Hairy cell leukemia is a chronic B-cell lymphoproliferative process that occurs with a predominant lesion of the bone marrow and spleen. Clinically manifested by hepatosplenomegaly, lymphadenopathy, lymphocytosis with “hairy” lymphocytes, pancytopenia. The diagnosis is established taking into account the data of the blood picture, immunophenotyping of lymphocytes, ultrasound / CT of abdominal organs, bone marrow puncture. Specific treatment includes the use of IFN-α, purine antagonists, BRAF inhibitor, monoclonal antibodies, etc. Splenectomy is sometimes effective.
ICD 10
C91.4 Hairy cell leukemia
General information
Hairy cell leukemia (HCL) is an oncohematological disease, the characteristic signs of which are a deficiency of all cellular elements of the blood, the presence of “villous” lymphocytes, an increase in the spleen, visceral and parietal lymph nodes. In the adult population, HCL accounts for up to 2% of all leukemias or 8% of other chronic lymphocytic leukemias. The increase in new cases of hemoblastosis is 1:150,000 per year. The average age of manifestation is 50-55 years, although an earlier onset of the disease is not excluded. In men, hairy cell leukemia develops 2-4 times more often than in women.
Causes of hairy cell leukemia
The etiology of hairy cell leukemia continues to be studied. To date, it is reliably known that more than 95% of cases of HCL are associated with the activating mutation V600E ‒ the replacement of the amino acid valine with glutamine (Val600Glu) in the 600th codon of the BRAF gene. This mutation is also dominant in melanoma, it can occur in other malignant tumors: colorectal cancer, NSCLC (non-small cell lung cancer), papillary thyroid cancer.
The exact factors triggering the proliferation of lymphoid cells have not been clarified. The probable determinants are:
- burdened family inheritance by leukemia;
- contact with carcinogens: radiation, chemicals (including radiation therapy, chemotherapy);
- ethnicity (hairy cell leukemia is more often diagnosed among Ashkenazi Jews).
Pathogenesis
The BRAF gene and its expression product, the protein serine-threonine protein kinase, are involved in the functioning of signaling pathways responsible for cell division and differentiation. The B-Raf protein is present in an inactive state in many cell types. The V600E mutation in the BRAF gene contributes to the maintenance of the B-Raf kinase in a constantly active state, which is of critical importance in the formation of malignant tumors of various tissues.
In hairy cell leukemia, a clone of B-lymphocytes is detected at a late stage of differentiation, having thin villous outgrowths (“hairy” lymphocytes), a round or elongated nucleus surrounded by pale blue cytoplasm. To the greatest extent, pathologically altered B lymphocytes infiltrate the bone marrow, the red pulp of the spleen, the sinusoids of the liver, which causes a characteristic clinical triad: pancytopenia, splenomegaly, hepatomegaly.
The clone of pathological lymphocytes produces a number of factors contributing to their survival and further proliferation: tumor necrosis factor, fibroblast growth factor, interleukins 4 and 6. Pancytopenia in HCL is caused by several mechanisms: hypersplenism, infiltration and fibrosis of the bone marrow, production of cytokines by leukemic cells.
Classification
Based on clinical manifestations in oncohematology , two forms of hairy cell leukemia are distinguished:
- classical (indolent) – occurs in 80-90% of patients; characterized by splenomegaly and pancytopenia.
- variant (leukemic, prolymphocytic) – it accounts for 10-20% of clinical observations; it is characterized by the absence of leukopenia, aggressive course and unfavorable prognosis.
The generally accepted division of the HCL has not been developed at the stage. In practice, the first identified cases are staged according to the phases of the course: initial and expanded. According to the response to standard therapy, partial / complete remission, resistant course, early / late relapse are distinguished.
Symptoms of hairy cell leukemia
The classic HCL has been developing gradually over the years. In 20% of cases, the disease is detected accidentally during examination, however, aggressive, rapidly progressive variants of hairy cell leukemia occur. The most characteristic clinical markers are splenomegaly (72-86%), cytopenia, and the presence of “hairy” lymphocytes in the blood (95%). Other symptoms (hepatomegaly, lymphadenopathy) are less pathognomonic.
The enlargement of the spleen can vary from insignificant to gigantic, causing pain in the left hypochondrium. Less common are variants of hemoblastosis without splenomegaly. Approximately 20% of patients have concomitant hepatomegaly. From 10% to 25% of cases of hairy cell leukemia are accompanied by an increase in abdominal, less often – intra-thoracic, peripheral lymph nodes.
There is a decrease in all cellular forms in the blood: leukopenia (monocytopenia, neutropenia, agranulocytosis), anemia, thrombocytopenia. The consequence of pancytopenia is fatigue, shortness of breath, dizziness, hemorrhagic syndrome. The number of villous lymphocytes can be different (from 2% to 90%).
Sometimes there is a lesion of the bones of the skeleton: spine, sacrum, pelvic bones, accompanied by pain syndrome. The course of hairy cell leukemia is often associated with autoimmune diseases (scleroderma, dermatomyositis, nodular periarteritis), as well as blood diseases (mastocytosis, paraproteinemia). Extremely rarely (1%) INCL is combined with chronic lymphocytic leukemia.
Complications
Opportunistic infections are a serious danger in hairy cell leukemia. Patients often have mycoses (aspergillosis, cryptococcosis, pneumocystosis), protozooses (toxoplasmosis), bacterial infections (mycobacteriosis, legionellosis, listeriosis). Often there are intermuscular phlegmons and abscesses, pneumonia. Infectious processes tend to generalize, can be complicated by sepsis with a fatal outcome.
Spontaneous, difficult-to-stop bleeding may occur. Hairy cell leukemia is associated with an increased risk of malignant neoplasia of various localizations. Neuroleukosis is not characteristic. Massive splenomegaly can lead to rupture of the spleen.
Diagnostics of hairy cell leukemia
Hairy cell leukemia is diagnosed based on a combination of clinical, instrumental and laboratory data. Patients need to consult a hematologist. When examined for HCL, an increase in the boundaries of the liver and spleen, sometimes palpable lymph nodes, indicates. Anemic syndrome is indirectly indicated by complaints of weakness, flickering of “flies”, shortness of breath during exercise, dizziness. Hyperthermia, bleeding, frequent infections are possible. The main methods of confirmatory diagnostics include:
- Clinical blood test. An expanded UAC with a leukocyte formula reveals agranulocytosis, monocytopenia, thrombocytopenia, and a decrease in hemoglobin. Against this background, absolute lymphocytosis is noted with the presence of “hairy” cells – this kind of appearance is given to them by uneven, fragmentary contours of the cytoplasm.
- Bone marrow biopsy. Punctate for hairy cell leukemia can be obtained with difficulty due to severe bone marrow fibrosis (dry puncture). In the sample of the material, there is an inhibition of hematopoiesis sprouts, the phenomenon of “honeycomb” (rarefaction areas). Villous lymphocytes, infiltration of the bone marrow by leukemic cells are also detected.
- Immunophenotyping of lymphocytes. It is carried out by flow cytometry in a blood or bone marrow sample. The following immunophenotypic markers are characteristic: CD19, CD20, CD22, CD79a, CD11c, CD25, CD103, FMC7, CD123, CD85. There is no expression of CD5, CD10, CD23, CD43 antigens.
- Genetic diagnosis. It is aimed at searching for the BRAF V600E mutation in blood lymphoid cells or bone marrow punctate. The analysis is performed by PCR or IHC. This gene defect is found in more than 90% of cases of hairy cell leukemia.
- Other tests. A specific diagnostic criterion for INCL is the detection of pathological tartrate-resistant acid phosphatase (TRAP) in the cytoplasm of cells. Immunochemical examination reveals the secretion of poly- or monoclonal immunoglobulins (more often IgG3) in blood serum, Bence-Jones protein in urine.
- Ultrasound and CT. The echostructure and size of the spleen are evaluated using ultrasound of the abdominal organs. To visualize the condition of visceral lymph nodes, CT of the abdominal cavity and CT of the chest organs are shown. In order to exclude bone tissue damage, a CT scan of the spine and bones is performed.
Differential diagnosis
During the diagnosis of hairy cell leukemia, other hematological, tumor and other diseases occurring with splenomegaly, pancytopenia, lymphocytosis are excluded:
- aplastic anemia;
- myelofibrosis;
- myelodysplastic syndrome;
- spleen lymphoma;
- T-cell lymphoma;
- Gaucher’s disease.
Treatment of hairy cell leukemia
In the initial asymptomatic phase, observation is carried out, treatment is prescribed in the expanded stage of HCL. Indications for the start of therapy are increasing pancytopenia, pronounced splenomegaly, infectious complications. The use of cytostatic drugs and glucocorticosteroids has no effect. For the treatment of hairy cell leukemia:
- Interferon therapy. It is recommended as a starting therapy for patients with newly diagnosed HCL. The effectiveness of interferon alpha treatment is 70-80%, but complete remission is usually not achieved.
- Purine antagonists. They are the main drugs for the therapy of HCL. Cytostatics of this group have shown efficacy both in newly diagnosed patients with hairy cell leukemia and in those who have already received other treatment. The absence of relapses within 5 years after the course of treatment is noted in 80% of cases.
- Other medicines. With refractory forms of hairy cell leukemia, the appointment of a BRAF kinase inhibitor is resorted to (with a proven BRAFV600E mutation). It is also possible to include alkylating drugs in the therapy regimen as monotherapy or in combination with monoclonal antibodies.
- Accompanying therapy. With the development of systemic infectious complications, antimicrobials are prescribed. A short-term course of erythropoietin is recommended for patients with severe anemia.
- Splenectomy. Removal of the spleen quickly normalizes the blood picture. However, in a number of patients, remission is short-lived, which requires further connection of drug therapy. As the first stage of treatment, surgery is indicated mainly for recurrent bleeding and infections.
Prognosis and prevention
Hairy cell leukemia tends to recur. During the 5-year follow–up period, relapses occur in 35% of patients, within 10 years – in 50%. Without treatment, the life expectancy of patients with HCL is less than 5 years. Methods of primary prevention of hairy cell leukemia have not been developed. After completing the course of therapy, all patients should be monitored by an oncohematologist with blood test monitoring twice a year and ultrasound of the spleen annually. Timely anti-relapse treatment allows you to achieve partial or complete remission, increase life expectancy.
