LEUKEMIA - LYMPHOMAS LEUKEMIA and LYMPHOMAS- PART OF LIQUID = HAEMATOLOGICAL MALIGNANCIES. proliferation or apoptosis are corrupted in blood cells

Overview… Mature differentiated cells => low growth fraction, indolent neoplasms [low-grade lymphomas or chronic leukemias ]=> expected survival of many years. More primitive stem cells => the highest growth fractions ,rapidly progressive life-threatening illnesses [acute leukemias or high-grade lymphomas]. Involvement of the pluripotent stem cells =>the most aggressive acute leukemias. In general, hematological neoplasms = d’ses of elderly patients, except acute lymphoblastic leukemia [children] and Hodgkin lymphoma [ in the 20-40-year age range]. What about in our setting?? Topic for research….

LEUKEMIAS Leukemias - malignant disorders of the hematopoietic stem cell compartment. Increased numbers of white cells in the bone marrow and/or peripheral blood. The course of leukemia may vary from a few days or weeks to many years, depending on the type

LEUKEMIAS: ACUTE vs CHRONIC: Acute leukemia => proliferation of primitive stem cells , accumulation of blasts, predominantly in the bone marrow, which causes bone marrow failure. Chronic leukemia=> the malignant clone is able to differentiate, resulting in an accumulation of more mature cells

LEUKEMIAS - 4 MAIN GROUPS: Acute Lymphoblastic Leukaemia (ALL) Myeloid Leukaemia (AML) Chronic Lymphocytic Leukaemia (CLL) Chronic Myeloid Leukaemia (CML).

Leukemias- Epidemilogy: Incidence of leukemia of all types in the general population = approxi 10/100 000 per yr. Just under half are acute leukemias. Males : females ratio - about 3:2 in acute myeloid leukemia, 2:1 in chronic lymphocytic leukemia and 1.3:1 in chronic myeloid leukemia. Acute lymphoblastic leukemia shows a peak of incidence in the 1-5 age group. All forms of acute myeloid leukemia have their lowest incidence in young adult life and there is a striking rise over the age of 50. Chronic leukemias occur mainly in middle and old age

Leukemias:Etiology / Risk factors: Although etiology unknown / RF: Radiation [ atomic bomb in Japan, Chernoboul atomic station catastrophe …]. Greater risk results from higher-dose radiation delivered over shorter periods to younger patients. Oncogenic viruses : [Human T-cell lymphotropic virus type I (HTLV-I) and adult T-cell leukemia (ATL); Epstein-Barr virus causes infectious mononucleosis, is associated with Burkitt's lymphoma and mature B-cell ALL].

Leukemias:Etiology / Risk factors:… Chemicals and Drugs: [Exposure to benzene and benzene-containing compounds ,e.g: kerosene and carbon tetrachloride => aplastic anemia, myelodysplasia , or AML. A link between leukemia and tobacco use has recently been reported. Use of Alkylating agents such as melphalan and the nitrosoureas might be associated with an increased risk of secondary AML in 4-6 years

Leukemias:Etiology / Risk factors:… Genetics: - Increased incidence of leukemia(20 %) in the identical twin of patients with leukemia -Approximately 95% of CML have the Philadelphia (Ph) chromosome -Increased incidence in Down's syndrome and certain other genetic disorders Immunological: -Immune deficiency states (e.g. hypogammaglobulinaemia, HIV are associated with an increase in hematological malignancy Philadelphia (Ph) chromosome is a shortened chromosome 22 and is the result of a reciprocal translocation of material with chromosome 9. The break on chromosome 22 occurs in the breakpoint cluster region (BCR). The fragment from chromosome 9 that joins the BCR carries the abl oncogene, which forms a chimeric gene with the remains of the BCR

ACUTE LEUKEMIAS Proliferation of cells Failure to mature. Accumulation of useless cells which take up more and more marrow space at the expense of the normal hematopoietic elements. Proliferation spills [se rependre ] into the blood. AML : 4 times more common than ALL in adults. In children the proportions are reversed, the lymphoblastic variety being more common. The clinical features are usually those of bone marrow failure (anemia, bleeding or infection

WHO CLASSIFICATION OF ACUTE LEUKEMIA FAB [FRENCH-AMERICAN-BRETISH classification]

CML -Myeloproliferative stem cell disorder resulting in proliferation of all hematopoietic lineages with predominancy in the granulocytic series. -Maturation proceeds fairly normally. -Occurs chiefly between the ages of 30 and 80 with a peak incidence at 55 years. -Accounts for 20% of all leukemias. -The disease is found in all races. -The etiology is unknown, but… - Approximately 95% of patients have chromosome abnormality -the Philadelphia (Ph) chromosome

CML- DIAGNOSIS About 25% of patients - asymptomatic at diagnosis. P/E: -Splenomegaly in 90% of patients. A friction rub may be heard in cases of splenic infarction. -Hepatomegaly occurs in about 50% of patients. -Lymphadenopathy is unusual.

CML- DIAGNOSIS… 1.FBC: - Normocytic, normochromic anemia. Hb = 70-150 g/l. -The mean leucocyte count is 220 × 109/l with a range of 9.5-600. -Myeloblast usually <10% of all white cells. -There is a dramatic increase in the number of circulating blasts as the disease enters blast transformation. -Increase in eosinophils and basophils, and nucleated red cells. -Basophilia tends to increase as the disease progresses.

CML- DIAGNOSIS… 2. Bone marrow should be obtained for chromosome analysis to demonstrate the presence of the Ph chromosome, and RNA analysis to demonstrate the presence of the BCR ABL gene product. 3. Other blood tests: -Very low neutrophil alkaline phosphatase score . -Very high vitamin B12 levels in the plasma. -Tumor lysis Sd [increased LDH,uric acid,K+,PO4,low serCa2+]

NATURAL HISTORY OF CML: 3PHASES 1 Chronic phase: disease is responsive to treatment and is easily controlled, typically lasting 3-5 years. 2. Accelerated phase: (not always seen): disease control becomes more difficult . 3.Blast crisis: disease transforms into an acute leukemia, either myeloid (70%) or lymphoblastic (30%) - relatively refractory to treatment. =>Blast crisis occurs at a rate of 10% per year and is the cause of death in the majority of patients. =>Patient survival is therefore dictated by the timing of blast crisis, which cannot be predicted.

CLL -The most common variety of leukemia: 30% of cases. -Male to female ratio =2:1 -Median age at presentation : between 65 and 70 years. - In this disease B lymphocytes, which would normally respond to antigens by transformation and antibody formation, fail to do so. An ever-increasing mass of immuno-incompetent cells accumulate, to the detriment of immune function and normal bone marrow hematopoiesis.

CLL-DIAGNOSIS 1.Peripheral blood: -Mature lymphocytosis (> 5 × 109/l) with characteristic morphology and cell surface markers. - Immunophenotyping - monoclonal B cells expressing the B-cell antigens CD19 and CD23 with either kappa or lambda immunoglobulin light chains and, characteristically; a T-cell antigen - CD5.

CLL-DIAGNOSIS… 2.Other tests: -Reticulocyte count . -Direct Coombs test as autoimmune hemolytic anemia may occur -Serum immunoglobulin levels should be estimated to establish the degree of immunosuppression. -Bone marrow examination by aspirate and trephine is not essential.

CLL STAGING =>PROGNOSIS

LYMPHOMAS =>Neoplasms from lymphoid tissues. =>Diagnosed from the pathological findings on biopsy as Hodgkin[Reed-Sternberg cells] or non-Hodgkin lymphoma. The majority are of B- cell origin. Non-Hodgkin lymphomas are classified as low- or high-grade tumors on the basis of their proliferation rate.

LYMPHOMAS: STAGE-GRADE-PERFORMANCE STATUS 1.Stage: -Clinical or pathologic assessment of tumor spread. -The major role of staging - to define the optimal therapy and prognosis in subsets of patients. -Treatment plans are generally determined by the stage of the tumor. -Local therapies: surgery, radiation are determined by regional spread of disease. -Systemic therapy, or chemotherapy also dependent on the stage of the tumor.

LYMPHOMAS: STAGE-GRADE-PERFORMANCE STATUS… 2.The tumor grade: -Defines its retention of characteristics compared to the cell of origin. -Designated as low, moderate, or high as the tissue loses its normal appearance [proliferation rate]. - Although grade is important in determining prognosis for many tumors, it is not used as commonly as stage in defining treatment plans.

LYMPHOMAS: STAGE-GRADE-PERFORMANCE STATUS… -A gauge of a patient's overall functional status. Two scales are commonly used: 1. Karnofsky performance status scale [100%-0%] and 2. Eastern Cooperative Oncology Group (ECOG)scale [0-4]. Performance status - essential component of the evaluation of cancer patients, helps predict response to treatment, duration of response, and survival: [For most solid tumors, patients with poor performance status are unlikely to derive significant benefit from systemic chemotherapy. However, patients with tumors that respond dramatically to chemotherapy may benefit from this treatment, even if they have poor performance status.]

LYMPHOID MALIGNANCIES:

HODGKIN LYMPHOMA (HL) EPIDEMIOLOGY AND ETIOLOGY:

STAGING OF HL-ANNARBOR CLASSIFICATION B symptoms include fever above 38.5آ°C, night sweats that require a change in clothes, or a 10% weight loss over 6 months. These symptoms suggest bulky disease and a worse prognosis.

HL: INVESTIGATIONS 1.FBC: -May be normal, -A normochromic, normocytic anemia may be present and, together with lymphopenia- bad prognostic factor. -An eosinophilia or a neutrophilia may be present. 2. ESR may be raised. 3. Renal function tests -to ensure function is normal prior to treatment. 4. Liver function may be abnormal in the absence of disease or reflect hepatic infiltration. An obstructive pattern may be caused by nodes at the porta hepatis. 5. LDH measurements, as raised levels are an adverse prognostic factor. 6. Chest X-ray may show a mediastinal mass. 7. CT scan of chest and abdomen to permit staging. Bulky disease (greater than 10 cm in a single node mass) is an adverse prognostic feature. 8. Lymph node biopsy. FNA – NOT USEFULL

NON-HODGKIN LYMPHOMAS [NHL] -NHL: monoclonal proliferation of lymphoid cells and may be of B-cell (70%) or T-cell (30%) origin. -The incidence of these tumors increases with age, to 62.8/million population per year at age 75, and the overall rate is increasing at about 3% per year.

NHL-EPIDEMIOLOGY, ETIOLOGY

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