Hairy cell leukemia
What every physician needs to know:
Hairy cell leukemia (HCL) is a neoplasm of mature B lymphoid cells. HCL is a rare disease accounting for only 2% of all lymphoid leukemias. It affects predominately middle-aged to elderly adults, with a median age of 50 years. It has been diagnosed in younger patients, but is exceptionally uncommon in children. It has a male predominance, with a male to female ratio of approximately 5 to 1.
Are you sure your patient has hairy cell leukemia? What should you expect to find?
Common clinical symptoms
Most common clinical symptoms include weakness and fatigue, as well as left upper quadrant pain. Patients often present with pancytopenia with very few circulating neoplastic hairy cells. Monocytopenia is a characteristic finding in classic hairy cell leukemia, but not in the hairy cell variant.
Another distinct manifestation is splenomegaly. Less common is hepatomegaly. Patients with hairy cell leukemia often develop reoccurring opportunistic infections, including atypical mycobacterial infections.
Sites of involvement
Tumor cells are predominately found in the peripheral blood, bone marrow and spleen. One has to consider hairy cell leukemia in the differential diagnosis and alert the pathologist as it is difficult to extract the tumor cells in a standard bone marrow aspirate due to the marrow fibrosis. Therefore, the diagnosis is often made solely on examination of the core biopsy material. A patient often has a large tumor burden within the bone marrow accounting for the pancytopenia.
Other sites of involvement other than the spleen and bone marrow are uncommon, but tumor infiltrates involving the liver and lymph nodes, as well as skin, have rarely been reported.
Beware of other conditions that can mimic hairy cell leukemia:
The differential diagnosis for hairy cell leukemia includes splenic marginal zone lymphoma and chronic lymphocytic leukemia as well as other low grade lymphomas. However, hairy cell leukemia has a distinct immunophenotype and CD103 is the most specific marker by flow cytometry. Annexin A1 can be performed on the core biopsy and is only seen in patients with hairy cell leukemia. Tartrate resistant acid phosphatase (TRAP) stain can also be used to differentiate hairy cell leukemia from other low grade lymphoproliferative disorders. In addition, myelofibrosis can also be confused with hairy cell leukemia due to the presence of cytopenias and splenomegaly, but a lymphoid infiltration brought out by CD20 staining can help differentiate between these two entities.
Which individuals are most at risk for developing hairy cell leukemia:
HCL is most often seen in middle-aged men, but it can occur at any age.
What laboratory studies should you order to help make the diagnosis and how should you interpret the results?
Bone marrow exam:
Diagnosis is best made by analyzing a bone marrow biopsy. The lymphoid infiltrate can be patchy and difficult to assess without immunoperoxidase studies such as CD20, DBA.44 or the TRAP stain. The lymphoid infiltrate due to abundant cytoplasmic area between the cells produces what is described as a “fried egg” appearance. Mitotic figures are usually absent given the low proliferative index. Infiltration is typically larger than can be appreciated and is illustrated by CD20 staining. In addition, increased reticulin fibers in the bone marrow are also noted in patients with hairy cell leukemia, thus leading to a misdiagnosis of myelofibrosis.
The only cytochemical stain that is utilized for the diagnosis of hairy cell leukemia is tartrate-resistant acid phosphatase (TRAP) stain. This is a technically challenging stain and has been largely replaced by immunophenotypic and histochemical techniques.
Immunophenotyping of either the blood, bone marrow aspirate or bone marrow biopsy is absolutely essential in making the diagnosis of hairy cell leukemia. Patients with classic hairy cell leukemia typically have bright monotypic surface immunoglobulin staining and coexpress CD20, CD22, CD11C, as well as CD103 and CD25. Annexin A1 (ANXA1) is the most specific stain, however it is somewhat technically challenging due to the high back ground staining within the myeloid precursor cells. In addition, DBA.44 is another stain that is often positive in patients with hairy cell leukemia, but is less specific. Most cases of hairy cell leukemia are negative for CD5 and CD10.
There is a hairy cell variant that is typically seen in older women with more progressive splenomegaly and it often has a lower response to chemotherapy. These patients are negative for CD25.
What imaging studies (if any) will be helpful in making or excluding the diagnosis of hairy cell leukemia?
Examination of peripheral blood and bone marrow aspirate will occasionally show medium-sized cells with an oval or indented (kidney bean) shaped nucleus. Nucleoli are usually absent. The cytoplasm is abundant with pale blue hair-like projections that can be difficult to appreciate on light microscopy. Rarely the cytoplasm may contain vacuoles or even rod-shaped bodies that are ribosome lamellar complexes.
Differential diagnosis in hairy cell leukemia is broad and requires a good pathologist as well as cytopathologist. First and foremost, diagnosis of hairy cell leukemia must be considered in order for the pathologist to employ the appropriate the immunoperoxidase studies. Differential diagnosis includes primary myelofibrosis since most patients will present with pancytopenia, splenomegaly, and marrow fibrosis. Other diagnoses in the differential include splenic B-cell lymphoma, as well as marginal zone lymphoma and chronic lymphocytic leukemia.
If you decide the patient has hairy cell leukemia, what therapies should you initiate immediately?
The treatment of hairy cell leukemia has developed over the last 30 years. Chemotherapy-based regimens have demonstrated a poor response rate, and were supplanted by splenectomy followed by interferon. Long-term remission has been noted with interferon-based strategies, but given the advent of nucleoside analogues, its use has been limited.
Both pentostatin and cladribine remain the standard of care for patients with hairy cell leukemia. Cladribine is administered as either a 7-day continuous infusion, or by a 5-day bolus, and can even be administered by a subcutaneous route. Remission rates using cladribine are in the 90% range and 60% of patients enjoy long-term disease-free survival. Similar response rates can be seen with pentostatin, which is typically administered every other week for 3 to 4 months.
The development of monoclonal antibodies is of interest. Rituximab is an anti-CD20 antibody that is used in the treatment of non-Hodgkin lymphoma. Its use as a single agent hairy cell leukemia is limited; it is currently being added to nucleoside analogue therapies, but no randomized trials exist to date. Other monoclonal antibodies are in development against CD22.
Many patients are left with minimal residual disease after initial reduction with purine nucleoside analogue therapy. There is some data suggestion that minimal residual disease can be eradicated with monoclonal antibody therapies such as rituximab; however, there are no long-term data regarding the efficacy of this approach.
More definitive therapies?
What other therapies are helpful for reducing complications?
Infections remain the most important complication during the treatment of hairy cell leukemia. There is no data suggesting that the use of myeloid growth factors is able to reduce the rate of infections and I only use them in cases of a severe infection. Since the CD4 count will remain low for some time, the use of acyclovir to reduce the incidence of HSV and VZV and Bactrim to reduce the rate of PCP infections are commonly employed. However, Bactrim may delay the return of normal hematopoiesis as it can be myelosuppressive. Prophylactic antibiotics such as fluoroquinolones should also be considered during the neutropenic period.
What should you tell the patient and the family about prognosis?
Hairy cell leukemia is an extremely indolent disease. Treatment is only indicated for severely low peripheral blood counts or symptomatic splenomegaly. When treatment is required, most patients respond to one cycle of therapy with response rates greater than 90 per cent and responses are extremely durable. In those patients who develop recurrent disease, remissions can often be obtained with another cycle of the same therapy.
What if scenarios.
Relapse of hairy cell leukemia
Approximately 40% of patients will relapse. It is important to differentiate patients who have rapid relapse, from those who have had a poor initial response to initial chemotherapy. One must also ask, “Does this patient have hairy cell variant?”, as these patients are unlikely to respond to subsequent rounds of chemotherapy.
Patients who have a short initial remission (that is, less than 1 year), often have inadequate response to repeat nucleoside analogue therapy. Patients have been successfully treated with combination chemotherapy and rituximab. For patients who have a late relapse beyond one year, a typical approach is to treat the patient again with the same nucleoside purine analogues or an alternative purine analogue, as there is no evidence that these agents develop cross-resistance.
Indication for initiation of therapy for patients with relapsed hairy cell leukemia includes patients who develop anemia at a level with 10 g/dL, a platelet count of less 100,000/uL or an absolute neutrophil count (ANC) of less than 1,000/uL or symptomatic splenomegaly.
Pathogenesis in hairy cell leukemia
The etiology of unusual cytoplasmic projections is still unclear. There are numerous hypotheses proposed as a mechanism for hairy cell leukemia. It is a clonal B-cell, derived from a mature memory B-cell. The leukemic hairy cell differs from the normal B-cell counterpart given its altered expression of both chemokine and cell adhesion receptors. The morphology is influenced by the activation members of the Rho family of GTPases. There is near uniform expression of fibrosis in patients with hairy cell leukemia, as hairy cells are able to synthesize fibronectin within the bone marrow microenvironment.
Most cases of classical hairy cell leukemia have an activating mutation within the BRAF gene (V600E). BRAF is an activating mutation of the RAS/RAF/MEK/MAPK signaling pathway that leads to enhanced cell proliferation and survival. Thus, BRAF is implicated in the pathogenesis of hairy cell leukemia. BRAF mutations have not been found in patients with variant hairy cell leukemia. However, the use of BRAF inhibitors has not been studied systematically.
There are no specific cytogenetic abnormalities known for hairy cell leukemia. Abnormalities for chromosome 5 and 7 have been described, but reciprocal translocations are relatively rare.
What other clinical manifestations may help me to diagnose hairy cell leukemia?
Most patients with hairy cell leukemia present with pancytopenia. Leukopenia is much more common as opposed to leukocytosis. Regardless, monocytopenia is a typical finding associated with classical hairy cell leukemia, but not variant hairy cell leukemia.
Splenomegaly is a characteristic feature of hairy cell leukemia and on occasion can become massive.
What other additional laboratory studies may be ordered?
The diagnosis of hairy cell leukemia is implicated by leukopenia and splenomegaly. In addition to a complete blood count, peripheral blood flow cytometry and a bone marrow diagnosis are essential in order to confirm the diagnosis.
What’s the evidence?
Greaver, MR. “How I treat hairy cell leukemia”. Blood. vol. 115. 2010. pp. 21-28. [Dr Greaver reviews the clinical features of hairy cell leukemia and the key treatment options.]
Greaver, MR, Lozanski, G. “Modern strategies for hairy cell leukemia”. J Clin Oncol. vol. 29. 2011. pp. 583-590. [This is an update of the various treatment options, both standard and experimental, for hairy cell leukemia.]
Robak, T. “Current treatment options in hairy cell leukemia and hairy cell leukemia variant”. Cancer Treat Rev. vol. 32. 2006. pp. 365-376. [This is an excellent review summarizing the different treatment options for both hairy cell leukemia and hairy cell leukemia variant.]
Catovsky, D. “The natural history and clinico-pathologic features of the variant form of hairy cell leukemia”. Leukemia. vol. 15. 2001. pp. 684-693. [This is an important and seminal review of the pathologic and clinical features of the variant form of hairy cell leukemia.]
Thomas, DA, Ravandi, F, Kantarjian, H. “Monoclonal antibody therapy for hairy cell leukemia”. Hematol Oncol Clin N Am. vol. 20. 2006. pp. 1125-1136. [This is a systematic and thorough review of the use of monoclonal antibodies in hairy cell leukemia.]
Kreitman, RJ, Stetler-Stevenson, M, Margules, I. “Phase II trial of recombinant immunotoxin RFB4 (dsFv)-PE38 (BL22) in patients with hairy cell leukemia”. J Clin Oncol. vol. 27. 2009. pp. 2983-2990. [This is the updated data on the role of BL22 in patients with hairy cell leukemia.]
Ravandi, F, O’Brien, S, Jorgensen, J. “Phase 2 study of cladribine followed by rituximab in patients with hairy cell leukemia”. Blood. vol. 118. 2011. pp. 3818-3823. [This is the initial report on the use of a combination strategy with cladribine and rituximab in patients with hairy cell leukemia.]
Golomb, HM. “Skeletal complications in hairy cell leukemia: diagnosis and therapy”. J Clin Oncol. vol. 6. 1988. pp. 1280-1284. [This is a retrospective review of the skeletal complications in patients with hairy cell leukemia.]
VanderMolen, LA, Urba, WJ, Longo, DL. “Diffuse osteosclerosis in hairy cell leukemia”. Blood. vol. 74. 1989. pp. 2066-2069. [This is one of the original references describing the bone marrow abnormalities in patients with hairy cell leukemia including fibrosis and osteosclerosis.]
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- Hairy cell leukemia
- What every physician needs to know:
- Are you sure your patient has hairy cell leukemia? What should you expect to find?
- Beware of other conditions that can mimic hairy cell leukemia:
- Which individuals are most at risk for developing hairy cell leukemia:
- What laboratory studies should you order to help make the diagnosis and how should you interpret the results?
- What imaging studies (if any) will be helpful in making or excluding the diagnosis of hairy cell leukemia?
- If you decide the patient has hairy cell leukemia, what therapies should you initiate immediately?
- More definitive therapies?
- What other therapies are helpful for reducing complications?
- What should you tell the patient and the family about prognosis?
- What if scenarios.
- What other clinical manifestations may help me to diagnose hairy cell leukemia?
- What other additional laboratory studies may be ordered?