What does “differentiation” mean?


Q. I have 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.

How to remember which genes are tumor suppressors vs. proto-oncogenes

molecular neoplasiaHere’s a question that I got by email yesterday and it’s such a good one that I want to share it with everyone.

Q. I love love LOVE your blog and your daily emails, and your book Clot or Bleed saved my butt for studying for my hematology exam. I was just wondering – do you have a good mnemonic or know of an easy way to remember which cancer gene mutations are proto-oncogenes and which are tumor suppressors? 

A. Thanks for letting me know you found the book and other stuff helpful! I’m so glad to hear that.

I don’t have a mnemonic for these genes (if anyone does, please comment below!). However, I think the best way to remember these is to learn what each gene product does (because then you’ll know whether it’s a proto-oncogene or a tumor suppressor gene).

For example: RAS encodes a signal-transducing protein associated with cell growth. It takes the signal from a growth receptor, and helps get that signal down to the nucleus so something can be done about getting the cell to grow. So it’s a growth-promoting gene (a proto-oncogene). If RAS is going to be a cancer-causing gene (an oncogene), it is going to have to be mutated in such a way that it is always turned on.

Here’s another example: the retinoblastoma (RB) gene. The RB gene product inhibits the cell cycle, turning off normal cell growth when necessary. So it is a tumor suppressor gene (this is a dumb name, but we can save that tirade for another time). If you’re going to cause cancer by mutating the RB gene, you’d have to mutate it in such a way that it doesn’t work well (and cells can just whiz through the G1/S checkpoint no problem). And actually, kind of like the brakes on your car, you typically need to mutate BOTH alleles of a tumor suppressor gene in order to cause tumors (if you just mutate one allele, you’ll still have some “brakes” left in the other allele).

Here is my favorite diagram (above) relating to this topic. It’s from Robbins, and it’s got all the important cancer-related genes (or at least the most important ones for you to learn) listed according to what their products do in the cell. Yay! You can see RAS up there just beneath the cell membrane, doing its job as a signal transducer. RB is down in the nucleus, acting as a cell cycle inhibitor.

A nice touch in this diagram is the color coding: all the red things are growth-promoting (so their genes would belong to the proto-oncogene category). Blue things are growth-inhibiting (so they would be encoded by tumor suppressor genes). The green things function as DNA repair mechanisms (the nice little scissors and hammer). If you look at this diagram long enough, you’ll start remembering which color things are – and if you freak out on a test, remembering the color just might get you grounded again.

I am sure that someone does have a snazzy mnemonic. But I figure that since you’re going to have to learn what these gene products do, you might as well just reason out which ones are proto-oncogenes vs. tumor suppressor genes, rather than try to memorize that list separately using a mnemonic.

It’s always best when you can get material to make sense! Cuts waaayyy down on the brute memorization – and also helps get the info into long-term memory. Maybe save the mnemonic strategy for stuff that you can’t reason out, like cranial nerve numbers, or clinical syndromes that don’t make sense, or well, pretty much all of micro.

How do you identify mitoses?

Q. How do you identify mitoses in histology slides?

A. Great question. This is something pathologists have to do a lot and nobody really talks about what specifically makes a mitotic figure.

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