Leukemias: Pathology review

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Case Study0:00–1:35

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 our rods in the cytoplasm.
Next, there's a mother with her five 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 and increased WBC S. 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% Ok.

Pathology1:35–3:19

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 is 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 keeps 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.

Leukemias3:19–4:37

All right. 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. These include T cells and B cells.
Ok. 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.

AML4:37–6:03

Acute leukemias include acute myeloid leukemia or AML and acute lymphoblastic leukemia or A LL. 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 HC.
All right. Now, let's take a closer look at these different types of leukemias starting with the acute ones.
A ML and A LL AML is more common in older adults with a median age of 65 years. Whereas A L 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 A LL is also due to chromosomal translocations like translocation of chromosomes 12 and 21 or translocation of chromosomes nine and 22 also called the philadelphia chromosome.
Another condition often associated with both AML and A LL is Down syndrome, which is caused by an extra chromosome. 21 myelodysplastic syndrome, which is characterized by defective maturation of myeloid cells and build up of blasts in the bone marrow can lead to A L.

APL6:03–6:42

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.

ALL6:42–7:12

Ok. Now, a variation of A ML is acute prom myeloic 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 ra ra which disrupts the retinoic acid receptor alpha gene.

CML7:12–9:03

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, A LL can further be classified into B cell A LL where there is proliferation of precursor B cells and T cell A LL where there's proliferation of precursor T cells.
B cell A LL accounts for approximately 70 to 80% of A LL cases. Now, an important fact to remember is that abnormal lymphoblasts in al can also infiltrate the lymph nodes and other lymphatic tissue.
So, it's also called lymphoblastic lymphoma. All right.
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's 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 nine's long arm switches with a portion of chromosome 20 two's long arm. This results in a modified chromosome nine 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 nine 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.

CLL9:03–10:27

Since BCR ABL helps control various cellular functions like cell division. Having it always on forces myeloid cells to keep dividing, which causes a build up 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 progresses into the more serious AML. This is called a blast crisis and is linked to trisomy of chromosome number eight or the doubling of the philadelphia chromosome treatment for CML consists of BCR ABL tyrosine kinase inhibitors.
On the other hand, CLL which is most commonly seen in the elderly is not caused by one particular mutation, but it can result from a variety of chromosomal mutations that affect lymphocytes in particular B cells mutations in the genes that code for Bruton's Tyrosine kinase.

HCL10:27–10:52

For example, is probably what stops B cells from maturing fully. And similar interference with other tyrosine kinases prevents cell apoptosis just like with the blast cells.

Symptoms10:52–12:56

And al these partially mature B cells can move into the lymphatic tissues like the lymph nodes and cause lymphadenopathy.
Eventually B cells in these nodes will accumulate into distinct masses or lymphomas, which is why CLL is sometimes called small lymphocytic lymphoma.
Further progression might take the form of a Richter transformation where those small lymphomas transform into an aggressive lymphoma, which is usually diffuse large B cell lymphoma.
Now, for some unknown reason in people with cll normal B cells are more likely to produce autoantibodies. This can lead to immune thrombocytopenia and autoimmune hemolytic anemia.
This is an important thing to watch for because the crowded bone marrow is already producing fewer rbcs and platelets. So the destruction of more rbcs in platelets can be especially problematic.
Finally, there's a special but rare type of chronic leukemia called hairy cell leukemia, which is sometimes also classified as a subtype of CLL.
It's almost always caused by an activating mutation in the B RAF gene which increases cell survival. The affected B cells have hair like projections, giving them a fuzzy appearance.
They typically build up in the bone marrow causing fibrosis that results in pancytopenia. And they're also found in large quantities in the spleen leading to severe splenomegaly.
Ok. Now, let's move on and talk about symptoms of acute leukemias.
Both AML and A LL can cause fatigue because of the anemia, easier bleeding due to thrombocytopenia and more frequent infections because of the leukopenia, pain and tenderness in the bones can occur when there's increased blast 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.

Diagnosis12:56–16:37

However, hepatosplenomegaly and lymphadenopathy are both seen more prominently in a ll than in AML. Since lymphoblasts settle more often in organs like the liver, the spleen and the lymph nodes in APL promyelocytes can activate the clotting process.
And this combined with the already decreased platelets can result in disseminated intravascular coagulation or d. Another subtype of AML called acute monocytic leukemia can cause swelling and bleeding of the gums because of monocytic infiltration.
A key clinical symptom in T cell al is that the abnormal lymphoblasts migrate to the thymus. Like normal T cells do and cause thymus enlargement which can present as a mass or growth in the mediastinum.
This mass can compress mediastinal structures such as large vessels like the superior vena cava causing superior vena cava syndrome or the esophagus causing dysphasia.
While compression of the trachea causes dyspnea and stridor. Now let's move on to chronic leukemias.
Symptoms of CML cll and hairy cell leukemia also include fatigue, easy bleeding and frequent infections due to anemia, thrombocytopenia and leukopenia.
In addition, hepatosplenomegaly is typical in CML and often causes a feeling of abdominal fullness. While cll is characterized by lymphadenopathy that often causes mild but localized pain in the lymph nodes.
Now, in hairy cell leukemia, patients typically present with massive splenomegaly but peripheral lymphadenopathy is uncommon.
All right, moving on to diagnosis of acute leukemias. The diagnosis of AML and al usually starts with a peripheral blood smear which shows a lot of blast cells, myeloblasts in the case of AML and lymphoblasts in the case of A, 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 to 2% to greater than 20%.
An important step in the diagnosis is to differentiate AML from A L. This can be done by identifying the blast cells as either myeloblasts or lymphoblasts.
In a stained smear. Myeloblasts are usually large cells with nuclei containing fine chromatin and prominent nucleoli.
Our rods in the cytoplasm which are crystallized aggregates of the myeloperoxidase enzyme are a classic feature of myeloblasts in AML, especially in acute promyelocytic leukemia.
On the other hand, lymphoblasts are relatively smaller cells with coarse chromatin which are clumped together and have scant nucleoli.
Lymphoblasts have very little cytoplasm which has glycogen Granules. In addition, immunophenotyping is done to detect certain markers.

Review16:37–17:28

For example, T DT, which is a DNA polymerase that's present only in the nucleus of the lymphoblast. Another concept that is frequently tested is that immunophenotyping can also distinguish precursor B cell from precursor T cell.
A precursor B cells express CD 19 and CD 22. While precursor T cells can variably express CD one C D2 C D3 CD four CD five CD seven and CD eight.
OK. Moving on to the diagnosis of chronic leukemias specifically CML, it also starts with a blood smear that shows a lot of immature white blood cells that might appear similar to mature cells in CML.

Summary17:28–22:04

There is an increased number of granulocytes, monocytes and immature forms of myeloid cells like metamyelocytes and myelocytes.
Now, the test might try to confuse you by having leukemoid reaction as an answer choice. And this is a benign neutrophilia where the neutrophils are functional.
Since CML has immature neutrophils that are not functional. We can differentiate the two by measuring a neutrophil enzyme called leukocyte alkaline phosphatase, also known as lap score in CML.
There's a low lap score as a result of the low activity in malignant neutrophils as opposed to leukemoid reaction, which has a normal or increased lap score.
Bone marrow biopsy will show less than 10% blasts but during a blast crisis, this could go above 20% for a conclusive diagnosis of CML.
Genetic testing must be done to look for the philadelphia chromosome. Now, in CLL, the blood smear often shows smudge cells which are immature B cells that broke apart during the smear.
A key feature of abnormal B cells is that they express particular proteins on their surfaces, including CD five CD 20 CD 23.
Genetic testing can also be done to look for chromosomal defects associated with CLL. Finally, in hairy cell leukemia, peripheral blood smear shows cells with characteristic filamentous hairlike projections.
Aspiration of the bone marrow is usually a dry tap. Since the bone marrow is hypocellular and cells are replaced by fibrous stroma flow cytometric immunophenotyping, looking for CD 20 CD 22 CD, 11 C and C D25 can also help with diagnosis.
Ok. To review, leukemias can occur when there's uncontrolled proliferation of immature WBCs which accumulate in the bone marrow crowding out the normal blood cells.
Leukemias include aml A LL CML cll and hairy cell leukemia. Leukemias can present with findings like anemia, thrombocytopenia, leukopenia, hepatosplenomegaly and lymphadenopathy.
Acute leukemias are usually caused by proliferation of blast cells and progress rapidly. While chronic leukemias progress more slowly and are caused by proliferation of more mature leukocytes that are not functional.
A diagnosis can be made based on the patient's history, physical examination, CBC with peripheral blood smear bone marrow biopsy, immunophenotyping and genetic testing.
Now, back to the patients, all three have problems with recurrent infections due to a decrease in functional WBC S. Mike has thrombocytopenia.
And his bone marrow biopsy showed more than 20% blasts in cells containing our rods. All of this points to acute prom myeloic leukemia.
APL is also the cause of his D IC which results in prolonged PT and PTT decreased fibrinogen elevated D dimer and schistocytes on peripheral blood smear.
Now, Luke also has blasts more than 20% and with his young age, he most likely has a immunophenotyping must be done to confirm the presence of lymphoblasts and then distinguish B cell leukemia from T cell leukemia.
Finally mia most likely has CML since there's increased granulocytes and immature forms of myeloid cells in her blood smear her low lap score rules out leukemoid reaction.
The severe splenomegaly is also a classic sign. Bone marrow biopsy shows blasts less than 10% which suggests that she is in the chronic phase of CML.
Leukemias: Video, Causes, and Symptoms | Osmosis