What is hairy cell leukemia (HCL)?
Hairy cell leukemia is the name of a type of chronic lymphoid leukemia, a subtype of blood malignancy or blood cancer. The name “hairy cell” is given to this subtype of leukemia due to hairlike projections found on the surface of aberrant B-cells. These are cytoplasmic projections, and the only way to see them and diagnose this subtype of leukemia is through a microscope. It is also diagnosed by the expression of certain surface antigens in B-cells that make up the differential diagnosis with similar diseases, such as multiple myeloma and chronic lymphocytic leukemia.
Pathophysiology of hairy cell leukemia
The abnormalities found in patients with hairy cell leukemia are due to changes in B-cell lymphocytes. The replication of these white blood cells becomes excessive, and the aberrant cells start infiltrating in the bone marrow, causing alterations. Infiltration occurs because the abnormal cells express a receptor that interacts with the vascular adhesion molecule 1, which can be found in the bone marrow, the liver, spleen, and other structures. In the majority of cases, this infiltration causes pancytopenia, which means a reduction of all types of functioning cells in the blood. Other sites of infiltration include the spleen and the liver, which is why these patients have enlarged abdominal organs, too. Lymph nodes are not usually involved or infiltrated by aberrant cells, which is a key feature of hairy cell leukemia.
The genetic cause of hairy cell leukemia is through the abnormal activation of a signaling pathway called RAF-MEK-ERK. This pathway becomes activated through a mutation called BRAF-V600E, which has been characterized and can be detected in genetic studies. As a result of this mutation, B-cells stop undergoing apoptosis (programmed cellular death), adopt a hairy pattern, and replicates excessively.
Another genetic abnormality usually found in hairy cell leukemia is the overexpression of a protein called cyclin D1. This protein is a regulator of the cell cycle and may be involved in the abnormal replication of B cells found in this type of leukemia.
The cause of such genetic change is not yet clear, but exposure to certain types of substances might be involved. Organophosphorus insecticides and exposure to benzene have been proposed as possible risk factors, but this is only a hypothesis. Exposure to radiation and previous infections with mononucleosis may also play an important role.
Hairy cell leukemia symptoms
Hairy cell leukemia is a chronic disease; it is slow-progressing and sometimes asymptomatic. In many cases, patients do not display any symptoms over the course of the disease. Thus, they are usually diagnosed by a routine blood test or one performed to rule out other ailments. Still, some patients start displaying symptoms, and when they do, there’s a chance they need treatment for their condition.
Common symptoms and features of hairy cell leukemia are as follows:
1) Fatigue and weakness
It is the most common symptom of hairy cell leukemia, and it is usually caused by a higher metabolic rate and anemia.
2) Bleeding episodes
Episodic bleeding is common in patients with hairy cell leukemia, and it is due to thrombocytopenia. Bleeding gums, skin rashes and bruises are common in these patients.
3) Fever
It is another common finding, and it is caused by a deficient immune system and propensity to infections due to neutropenia. It is usually a low-grade fever.
4) Increased susceptibility to infections
The most common infections in patients with hairy cell leukemia are bacterial infections, disseminated fungal infections and atypical mycobacterial infections that may aid in leading the diagnosis.
5) Enlarged organs
They are usually found in the physical examination or in an ultrasound exam. Both the liver and the spleen are usually enlarged in patients with hairy cell leukemia. The most common is splenomegaly, which can be massive in up to 80% of cases. Hepatomegaly is found in 20% of patients.
6) Abdominal discomfort and early satiation
These symptoms are a consequence of enlarged organs. Patients may have gastrointestinal problems and abdominal cramps or report early satiety with small portions of food as the spleen creates pressure on the stomach.
7) Weight loss
It is not usually an aggressive weight loss, but patients may reduce their size without noticing or planning it in the first place.
8) No lymphadenopathy
An important combination that increases suspicion in these patients is that they have signs and symptoms of myeloproliferative diseases but do not usually have enlarged lymph nodes. Lymphadenopathy is uncommon and only found in 10% of cases.
Hairy cell leukemia diagnosis
Diagnosing hairy cell leukemia requires looking at the signs and symptoms, suspecting the disease, and then running diagnostic tests to find out the cause of the symptoms. The workup of hairy cell leukemia usually includes:
1) Complete blood count
The first step, and usually the main reason why patients are diagnosed is after a complete blood count with characteristic pancytopenia (anemia, monocytopenia, neutropenia, and thrombocytopenia with an elevated white blood cell count).
2) Peripheral blood smear
It is important for the diagnosis of hairy cell leukemia due to the characteristic morphology of the B cells. They have cytoplasmic projections that look like microvilli under the microscope.
3) Bone marrow biopsy or aspiration
An important phase of the diagnosis is the aspiration or biopsy of the bone marrow. In this test, it is possible to perform the immunophenotypic profile of the B-cells. They will be positive for certain surface proteins (CD11c, CD25, CD103, and CD123) and negative or very dim for others (CD5, CD10, CD23, CD27, CD79b).
4) Imaging studies
They are very useful to evaluate splenomegaly and hepatomegaly in mild forms of hairy cell leukemia. In the majority of cases, they are palpable and encountered in physical examination. However, when a measurement is required, ultrasound will be the most appropriate scan.
Additionally, it is possible to include either immunohistochemistry studies or flow cytometry to distinguish hairy cell leukemia with other types of B-cell lymphoid leukemia. It is possible to test for genetic mutations, in which case it is useful to search for the BRAF-V600E mutation.
Hairy cell leukemia prognosis
Hairy cell leukemia is a type of chronic leukemia, and it is a long-standing disease with a slow progression and a high survival rate. Survival after 5 years is as high as 94% and higher in Whites as compared to African Americans.
However, patients with hairy cell leukemia have a very high chance of developing a second malignancy. The most common second malignancy is skin cancer, which can be sometimes melanoma. Other common malignancies include colon cancer, prostate cancer, lymphoma, and breast cancer. Up to 31% of patients with hairy cell leukemia develop a second malignancy, and some of them were diagnosed before hairy cell leukemia.
Risk stratification of hairy cell leukemia depends on the severity of pancytopenia, the presence of lymphadenopathy, and the presence of additional mutations in the TP53 gene.
Hairy cell leukemia treatment
The treatment approach for hairy cell leukemia depends on the stability and the symptoms of the patient. Patients with stable cell counts in their complete blood test might benefit from a conservative stay-and-watch approach using continuous blood tests and recurrent physical examinations to determine whether or not it is necessary to start treatment. In some cases, patients will remain asymptomatic over the course of the disease, and some of them never start therapy, especially in the case of elderly men who are diagnosed in later years.
However, I when the blood cell count shows persistently declining numbers and the patient starts displaying symptoms, patients might start therapy with purine analogs to avoid reaching very low levels of pancytopenia. During the first stage of therapy, it is possible that blood cell counts become lower, so it is recommended to follow-up patients closely and start treatment before blood values are excessively low.
The most commonly prescribed medications are cladribine and pentostatin, and they are often used in monotherapy. The both have similar side effects, and they are equally effective in improving the symptoms and increasing the duration of remission. Monitoring during treatment is recommended to keep track of adverse effects. Other medications that might be used include a granulocyte colony-stimulating factor to increase the neutrophil count, but the clinical advantage of using this drug is not yet clear.
Additionally, treatment of patients with hairy cell leukemia should include follow-up of the renal function and early detection and treatment of infections. Antibiotic and antifungal treatments are usually required at some point in the disease, and pentostatin is the most nephrotoxic drug and requires monitoring of the renal function. In the case of using pentostatin, it is important to increase fluid intake and perform continuous tests of serum creatinine.
Some patients with hairy cell leukemia may need splenectomy, surgical resection of the spleen. This is only required in patients that do not respond to treatment and those with severe thrombocytopenia and hemorrhagic episodes. The most appropriate surgical method is laparoscopy, and after this procedure, up to 70% of patients improve their cell counts in all three bloodlines.
References
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Tiacci, E., Pettirossi, V., Schiavoni, G., & Falini, B. (2017). Genomics of hairy cell leukemia. Journal of Clinical Oncology, 35(9), 1002.
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