‘Hairy’ cells: where are the roots of this leukemia?

Hairy cell leukemia (HCL) is a rare but distinct indolent lymphoproliferative disorder with characteristic clinical and laboratory features and an excellent prognosis with appropriate therapy. Patients display typical neoplastic cells in the blood and bone marrow with or without cytopenia, splenomegaly, and immune incompetence [1,2]. Unique features include the well-recognized male to female ratio of 4:1, which is the highest among the lymphoproliferative disorders (LPD), and its typical cytology, histopathology, and immunohenotype, which are clearly diagnostic of the disease [3]. In recent years the explosion of genetic research has identified new characteristic abnormalities for most types of leukemia, yet this was not the case for HCL, which still remains in the shadows. Because of impressive advances in the understanding of the biology of other leukemias [4], a wide variety of targeted therapies are currently being evaluated, so far with limited success except in chronic myeloid leukemia. Nevertheless, in contrast to other leukemias, during the 1980s and 1990s HCL became the disease with the best track record of therapeutic success, basically without any additional knowledge concerning the possible pathogenesis or specific targets involved. Following its first comprehensive description by Bouroncle et al. in 1958 [1], HCL was recognized as an indolent LPD but with poor survival due to accompanying infectious complications and poor response to the available chemotherapy [5]. Splenectomy and no chemotherapy was then regarded as the best choice of treatment [6]. Thereafter in the 1980s several opportune observations placed HCL on the map for successful development of therapies, and it became the first approved indication for three drugs, recombinant interferon- α, deoxycoformycin (pentostatin), and 2-chlorodeoxyadenosine (cladribine) [7]. Using the latter two drugs in particular, impressive responses and complete remissions were achieved with dramatic improvement of outcome and overall survival. HCL is now regarded as a triumph of effective therapies, and although not often curable, a prolonged life without symptoms and further therapy can generally be expected.

What is known about HCL and its pathophysiology today since the historic debate in the 1970s about the cellular origin of the hairy cell? We now know that hairy cells are activated differentiated clonal B-cells with a gene expression indicative of post-germinal memory B-cells [8]. Recently, Kreitman et al. reported that most (83%) patients with classical HCL had immunoglobulin gene heavy chain variable domain (IGHV) mutations, whereas the even rarer but problematic variant form of HCL, which is more difficult to treat, was mostly of the unmutated type [9]. Furthermore, in chronic lymphocytic leukemia (CLL) there is a biased utilization of IGVH genes and clusters of quasi-identical stereotypic IG gene rearrangements, suggestive of an antigen-driven pathogenesis whereby the immunoglobulin may be directed toward cytoskeleton proteins exposed in apoptotic cells or bacterial products [10]. Interestingly, a similar preference of IGVH genes is seen in HCL, such as VH1-69 and 3-23, but sometimes with different clinical implications: VH4-34 identifies a CLL subset with very good prognosis, whereas in HCL VH4-34 is most common in the variant form with poor prognosis [9,10].

Indeed, one can now ask: who in fact gets HCL? Only a few epidemiologic studies relating to the etiology of the disease have been performed. In general the median age is just over 50 years [1]; however, in Sweden, population-based registries show that not all patients with HCL are young, and the median age is a little over 60 years, similar to that of follicular lymphoma [11]. The male incidence in the age group 30–50 years is about 3/million/year, while in ages 50–70 years it is about 10/million/year, increasing to 15–20/million at older ages [11]. There have been some studies relating to occupational and environmental risk factors in HCL that did not demonstrate an unequivocal increased risk in cattle farmers or with exposure to pesticides, petroleum products, diesel, and ionizing radiation [12,13], and there appears to be a decreased risk of HCL in smokers in France [14]. In this issue of Leukemia and Lymphoma, Aristeguieta reports an unusual cluster of three coal-miners exposed to coal dust and diesel during 6–14 years in a small geographical area who developed HCL within a 10-year period [15]. This has never been described in association with HCL until now, but was reported to play a possible role in the development of gastric and lung cancer [16]. Such an association does not necessarily imply causality, but represents an interesting observation which could be significant in terms of pathogenesis in these cases. In this context it is interesting to note that a novel mineral dust-induced gene, mdig, was identified recently and found to play a role in the regulation of cell growth and possibly the development of cancer. It is still unknown whether there are other genes that can be regulated by mineral dusts and associated with carcinogenesis [17]. With the developing interest in a possibly antigen-driven etiology of lymphoproliferative disorders, further studies on various exposures combined with genome-wide polymorphism analyses could be a future research area of interest. The Hairy Cell Leukemia Consortium (www.hairycell.org) was founded in 2008 on the 50-year anniversary of description of the disease to encourage research activity, which had significantly declined since the advent of successful routine management with new therapies in the 1990s. However, there are still patients with HCL with advanced refractory disease, and eradication of the disease is rare. We believe that continuing research on HCL can still provide new biological insights to improve not only the outcome for future patients with HCL but also our understanding of pathophysiological mechanisms involved in lymphoproliferative disorders, as well as identify new targets for future treatment of the disease.

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