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! And I’m so happy you caught that error, because that means you really understood the heme malignancies in 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.

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.