How to study diseases

If you want to be precise, the word pathology means “the study (logos) of pain (pathos).” And it’s true, in a way, because a lot of the things we discuss in pathology involve some sort of pain. Not to mention the pain of studying pathology itself, but we won’t get into that, since this is a pain-free space.

What we really study in pathology isn’t pain, exactly, but disease. So if you’re starting out in a pathology course – or even if you’re halfway through – it’s not a bad idea to come up with a little plan of attack for studying diseases.

Why use a plan when learning new diseases?

Because it reduces your cognitive load. You have to hold and process information in your working memory before you can put it in your long-term memory. And your working memory has limited space! So if you approach every disease a different way, and just try to memorize everything, you won’t actually get that information into your long-term memory – and obviously, that’s important for passing exams.

But if you have a little mental template that you use for each disease, that organizes the information into smaller, meaningful chunks that WILL stay in your working memory. Also, if you do that for every disease, it lets your brain relax a bit, because your brain likes categories and consistency.

Here’s a good plan.

Here is a disease plan that works well for pathology because it’s simple, straightforward, and widely applicable. It breaks information down into four categories:

  1. Etiology (cause)
  2. Pathogenesis (mechanism)
  3. Morphology (gross and microscopic appearance)
  4. Clinical manifestations (signs and symptoms)

Can I see an example?

But of course! Let’s take a look at how this would work for a particular disease: squamous cell carcinoma of the lung.

  1. Etiology: smoking
  2. Pathogenesis: The epithelium of the lung passes through several stages – including dysplasia and carcinoma in situ – before developing into invasive carcinoma. Each stage is characterized by different and new genetic abnormalities within the epithelial cells.
  3. Morphology: squamous cell carcinoma cells are large, with abundant cytoplasm and intercellular bridges.
  4. Clinical manifestations: persistent cough and weight loss.

There you go! Obviously you’d want to flesh out these categories a bit more – but this would be a good start.

One last piece of advice

One more nice thing about this plan is that it helps you avoid the “can’t see the forest for the trees” problem so common when you’re first learning about a disease. This plagued me during medical school. I’d learn so much about tiny details that I couldn’t zoom out and give you a big picture. It’s better to start with the big picture and then add in details later.

Your brain will say “Thank you for reducing my cognitive load! I’m so happy!”

How to tell apart promyelocytes and myelocytes

Here’s a quandry you may find yourself in soon, if you have a habit of sitting at the multiheaded scope down in hematopathology.

You’re looking at a bone marrow smear, and you can differentiate between some of the myeloid cells (blasts have a high nuclear-cytoplasmic ratio; segmented neutrophils are all mature with their multilobed nuceli; metamyelocytes look kinda like mature neutrophils only with a more horseshoe-shaped nucelus.)

But two cells will give you gout or a migraine if you don’t learn a couple simple facts: promyelocytes and myelocytes. How are you supposed to tell them apart, when they can look quite similar? They’re both kinda big, they both kinda have granules…so what gives?

Let’s do a little pre-test here to see what you think about these cells, before we discuss the “official” way of distinguishing between the two. We can leave the lymphoycte and the red cell precursors out of the discussion (top of the slide). But what’s your diagnosis on cells 1, 2, and 3? Are they promyelocytes, myelocytes, or a mixture of the two?

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Here’s the morphologic criteria from my path residency (and my histology course as a medical student) that we used to differentiate between promyelocytes and myelocytes:

  • The promyelocyte is the biggest cell in the neutrophil series.
  • It also has huge, dark purple, primary (azurophilic) granules both in the cytoplasm and overlying the nucleus.
  • However, it does NOT have the beginnings of secondary (specific, pink, salmon-colored) granulation! If you see any of that (even just a little blush of it in the cytoplasm), you HAVE to call a myelocyte.

So for our cells above:

  • Cell #2 is a pretty spectacular promyelocyte. It’s huge, it’s got tons of dark granules, and no specific granulation. It does have the beginnings of a little “hof” (a clear zone next to the nucleus) but that should not be confused with specific granulation.
  • Cell #3 is pretty clearly a myelocyte. It’s a smaller cell, and there are very few azurophilic granules left; the cytoplasmic granules are mostly just pale, specific granules.
  • Cell #1 could be a bit of a challenge because it’s a rather large cell, with abundant dark purple granulation…but it also has the clear beginnings of specific granulation in the cytoplasm. So this cell should rightly be classified as a myelocyte. It’s a pretty early one, for sure – but the presence of the specific granulation pushes it into the myelocyte category.

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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