Leukemias: Pathology review

A 65-year-old man, named Mike is admitted to the hospital for a lower respiratory tract infection. He reports easy bruising for the past months, and a few hours after admission, he rapidly deteriorates and starts to bleed from venipuncture sites. Lab tests show low platelet count, and bleeding time, PT and PTT are prolonged. Fibrinogen is decreased and d-dimer is elevated. Peripheral blood smear shows schistocytes. Bone marrow biopsy shows more than 30% blast cells with Auer rods in the cytoplasm.

Next, there’s a mother with her 5-year-old son, Luke. Luke’s mother has noticed that he’s been less active and had recurrent upper respiratory tract infections in the past few months. Clinical examination reveals diffuse lymphadenopathy. CBC shows anemia and leukopenia, while bone marrow biopsy shows more than 30% blast cells.

The last person is a 40-year-old woman, named Mia, who reports recurrent upper respiratory tract infection, progressive fatigue, and abdominal fullness. Clinical examination reveals severe splenomegaly. CBC shows anemia, increased WBCs, while blood smear shows increased granulocytes and immature forms of myeloid cells. The lap score is low. Bone marrow biopsy shows blast count of 8%.

Okay, so all three people have leukemia. Leukemias can occur when there’s uncontrolled proliferation of immature white blood cells. The most immature type of cells are called blast cells, but sometimes cells near maturity that resemble normal white blood cells can also be affected. Whatever the stage, these abnormal cells accumulate in the bone marrow or blood. This differentiates them from lymphomas which can also arise from white blood cells, but they typically form solid tumors in lymphatic tissue such as lymph nodes, thymus, or spleen.

Leukemias are most commonly caused by genetic mutations. These mutations can be chromosomal deletions, where part of a chromosome is missing; trisomies, where there’s one extra chromosome; and translocations, where two chromosomes break and swap parts with one another. Regardless of the type of mutation, these abnormal cells can lead to decreased levels of functional white blood cells, which weakens the immune system and results in increased susceptibility to infections.

As these abnormal cells keep proliferating in the bone marrow, they take up a lot of space and this means that the other normal blood cells growing in the bone marrow get “crowded out”, resulting in cytopenias, including anemia, thrombocytopenia, and leukopenia.

As the number of abnormal cells in the bone marrow keep increasing, they spill out into the blood. Now, some of them can deposit in organs and tissues throughout the body, like the liver and spleen causing hepatosplenomegaly, or the lymph nodes causing lymphadenopathy, or the skin causing purple or flesh-colored plaques or nodules called leukemia cutis.

Alright, now, leukemias can be divided into two groups based on the cell type. Myeloid leukemias are caused by proliferation of cells from the myeloid line. These are cells like monocytes or granulocytes, which include eosinophils, basophils, and neutrophils. But lymphoid leukemias can also arise and are caused by the proliferation of cells from the lymphoid line. This includes T-cells & B-cells.

Okay, now, a high yield fact is that leukemias can be further divided into acute or chronic leukemias. In general, chronic leukemias are caused by the increased proliferation of immature leukocytes, and these can have a similar appearance to mature cells but lack their functionality.

This is a key distinction from acute leukemias, where the abnormal white blood cells don’t mature at all, and usually remain in the earlier “blast” form. Acute leukemias include acute myeloid leukemia, or AML, and acute lymphoblastic leukemia, or ALL, and they tend to progress rapidly. Chronic leukemias tend to progress more slowly and they include chronic myeloid leukemia, or CML, chronic lymphocytic leukemia, or CLL, and hairy cell leukemia, or HCL.

Alright, now let’s take a closer look at these different types of leukemias, starting with the acute ones, AML and ALL. AML is more common in older adults with a median age of 65 years, whereas ALL is more common in children, and that’s something you have to remember for the exams since the age of the patient can be an important clue!

AML is usually caused by chromosomal translocations, like translocation of chromosomes 15 and 17. ALL is also due to chromosomal translocations, like translocation of chromosomes 12 and 21, or translocation of chromosomes 9 and 22, also called the Philadelphia chromosome.

Another condition often associated with both AML and ALL is Down syndrome, which is caused by an extra chromosome 21.

Myelodysplastic syndrome, which is characterized by defective maturation of myeloid cells and buildup of blasts in the bone marrow, can lead to AML. 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.

Finally, there are also some risk factors for acute leukemia like exposure to radiation, and alkylating chemotherapy, which may have been used as a treatment for certain types of cancer.

Okay, now, a variation of AML is acute promyelocytic leukemia, or APL. This type of AML arises from promyelocytes, which are more mature myeloblasts. It’s caused by translocation of chromosomes 15 and 17, which results in the formation of a fusion gene called PML-RARA, which disrupts the retinoic acid receptor alpha gene. This gene codes for a protein that regulates normal cell division. The treatment is all-trans retinoic acid, or vitamin A, and arsenic which induces the differentiation of promyelocytes.

Now, ALL can further be classified into B-cell ALL, where there’s proliferation of precursor B-cells, and T-cell ALL, where there’s proliferation of precursor T-cells. B-cell ALL accounts for approximately 70-80% of ALL cases. Now, an important fact to remember is that abnormal lymphoblasts in ALL can also infiltrate the lymph nodes and other lymphatic tissue, so it’s also called lymphoblastic lymphoma.

Alright, now let’s switch gears and talk about chronic leukemias, CML, CLL, and Hairy Cell Leukemia. The most common cause of chronic leukemias are mutations, just like in acute leukemias.

Now, it is also important to remember for the exams that CML is most commonly caused by a particular chromosomal translocation that results in a Philadelphia chromosome. And that’s where a portion of chromosome 9’s long arm switches with a portion of chromosome 22’s long arm. This results in a modified chromosome 9 and modified chromosome 22, and it’s the chromosome 22 that is called the Philadelphia chromosome.

So, in the Philadelphia chromosome, a chromosome 22 gene, which is the BCR gene, ends up sitting right next to a chromosome 9 gene, the ABL gene. When they’re combined, it forms a fusion gene called BCR-ABL, which codes for a protein also called BCR-ABL, which is a constitutively active tyrosine kinase, meaning that BCR-ABL is like an “on/off” switch stuck in the “on” position. Since BCR-ABL helps control various cellular functions like cell division, having it always “on” forces myeloid cells to keep dividing, which causes a buildup of the premature leukocytes in the bone marrow. The premature leukocytes then spill into the blood and build up in the liver and spleen over time, causing “hepatosplenomegaly.” And because these CML cells divide more quickly than they should, there’s a high chance that further genetic mutations can happen! This is when CML progress into the more serious AML. This is called a blast crisis and is linked to trisomy of chromosome number 8 or the doubling of the Philadelphia chromosome. Treatment for CML consists of BCR-ABL tyrosine kinase inhibitors.