Pathology Student

Q. I was wondering what the difference was between labeling something as a “leukemia” vs labeling it as a “chronic myeloproliferative disorder.” I understand that leukemias are neoplastic proliferations of hematopoietic stem cells in the bone marrow, but aren’t myeloproliferative disorders the same thing? In particular, what category would chronic myelogenous leukemia be placed into? I have been grouping it with the MPDs, but then I get confused when I start to compare it to acute myelogenous leukemia, which is just labeled as a leukemia, and not a myeloproliferative disorder…?

A. You are right: leukemias are neoplastic proliferations of hematopoietic stem cells in the bone marrow. There are two big categories of leukemias: acute leukemias and chronic leukemias. The acute leukemias are divided into acute myeloid leukemia and acute lymphoblastic leukemia; the chronic leukemias are divided into chronic myeloproliferative disorders and chronic lymphoproliferative disorders.

Under these big acute and chronic categories, there are many different types of leukemia. Acute myeloid leukemia is divided into five main types: AML with genetic abnormalities (like t[8;21]), AML with FLT3 mutation, AML with multilineage dysplasia, therapy-related AML, and AML not otherwise categorized. ALL is divided into three main types: T-cell ALL, B-cell precursor ALL, and B-cell ALL (same as Burkitt lymphoma). The main chronic myeloproliferative disorders are: chronic myeloid (or myelogenous) leukemia (shown above), chronic (or idiopathic) myelofibrosis, polycythemia vera, and essential thrombocythemia. The main chronic lymphoproliferative disorders are: chronic lymphocytic leukemia, hairy cell leukemia, prolymphocytic leukemia, and large granulated lymphocyte leukemia.

I don’t know why they don’t just call the chronic myeloproliferative disorders and chronic lymphoproliferative disorders “chronic myeloid leukemias” and “chronic lymphoid leukemias,” but they don’t. Maybe it’s because one of the chronic myeloproliferative disorders is chronic myeloid leukemia, and to call the whole group of them “chronic myeloid leukemias” would be confusing. In fact, the term “chronic leukemia” isn’t really an official term either. But I like to use it because it shows that the chronic myeloproliferative and lymphoproliferative disorders really are leukemias, not some sort of benign proliferative disorders.

Q. I’m currently doing a research report on acute lymphoblastic leukaemia and I was wondering, are cytomorphology and cytochemistry important in the diagnosis of ALL? It seems like the two techniques are only important because they are able to diagnose AML and therefore, if AML is not diagnosed, by elimination, the condition is ALL. Also, for FISH and cytogenetics, why do metaphases have to be generated?

A. Cytomorphology (looking at the cells under the microscope) and cytochemistry (using stains like myeloperoxidase) are indeed important in differentiating acute myeloid leukemia from acute lymphoblastic leukemia. But that’s not all! It’s important to look under the microscope at a blood smear or bone marrow biopsy if you suspect any hematologic disorder; that’s an unspoken rule. First you look at the slides under the microscope, then you order special studies as needed to verify your presumptive diagnosis.

Diagnosing AML often involves the use of cytochemical stains. These stains are directed against certain parts of the cell. For example, the myeloperoxidase stain is directed against – you guessed it – myeloperoxidase in neutrophil granules; the non-specific esterase (NSE) stain (shown in the photo above) is directed against the NSE enzyme, which is present only in cells of the monocytic series. Cytochemical stains are useful for differentiating AML from ALL, and for subcategorizing the type of AML (some types of AML involve the monocytic series, some involve only promyelocytes, etc.). Diagnosing ALL involves more than simply ruling out AML; other studies are needed to a) confirm that the leukemia is lymphoid, and b) subcategorize the type of ALL (there are many different types, including T-cell ALL, B-cell ALL, and B-cell precursor ALL, each with their own prognosis). For this confirmation and subcategorization, immunophenotyping (looking for markers on the surface of the cell, usually using flow cytometry) is necessary.

Analysis of genetic changes is often useful in the diagnosis and prognosis of hematologic malignancies. You can look for genetic changes a number of different ways, including the two you mentioned: traditional cytogenetics and FISH (fluorescent in-situ hybridization). In traditional cytogenetic techniques, you need to get the cells into metaphase in order to see the chromosomes in their fully formed and separated state (in interphase, the chromosomes are all long and loose, forming kind of an amorphous mass referred to as “chromatin.”) After you get the chromosomes into metaphase, you take a picture of the chromosomes, cut them apart (or do it on a computer) and then sort them into their little corresponding pairs (two chromosome 1s, two chromosome 2s, etc.). The final picture, with all the chromosomes neatly lined up in order, is called a karyotype. This technique is nice because it gives you a good rough look at all the chromosomes; if there are big deletions, or translocations, or inversions, you’ll see those in the karyotype.

FISH is a little different in that you don’t have to get the cells into metaphase (although you can do so if you want). In this technique, you simply use fluorescent markers (hence the name) directed against certain genes. For example, you might use a green marker to “paint” the bcl gene on chromosome 9, and a red marker to “paint” the abl gene on chromosome 22. In a normal cell, the red and green dots would appear separated (since they are on different chromosomes). In a case of chronic myeloid leukemia, in which the malignant cells always have the 9;22 translocation, you’d see red dots right next to green dots (because the bcl gene is sitting right next to the abl gene). There are lots more uses for FISH, but this is the way it’s commonly used in hematologic malignancies.

The bottom line is that you always look at blood smears and bone marrow biopsies under the microscope. If you see what looks like a hematologic malignancy, you usually do additional studies (cytochemistry, immunophenotyping, and/or cytogenetic studies) to confirm the diagnosis and add prognostic information.

Another quiz – this time on acute leukemia. Answers and explanations are in the first comment following this post.

1. Patients with which of the following leukemias may go into DIC if given routine chemotherapeutic agents?

A. Acute promonocytic leukemia
B. Acute promyelocytic leukemia
C. Acute lymphoblastic leukemia
D. Chronic myeloid leukemia
E. Chronic lymphocytic leukemia

2. All of the following terms are technically incorrect, EXCEPT:

A. Acute lymphocytic leukemia
B. Chronic myeloblastic leukemia
C. Chronic lymphoid leukemia
D. Leukemoid reaction
E. Chronic myeloid leukemia

3. Which of the following leukemias is likely to show a panmyelosis:

A. Acute lymphoblastic leukemia
B. Acute monoblastic leukemia
C. Acute erythroblastic leukemia
D. Chronic lymphocytic leukemia
E. Chronic myeloid leukemia

4. A bone marrow biopsy shows 5% myeloblasts and some funny-looking neutrophils and precursors. The most likely diagnosis is:

A. Acute myeloid leukemia
B. Acute lymphoblastic leukemia
C. Myelodysplastic syndrome
D. Bacterial infection
E. Chronic myeloid leukemia

5. While looking around a blood smear, you notice a blast with an Auer rod in it. This patient has:

A. A bacterial infection
B. No disease, unless 20% of the nucleated cells have Auer rods
C. A myelodysplastic syndrome
D. Acute myeloid leukemia
E. Acute lymphoblastic leukemia

6. Acute lymphoblastic leukemia:

A. Often has a good prognosis
B. Never occurs in children
C. Is classified according to morphologic appearance
D. Is only diagnosed when 20% or more of the nucleated cells are lymphoblasts
E. Is an indolent disease

7. Which of the following is a GOOD prognostic indicator in acute lymphoblastic leukemia?

A. Age less than 1
B. A WBC >10,000
C. B-lineage immunophenotype
D. Normal cytogenetics
E. Age >10