Q. Can you tell me the morphological features of AML M0 and M1 blasts versus ALL blasts to differentiate the two? And are there some hints in the other peripheral WBC cells to tell whether one is dealing with ALL or AML? For example, more lymphocytes possibly pointing to ALL?

A. Those are very good questions. The short answer is that it can be very difficult, and sometimes impossible, to tell the difference between myeloblasts and lymphoblasts without special studies (immunophenotyping or cytochemical stains). However, there are a few things that I think are worth noting. 

Malignant myeloblasts

1. Auer rods

Here’s perhaps the most usefult tip of all. If you see a blast with an Auer rod in it, that is definitive evidence that that cell is a malignant myeloblast (with a tiny exception that I’ll mention in a sec). Auer rods are linear arrangements of primary granules (which are only seen in the neutrophil lineage) and for some reason, they tend to show up in some cases of AML. There’s a tiny little Auer rod in the cytoplasm of the cell farthest to the right in the image above (it’s above the nucleus, and if you weren’t looking for it, you could easily miss it. 

A couple things to note about Auer rods. First, they don’t occur in every case of AML (see the comments about AML M0 below). And second, when they do occur in a a particular case of AML, they don’t show up in every single blast. SO: A blast without an Auer rod could still be a myeloblast! In other words, they’re only helpful if they are present. 

Second, there’s a particular type of AML that is composed predominantly of malignant promyelocytes (rather than malignant myeloblasts). This type of AML is called acute promyelocytic leukemia (or APL). In APL, you can see Auer rods in some of the promyelocytes. And actually, there is a diagnostic cell called a faggot cell (faggot in this case is from the old English word for “bundle of sticks”), which is a promyelocyte with a TON of Auer rods (like 20, or 30 or more). 

2. The myeloblasts in M0 are totally undifferentiated.

Therefore, it’s impossible to tell apart from other types of blasts (like lymphoblasts). They never have Auer rods, and there are no tiny granules like you sometimes see in myeloblasts in other types of AML. Cytochemical stains (like MPO) won’t work either (that’s how undifferentiated they are!). For these myeloblasts, you really need immunophenotyping to definitively call them myeloblasts.

3. The myeloblasts in M1 and M2 are a bit more differentiated.

There are occasionally Auer rods present, and some of the blasts may have a few fine granules in the cytoplasm. If you see an Auer rod, you know it’s a malignant myeloblast! Check out the blood smear above. It is from a case of AML-M2, and there are three blasts in the photo. The one at the top right has an Auer rod in it. But the other two blasts – if you just saw them alone, you wouldn’t know whether they were myeloblasts or lymphoblasts).

4. In M0, M1, and M2, you can sometimes see dysplastic changes. 

Examples of dysplastic changes in the neutrophil lineage include include hypogranularity (a lack of secondary granules in the cytoplasm, which makes the neutrophil/neutrophil precursor look like it has clear cytoplasm) and/or hyposegmentation (mature neutrophils with just two – or even NO – lobes/segments). Seeing dysplastic changes in the neutrophils that are hanging around can be a ueful clue that youre dealing with an AML as opposed to an ALL (in which the neutrophils should look completely normal, since they’re not part of the malignant process).

Malignant lymphoblasts

In ALL, morphology (just looking at the cells under the microscope) is not enough, because lymphoblasts don’t have any definitive diagnostic morphologic characteristics. So in every case, we always do immunophenotyping to identify and classify the blasts. The two big goals are a) to prove that the blasts are lymphoid in nature, and b) to classify the lymphoblasts into specific categories using different panels of markers. Both of these things are critical for diagnosis, but also for treatment (different types of ALL get different treatment) and prognosis (some subtypes of ALL have a distinctly good or bad prognosis).

However, there are some soft morphologic clues that are often present in cases of ALL. These aren’t good enough for making a definitive diagnosis in a real patient – but they can help in certain situations.

Situation 1: you’re sitting around a multiheaded scope looking at a case, and your attending asks you “what kind of acute leukemia do you think this is?” Situation 2: you’re doing a path rotation or residency and encounter the dreaded “unknowns.” These consist of a tray of slides with little or no corresponding history that are usually made available to you late in the afternoon. You have to look at each slide and come with at least something intelligent to say (and hopefully a nice little differential diagnosis), because you will be grilled on these during an “unknown” conference (usually the following morning). UGH. I don’t miss those. 

Here are a couple soft clues that can make you lean towards ALL.

1. Many cases of ALL have two morphologically distinct populations of blasts. 

This is sometimes called “dimorphism.” It means that some of the blasts look one way (e.g., they’re large, with big nuclei and fine chromatin) and some of the blasts look another way (e.g., they’re smaller, with more condensed chromatin). You can get dimorphism in leukemias for other reasons too (sometimes you get two different populations of malignant blasts with different immunophenotypes – like myeloblasts and lymphoblasts). This is pretty uncommon, though, so if you see two morphologically distinct groups of blasts, your first thought should be ALL. 

2. Smudge cells are often present in ALL.

Malignant cells of the lymphoid lineage are more fragile than those of myeloid lineage. So when you make a blood or bone marrow aspirate smear, some of the malignant lymphoid cells will burst open. These damaged cells are called smudge cells (or ghost cells, or basket cells), and they can be present in any lymphoid malignancy.

For some reason, everyone loves to talk about smudge cells as a characteristic of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). It’s true that they do occur in many cases of CLL/SLL – but they also occur in other lymphoid malignancies.

So: smudge cells are not diagnostic or pathognomonic of CLL/SLL (because they don’t occur in all cases of CLL/SLL, and they also occur in other lymphoid malignancies.

However, when you see smudge cells, and you’re on the fence about what kind of malignancy you’re looking at (or IF you’re looking at a malignancy, for that matter!), they are a nice hint that you’re likely dealing with some kind of lymphoid malignancy. Again: not enough for real-life definitive diagnosis, but good enough for unknowns or impromptu pimping sessions at the multiheaded scope. 

Bottom line

1. If you see a blast with an Auer rod in it, it’s a malignant myeloblast (or, less commonly, a malignant promyelocyte, especially if there are TONS of Auer rods in a single cell).

2. Malignant lymphoblasts don’t have any kind of definitive diagnostic feature akin to the Auer rod – but there are a few soft signs that can help point you in the right direction: dimorphism and smudge cells. 

3. Probably the most succinct way to sum it all up is this: if all you have is a population of plain old undifferentiated blasts (without Auer rods), you need to do further studies (immunophenotyping is the gold standard) to tell what kind of blasts they are.