University of Virginia Health System

Hairy Cell Leukemia

(a) Hairy cell leukemia with round nucleus- Peripheral blood smear, Wright-Giemsa stain, 1000x

(b) Hairy cell leukemia with oval nucleus- Peripheral blood smear, Wright-Giemsa stain, 1000x

(c) Hairy cell leukemia with reniform nucleus- Peripheral blood smear, Wright-Giemsa stain, 1000x

(d) Hairy cell leukemia with characteristic honeycomb appearance on a bone marrow biopsy- Bone marrow biopsy, H&E stain, 500x

(e) Hairy cell leukemia variant- Peripheral blood smear, Wright-Giemsa stain, 1000x

Introduction: 

Hairy cell leukemia (HCL) was so named because of the unique appearance of the clonal cells by light microscopy and transmission electron microscopy. Initial reports of the disorder appeared under various designations: leukemic reticuloendotheliosis, lymphoid myelofibrosis, malignant reticulosis, medullosplenic histiolymphocytosis, chronic reticulolymphocytic leukemia, aleukemic reticulosis. These terms reflect the initial belief that the disorder was of reticulum (histiocyte) origin. The disorder was characterized as a distinct entity from a publication by Bauroncle BA, Wiseman BK, and Doan CA (Blood 13:609, 1958). Multiple other studies have established that HCL is of B cell origin representing proliferation of cells at a late stage of B cell differentation. The finding of clonal cases expressing either IgG, IgA, IgM, or IgD support a stage that is post-germinal center, and just prior to differentiation to plasma cells.

Description:

The morphologic appearance of hairy cells on a Wright-Giemsa stain is essentially diagnostic (a,b,c.) The cells are larger by 1½-2 times those in B-CLL or mantle cell leukemia, have more abundant cytoplasm, and the nuclear chromatin is much less clumped and lighter staining. The nuclei vary in size and may be round (a), oval (b) or reniform (c), and nucleoli usually are not visible. The cytoplasm is mostly grey, but may have a light blue-grey color. The characteristic and near pathonomonic feature is the fine hair-like cytoplasmic membrane projections which are circumferential and variable in size.

On a bone marrow biopsy, the pattern of infiltration usually is diffuse, but may be patchy and gives a "honeycomb" appearance with the nucleus of each hairy cell surrounded by a halo of cytoplasm, resembling "fried eggs" (d). Another characteristic finding is reticulin fibrosis as revealed by a reticulin stain. This feature probably explains the frequent failure to obtain an adequate aspirate ("dry tap".)

Two variant forms of HCL have been well characterized; a blastic form (see under ALL) and a subtype referred to as "a variant HCL". The variant form (e) is characterized by clonal cells that are usually slightly larger than classic hairy cells, the cytoplasm is basophilic (blue) in contrast to the grey cytoplasm in classic hairy cells, and prominent nucleoli are often visible.

Cytochemistry:

Prior to the availability of immunophenotyping, a positive tartrate-resistant acid phosphatase (TRAP) stain was considered confirmatory if the leukemic cells had the classic hairy cell appearance. An important finding on the TRAP stain was that the staining was actually brighter when tartrate was added (Yam LT, et al. Leukemia 1:285, 1987). The tartrate-resistant bright staining for acid phosphatase is due to the increased expression of isoenzyme 5 of acid phosphatase in the cytoplasm of hairy cells.

Immunophenotype:

The characteristic and essentially diagnostic profile is CD19+, CD123+, CD103+, CD11c+ (strong). CD25+, FM7+, and SIg+ (strong). CD5 and CD23 are negative, and CD10 is usually negative. The SIg heavy chain may be IgG, IgA or IgM, indicating a stage in B cell differentiation after antigen exposure and heavy chain class switching.

Cytogenetics:

No signature cytogenetic abnormality has been identified. Mutations involving the p53 gene are found in more than 75% of cases (Vallianatou K, et al. Leuk Res 23: 1041, 1999.)

Clinical and Laboratory Manifestations:

The classic presentation is a variable pancytopenia, splenomegaly, and absence of lymphadenopathy in a male in his mid-50s (male:female ratio is approximately 5:1.) The bone marrow is always involved and hairy cells are found in the peripheral blood in 90% or more of cases. A unique feature is monocytopenia seen in 90% or more of cases. Lytic bone lesions and involvement of other organs (e.g. skin) is distinctively unusual (<5%.)

The clinical manifestations are related to the splenomegaly and cytopenias. An increased incidence of autoimmune disorders, especially vasculitis has been observed. Infections are frequent manifestations, and especially with mycobacterial organisms.

The manifestations are similar in the variant form except for a usually much higher lymphocytosis, and CD25 is usually negative.

Differential Diagnosis:

The appearance of hairy cells on a Wright-Giemsa stain leaves little reason to formulate a differential diagnosis. From a clinical standpoint, however, there are several entities characterized by splenomegaly and a variable pancytopenia that can mimic HCL.

• Splenomegalic lymphoproliferative disorders
• Splenic marginal zone lymphoma- The morphology of the splenic marginal zone (monocytoid B) cells on a Wright-Giemsa stain are quite distinctive. The cells are large, about 1½-2 times the size of normal small lymphocytes with rather abundant grey to grey-blue cytoplasm and without cytoplasmic membrane projections. The nuclear chromatin is mature with variable clumping, and nucleoli may be present. Immunophenotype is similar except CD103 is usually negative.
• Splenic lymphoma villous lymphocytes- In contrast to HCL cells, the lymphocytes are small with scant grey to grey-blue cytoplasm, the membrane projections are polar in distribution, and do not express CD103.
• A subset of B-CLL and mantle cell leukemia-lymphoma presents with splenomegaly as the major clinical manifestation. The morphology of the clonal B cells are distinct from HCL cells, and both express CD5, and again CD103 is negative. To distinguish between mantle cell and small B-CLL requires immunophenotyping, and sometimes cytogenetics. Mantle cells express FMC7 and are negative for CD23 while the opposite occurs with B-CLL.
• Prolymphocytic B or T cell leukemia- The presence of a marked lymphocytosis with morphologically typical prolymphocytes defines these entities. Immunophenotyping is needed to distinguish the B-PLL from the T-PLL.
• Large granular lymphocyte syndrome (leukemia.) The morphologic features on light microscopy (large lymphocytes with abundant cytoplasm and azurophilic granules) serves to differentiate this entity. Splenomegaly usually is not as pronounced. To confirm and differentiate between the NK and T cell subtypes requires immunophenotyping and molecular genetic analysis.
• Splenomegaly and cytopenias due to congestive splenomegaly (e.g. intrinsic liver disease, portal or splenic vein occlusion.) The absence of lymphocytosis or atypical lymphocytes on a peripheral blood smear, and the absence of clonal lymphocytes in the peripheral blood or bone marrow essentially eliminates a lymphoproliferative process as the etiology of the splenomegaly. An MRI with vascular phases will differentiate between intrinsic liver disease and venous occlusions.
• Myelofibrosis with myeloid metaplasia (chronic idiopathic myelofibrosis)- The finding of leukoerythroblastosis and teardrop red cells on a peripheral blood smear is highly suggestive of this disorder, particularly if thrombocytosis is also present. The diagnosis is established by bone marrow biopsy revealing myelofibrosis, usually collagenous fibrosis, and the presence of atypical megakaryocytes with a tendency to cluster.
• Systemic mast cell disease with or without splenomegaly- The pattern of bone marrow involvement on a bone marrow biopsy specimen may have a "honeycomb" appearance, very similar to HCL. The pattern is usually spotty and not diffuse. Demonstration that the infiltrating cells are mast cells by immunohistochemistry (e.g. tryptase and CD117 positivity) establishes the diagnosis.
• Other causes of massive splenomegaly with variable cytopenias such as storage diseases (e.g. Gaucher's disease) need to be considered if a diagnosis is not established by the peripheral blood findings including immunophenotypic studies.

Prognosis:

Prior to the availability of interferon-α, and later the purine analogues (pentostatin and cladribine,) chemotherapeutic agents that were effective in other lymphomas and leukemias demonstrated very little to no activity in HCL. Splenectomy, especially in those patients with massive splenomegaly, usually resulted in a resolution of the cytopenias and other manifestations of massive splenomegaly (e.g. hypermetabolism, early satiety), and many patients would often survive for 10 years or more, relatively asymptomatic. With the purine analogues, 90% or more of patients achieve a complete remission which is sustained in a majority for long durations with many probably cured (Else M, et al. Cancer 104:2442, 2005.) Response to purine analogues in the variant form is poor. Response to purine analogues seems to correlate with expression of CD25 on the cells. If absent, response is poor. 

General References:

• Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. Pathology and genetics of tumours of hematopoietic and lymphoid tissues. Vol. 3 of World Health Organization classification of tumors, Lyon, France: IARC Press, 2001
• Hess CE. Hairy cell leukemia, malignant histiocytosis, and related disorders. In Lee CR, Bithell TC, Foerster J, et al (eds). Wintrobe's Clinical Hematology, 9th ed. Philadelphia, Lea and Febiger, 1993, pp 2170-2201.
• Wanko SO, DeCastro C. Hairy cell leukemia: an elusive but treatable disease. The Oncologist 11:780, 2006
• Saven A (ed). Hairy cell leukemia. Hematol-Oncol Clin N Am 20(5), 2006
• Keren DF, McCoyd JP, Carey JL (eds). Flow cytometry in clinical diagnosis, 3rd ed. Chicago, ASCP Press, 2001

 For all publication requests, please complete the image permission form and we will respond to your request shortly.