphocytic leukemia, a much more common lymphoproliferative disorder, has also been associated with an increased incidence of secondary neoplasms.18 However, these explanations do not account for patients diagnosed with primary cancers prior to their HCL diagnosis.

Three studies suggest a greater risk of a different primary cancer predating the diagnosis of HCL. In an epidemiologic study of HCL in Los Angeles County, 27% of patients had another primary malignancy diagnosed at least 1 year prior to their HCL diagnosis, including 4 female patients diagnosed with breast cancer. HCL patients were more than twice as likely as other cancer patients to have an additional malignancy.4 A population-based study of HCL in Israel identified 6% of patients with a cancer diagnosed before their HCL. In the 2 female patients with a cancer antecedent to their HCL, both were diagnosed with breast cancer.19 In the Scripps Clinic experience, 11% of patients were diagnosed with an antecedent malignancy predating cladribine treatment for HCL. In this single-institution series, 3 women had a prior diagnosis of breast cancer.17 Of note, those patients with a malignancy predating their HCL diagnosis had a 3.7-fold increased risk of developing an additional malignancy compared with those who did not.11 There is no information regarding what these breast cancer patients received in terms of systemic therapy. Bernstein and associates proposed that patients who develop HCL may have an underlying, impaired immune function, which may be partly responsible for malignancies predating HCL.4 It has been postulated that impaired T-cell function and deficient natural killer cell activity may compromise immune surveillance and thereby predispose patients to second malignancies.20,21

The report by Mikler and colleagues12 correctly specifies that no causal association has been directly identified between the systemic agents this patient received for her invasive breast cancer and the subsequent development of HCL, though studies have clearly linked breast cancer therapy with treatment-related acute leukemia and myelodysplastic syndromes.22,23 While it is impossible to rule out her prior systemic therapy being the etiology predisposing her to HCL, it seems more probable that this reflects a de novo HCL diagnosis. We agree with their decision to withhold therapy and instead perform active surveillance in this HCL patient without current treatment indications.


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