B-cell hairy cell leukemia (B-HCL)

HAIRY CELL LEUKEMIA (HCL) / TRICHOLEUKEMIA / LEUKEMIC RETICULOENDOTHELIOSIS (95 % of all HCLs): a form of (indolent) chronic leukemia

Cawley variant (type II HCL) (identified in 1980) : splenomegaly > 20 cm below ribs, normal neutrophil and monocyte counts, preserved bone marrow hematopoiesis, larger and shorter villi, recovery with IFN-g therapy
Katayama variant (identified in 1983): no TRAP, no villi^ref
hairy-cell leukemia-variant (HCL-V) is a rare B-cell disorder which accounts for 10% of HCL cases (CD11c⁺25^-103⁺)

Aetiology :

familial HCL is rarely encountered among the first degree relatives of HCL patients. A father and son, both of whom developed hairy cell leukemia, is presented in this report. The HLA haplotype shared by the father and son was A2, B18, BW6, CW7, DR3, DR10, and DQ8. Among these haplotypes, HLA A2 and Bw6 have previously been reported^ref

Symptoms & signs : maculopapular rash (5%), ecchymoses and purpura (20%), bronchopulmonary infections (30%), massive splenomegaly

(90%) => occupation syndrome (20-40%), mild hepatomegaly (50%), osteolysis (3%). Superficial lymphadenomegaly is rare, while splenic hilar lymphadenopathy is commonly seen at abdominal CT. Association with other autoimmune disorders such as vasculitis

(expecially giant cell arteritis

), glomerulonephritis

, and AIHA

. Jansen staging, 1982 :

stage I :

HGB > 12 g/dl + splenomegaly < 10 cm
HGB 8.5-12 g/dl + splenomegaly < 4 cm

stage II :

HGB < 12 g/dl + splenomegaly > 10 cm
HGB 8.5-12 g/dl + splenomegaly 4-10 cm

stage III

HGB 8.5-12 g/dl + splenomegaly > 10 cm
HGB < 8.5 g/dl + splenomegaly > 4 cm

Laboratory examinations :

leukopenia (< 3,000/ml in 80%, < 1,000/ml in 20%; monocytopenia , neutropenia and eosinopenia ) with mild lymphocytosis (hairy cells 10-30% of WBCs). The white blood cell count rarely goes above 20 x 10⁹/L but neutropenia and monocytopenia are constant features (Catovsky D. Chronic lymphoid leukaemias. In: Hoffbrand AV, Lewis SK Tuddenham EG, eds. Postgraduate haematology, 4th ed. Oxford: Butterworth-Heinemann 1999:405–33)
anemia (< 8.5 g/dl in 60%; median : 9.5 g/dl)
thrombocytopenia (< 100,000/ml in 80-90%, < 50,000/ml in 40%)
polyclonal hypergammaglobulinemia (20%); hypogammaglobulinemia is unusual
transaminitis (20%)
cytomorphology : abundance of abnormal large mononuclear cells covered by hairlike villi (hairy cells) (absent in Katayama variant) in the bone marrow, spleen, liver, and peripheral blood
cytogenetics : trisomy 12, 14q+
cytochemistry : hairy cells are diffusely and strongly positive for tartrate-resistant acid phosphatase (TRAP)^ref (negative in Katayama variant). LAP elevated in 74%, normal in 26%^ref
bone marrow biopsy : although circulating cells and clinical setting are similar to SMZL , in the bone marrow, hairy cells produce patchy infiltration with progressive replacement (60-90%) of normal hematopoietic series and low cellular density. Neoplastic infiltration is characteristically intermingled with extravasated red cells. The reticulin fiber content is almost invariably increased (spongy lymphoid myelofibrosis) and accounts for the high frequency of "dry taps".

immunocytochemical detection of annexin A1 (ANXA1)^ref

in the spleen, HCL diffusely involves the red pulp, whereas the white pulp is atrophied.
ultrastructural analysis shows characteristic ribosome-lamella complex in hairy cell cytoplasm.
immunophenotype (CD5^-10 / CALLA^-11c^hi19⁺20⁺23^-25⁺27^-^ref52^+ref103⁺, FMC7⁺, sIg⁺, cIg⁺)
k (60%) > l (40%)
IgG (50%) > IgM (25%)
V_H gene analysis reveals a homogeneous mutation status and suggests its marginal zone B-cell origin^ref

Differential diagnosis : SMZL

Therapy :

cladribrine / 2-chlorodeoxyadenosine (2-CdA) : 0.1 mg/kg/day IV continuous infusion days 1-7. Administer 1 cycle. Neutropenia grade 3 (16%) or 4 (71%) in first 135 consecutive patients treated, anemia grade 3 (20%) or 4 (2%), neutropenic fever (42%), documented infections (13%), thrombocytopenia (20%) => infectious mortality (1%), viral reactivation (3%). Emetogenic potential days 1-5 level 1^ref
IFN-a_2b : 2 MIU/m2 subcuteneously 3 times a week (escalation to 10 MIU/m² for nonresponders). Appropriate premedications. Grade 3 flu-like symptoms (19%), injection-site reaction (3%), CNS and PNS (2%), skin disorders (2%). Emetogenic potential level 1^ref
pentostatin / deoxycoformicin produces initial responses rates as high as 96%^ref
GR agonists are not effective

Codiagnosis :

HCL and polycythaemia rubra vera (PRV); however, in this patient, HCL occurred after the treatment of PRV with radioactive phosphorus^ref. Kampmeier et al described one case of PRV that followed the treatment of HCL with interferon; however, no cytogenetic abnormalities were found^ref
HCL and CML ^ref1,
ref2

Prognosis : causes of death

bronchopulmonary infections and septicemia (60-70%)
cerebral hemorrhages (10%)
cardiac heart failure (5-10%)
spleen rupture (0.5%)
necrotizing vasculitis (0.5%)
the incidence of second malignancies in HCL is reported as 8.7%^ref. Most of the second malignancies occurring in HCL are either solid tumours or other lymphoproliferative disorders, most commonly large cell lymphoma, but also multiple myeloma and T cell leukaemia/lymphoma^ref. HCL => CML ^ref (cytogenetics confirmed the t(9;22) translocation. The patient ultimately developed ALL with additional chromosome abnormalities). There are reports that prolonged interferon treatment leads to an increased incidence of second malignancies in HCL. Kampmeier et al reviewed 69 patients with HCL who were given interferon and found that 6 patients developed haematological malignancies^ref. 3 patients had malignant lymphoma, one patient developed acute myeloid leukaemia , and one developed PV . However neither no patient received IFN-a^ref. The study of Jacobs et al revealed 2 patients with HCL and haematological malignancies who had received chlorambucil^ref. A patient was treated with deoxycoformycin. Therefore, factors that lead to the development of second malignancies in HCL remain to be determined. It is possible that CML might have had its origin even before HCL was diagnosed in our patient; CML might have a prolonged silent or quiescent phase during which it can be cytogenetically detected despite an apparently normal blood count and film

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