Acute myeloid & lymphoblastic leukemia – causes, symptoms & pathology

Acute myeloid & lymphoblastic leukemia – causes, symptoms & pathology


Learning medicine is hard work! Osmosis makes it easy. It takes your lectures and notes to create
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much more. Try it free today! With acute leukemia, leuk- refers to white
blood cells, and -emia refers to the blood, so in acute leukemia, there’s uncontrolled
proliferation of partially developed white blood cells, also called blast cells, which
build up in the blood over a short period of time. Although leukemia means cancer white blood
cells, it can also be used to refer to cancer of any of the blood cells, including red blood
cells and platelets. Acute leukemia can be broadly classified into
acute myeloid leukemia, or AML; and acute lymphoblastic leukemia, ALL. AML is more common in old age, where as ALL
is more common in children. In both cases, accumulation of blast cells
interferes with the development and function of healthy white blood cells, platelets, and
red blood cells. Now, every blood cell starts its life in the
bone marrow as a hematopoietic stem cell. Hematopoietic stem cells are multipotent — meaning
that they can give rise to both myeloblasts, which are precursors of myeloid blood cells,
and lymphoblasts, which are precursors of lymphoid blood cells. These lymphoblasts can be pre-B cells, which
develop into B lymphocytes; or pre-T cells, which develop into T lymphocytes. If a hematopoietic stem cell develops into
a myeloid cell, it’ll mature into an erythrocyte — or a red blood cell, a thrombocyte — or
a platelet, or a leukocyte — or a white blood cell, like a monocyte or granulocyte. Granulocytes are cells with tiny granules
inside of them — they include neutrophils, basophils, and eosinophils. If a hematopoietic stem cell develops into
a lymphoid cell, on the other hand, it’ll mature into some other kind of leukocyte:
a T cell, a B cell, or a natural killer cell, which are referred to as lymphocytes. Once the various blood cells form, they leave
the bone marrow, and travel around the blood, or settle down in tissues and organs like
the lymph nodes and spleen. Acute leukemia is caused by a mutation in
the precursor blood cells in the bone marrow. In the case of ALL it’s usually due to a
chromosomal translocation or due to an abnormal chromosome number. Common chromosomal translocations include
translocation of chromosome 12 and 21 and translocation of chromosome 9 and 22, also
called the Philadelphia chromosome. These result in production of abnormal intracellular
proteins, which affect the cell’s function and cell division. ALL can further be classified into T-cell
ALL, where there’s proliferation of T-cell precursors, and B-cell ALL, where there’s
proliferation of B-cell precursors. AML is caused by a wide variety of abnormalities
like chromosomal translocations, which are used to subclassify AML into a few different
types. AML can also be classified based on the morphology
of the myeloblast into AML without maturation; AML with minimal maturation, AML with maturation;
acute promyelocytic leukemia; acute myelomonocytic leukemia, acute monocytic leukemia, acute
erythroid leukemia, and acute megakaryoblastic leukemia. Of these, acute promyelocytic leukemia is
an important subtype. It is characterized by translocation of chromosome
15 and 17 which disrupts the retinoic acid receptor alpha gene, which is required for
normal cell division. Now, there are also certain conditions that
can actually lead to AML, like myelodysplastic syndrome, which is characterized by defective
maturation of myeloid cells and buildup of blasts in the bone marrow. Usually the buildup is initially less than
20% blasts. But that’s enough to cause a decrease in
the function of red blood cells, granulocytes, and platelets. As the disease progresses, the blast percentage
may go over 20%, resulting in AML with a background of myelodysplasia. Another condition often associated with both
AML and ALL is Down syndrome, which is caused by an extra 21st chromosome – so that there’s
a trisomy 21. Finally, there are also some risk factors
for acute leukemia like exposure to radiation, and alkylating chemotherapy, which may have
been used as treatment of some other type of cancer. Alright, now regardless of the type of mutation,
acute leukemias share a similar pathogenesis. The mutation does two things. First, it causes these precursor blood cells
to lose their ability to differentiate into mature blood cells. This means that they’re stuck in the blast
stage of development, and the blast cells don’t function effectively. Second, it makes the blast cells divide uncontrollably,
and in the process take up a lot of space and nutrition in the bone marrow. This means that the other normal blood cells
growing in the bone marrow get “crowded out”, and it’s tough for them to survive
with the extra competition for nutrients. This causes cytopenias, or a reduction in
the number of healthy blood cells, like anemia, which is a reduction of healthy red blood
cells, thrombocytopenia, a reduction of healthy platelets, and leukopenia, or a reduction
of healthy leukocytes. As the number of blast cells in the bone marrow
keep increasing, they spill out into the blood. Now some of these guys, especially lymphoblasts,
settle down in organs and tissues across the body, like the liver and spleen. Sometimes, pre- T cells, in T- cell ALL migrate
to the thymus or lymph nodes like normal T-cells do, and settle down there, causing these structures
to enlarge. Also, in acute promyelocytic leukemia, the
promyelocytes activate the clotting process, and this combined with the already decreased
platelets, results in disseminated intravascular coagulation. Symptoms of both AML and ALL include fatigue,
because of the anemia, easier bleeding, because of the thrombocytopenia, and more frequent
infections, because of the leukopenia. Pain and tenderness in the bones can occur
when there’s increased cell production which causes the bone marrow to expand. Hepatosplenomegaly often causes a feeling
of abdominal fullness, while the lymphadenopathy often causes mild, but localized pain in the
lymph nodes. However, hepatosplenomegaly and lymphadenopathy
are both seen more prominent in ALL than in AML. In addition, monocytic variety of AML causes
swelling of gums because of monocytic infiltration. Thymus enlargement in T-ALL may present as
a mass, or growth in the mediastinum. The diagnosis of AML and ALL usually starts
with a peripheral blood smear, which shows a lot of blast cells, myeloblasts in case
of AML, and lymphoblasts in case of ALL. This is usually followed up by a bone marrow
biopsy, which also shows an increase in blast cells. In acute leukemia, the percentage of blast
cells in the bone marrow goes up from their normal value of 1-2% to greater than 20%! An important step in the diagnosis is to differentiate
AML from ALL. This can be done by identifying the blast
cells as either myeloblast or lymphoblasts in a specially stained smear. Myeloblasts are usually large cells with nuclei
containing fine chromatin and prominent nucleoli. A classic feature of myeloblasts in AML, especially
acute promyelocytic leukemia, is the presence of Auer rods in the cytoplasm, which are crystallized
aggregates of the myeloperoxidase enzyme. On the other hand, lymphoblasts are relatively
smaller cells with coarse chromatin, which are clumped together and have small nucleoli. Lymphoblasts have very little cytoplasm, which
has glycogen granules. In addition, immunophenotyping is done to
detect certain markers, for example, TdT, which is a DNA polymerase that’s present
only in the nucleus of the lymphoblast, is a marker for lymphoblasts, and CD10 is a surface
marker for pre-B cells. Treatment of acute leukemia is mainly aimed
at reducing the number of blast cells, to allow the other blood cells to develop normally. Treatment of AML and ALL is based on the type
and stage of the cancer, but in general involves chemotherapy, biological therapy, stem cell
transplants, or bone marrow transplants. Acute promyelocytic leukemia can be treated
with all-trans-retinoic acid, or ATRA, which is a derivative of vitamin A. ATRA binds to
the disrupted retinoic acid receptor, and causes the blasts to mature into neutrophils,
which eventually go on to die, thereby clearing out a lot of the blasts from the blood. All right, as a quick recap.. Acute leukemia is a cancer of the blood cells,
and is classified into AML and ALL. AML can be further subdivided into different
types based of cytogenetic abnormalities or based on blast cells morphology. ALL on the other hand is classified into T-cell
ALL and B-cell ALL. Both AML and ALL lead to accumulation of blast
cells in the bone marrow, which interferes with the development and function of healthy
white blood cells, platelets, and red blood cells. Major symptoms include fatigue, easy bleeding,
fever, bone pain, hepatosplenomegaly, gum swelling in monocytic type, and mediastinal
mass in T-ALL.

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