Can you answer (and explain) this multiple-choice question on anemia?

Q. I am a 4th year medical student in Sri Lanka. I have a question regarding this anemia question:

Your next patient, a 65 year old Finnish bachelor, is a self-proclaimed heavy drinker. He has the following indices:

Hgb 8 g/dL (12-16)
MCV 110 fL (80-100)
RDW 13% (12–13.5)
RBC 3.5 x 1012/L (4.5-6.0)
WBC 7.2 x 109/L (4-11)
Plt 420 x 109/L (150-450)

What is the most likely diagnosis?

A. Iron-deficiency anemia
B. Thalassemia
C. Megaloblastic anemia
D. Hereditary spherocytosis
E. Sickle cell anemia

Read no further if you want to do this question on your own! Scroll down (only after you’ve figured out the answer) to see the rest of this MS4’s question.

 

 

 

Keep scrolling…(I have to put it way down on the page, so you won’t accidentally see the answer before you are done!)

 

 

 

 

Okay. Here’s the rest of this person’s question:

I know you said the answer is c, but in Kumar and Clark it mentions that chronic alcoholism leads to a non-megaloblastic macrocytosis.

A. Yay! I see you found my little Anemia Quiz from a while back. I remember writing this one and making the history both a little revealing AND a little confusing. Hey, they can’t be all super easy, or you’d never have to look at the indices! And then you wouldn’t learn anything.

Let’s look at the indices first, and figure out what it is, and then we’ll get back to your question.

Here they are again:

Hgb 8 g/dL (12-16)
MCV 110 fL (80-100)
RDW 13% (12–13.5)
RBC 3.5 x 1012/L (4.5-6.0)
WBC 7.2 x 109/L (4-11)
Plt 420 x 109/L (150-450)

Right off the bat, this patient has a hemoglobin that is well below the normal range, meaning that this patient is moderately anemic.

After I see a low hemoglobin, the next thing I look at is the MCV, because the MCV can help you narrow down your list of possible diagnoses. If the MCV is decreased, it means you have a microcytic anemia, which narrows your diagnosis down to iron-deficiency anemia and thalassemia (well, three, I guess, since occasional cases of anemia of chronic disease are microcytic, but that’s pretty uncommon). If the MCV is increased, it means you have a macrocytic anemia, which narrows your diagnosis down to the two types of macrocytic anemia: megaloblastic (due to B12/folate problems) and non-megaloblastic (due to lots of stuff, including alcohol toxicity). If the MCV is normal, well, you’re kind of screwed in terms of narrowing down your list of diagnoses – because the normocytic anemias are a pretty long list.

So we have a patient with a macrocytic anemia. Now what?

It would be nice if we could determine whether the patient has a megaloblastic or non-megaloblastic macrocytic anemia. However, the rest of the indices are unhelpful in determining whether a macrocytic anemia is megaloblastic or non-megaloblastic; you need to look at a blood smear for that. In a blood smear showing non-megaloblastic anemia, the neutrophils look boring and normal. But in a smear showing megaloblastic anemia, you see very cool-looking hypersegmented neutrophils (with 6 or more nuclear lobes) like this one:

 

Which brings us to the history part of this question, which is what you’re asking about.

When I wrote this question, I threw in “self-proclaimed heavy drinker” as a pretty obvious clue that this patient might have alcoholism. Alcoholics may develop a non-megaloblastic macrocytic anemia due to alcohol toxicity alone. However, a much more common scenario in alcoholics (weird that Kumar and Clark don’t mention this) is the development of a megaloblastic macrocytic anemia due to folate deficiency (which is fairly common in alcoholics). Dietary B12 deficiency in alcoholics – or in anyone – is pretty rare, because the stores of B12 in the body are so big that it takes on the order of years with absolutely no B12 in order to get deficient.

I also threw in “Finnish bachelor” as a seemingly obscure clue to the fact that this patient may go back to Finland once in a while to fish (I know, hang in there, it gets better), and maybe he might have eaten raw fish that contained diphyllobothrium latum (fish tapeworm), which is a rare but possible cause of B12 deficiency.

You may think I’m crazy, and maybe you’re right…but if I had $5 for every time I’ve seen “Finnish bachelor” or “Finnish farmer” in a boards or boards-style question in which the answer was megaloblastic anemia, I’d be mildly rich. Well, no, not even…I’d probably have $200 or so. But still. I can’t believe the play that phrase gets. I mean, come ON – that’s a wild series of inferences to get to megaloblastic anemia. Good thing they always give you a blood smear (or describe “hypersegmented neutrophils”) when they want you to pick megaloblastic anemia.

So to sum up our question: this patient has a macrocytic anemia, and although he could have either megaloblastic or non-megaloblastic versions, we don’t know which one he has because there’s no blood smear. Fortunately, the only anemia in the list of answers that is macrocytic is C., megaloblastic anemia. So there you go.

By the way, you can rule out the other answers simply on the basis of the MCV. Iron-deficiency anemia and thalassemia are both microcytic, and hereditary spherocytosis and sickle cell anemia are both normocytic.

Bottom line

A macrocytic anemia (MCV>100) can be either megaloblastic or non-megaloblastic, and to prove which is which, you need a blood smear (which will show hypersegmented neutrophils in megaloblastic anemia).

 

What does “differentiation” mean?


Q. I’ve Googled and YouTubed this thing to death, and I still can’t grasp the meaning of “differentiation.”

It seems the opposite of its definition. To “differentiate” means to recognize what makes something different. But according to your post on tumor differentiation, well-differentiated tumors resemble (don’t look different from) their tissue of origin. I would think if something is well-differentiated, it would look very different from the thing it’s being compared to. Why is the use here opposite of its meaning?
 

A. I totally get where you’re coming from.

It’s REALLY frustrating in pathology when things are described in terms that don’t seem to make sense. You are not alone in questioning the use of this term!

The problem is that the word in question – differentiation – has a specific meaning in the real world. You’re exactly right in your definition: to differentiate between two things means to recognize what’s different or unique.

So you’d think that “differentiation” in the pathology world would mean the same thing: the recognition of things that are unique, different, or not the same. By logical reasoning, then, a “differentiated” tumor would be one that looked different from its cell of origin. And you’d think a “well-differentiated” tumor would be one that looked very different from its cell of origin.

Unfortunately, “differentiation” doesn’t have the same definition in the pathology world. So we have to put aside our logic and knowledge of vocabulary for a moment, irritating as that may be, and learn a new definition for this word.
 

The definition of “differentiation” in pathology-speak.

When we’re talking about tumors, the definition of “differentiation” is simply this: the degree to which tumor cells resemble their cell of origin. A well-differentiated tumor is one in which the tumor cells look very much like their cell of origin. A poorly-differentiated tumor (like the poorly-differentiated squamous cell carcinoma shown above) is one in which the tumor cells barely resemble their cell of origin.

That’s it. Yes, it’s an annoying word choice, because it is used here in a way that seems counterintuitive. But maybe it’s not as far off as it seems.
 

Maybe this will help.

I think about it (okay, rationalize it) this way. When cells are really immature, they don’t have a lot of features that make them look different from other cells. Myeloblasts don’t look very different than lymphoblasts, for example. So we could say that these immature cells are undifferentiated; it’s hard to tell what kind of cell they really are, and hard to tell them apart from other cells.

The same thing is true of the cells in poorly-differentiated tumors! The cells show practically no features that give away their identity; it’s hard to even tell what kind of cells they are. They are, in effect, undifferentiated.

If you think about “differentiation” this way (undifferentiated cells lack identifying features; it’s hard to tell what kind of cell they are), then the concept of tumor differentiation is a little easier to swallow. A little.

Do all leukemias arise from hematopoietic stem cells?

Q. I have a quick question on the cell of origin in leukemia.

In our pharmacology class, we went through a section on cancer. There was a slide that said leukemia is a tumor of hematopoietic stem cells. But leukemia involves more than just hematopoietic stem cells, right? I think I remember from our pathology class that leukemia can also involve cells downstream of hematopoietic stem cells.

A. You’re absolutely right! Which means you really understood the heme part of our pathology class 🙂

Just to back up a bit: all leukemias arise from hematopoietic cells (either myeloid or lymphoid cells). But not all leukemias arise in hematopoietic stem cells. Let’s take a look.

Some leukemias arise in stem cells.

All of the chronic myeloproliferative disorders, for example, originate in stem cells. As a result, when you look in the blood and bone marrow, you see a proliferation of all different kinds of myeloid cells (red cells, neutrophils, and megakaryocytes) at all stages of maturation (neutrophils, myelocytes, metamyelocytes, etc.). In most of the chronic myeloproliferative disorders, a particular myeloid cell line dominates (in chronic myeloid leukemia (CML), for example, most of the malignant cells are neutrophils and precursors) – but because of the stem cell origin, there are other malignant myeloid cells present as well.

Here’s a cool thing. You’d think that the stem cell of origin in these chronic myeloproliferative disorders would be a myeloid stem cell, right? I mean, these disorders are composed of all kinds of myeloid cells – so the origin should be a myeloid stem cell. It turns out that the stem cell involved is actually a very young stem cell – it hasn’t even decided whether it wants to be myeloid or lymphoid! We know this because the characteristic genetic abnormality (for example, the Philadelphia chromosome in CML) is also present in lymphocytes. That explains why when CML evolves into blast crisis, the blasts may be either myeloid or lymphoid

Other leukemias arise in non-stem cells that belong to a specific cell lineage.

Acute promonocytic leukemia, for example, originates in a promonocyte (a stage of development between monoblast and monocyte). This means that when you look at the blood and bone marrow, you see mostly promonocytes (the cells in the image above with the lovely tissue-paper-like nuclei). Cells of other myeloid cell lineages (like red cells or neutrophils) are not present. These types of leukemias are a lot more straightforward.

Heme mistakes like this are common!

This kind of mis-statement (“all leukemias arise from stem cells”) happens a lot when people talk about hematopoietic diseases. Even the names of diseases are often stated incorrectly (e.g., “acute lymphoid leukemia” or “acute lymphocytic leukemia” instead of “acute lymphoblastic leukemia”). Heme is an area that many people shy away from, for some reason. I love it and find it really straightforward, but depending on how it’s taught, it can seem really confusing.

If you’re struggling with heme, there are tons of heme-related posts here on Pathology Student. You might also find my Complete Hematopathology Guide useful; it covers all the main hemepath stuff in a straightforward, no-BS way.

Tumor invasion and metastasis: are they the same thing?

Here are a couple great questions from one of my lovely students regarding invasiveness and metastasis.

Q. I have a quick question on today’s lecture. There is a slide near the end that has a picture of non-invasive carcinoma. For a tumor to be malignant, should it not be invasive?

A. Great question! I think you may be referring to the image above, which shows a gland with either severe dysplasia or carcinoma in situ.

Cancers are usually invasive, as opposed to benign tumors, which grow with pushing borders and are typically encapsulated.

However, very early cancers are called “carcinoma in situ”, which means they have not broken through the basement membrane yet (and thus are non-invasive). Every cancer has to start somewhere!

The only really definitive quality of malignancy is metastasis. If a tumor has metastasized, that is definite evidence of malignancy.

Q. But is invasiveness different from metastasis? That is, can a cancer metastasize without first invading tissue? Or are we talking about a tumor that has the ability to metastasize, but has not yet metastasized?

A. I’ll answer your questions separately.

1. Yes – invasiveness is different than metastasis.

  • Invasiveness is the ability of a tumor to extend into the surrounding tissue, and it is almost always a sign of malignancy. Benign tumors (with very few exceptions), are encapsulated and grow simply by expanding and pushing the surrounding tissue aside. Malignant tumors (with very few exceptions), are unencapsulated and grow by reaching into the surrounding tissue.
  • Metastasis is the ability of the tumor to move to a different location in the body and set up shop (start growing) there. Benign tumors NEVER metastasize. Malignant tumors usually do, although if detected early, they may be removed before they have the chance.

2. No: a cancer cannot metastasize without first invading tissue. In order to metastasize, tumor cells must first invade tissue, then make their way into vessels (either blood vessels or lymphatics), and then make their way out of those vessels and into new tissue.

3. Yes, the image above shows a non-invasive malignancy (carcinoma in situ), which is a malignant tumor that has not yet metastasized (or even invaded) yet. Left to its own devices, carcinoma in situ almost always becomes invasive carcinoma. As the tumor grows, some cells will most certainly develop the ability to become metastatic. So it’s way better to detect a carcinoma when it is in the carcinoma in situ stage rather than the invasive stage.