Clinical features and diagnosis of hairy cell leukemia

INTRODUCTION — Hairy cell leukemia (HCL) is an uncommon indolent lymphoid malignancy characterized by the accumulation of neoplastic B cells with abundant cytoplasm and "hairy" projections within the peripheral blood, bone marrow, and splenic red pulp. HCL typically causes splenomegaly and variably reduced production of red blood cells, platelets, granulocytes, and monocytes. The resulting cytopenias have a variety of systemic consequences, including anemia, bleeding, and an increased risk of infection.

The clinical features and diagnosis of HCL will be reviewed here; treatment of this disorder is discussed separately. (See "Treatment of hairy cell leukemia".)

PATHOGENESIS — The pathogenesis of HCL is incompletely understood. Most cases are postulated to arise from a late, activated memory B cell that acquires a BRAF V600E gene mutation. The resultant aberrant activation of the RAF-MEK-ERK signaling pathway leads to a distinct phenotype and enhanced cell survival. (See 'BRAF mutations' below.)

Exposures to ionizing radiation, pesticides, and farming have been mentioned as possible causes [1-3]. Exposure to solvents, cigarette smoke, alcohol consumption, and obesity do not appear to be risk factors [1,4,5]. Familial cases have been described [6,7].

Cell of origin — HCL is postulated to arise from a late, activated memory B cell exhibiting preplasma cell or postgerminal center features [8,9]. The malignant cell in HCL has the following features:

●Clonal immunoglobulin light and heavy chain gene rearrangements and monoclonal surface immunoglobulin expression [10-13]

●Expression of pan B cell surface antigens (CD19, CD20, and CD22) and an early plasma cell marker (PCA-1), and lack of expression of CD10 and CD21, markers of earlier stages of B cell development

●Expression of surface antigens that are not found on most normal B cells, such as CD11c (monocytes and neutrophils), CD25 (activated T cells), and CD103 (intraepithelial T cells)

Specific details concerning the immunophenotype of HCL are presented below. (See 'Immunophenotype' below.)

BRAF mutations — Virtually all cases of HCL demonstrate a clonal somatic V600E activating mutation in the serine/threonine kinase BRAF (an isoform of RAF), leading to constitutive activation of the RAF-MEK-ERK signaling pathway and enhanced cell survival [14-20]. This BRAF V600E mutation is not present in HCL variant [18], a high percentage of which has IGHV4-34 immunoglobulin rearrangements [18]; these and other distinct findings have led to classification of HCL variant as a unique entity. (See 'HCL variant' below.)

Accumulating data implicate aberrant BRAF signaling as the fundamental cause of HCL's biologic features, including the "hairy" morphology, enhanced cell survival, and gene expression signature [21]. Inhibition of BRAF reverses these changes in vitro and has been used as an effective therapeutic strategy. (See "Treatment of hairy cell leukemia", section on 'BRAF inhibition (vemurafenib or dabrafenib)'.)

Aberrant activation of the RAF-MEK-ERK signaling pathway transduces signals that promote cell survival and proliferation. Of these effects, enhanced cell survival (inhibition of apoptosis) is believed to be more important, since HCL has a very low proliferative index [22].

Initial studies using sensitive molecular assays (eg, next generation sequencing, allele-specific polymerase chain reaction) identified the BRAF V600E mutation in the entire tumor clone in the vast majority of cases of HCL and not in other peripheral B cell lymphomas or leukemias [14,15,18,20]. Subsequent studies have demonstrated BRAF V600E mutations in subsets of patients with Erdheim-Chester disease and Langerhans cell histiocytosis [23,24], splenic diffuse red pulp small-B cell lymphoma [25], rare cases of acute myeloid leukemia, and many different solid tumors (eg, melanoma, non-medullary thyroid carcinoma, and colonic adenocarcinoma).

The presence of BRAF V600E mutations in other entities is presented separately. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis", section on 'Pathophysiology' and "Pathology and prognostic determinants of colorectal cancer", section on 'RAS and BRAF' and "The molecular biology of melanoma", section on 'MAPK pathway'.)

Other mechanisms — HCL cells produce and assemble fibronectin [26] and elaborate several cytokines, such as basic fibroblast growth factor (bFGF, FGF-2) [27], transforming growth factor-beta (TGF-beta1) [28], and tumor necrosis factor (TNF)-alpha [27,29-31]. The first three may be responsible for the fine reticulin fibrosis caused by increased elaboration of type III collagen by fibroblasts that is characteristically seen in bone marrows involved by HCL, while TNF may be responsible for the marrow suppression and consequent pancytopenia [29].

Mutations in the cell cycle inhibitor CDKN1B (p27), the transcription factor KLF2, KMT2C (MLL3), and MAP2K1 (which encodes MEK1) have been identified. As examples:

●In one study, somatic mutations in the cell cycle inhibitor CDKN1B (p27) were identified in 13 of 81 (16 percent) of HCL patients [32]. These mutations coexisted with BRAF V600E mutations and were clonal, implying an early role in the pathogenesis of HCL. Another study identified mutations in KMT2C (MLL3) and CDKN1B in 15 and 11 percent of cases of classical HCL, respectively [33].

●In another study, mutations in the transcription factor KLF2 were identified in 4 of 24 (16 percent) of HCL patients [34].

●In another study, 15 of 31 (48 percent) cases of IGHV4-34 expressing HCL demonstrated mutations in the MAP2K1 gene, which encodes MEK1, a downstream mediator in the RAF-MEK-ERK signaling pathway [35]. IGHV4-34 expressing HCL do not exhibit the BRAF V600E mutation and have a more aggressive clinical course with high white cell count at presentation and suboptimal response to purine analog therapy [18,36]. These features are the same as those associated with HCL variant, suggesting that these cases belong to that entity rather than "classic" HCL.

EPIDEMIOLOGY — HCL is an uncommon malignancy, representing approximately 2 percent of all leukemias and less than 1 percent of lymphoid neoplasms. In the United States, the estimated incidence is three per million persons per year, which equates to 600 to 800 new cases each year [37]. Due to its indolent course, the prevalence of HCL is much higher.

The median age at onset is 50 to 55 years. While HCL has been diagnosed in younger adults, it is almost never seen in children. There is a strong male predominance with a male:female ratio of approximately four to one [38,39]. The incidence is approximately three times higher in White compared with Black populations [40].

First-degree family members of patients with HCL have a higher-than-expected frequency of developing HCL, although the absolute risk remains low. In one large database, the diagnosis of HCL was 8.3-fold higher among first-degree relatives than among the general population [41].

CLINICAL FEATURES

Presenting symptoms or signs — Most patients with HCL present with symptoms related to splenomegaly or cytopenias (eg, anemia, thrombocytopenia, neutropenia, monocytopenia), including weakness and fatigue, infections of variable severity, and/or hemorrhagic findings such as gingival bleeding, ecchymoses, epistaxis, or menorrhagia. Combinations of these symptoms are common. HCL can present to the clinician in several ways [42,43]:

●Approximately one-quarter presents with abdominal fullness or discomfort due to splenomegaly, which may be massive. Spontaneous splenic rupture may occur and, while rare, constitutes a medical emergency [44].

●Another one-quarter presents with systemic complaints, such as fatigue, weakness, and weight loss. Patients do not usually complain of fever or night sweats.

●Another one-quarter presents either with bruising and bleeding secondary to severe thrombocytopenia, or with recurrent infections, which may be life-threatening, secondary to neutropenia and monocytopenia.

●The remaining one-quarter is generally asymptomatic and comes to the clinician's attention because of an incidental finding of splenomegaly or cytopenias during evaluation for an unrelated cause.

●Occasional patients have vasculitis, usually polyarteritis nodosa or cutaneous leukocytoclastic vasculitis, or other autoimmune manifestations [45,46]. Rare patients present with symptoms due to involvement of soft tissue or bone [47-51].

Physical examination — Palpable splenomegaly is a classic feature of HCL and is usually the sole finding on the physical examination. Case series report palpable splenomegaly in 80 to 90 percent of cases, with the splenic edge extending more than 8 cm below the left costal margin in 25 percent [39,42,43]. The incidence and severity of splenomegaly may be decreasing as patients are diagnosed earlier in the disease course [39,52].

Hepatomegaly and lymphadenopathy are not major features of HCL, being present in approximately 20 and 10 percent of patients, respectively. B symptoms (ie, fevers, night sweats, weight loss) are usually not associated with HCL, and if fever is present, it is likely indicative of a superimposed infection.

Rare physical findings include soft tissue infiltration, vasculitic skin rash, ascites, and pleural effusion. (See "Cutaneous manifestations of internal malignancy", section on 'Vasculitis'.)

Laboratory findings — Sixty to 80 percent of patients with HCL present with pancytopenia, with hematocrits in the range of 20 to 35 percent, a total white blood cell count usually below 4000/microL, and platelet counts in the range of 20,000 to 100,000/microL [39,42,43]. Monocytopenia and neutropenia are common. Lactate dehydrogenase (LDH) is usually normal. The approximate frequency of the major laboratory abnormalities in HCL is as follows:

●Anemia – 85 percent

●Thrombocytopenia – 80 percent

●Neutropenia – 80 percent

●Monocytopenia – 80 percent

●Azotemia (elevated blood urea nitrogen [BUN]) – 30 percent

●Abnormal liver function tests – 20 percent

●Hypergammaglobulinemia – 20 percent

●Leukocytosis (total white blood cell count >10,000/microL) – 10 to 20 percent

PATHOLOGIC FEATURES

Morphology

Peripheral blood — The peripheral blood usually demonstrates pancytopenia, including monocytopenia, and circulating tumor cells characteristic of HCL. In approximately 90 percent of cases, HCL cells are identified in Romanowsky-stained peripheral blood films, where they usually comprise 20 percent or less of the total white blood cell count. However, in the 10 percent of patients who present with leukocytosis, the HCL cell is the predominant circulating white blood cell. A very small number of patients present with marked leukocytosis, with white blood cell counts >200,000/microL. Patients with this degree of leukocytosis are likely to have HCL variant rather than HCL. (See 'HCL variant' below.)

The HCL cell is a mononuclear cell that is usually one to two times the size of a mature lymphocyte (picture 1) [53]. The nuclei are often eccentric in position but may be central. The nuclei are most commonly ovoid, but may be round, oval, reniform, or horseshoe shaped. Atypical morphologic appearances are more frequent in HCL variant cases. The chromatin pattern is reticular or net-like in appearance; nucleoli are indistinct or absent.

The cytoplasm is variable in amount but usually fairly abundant, pale blue to blue-gray in color, and occasionally described as "fluffy." The cytoplasmic outline is often indistinct due to the presence of varying numbers of projections, best seen on phase-contrast microscopy, giving the cell a "hairy" appearance when the projections are thin, and a "ruffled" appearance when they are wider. The hairy projections are readily evident on electron microscopic examination [54] and particularly on scanning electron microscopy [55].

Bone marrow — The bone marrow (BM) is often difficult or impossible to aspirate (dry tap) due to HCL-induced marrow fibrosis and the interlocking cell borders of hairy cells. As such, the diagnosis relies heavily on analysis of peripheral blood and trephine biopsies.

The hairy cell nuclei are widely separated from each other by virtue of the cell's abundant cytoplasm, producing a halo or "fried egg" appearance in biopsy and tissue specimens (picture 2). Admixed mast cells may be numerous. Extravasated red cells are frequently seen and "blood lakes", collections of red cells in spaces lined by hairy cells that are most commonly observed in the spleen, may also be present. Mitotic figures are uncommon, and necrosis and apoptosis of tumor cells are absent.

The extent of involvement of the BM is usually best estimated by immunohistochemical staining of sections for B cell associated antigens such as CD20. In most cases the marrow is hypercellular due to a diffuse/interstitial infiltrate of hairy cells [19]. Nodular patterns of marrow infiltration occur rarely, if ever; if present, another diagnosis should be considered. In a minority of cases, perhaps 10 to 20 percent, the marrow is hypocellular. Occasionally, the hypocellularity is so profound as to suggest marrow aplasia, and careful observation is required to identify small numbers of hairy cells infiltrating around fat cells [56-62].

In patients with diffuse involvement, large areas of the BM may be completely effaced by hairy cells. In one study, as an example, the median percent bone marrow involvement was 85 percent [19]. When the BM is focally involved, there is some preservation of fat and hematopoietic elements and the infiltrates are randomly situated.

Staining of the BM trephine biopsy for reticulin almost always shows a moderate to marked increase in reticulin fibers. In some cases, the reticulin fibers appear to surround individual hairy cells and may extend into the adjacent, more normal appearing BM tissue. Osteosclerosis has been rarely reported [63-65]. (See "Evaluation of bone marrow aspirate smears", section on 'The dry tap'.)

Spleen, liver, lymph nodes, and other sites — While not usually necessary for diagnosis, histologic examination of the spleen will demonstrate tumor infiltration in virtually all cases. In rare instances in which liver biopsies are obtained for other indications, patchy involvement of hepatic sinusoids is not unusual, but hepatomegaly is distinctly rare. Lymph nodes are typically not involved.

●Spleen – The spleen demonstrates marked enlargement due to diffuse infiltration and expansion of the red pulp by tumor cells, accompanied by atrophy of the white pulp [66]. The tumor infiltrate is comprised of a monotonous population of medium-sized cells with clear cytoplasm, producing a "fried egg" appearance (picture 3). Dilated sinuses may be filled with red cells, forming "blood lakes" (also called "pseudosinuses").    

●Liver – Liver involvement, if present, is subtle and usually confined to sinusoids [66].

●Lymph nodes – Infiltration of the lymph nodes can be seen in patients with advanced HCL [66]. The tumor cells variably involve the interfollicular and paracortical zones. The follicles and sinuses are typically spared.  

●Other sites – Very rarely, otherwise typical HCL may present in soft tissues sites, such as the breast [67,68]. The basis for these unusual presentations is unknown.

Immunophenotype — The neoplastic hairy cells exhibit a mature B cell phenotype and typically express one or more immunoglobulin heavy chains [69] and monotypic light chains. Hairy cells strongly express pan-B cell antigens including CD19, CD20, and CD22, and usually lack expression of CD5, CD10, CD21, CD23, and CD27 (table 1) [19,70]. Hairy cells also characteristically express CD11c, CD25, CD103, CD123 (bright), and cyclin D1 (usually weak). Staining for CD200 expression is intense [71,72].

A majority (74 percent) of HCL also expresses annexin A1, which is not expressed in any other type of B cell neoplasm [19,73,74]. Of note, HCL variant is typically negative for annexin A1, which can be a helpful distinguishing feature. Annexin A1 staining must be interpreted in conjunction with staining for a B cell antigen since it is also expressed by myeloid cells and by some T cells.

The mucosal lymphocyte antigen, CD103, is a sensitive marker for HCL [75]. CD103 is a member of the integrin family and is also present on mucosa-associated T cells and some activated lymphocytes. The presence of CD103, when co-expressed with other pan-B cell markers, is highly suggestive of HCL [76].

Hairy cells also strongly express CD11c, a marker associated with myelomonocytic cells, and CD25, the alpha chain of the interleukin-2 receptor [70,77]. B cell-specific markers such as CD20 and DBA44 can be used to detect hairy cells in fixed, routinely processed tissue sections. Although these antibodies are not specific for HCL, they document the process as a B cell proliferation and are useful in quantifying the extent of BM infiltration at the time of diagnosis and following therapy [78-81].

Genetic features — While numerous genetic abnormalities have been described, none has been incorporated into the diagnostic criteria for HCL. Nevertheless, screening for the BRAF V600E mutation can be diagnostically helpful in some cases and is included in the pretreatment evaluation to help guide management.

Analysis of the immunoglobulin variable region genes shows somatic mutations in the majority (>85 percent) of cases [66,82]. Unlike other lymphoid neoplasms, HCL cells often co-express several clonally related immunoglobulin heavy chain isotypes.

Clonal karyotypic abnormalities are present in approximately two-thirds of patients. Abnormalities of chromosome 5 are present in approximately 40 percent, most commonly trisomy 5, pericentric inversions, and interstitial deletions involving band 5q13 [83].

As described above, sensitive molecular assays (eg, next generation sequencing, allele-specific polymerase chain reaction) will identify BRAF V600E mutations in the vast majority of cases without IGHV4-34 immunoglobulin rearrangement. While highly sensitive, this mutation is not specific for HCL since it has also been detected in other entities, including Erdheim-Chester disease, Langerhans cell histiocytosis, unclassifiable splenic B cell lymphoma/leukemia, as well as in subsets of solid tumors (eg, melanoma, non-medullary thyroid carcinoma, and colonic adenocarcinoma). (See 'BRAF mutations' above.)

Also discussed above, mutations in the MAP2K1 gene may be detected in almost half of cases with IGHV4-34 immunoglobulin rearrangement, many of which have features of HCL variant; the sensitivity and specificity of this finding and its role in distinguishing classic HCL from HCL variant requires additional study. (See 'Other mechanisms' above.)

EVALUATION — HCL is initially suspected in patients, often a middle-aged man, presenting with pancytopenia (including monocytopenia), splenomegaly without lymphadenopathy, and circulating mononuclear cells in the peripheral blood with a "hairy" or "ruffled" appearance (picture 1). These "hairy" cells usually comprise 20 percent or less of the total white blood cell count.

Evaluation requires a bone marrow trephine biopsy and aspirate with immunophenotyping by flow cytometry [56-60]. It is common for the bone marrow aspirate to result in a "dry tap" because the bone marrow cannot be aspirated due to the diffuse fibrosis. Splenectomy is usually not necessary but can be diagnostic in patients presenting with a massively enlarged spleen. (See 'Morphology' above.)

DIAGNOSIS — The diagnosis of HCL is usually made by bone marrow biopsy and aspirate in conjunction with immunophenotyping by flow cytometry [52,66,84]. The abnormal cells (ie, "hairy" cells) display expression of pan-B cell antigens (eg, CD19, CD20, CD22) along with CD103, CD11c, and CD25. Expression of annexin A1 in B cells is specific, but not sensitive for the diagnosis of HCL.

On occasion, HCL may have an atypical immunophenotype and express markers such as CD5 and CD10. These aberrant phenotypes generally do not create diagnostic difficulties, since other features of HCL, including its distinctive morphology and pattern of marrow infiltration, distinguish it from other CD5-positive tumors, such as mantle cell lymphoma, chronic lymphocytic leukemia, as well as CD10-positive tumors such as follicular lymphoma.

HCL is included in the lymphoid malignancies sections of the International Consensus Classification (ICC) [85] and the World Health Organization 5^th edition classification [86] as a mature B cell neoplasm.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of HCL includes other B cell lymphoid neoplasms associated with splenomegaly [87], such as the variant form of HCL (picture 4) [88-90], splenic marginal zone lymphoma [91-94], splenic diffuse red pulp small B cell lymphoma, other unclassifiable splenic lymphomas, chronic lymphocytic leukemia, prolymphocytic leukemia [95-97], and mantle cell lymphoma (table 2). These entities can usually be excluded based on morphologic and immunophenotypic features.

The causes of an enlarged spleen are multiple; most reflect the presence of hepatic or hematologic disease, infection, or inflammation. A general approach to the evaluation of patients with splenomegaly is presented separately. (See "Splenomegaly and other splenic disorders in adults".)

HCL variant — HCL variant (HCL-v) is a rare chronic B cell lymphoid neoplasm that was previously thought to be a subtype of HCL, but is now considered to be a biologically distinct entity [19,66,98].

The two most recent hematologic malignancy classification systems, the International Consensus Classification (ICC) [85] and the World Health Organization 5^th edition [86], agree that HCL-v differs from classic HCL but handle HCL-v differently. The ICC maintains HCL-v as a distinct provisional entity, whereas the World Health Organization 5^th edition lumps cases previously considered HCL-v and B prolymphocytic leukemia together under the umbrella category "splenic B-cell lymphoma/leukemia with prominent nucleoli" [86].

HCL-v cells exhibit morphologic features intermediate between hairy cells and prolymphocytes. Unlike HCL cells, HCL-v cells typically have prominent nucleoli and produce less marrow infiltration. HCL-v may be associated with extreme leukocytosis, often without the cytopenias seen in HCL [36].

HCL and HCL-v are best distinguished from each other based upon immunophenotype (table 1) [19]. Both HCL and HCL-v express CD20, CD22, CD11c, and CD103. Unlike HCL, which typically has bright expression of CD123 and CD25, HCL-v does not express CD25 and is usually dim or negative for CD123. In addition, annexin A1 is expressed in approximately 75 percent of HCL cases and is universally negative in HCL-v [19,73,74].

HCL-v lacks the BRAF V600E mutation and a subset have activating mutations in MAP2K1, a gene that encodes MEK1, a downstream component of the BRAF-MEK-ERK signaling cascade [19,35]. Mutations in KMT2C, CCND3, and U2AF1 are also seen in a subset [33]. Further study is needed to determine the role of testing for these mutations in the diagnosis of HCL-v.

Splenic marginal zone lymphoma — Both splenic marginal zone lymphoma (MZL) and HCL can present with splenomegaly and circulating lymphocytes with cytoplasmic projections. While the circulating lymphocytes in HCL usually have long cytoplasmic projections around the entire perimeter of the cell, splenic MZL cells usually have short polar villi (picture 5), although this may be masked by poor slide preparation. (See "Splenic marginal zone lymphoma".)

Splenic MZL does not express CD103, CD11c, and CD25, all of which are commonly expressed in HCL (table 1) [96]. MZL is negative for annexin A1 which is positive in the majority of HCL. In difficult cases, pathologic evaluation of the bone marrow, spleen, and hilar lymph nodes may be used in concert to determine the most likely diagnosis.

Additional distinctions include:

●Splenic involvement – Splenic involvement in HCL is typically limited to the red pulp. In contrast, both the splenic white pulp and red pulp are involved in MZL, and marginal zones are usually prominent due to expansion by cells with abundant pale cytoplasm.

●Bone marrow involvement – Bone marrow infiltrates, when present, are often nodular [66], in distinction to the diffuse interstitial infiltrates of HCL, and sometimes include reactive-appearing follicles surrounded by marginal zones.

●Genetic findings – BRAF mutations are absent or very rare in splenic MZL, while mutations in other genes not mutated in HCL, such as NOTCH2, are frequent [99].

Chronic lymphocytic leukemia — Both HCL and chronic lymphocytic leukemia (CLL) can present with splenomegaly and circulating lymphoid cells. Compared with typical HCL cells, CLL cells usually have a regular, smooth cytoplasmic outline (picture 6). Unlike HCL, the abnormal B cell in CLL usually expresses CD5 and lacks expression of CD103 (table 1). Most cases of splenic involvement in CLL demonstrate diffuse and nodular infiltrates due to involvement of both the red and white pulp, while HCL predominantly involves the red pulp. (See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma".)

B cell prolymphocytic leukemia — Both HCL and B cell prolymphocytic leukemia (PLL) can present with splenomegaly and circulating lymphoid cells. In HCL, the malignant cells are usually present in small numbers in the peripheral blood. In PLL there is a marked elevation of the white blood cell count by cells with the characteristic morphology of prolymphocytes. Compared with typical HCL cells, prolymphocytes are larger cells with no cytoplasmic projections and somewhat immature-appearing nuclear chromatin, a prominent nucleolus, and a moderate amount of cytoplasm (picture 4). (See "B cell prolymphocytic leukemia".)

Mantle cell lymphoma — Mantle cell lymphoma (MCL) can present with splenomegaly and peripheral blood involvement. However, ruffled or "hairy" cytoplasm is not a feature of circulating MCL cells, and MCL has a different immunophenotype that typically includes expression CD5, strong expression of cyclin D1, and lack of expression CD25, CD103, and annexin A1 (table 1). (See "Mantle cell lymphoma: Epidemiology, pathobiology, clinical manifestations, diagnosis, and prognosis".)

Aplastic anemia — Occasionally, the bone marrow biopsy of patients with HCL may resemble that seen in patients with aplastic anemia [66]. Such cases will demonstrate hypocellularity due to loss of hematopoietic elements, especially the granulocytic lineage. Immunostaining for a B cell antigen such as CD20 will identify an abnormal B cell infiltrate. The diagnosis of HCL can then be confirmed using other immunohistochemical stains. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Evaluation'.)

Splenic diffuse red pulp small B cell lymphoma — Splenic diffuse red pulp small B cell lymphoma is a provisional entity in both the International Consensus and the World Health Organization 5^th edition classifications [66,84-86]. It is a rare entity characterized by diffuse infiltration of the bone marrow, peripheral blood, and splenic red pulp by small monomorphous B lymphocytes, usually with villous projections. In contrast to HCL, these tumor cells typically do not express annexin A1 or CD25 and show more variable expression of CD103 and CD123.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hairy cell leukemia".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Hairy cell leukemia (The Basics)")

SUMMARY

●Definition and epidemiology – Hairy cell leukemia (HCL) is an indolent neoplasm of mature B lymphoid cells representing approximately 2 percent of all leukemias and <1 percent of lymphoid neoplasms. HCL presents in adulthood with a median age at onset of 50 to 55 years. (See 'Epidemiology' above.)

●Clinical presentation – Most patients have symptoms related to splenomegaly or cytopenias, including fatigue, infections of variable severity, and/or hemorrhagic findings. Approximately one-quarter are asymptomatic and come to the clinician's attention because of incidental findings of splenomegaly or cytopenias during evaluation for an unrelated cause. (See 'Presenting symptoms or signs' above.)

The spleen is palpable in most patients. Hepatomegaly and lymphadenopathy are not major features. Pancytopenia occurs in 60 to 80 percent; monocytopenia and neutropenia are common. (See 'Physical examination' above and 'Laboratory findings' above.)

●Diagnostic evaluation – HCL is initially suspected in patients presenting with pancytopenia (including monocytopenia), splenomegaly without lymphadenopathy, and circulating mononuclear cells in the peripheral blood with a "hairy" or "ruffled" appearance (picture 1). (See 'Evaluation' above.)

Evaluation requires a bone marrow biopsy and aspirate with immunophenotyping and flow cytometry. Difficulty aspirating the bone marrow (ie, "dry tap") is common due to diffuse fibrosis. Splenectomy is usually not necessary but can be diagnostic in patients presenting with a massively enlarged spleen. (See 'Diagnosis' above and 'Spleen, liver, lymph nodes, and other sites' above.)

•The peripheral blood usually demonstrates pancytopenia with monocytopenia and occasional circulating tumor cells. The HCL cell is mononuclear and one to two times the size of a mature lymphocyte (picture 1). The nuclei are often eccentric, lack prominent nucleoli, have a reticular chromatin pattern and are surrounded by abundant pale blue to blue-gray cytoplasm. The cytoplasmic outline is indistinct with varying numbers of cytoplasmic projections giving the cell a "hairy" or "ruffled" appearance. (See 'Peripheral blood' above.)

•The bone marrow is usually hypercellular due to patchy interstitial or diffuse infiltration by HCL (picture 2). The hairy cell nuclei are widely separated from each other by virtue of the cell's abundant cytoplasm, giving the cells a "fried egg" appearance in biopsy and tissue specimens (picture 3). Staining for reticulin shows a moderate to marked increase in reticulin fibers. (See 'Bone marrow' above.)

•The tumor cells exhibit a mature B cell phenotype with monotypic light chains. They express pan-B cell antigens (eg, CD19, CD20, CD22) along with CD103, CD11c, CD25, and (often, but not always) annexin A1 (table 1). Most cases lack expression of CD5, CD10, CD21, CD23, and CD27. (See 'Immunophenotype' above.)

●Differential diagnosis – The differential diagnosis of HCL includes other small B cell lymphoid neoplasms associated with splenomegaly such as HCL variant, splenic marginal zone lymphoma, and chronic lymphocytic leukemia (table 2). Occasionally, the bone marrow biopsy of patients with HCL may resemble that seen in patients with aplastic anemia. (See 'Differential diagnosis' above.)