Hairy cell leukemia variant (ORPHA:300878)
A rare, malignant splenic B-cell lymphoma/leukemia characterized by circulating abnormal lymphocytes with intermediate morphology between prolymphocytes and hairy cells with positive expression of CD11c and negative expression of CD25, CD123 and the BRAFV600E mutation. Manifestations include splenomegaly, elevated white blood cell (WBC) count, hyper-cellular bone marrow and anemia/thrombocytopenia, but no monocytopenia.
Epidemiology
Hairy cell leukemia variant (HCL-V) constitutes about 10% to 20% of patients with hairy cell leukemia (HCL) and 0.4% of all lymphoid malignancies. There is a slight male predominance (male/female: 1.6).
Clinical description
HCL-V onset is in adulthood, most frequently in the elderly population (median age: 71 years). Initial manifestations are typically of abdominal discomfort or distension, usually related to splenomegaly, hepatomegaly and manifestations derived from cytopenias such as anemia, bleeding and/or infections. HCL-V is more aggressive and resistant to therapy than classical HCL (HCL-C). A disease closely resembling HCL-V has been described in Japan and has been called the HCL Japanese variant (HCL-Jv).
Etiology
The etiology is unknown but there is no evidence of an association between exposure to carcinogens, radiation or viral infections. P53 dysfunction, due to either monosomy, monoallelic deletion or a TP53 mutation (17p13.1), has been reported in many patients (estimate 30% of patients) as well as mutations in the gene  MAP2K1 (15q22.31) (estimate 50%). The VH gene family, IGHV4-34, appears to be over-expressed, but is also found in other B-cell malignancies. HCL-V is not considered to be biologically related to HCL-C, and HCL-V patients are negative for the BRAF-V600E mutation.
Diagnostic methods
Diagnosis is suspected on physical examination, bone marrow biopsy, and abdominal computed tomography (CT) scan, as well as laboratory tests which show raised white blood cell count (>10×109/l). HCL-V cells do not demonstrate reactivity to annexin A1 and are either weakly positive or negative for tartrate-resistant acid phosphatase (TRAP). HCL-V cells are negative for BRAFV600E mutation. The diagnosis of HCL-V is confirmed by flow cytometry immunophenotyping (positive for CD11C, and negative for CD123 and CD25 with variable expression of CD103, CD19, CD20, and CD22).
Differential diagnosis
Differential diagnosis includes splenic marginal zone lymphoma, splenic diffuse red pulp lymphoma (SRPL), HCL-C, mantle-cell lymphoma, and B-cell prolymphocytic leukemia (B-PLL).
Management and treatment
Asymptomatic patients with moderate splenomegaly and no cytopenias may be managed with close monitoring. Therapy is indicated for symptomatic disease (progressive splenomegaly and/or elevated lymphocyte counts with cytopenias). There are no formal guidelines for management and treatment, and information on the efficacy of the various agents is derived from the results on small series of patients or single case reports with limited follow-up. Splenectomy has been utilized in some patients resulting in improvement in anemia and thrombocytopenia; however, the response eventually results in progressive disease. A combination of purine analog (cladribine) and a monoclonal anti-CD20 antibody has resulted in complete remission in patients treated (although follow-up is limited). Immunotherapy alone may be considered and include rituximab (successful treatment in several case reports), and anti-CD22 recombinant immunotoxins (response observed in a limited number of patients but relapse reported). Treatment with interferon alpha and purine analogs alone is unsatisfactory and fails to achieve a durable, high complete remission rate.
Prognosis
HCL-V is an aggressive disorder with a chronic clinical course. The reported survival at five years is approximately 60%; however, complete remission has been reported, in particular with combined purine analog and rituximab treatment or immunotherapy alone. In general, significant anemia, older age, and mutations in TP53 are associated with a worse prognosis.

                            Last update: 
                            April 2020


                            - Expert reviewer(s): 
                            Dr Michael GREVER