USMLE® Step 1 style questions USMLE
USMLE® Step 2 style questions USMLE
A 71-year-old man comes to the clinic because of fatigue and malaise for the past three months. He reports that he has lost 4.5 kg (10 lbs) over the past 3 months without changing his diet or exercise routine. His past medical/surgical history and family history are non-contributory. Physical examination shows prominent bilateral cervical and inguinal lymphadenopathy, and splenomegaly. Which of the following is the most likely diagnosis?
Content Reviewers:Rishi Desai, MD, MPH
With chronic leukemia, “leuk” refers to white blood cells, and “emia” refers to the blood; so in chronic leukemia there are lots of partially developed white blood cells in the blood over a long period of time.
These partially developed white blood cells interfere 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 myeloid or lymphoid blood cells.
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.
Chromosomal abnormality in hematopoietic stem cells that are destined to become leukocytes is the most common cause of chronic leukemia.
Some examples of abnormalities include a chromosomal deletion, where part of a chromosome is missing, a trisomy, where there’s one extra chromosome, and a translocation, where two chromosomes break and swap parts with one another.
Now there are two types of chronic leukemia.
The first is chronic myeloid leukemia, CML, which is caused by a particular chromosomal translocation that affects granulocytes.
Both CML and CLL cause cells to mature only partially, and that’s a key distinction from acute leukemias where the cells don’t mature at all.
As a result, these abnormal, premature leukocytes don’t work effectively, which weakens the immune system.
In addition, the chromosomal changes alters the cell’s normal cell cycle.
As a result, in CML the cells start to divide way too quickly and in CLL the cell’s don’t die when they should -- and in both situations, we’re left with way too many of these premature cells.
So over time, premature leukocytes accumulate in the bone marrow, until eventually they spill out into the blood.
Now some of these guys settle down in organs and tissues across the body, but others keep circulating in the blood.
With a bunch of extra cells in the blood, all the healthy cells 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.
In chronic myeloid leukemia, the most common cause is a chromosome translocation which 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 -- and we write that as t(9;22) -- t because it’s a translocation, and 9 and 22 because those are the chromosomes that switch genetic information.
This results in a modified chromosome 9 and modified chromosome 22, and it’s the chromosome 22 that’s 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 quicker than they should, which causes a buildup of the premature leukocytes in the bone marrow, that eventually spill into the blood.
The premature leukocytes then move to the liver and spleen, causing swelling of those organs or “hepatosplenomegaly”.
And because these CML cells divide quicker than they should, there’s a high chance that further genetic mutations can happen!