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Chronic Lymphocytic Leukemia (CLL) : Causes, Pathogenesis, Lab findings, Symptoms & Treatment

Chronic Lymphocytic Leukemia CLL : Overview, Pathogenesis, Lab findings, Symptoms & Treatment

Definition

  • Chronic lymphocytic leukemia CLL is a type of Cancer (Blood cancer) in which Bone marrow or lymphoid tissue excessively (Uncontrolled & unregulated) produce Lymphocytes-a type of WBC.
  • Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are essentially identical, differing only in the extent of peripheral blood involvement. Somewhat arbitrarily, if the peripheral blood lymphocyte count exceeds 4000 cells/μL, the patient is diagnosed with CLL; if it does not, a diagnosis of SLL is made. CLL/SLL is a neoplasm of mature B cells expressing the pan-B cell markers CD19, CD20, and CD23 and surface immunoglobulin heavy and light chains.
  • The tumor cells also express CD5. This is a helpful diagnostic clue, since among B cell lymphomas only CLL/SLL and mantle cell lymphoma commonly express CD5.

Pathogenesis

  • CLL/SLL is an indolent, slowly growing tumor, suggesting that increased tumor cell survival is more important than tumor cell proliferation in this disease.
    – In line with this idea, the tumor cells contain high levels of BCL2, a protein that inhibits apoptosis.
    – Unlike in follicular lymphoma, the BCL2 gene is not rearranged.
    – Some evidence suggests that BCL2 is upregulated in the tumor cells as a consequence of the loss of several regulatory micro-RNAs that are encoded on chromosome 13.
  • Another important pathogenic aspect of CLL/SLL is immune dysregulation.
    – Through unclear mechanisms, the accumulation of CLL/SLL cells suppresses normal B cell function, often resulting in hypogammaglobulinemia.
    – Paradoxically, approximately 15% of patients have autoantibodies against their own red cells or platelets.
    – When present, the autoantibodies are made by nonmalignant bystander B cells, Indicating that the tumor cells somehow impair immune tolerance.
    – As time passes the tumor cells tend to displace the normal marrow elements, leading to anemia, neutropenia, and eventual thrombocytopenia.

Lab findings & Morphology

The diagnosis of  Chronic lymphocytic leukemia CLL can usually be made on the basis of physical findings and blood smear examination:

  • BLOOD PICTURE : The findings of routine blood picture are as under:
    – Anaemia : Anaemia is usually mild to moderate and normocytic normochromic in type.
    – Mild reticulocytosis may be present.
    – About 20% cases develop a Coombs’-positive autoimmune haemolytic anaemia.
    – White blood cells : Typically, there is marked leucocytosis (lymphocytosis) but less than that seen in CML (50,000-200,000/μl). Most of lymphocytes are mature small resting lymphocytes with dark, round nuclei, and scanty cytoplasm. The circulating tumor cells are fragile and during the preparation of smears frequently are disrupted, producing characteristic Smudge or basket cells (degenerated forms). The foci of mitotically active cells are called proliferation centers, which are pathognomonic for CLL/SLL. The absolute neutrophil count is, however, generally within normal range.  Granulocytopenia occurs when disease is fairly advanced.
    – Platelets : The platelet count is normal or moderately reduced as an autoimmune phenomenon.
  • BONE MARROW EXAMINATION : The typical findings are as under:
    – Increased lymphocyte count (25-95%).
    – Reduced myeloid precursors.
    – Reduced erythroid precursors.
  • LYMPH NODE BIOPSY :
    – Scattered ill-defined foci of larger, actively dividing cells diffusely efface involved lymph nodes.
    – Cases with lymphadenopathy at presentation show replacement of the lymph node by diffuse proliferation of well-differentiated, mature, small and uniform lymphocytes without any cytologic atypia or significant mitoses.
    – These cells are of monoclonal B-cell origin having immunologic features of mantle zone B-cells.
  • OTHER INVESTIGATIONS : These include the following:
    – Erythrocyte rosette test with mouse red cells is positive in more than 95% of cases indicating that CLL is a monoclonal B cell neoplasm.
    – Positive for B-cell markers e.g. typically CD5 positive; other pan-B cell markers are CD19, CD20, CD23, surface immunoglobulins of various classes, monoclonal light chains (λ or κ type).
    – Serum immunoglobulin levels are generally reduced.
    – Coombs’ test is positive in 20% cases.
    – Cytogenetic abnormalities, most commonly trisomy 12 seen in about 25% cases.

Clinical symptoms

When first detected, CLL/SLL is often asymptomatic.
The condition may remain asymptomatic, or may have an insidious onset and may present with nonspecific clinical features.
The most common clinical signs and symptoms are nonspecific and include :

  • Features of anaemia such as gradually increasing weakness, fatigue & dyspnoea.
  • Enlargement of superficial lymph nodes is a very common finding.Splenomegaly & Hepatomegaly are usual.
  • Haemorrhagic manifestations are found in case of CLL with thrombocytopenia.
  • Susceptibility to Infections, particularly of respiratory tract, are common in Chronic lymphocytic leukemia CLL.
  • Less common findings are: mediastinal pressure, tonsillar enlargement, disturbed vision, and bone and joint pains.

The course and prognosis are extremely variable. Many patients live more than 10 years after diagnosis and die of unrelated causes.
The median survival is 4 to 6 years, however, and as time passes, CLL/SLL tends to transform to more aggressive tumors that resemble either prolymphocytic leukemia or diffuse large B cell lymphoma.
Once transformation occurs, the median survival is less than 1 year.
Prognosis of CLL/SLL is generally better than CML since blastic transformation seldom occurs.

Treatment

Unlike other leukaemias, none of the available drugs and radiation therapy are capable of eradicating Chronic lymphocytic leukemia CLL and inducetrue complete remission.
Treatment is, therefore, palliative and symptomatic, and with optimal management patient can usually lead a relatively normal life for several years.

  • These approaches include: alkylating drugs (e.g. chlorambucil, cyclophosphamide), corticosteroids and radiotherapy.
  • Splenectomy is indicated in cases of CLL with autoimmune haemolytic anaemia.

Also Read : Chronic Myeloid Leukemia (CML)

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