Leukemia (Part Two)

What are the risk factors for the development of malignant hematologic pathologies?

A number of chemical, physical, and biological agents can cause changes in the DNA molecule. These factors are called mutagens. Mutagens that increase the probability of a normal cell's malignant transformation are known as carcinogens. For a tumor to develop, not only is genetic predisposition required, but also the action of these carcinogens (environmental influence). The disruption of the balance between oncogenes and anti-oncogenes based on DNA changes can be caused by several reasons, but none of them is fully proven. The risk factors for the development of hematologic tumor diseases are:

1. Hereditary: Every disease has a genetic basis (of course, environmental influence is also required), except for accidents. Some diseases are subject to the laws of inheritance, some are not. It has been observed that in people with Down Syndrome, ALL is 10-18 times higher than in other normal people. Thus, chromosomal breaks in these diseases favor the disruption of the above equilibriums. Similarly, it was mentioned that individuals with heterozygous forms of damage or inactivation of anti-oncogenes have a predisposition for the development of some familial character tumors e.g., retinoblastoma. First-degree relatives have a 3 times higher risk of developing AML.
2. Chemical substances: e.g., chemotherapeutic agents that act on DNA (Alkeran, Leukeran, Procarbazine, Hydroxyurea, etc.) especially when accompanied by radiotherapy. The cause is DNA damage and/or immunosuppression that causes a reduction in the body's resistance. Chronic exposure to benzene can be a cause for aplasia of the bone marrow, myelodysplasia, and AML. Therefore, gas stations must be in open environments to reduce as much as possible the exposure to benzene for people working in these environments. There are also other industrial chemicals (chemical dyes, disinfectants, etc.) that can cause leukemia although less than benzene.
3. Radiation: especially of the bone marrow is leukemogenic. This was observed in people who survived the atomic bomb in Japan. Children of mothers who received abdominal radiation during pregnancy, people who stay in environments with radiation (below high voltage power lines, radiologists, etc.) are at increased risk. It is thought that chromosomal breaks and activation of oncogenes by various mutations might be the causes. Smoking is a risk factor as well as age.
4. Existing hematologic diseases: have a greater predisposition to develop AML (e.g., CML and other myeloproliferative syndromes), myelodysplasia, paroxysmal nocturnal hemoglobinuria, AA, MM, and Morbus Hodgkin’s). In these cases, the cause is the progression of the disease as a result of new chromosomal anomalies. In most cases, secondary leukemias are of the myeloid type and are resistant to treatment.
5. 5. Biological Factors

   a) Viruses: it has been seen that viruses especially retroviruses become a cause for tumor development, but more in animals and birds than in humans. For example, the HTLV-1 virus can cause leukemia, but not all people with this virus may develop a malignant disease. The Epstein Barr virus is seen in M.Hdg, Burkitt's Lymphoma, but not in other types of lymphomas. Similarly, this virus causes lymphoma in patients receiving immunosuppressants for various organ transplants. Patients with congenital or acquired immunodeficiency (AIDS) develop lymphomas or other tumors. The cause is the disorder of cellular immunity (T cells).

   b) Bacteria: such as Helicobacter pylori can be a cause for the development of MALT lymphoma of the stomach.

Acute Leukemia

Acute Leukemia is the most malignant (aggressive), systemic (metastatic) tumor disease from the beginning, characterized by the proliferation and accumulation of tumor cells (blasts), structurally and functionally abnormal cells in the bone marrow (intramedullary), peripheral blood and metastasis in extramedullary organs (spleen, liver, lymph nodes, solitary lymphatic follicles, skin, gingiva, meninges). In this way, it leads to damage to the structures and normal function of these organs, the replacement of their parenchyma with abnormal tumor tissue, accompanied by enlargement of these organs (tumor syndrome), in the bone marrow characterized by bone pain, with its insufficiency (decrease of normal erythrocytes, leukocytes, and platelets, with the respective consequences - Anemic, Infectious, Hemorrhagic Syndromes) and progressive humoral and cellular immunological disorders with tendency for infections and secondary tumors {in survivors and as a result of the use of chemotherapy/radiotherapy (meninges prophylaxis)}.

ALL (Acute Lymphoid Leukemia) is more common in children, with a decline after the age of 10 and for adults, the frequency increases after the age of 40. AML (Acute Myeloid Leukemia) can occur in all age groups, but is more common in adults.

Rarely, Biphenotypic (Undifferentiated) Leukemia - two different cell lines at the same time or tumor cell presents cell markers of two different lines and cannot be classified (cytochemistry and immunophenotyping diagnosis).

Clinic

Relatively quick history (high rate of cellular proliferation with rapid increase in tumor mass). Clinical signs of leukemia are determined by the total number of leukemic (tumor) cells in the bone marrow. When the number reaches 10^9 the disease becomes visible under the microscope (cytological examination of peripheral and central blood). When the number reaches 10^12 the disease fully manifests, with pronounced insufficiency of the bone marrow. When the number of leukemic cells exceeds 60% or more of the total cells in the bone marrow these cells appear in the peripheral blood and infiltrate other organs like the spleen, liver, lymph nodes, meninges, testes. The clinical manifestation and mortality in the case of AL are related to the insufficiency of the bone marrow (neutropenia, thrombocytopenia, and anemia) and less from the infiltration of other organs. Clinic of AL:

1. Related to the Insufficiency of the Bone Marrow (from infiltration of the bone marrow by leukemic cells and replacement of the normal population).

   Anemic Syndrome - Symptoms: Weakness, fatigue, breaking, more pronounced in physical exertions, palpitations, difficulty in breathing, headache (in its back part), flies before the eyes, noise in the ears. In older ages and when it sets in quickly, symptoms of angina pectoris, etc., can also appear. Signs include pallor of the skin and mucous membranes (which appear when Hb is less than 9-10 gr/dl). Anemia is better seen in mucous membranes (lips, mouth, pharynx, conjunctivae), earlobes, palms of the hands, and soles of the feet (when Hb < 7 gr/dl). In cases where anemia sets in quickly and is severe, there may be tachycardia, rapid and pounding pulse, loud heart tones, systolic murmur, cardiomegaly, cardiac insufficiency, acute pulmonary edema.

   Infectious Syndrome - Fever, skin, throat, mouth, respiratory system infections, perianal region, etc., from neutropenia and damage to immune processes.

   Hemorrhagic Syndrome - Spontaneous hemorrhagic phenomena from the nose, mouth, menorrhagia, from injection sites, cerebral hemorrhage, etc., from thrombocytopenia. AML3 often accompanies DIC.

2. From the infiltration of other organs (organomegaly, damage to their structure and function)
   Bone pain from hyperplasia of the bone marrow.
   Lymphadenopathy more in ALL.
   Splenomegaly, hepatomegaly more in ALL.
   Gingival hypertrophy, skin involvement more in AML4 and AML5.
   Meningeal syndrome more in ALL and in AML4, AML5.
   Testicular infiltration in ALL or mediastinal compression in ALL-T.

3. Hypermetabolism Syndrome (sweat, fever, weight loss).
4. Complications:

   Hyperleukocytosis/Leukostasis Syndrome (when circulating leukocytes are > 100.000 mm3), Disseminated Intravascular Coagulation, Tumor Lysis Syndrome, Hypercalcemia.

Laboratory

• Anemia is normochromic normocytic.
• The total number of leukocytes can be normal, increased, or decreased.
• Thrombocytopenia is common.
• In the smear of central blood (bone marrow smear) and peripheral blood, leukemic cells (myeloblasts or lymphoblasts depending on the type of AL) are shown. Precisely based on the morphology (FAB classification), the type and subtype of AL will be determined.
• The bone marrow is hypercellular with proliferation and accumulation of leukemic blast cells over 30 (20)% of all bone marrow cells. Often leukemic cells occupy 75-100% of the total number of bone marrow cells. Not infrequently, aspiration of the bone marrow (bone marrow smear) may not have material, due to hyperplasia.