Chapter 21: Hematopoietic Pathology

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Welcome back to The Deep Dive.

Today we are wading into what I can only describe as the heavy machinery of the human body.

We're talking about blood, but not just, you know, the red stuff you see when you cut your finger.

We're talking about the defense system, the white blood cells, the entire army.

Exactly.

And specifically, what happens when that system either reacts to a threat, adapts to stress, or in the absolute worst case scenarios goes completely rogue.

It's an incredibly complex landscape.

You can think of the hematopoietic system, the blood making system, as the body's standing army.

Okay.

And today we're going to discuss what happens when they mobilize for war, which we call a reactive change, and what happens when they stage a coup.

Which is neoplasia, cancer.

That's right.

Right.

And our roadmap for this session is chapter 21 of the USMLE Step 1 Pathology Lecture Notes.

We're doing a comprehensive walkthrough of hematopoietic pathology.

It's a big one.

It is.

And I have to be honest with you, looking at the outline for this chapter, it feels a bit like staring at a bowl of alphabet soup.

I hear that all the time.

You have AML, CLL, CML, DLBCL.

I mean, it feels like you need a cryptographic decoder ring just to get through the table of contents.

It often feels that way to students encountering it for the first time.

It is a dense forest of acronyms.

Yeah.

But the mission of this deep dive is to stop treating these as random letters to memorize for a test.

We need to decode the logic behind them.

Okay.

We need to understand the morphology, what these cells actually look like under the microscope and the mechanism, why they're behaving the way they are.

That's the key, right?

Because otherwise, it's just rote memorization.

But if we can understand that a specific translocation moved a specific gene to a new neighborhood on a chromosome, the disease behavior suddenly starts to make sense.

Exactly.

Once you understand the mechanism, the symptoms aren't just a random list to memorize.

There are the inevitable consequences of that initial mistake.

So whether you are actually prepping for an exam and need to nail down those high -yield buzzwords, or you're just insanely curious about how the body breaks down, stick with us.

We are going to start with the benign stuff, how the body reacts to infection, and then we're going to climb the ladder into the lymphomas and leukemias.

It's a very logical progression.

We should start where the pathology usually starts in a clinical setting,

reactive changes.

Okay, let's do it.

Let's look at the first concept here, leukocytosis.

Now in plain English, this just means a high white blood cell count.

Correct.

But the text makes a point that high white count is a bit of a, I guess, a lazy description.

You have to ask who is invited to the party.

Precisely.

You have to look at the differential.

The type of cell that is elevated tells you the story of the disease.

So let's start with the first responders, the neutrophils.

Right.

If the neutrophils are high, we call that neutrophilia.

And the notes give us a very clear mechanism for why this happens.

It's almost always acute inflammation.

Like an infection.

Pyogenic bacterial infections, a post -forming bacteria, or significant tissue necrosis, like from a heart attack.

Okay.

So if I have a nasty bacterial infection, my bone marrow cranks up production.

That makes intuitive sense.

It does.

But I'm looking at the section on mechanisms, and there's a distinction here that, oh, that always confused me.

It says you can have a massive spike in white cells essentially overnight.

How is that biologically possible?

I mean, doesn't it take time to grow new cells?

That is a great question, and it's a critical concept.

Yeah.

We call this the difference between increased production and increased release.

Okay.

Think of the bone marrow like a parking garage.

You have the cars driving out on the street.

That's your circulating white blood cell count that we measure.

Right.

The ones in the blood.

But you also have a massive fleet parked on the lower levels, just waiting.

They're fully built, gassed up, and ready to go.

That's the storage pool.

So they are already built, just parked.

Exactly.

They're just adhered to the walls of the blood vessels inside the marrow.

When you take corticosteroids, or you're under acute stress, or there's an endotoxin release from a bad infection.

The gate lifts.

The gate lifts.

The marrow dumps that entire storage pool into the blood.

You haven't built new cars.

You've just emptied the garage.

That's why the count spikes so fast.

That makes perfect sense.

It's not production.

It's deployment.

It's purely deployment.

But what happens when the reserves run out?

I mean, if the infection is bad enough, the marrow has to start sending out cells that aren't quite ready for prime time, right?

Correct.

And that is a huge clue.

When the storage pool is depleted, but the demand from the infection is still high,

the bone marrow starts sending out the cadets,

the rookies.

And this is what we call the left shift.

This is the concept of the left shift.

I have to ask why do we call it a left shift?

It sounds so random.

It's a bit of an archaic term.

It refers to how we used to chart cell maturity on paper with the most immature cells written on the left side of the page and mature cells on the right.

So in the blood, what you'll see is an increase in bands.

These are immature neutrophils where the nucleus hasn't segmented into its final lobe shape yet.

So it just looks like a band.

It looks like a curve band or a sausage.

The marrow is so desperate to fight the infection that it pushes them out the door before they're fully mature.

Now, this is where the deep dive gets really visual.

The notes mentioned that if I'm a pathologist looking at these neutrophils under a microscope during a severe infection, they don't look pristine.

They look beaten up.

They show clear signs of metabolic stress.

The text highlights three specific reactive changes you need to recognize because they scream infection, not leukemia.

Okay, what's the first one?

First, you have dellal bodies.

Describe those for me.

What am I looking at?

Dellal bodies are visible blue -gray patches in the cytoplasm of the neutrophil.

They're usually off to the side.

Biologically, they are actually aggregates of rough endoplasmic reticulum.

The RER?

Yes.

The cell is ramping up protein synthesis -making enzymes and weapons so aggressively that the machinery literally clumps together and becomes visible.

Wow.

So dellal bodies are clumps of overworked factory machinery.

You see toxic granulations.

The normal, faint granules in the cytoplasm become much more prominent, dark, and purple.

It's like the cell is loading up on extra ammunition.

And finally, you can see cytoplasmic vacuoles.

You'll actually see little clear holes or bubbles in the cell, which is a sign of phagocytosis and degeneration.

So if I see all three dellal bodies, toxic granulations and vacuoles, that tells me this is a reactive, stressed neutrophil fighting for its life.

It's a clear sign of severe inflammation, usually sepsis.

It's a reactive process, not a malignant one.

Got it.

So that's neutrophils.

Now, what if the eosinophils are the ones that are high?

The notes give us a mnemonic or at least a very strong association list?

Eosinophilia is almost always one of a few things.

We often teach students to remember the letters P and A.

P and A.

Parasites and allergies.

Eosinophils are specifically designed to fight multicellular parasites, helminths, worms, things like that.

And they're the key players in hypersensitivity reactions.

So asthma, hay fever.

Exactly.

Asthma is a big one.

But the text also flags drugs as a major cause here.

Yes.

And that is often overlooked in real life.

In a hospital setting, if a patient who was previously fine suddenly spice her eosinophil count, the first thing you do is check their medication list.

Drug reactions are very, very common cause.

And there's a darker association there too, right?

It's not always something benign like an allergy.

True.

You have to keep a broad differential.

Certain malignancies can drive eosinophilia, specifically Hodgkin lymphoma and some adenocarcinomas.

How does a tumor cause that?

The tumor cells themselves can release cytokines, specifically interleukin -5 or IL -5.

And IL -5 is the primary growth and differentiation factor for eosinophils.

So the tumors are basically farming its own eosinophils.

In a way, yes.

So while you hope it's just hay fever, you have to keep cancer on the list of possibilities.

Okay, moving on to the mononuclear cells.

If my monocytes are high, what's the story there?

Think chronic.

Neutrophils are the first responders.

They show up fast, fight hard, and burn out fast.

Monocytes are the heavy lifters for long -term inflammation.

They come in later and clean up the mess.

So monocytosis is associated with chronic disease states.

Tuberculosis is the classic one.

Okay, TB.

But also things like inflammatory bowel disease, like Crohn's, or collagen vascular diseases like lupus.

If the war has been going on for months, the monocytes are the ones fighting it.

And finally, lymphocytosis, high lymphocytes.

This usually points towards viral infections,

acute viral diseases, or some chronic inflammatory states.

And there is one viral disease in particular that the notes take a massive deep dive into, which we absolutely must unpack because the pathology is just fascinating.

Infectious mononucleosis.

The kissing disease.

The bane of high school and college students everywhere.

Right.

It's caused by the Epstein -Barr virus, EBV.

Which is a herpes virus, and it primarily targets adolescents and young adults.

I feel like everyone kind of knows the symptoms.

You're tired, your throat hurts.

But let's be really precise here.

The notes call it the classic triad.

Right.

The triad is fever, sore throat, and lymphadenitis.

But let's look closer at each of those.

The sore throat isn't just a red throat.

It often presents with a gray -white exudative membrane on the tonsils.

It can look really nasty, almost like diphtheria.

And the lymphadenitis.

The swollen nodes.

It's quite specific.

While it can be generalized, it typically involves the posterior auricular nodes, the ones right behind the ear or the posterior cervical chain.

If you feel swollen, tender nodes there, and a teenager with a fever, you have to be thinking about mono.

The notes also mention hepatosplenomegaly.

Yes, an enlarged liver, and more importantly, an enlarged spleen.

And this leads to one of the most critical warnings for a patient with mono, right?

Absolutely.

Because the spleen is enlarged and infiltrated with lymphocytes, the capsule surrounding it is stretched thin and becomes incredibly fragile.

So it can rupture.

They are at a very high risk for splenic rupture, which is a life -threatening hemorrhage.

So absolutely no contact sports for at least a month, sometimes more.

One hard tackle in a football game could be fatal.

There's also a really interesting clinical pearl here about a rash.

It sounds like a medical trap you'd see on an exam.

It is a classic board question scenario.

A patient comes in with a fever and a nasty sore throat.

The doctor thinks it's strep throat and prescribes ampicillin or amoxicillin.

A reasonable guess.

A very reasonable guess.

But a few days later, the patient breaks out in a full -body maculopapular rash.

So they're allergic to penicillin.

That's what I would think.

That's the assumption everyone makes.

Yeah.

But no, in the setting of an active EBV infection, the virus interacts with the antibiotic to cause this rash.

It is not a true allergy.

Wow.

So if you suspect mono, avoid ampicillin or you'll trigger this predictable reaction.

Now this is a deep dive into pathology, so we need to look at the cells.

In mono, you have a high white blood cell count.

If you just looked at the number and you saw these weird looking cells on the smear, you might panic and think leukemia.

That is the big fake out.

The peripheral blood shows a significant lymphocytosis and, more importantly, the presence of atypical lymphocytes.

What makes them atypical?

These are large reactive cells.

They have abundant deep blue cytoplasm that often looks like it's being indented by the surrounding red blood cells.

The nucleus looks a bit stretched or folded.

They can look wild and scary, and they absolutely can mimic leukemia cells to the untrained eye.

But they aren't cancer cells.

They are not.

And here is the real plot twist of the disease.

EBV infects B cells.

That's its primary target.

Okay.

But these atypical lymphocytes that you see in the blood, they're actually T cells.

Wait, what?

So the virus is hiding in the B cells, but the scary looking cells that are flooding the bloodstream are the T cells.

Exactly.

The atypical lymphocytes are the body's own CD8 plus cytotoxic T cells that have become activated and are expanding a number to go hunt down and kill the infected B cells.

So it's a civil war in the blood.

It is a massive T cell response to the B cell infection.

It's a beautiful example of the immune system in action.

So how do we prove it's not leukemia and that it's actually mono?

We use the monospot test as a screening test to detect something called IgM -heterophile antibodies.

Heterophile antibodies?

What are those?

It's a weird biological quirk.

The EBV -infected B cells start churning out these random, non -specific IgM antibodies that just so happen to stick to sheep or horse -red blood cells.

It is, but it allows for a very quick and easy diagnosis.

You mix the patient's serum with the animal red cells, and if they clump up, the test is positive.

Is there a catch?

There's always a catch?

There is always a catch.

The monospot test is often negative early in the infection, especially in the first week.

The antibody response hasn't ramped up yet.

So a negative test doesn't rule it out?

It does not.

If you are very suspicious, you might need to test for specific EBV viral capsid antigens to confirm the diagnosis.

Okay, let's flip the coin.

That was leukocytosis, too many cells.

What about leukopenia, too few?

This is often much more dangerous clinically.

If you have neutropenia, a low neutrophil count, you're essentially a sitting duck for infection.

Specifically, what kind of infections?

Bacterial and fungal infections.

You lose your first line of defense.

This can happen due to decreased production, like in a plastic anemia where the whole bone marrow factory shuts down, or after chemotherapy, which targets rapidly dividing cells.

Or it can be increased destruction.

Right.

Like in an autoimmune disease like lupus, where you can make antibodies against your own neutrophils and they get cleared out by the spleen.

The notes also mention sequestration.

This brings us back to the parking garage, maybe?

Sort of.

In a state of septic shock,

bacterial endotoxins can cause the widespread activation of adhesion molecules on the inner walls of your blood vessels.

So the walls get sticky.

The walls get very sticky.

And the neutrophils, instead of circulating freely, just cling to the endothelium, especially in the lungs and small vessels.

So when you draw blood from a vein in the arm?

The count looks artificially low, because a huge number of the neutrophils are just stuck to the walls elsewhere in the body.

They're hiding.

Okay, what about low lymphocytes?

Yeah.

Lymphopenia.

Think immunodeficiency.

HIV is the big one.

Yeah.

The virus directly infects and destroys CD4 plus T cells.

Right.

You can also have congenital immunodeficiencies, like DeGeorge syndrome, where the thymus fails to develop properly so T cells can't mature.

But also, think about high cortisol states.

Like from stress or Cushing's disease?

Exactly.

Cortisol is a powerful steroid and it induces apoptosis -programmed cell death in lymphocytes.

And there's a note here about radiation that I found particularly chilling.

Yes.

This is a very important point.

Lymphocytes are the most radiation sensitive cells in the entire body.

More than any other cell.

More than any other cell.

If someone is exposed to a high dose of whole body radiation, like in a nuclear accident, the lymphocyte count is the very first thing to plummet.

It's a key marker of significant radiation injury.

Wow.

Okay.

Let's move from the blood counts to the lymph nodes themselves.

Lymphadenopathy.

Enlarged nodes.

I always tell my friends, and this is probably bad advice, if the lump hurts, it's probably okay.

If it doesn't hurt, that's when you worry.

Is that medically accurate at all?

As a general rule of thumb, it's not a bad starting point.

Acute nonspecific lymphadenitis, which is a reactive enlargement, is usually tender.

And why does it hurt?

It's a purely mechanical issue.

The node swells up so fast that it stretches the fibrous capsule that surrounds it.

That rapid stretching causes the pain.

Okay.

Bacterial infections usually cause focal, tender nodes, like the ones in your neck during strep throat.

Viral infections, like mono, tend to cause more generalized tender nodes.

But if it's a chronic issue?

Chronic nonspecific lymphadenitis is usually non -tender because the capsule has had time to stretch and adapt to the slow growth.

And in those cases, the histology, the pattern inside the node, tell us the cause.

Exactly.

You have to look at which part of the lymph node is actually growing.

Walk us through the zones.

If you see follicular hyperplasia, meaning the germinal centers are big and expanding, that's a B cell response.

We see this in things like rheumatoid arthritis or even early HIV infection.

Okay.

So follicles are B cells.

Right.

If you see paracortical hyperplasia, which is the expanding of the zone between the follicles that represents the T cell zone, this is what happens in viral infections, like the mono we just talked about.

There's one specific infection mentioned here with a very cool visual description, cat scratch fever.

Caused by the bacteria, Bardenella hensile.

Usually a child gets scratched by a kitten.

A few weeks later, they develop swollen tender nodes, usually in the armpit or the neck.

And if you biopsy that node?

If you biopsy that node, you see a very characteristic pattern, stellate micro abscesses.

Stellate means star -shaped.

Yes.

You see these irregular star -shaped areas of necrosis that are filled with neutrophils.

It's a very specific morphologic finding.

If you see star -shaped abscesses in a lymph node, you should be thinking cat scratch disease.

And then we get to the nodes we really worry about, the non -tender ones that aren't just reacting.

Neoplasia.

Cancer in the lymph nodes is usually non -tender because it grows progressively, but doesn't necessarily stretch the capsule aggressively in that acute painful way.

And here's a really important point from the text.

The most common tumor in a lymph node is not lymphoma.

It is not.

That's a common misconception.

So what is it?

It is metastatic cancer,

breast cancer, lung cancer,

melanoma, cancer cells that have broken off from the primary tumor, traveled through the lymphatic system, and gotten stuck in the node.

So the node is just a filter, and it's catching the cancer cells that are drifting by.

Exactly.

So an enlarged supraclavicular node is more likely to be metastatic lung cancer than primary lymphoma.

So up to this point, everything we've discussed, the swollen nodes, the high counts, it's all the body trying to save you.

It might hurt, it might be uncomfortable, but it's functional.

It's a physiological response.

But there's a line in the sand where that function breaks.

And this is the pivot point in the entire chapter, and in pathology.

We stop asking, what is the body fighting?

And we start asking, why is the body fighting itself?

We are now crossing into the lymphoid neoplasms.

OK.

The WHO classification groups these generally into mature B -cell neoplasms, mature T -cell, and Hodgkin lymphoma.

We should probably start with the B -cells.

That's the biggest group.

And we're starting with a pair of conditions that are essentially twins separated at birth.

CLL and SLL.

Chronic lymphocytic leukemia and small lymphocytic lymphoma.

What's the deal with these two?

They are biologically the exact same disease.

It is a slow abnormal proliferation of neoplastic B -cells.

The only difference is where they present.

So location, location, location.

Exactly.

If the patient comes in with a high white count in the blood and bone marrow involvement, we call it CLL, the leukemia.

OK.

If they present primarily with enlarged lymph nodes and not much in the blood, we call it SLL, the lymphoma.

But the cells are identical.

Same disease, different address.

Who gets this?

This is a disease of older adults.

The mean age at diagnosis is around 60.

And it is generally very indolent, which means it's lazy or slow moving.

Patients can live with this for a very long time without treatment.

How do we diagnose it?

This is where we get into the alphabet soup of CD numbers.

Flow cytometry is absolutely key here.

These are B -cells.

As you expect, they express normal B -cell markers like CD19 and CD20.

Right.

But here is the critical twist.

They also express CD5.

CD5?

Wait a minute.

Isn't that a T -cell marker?

Normally.

Yes.

And that's why it's so important.

Finding CD5 on a population of B -cells is a huge red flag.

It's an aberrant marker.

They are also characteristically CD23 -mositive.

Visuals are everything for me.

If I'm the pathologist looking at the blood smear, what do I see that tells me it's CLL?

You see smudge cells.

They're also sometimes called parachute cells.

Smudge cells.

These neoplastic B -cells are structurally incredibly fragile.

When the lab tech makes the slide and smears the drop of blood across the glass,

they burst.

They get crushed by the physical force of the smear.

So they look like a little smudge of a purple thumbprint on the glass slide.

Seeing a lot of smudge cells is highly characteristic of CLL.

So smudge cells equals CLL.

Got it.

Now, you said it's indolent, but does that mean it's harmless?

Not at all.

These malignant cells are non -functional.

They take up space, they accumulate, but they don't do their job.

Remember, the job of a B -cell is to mature into a plasma cell and make antibodies.

Right.

Immunoglobulins.

These cells don't do that.

So over time, patients develop hypogammaglobulinemia, very low antibody levels in their blood.

Which means a huge risk of infection.

Exactly.

Infection is the most common cause of death in patients with CLL.

And interestingly,

while they don't make good antibodies, they sometimes make bad ones.

What do you mean by that?

About 10 % of patients with CLL will develop a warm autoimmune hemolytic anemia.

The body starts producing antibodies that attack its own red blood cells, causing anemia.

And is there a risk of it turning into something worse, something more aggressive?

Yes.

It's called Richter transformation.

The slow -growing indolent CLL suddenly transforms into a very aggressive, diffuse large B -cell lymphoma.

The patient rapidly gets worse.

Their spleen enlarges, fever spikes.

It's a very poor prognostic sign.

OK, let's move to another B -cell neoplasm with a very descriptive name.

Hairy cell leukemia.

This one is rare, but it's very memorable because of its features.

It typically affects middle -aged to older men.

And the neoplastic B -cells have these fine hair -like cytoplasmic projections.

So you can actually see the fuzziness on the microscope.

You really can.

They look hairy.

What's the clinical picture for these patients?

Two things are classic.

One is massive splenomegaly.

The spleen gets huge because the red pulp is infiltrated by all of these hairy cells.

But strangely, the other classic finding is that if you try to do a bone marrow aspirate, you get a dry tap.

A dry tap, like you put the needle in and nothing comes out.

Exactly.

Normally, bone marrow has a liquid, jelly -like consistency that you can suck out.

But in hairy cell leukemia, these cells induce fibrosis or scarring in the marrow.

The marrow becomes stuck in a web of reticulum fibrosis, so you can't suck anything out.

And what's the buzzword stain for this one?

It is TRAP -positive.

That stands for tartrate -resistant acid phosphatase.

We tell students hairy cells are stuck in the TRAP.

I love that.

Easy to remember.

And the treatment for this is actually really interesting mechanistically.

It sounds like we're poisoning the cells in a very specific way.

It is incredibly elegant.

We use a drug called 2 -CDA, which is cladribine.

This drug inhibits an enzyme called adenosine deminase.

Adenosine deminase.

So that breaks down adenosine.

Right.

So if you block the enzyme, adenosine accumulates inside the cell.

And adenosine, at high levels, is toxic to lymphocytes.

So the drug causes the hairy cells to poison themselves from the inside out.

Precisely.

It's highly effective and often induces very long -term remissions.

Okay.

Moving on to the most common lymphoma worldwide,

diffuse large B -cell lymphoma, or DLBCL.

This is the big bad wolf of lymphomas.

It's aggressive.

It's clinically high -grade.

It can rise out of nowhere or it can arise from the transformation of a low -grade lymphoma, like we just discussed with CLL.

What does it look like?

It involves large, ugly B -cells that are growing diffusely in sheets, completely wiping out the normal architecture of the lymph node.

But despite being so aggressive, the text says it's potentially curable.

Yes, and that's a key concept in oncology.

Because it grows so fast, it is very sensitive to chemotherapy.

Aggressive lymphomas often have better cure rates than indolent ones because chemotherapy preferentially targets rapidly dividing cells.

Contrast that with follicular lymphoma.

Follicular lymphoma is the second most common non -Hodgkin lymphoma.

It is a very indolent course.

It usually presents in older adults with generalized, painless lymphadenopathy.

But the mechanism here is pure gold for understanding pathology.

It involves a very specific translocation, T1418.

It's the classic example of how a translocation causes cancer.

Okay, let's unpack T1418.

What is moving where?

And more importantly, why does it matter?

To understand this, you have to know what important genes live on these two chromosomes.

Chromosome 14 is the home of the immunoglobulin heavy chain gene.

Okay.

In a B -cell, this gene is always turned on to the max.

Because a B -cell's whole job is to be an antibody factory.

So you can think of that location on chromosome 14 as being a very active neighborhood with a very powerful promoter.

It's a loud construction site that's always working.

A perfect analogy.

Now over on chromosome 18, that's the home of the B -CL2 gene.

And what does B -CL2 do?

B -CL2 is a gene that stabilizes the mitochondrial membrane and prevents apoptosis.

It's an anti -cell death gene.

Its job is to say, don't die.

Okay.

Normally B -CL2 is very tightly regulated.

We want cells to be able to die when they're old or damaged.

So in the translocation, we swap them.

We take the don't die gene from chromosome 18 and we move it right into that loud construction site on chromosome 14.

Exactly.

You put the B -CL2 gene right next to that maximum volume heavy chain promoter.

The result is massive,

unregulated overexpression of B -CL2 protein.

So the B -cells lose the ability to undergo apoptosis.

They become immortal.

So they become immortal.

And this explains the name, follicular lymphoma.

How so?

Think about the normal life of a B -cell.

It goes into the lymph node follicle.

Think of it as a school to learn how to make better antibodies.

Why?

This process is called somatic hypermutation.

If they fail the test, if they make a bad antibody, they're supposed to die via apoptosis.

That's the body's quality control system.

But because of the T1418 translocation, these cells fail the test but refuse to die.

So they just pile up.

They just pile up in the follicles.

That's why you see this nodular or follicular pattern of growth.

So they aren't necessarily growing super fast.

They just aren't leaving the party.

Precisely.

That's why it's an indolent disease.

It's a disease of accumulation, not rapid explosion.

That is such a clear explanation of how a single genetic mistake drives the entire disease.

It's a beautiful model.

Now let's talk about Burkitt lymphoma.

This is one of the most famous histologic descriptions in all of medicine.

The starry sky appearance.

It is a very striking image under the microscope.

The sky is the sheet of dark blue monotonous tumor cells.

They are growing incredibly fast.

And the star.

Because they grow so fast, many of them outgrow their blood supply or just die from metabolic stress.

The stars are benign macrophages that have come in to eat the dead tumor cells.

These macrophages have clear cytoplasm.

So you get these white pockets against the dark blue background.

And it looks like stars in the night sky.

Exactly.

What's the genetics here?

Is it another translocation?

It's another translocation.

This time it's the T814.

Okay, so chromosome 14 is involved again.

The loud neighborhood.

The heavy chain locus is involved again.

But this time it swaps with chromosome 8 which is the home of the CMYC gene.

And CMYC is not a don't die gene like BCL2.

No.

CMYC is a nuclear transcription factor that is a master regulator of the cell cycle.

It's a gas pedal.

It tells the cell to grow and divide.

So instead of just not dying like in follicular lymphoma.

These cells are being told to grow, grow, grow as fast as possible.

This is why Birkitt is one of the fastest growing human tumors.

It's a very high grade, very aggressive lymphoma.

And the notes mention two types, African and American.

Yes.

The African type is endemic and is very strongly associated with EBV infection.

It characteristically presents as a massive tumor mass involving the jaw or the facial bones in children.

And the American type.

That's the sporadic type.

It often involves the abdomen, particularly the bowel or the ovaries.

And it's also common in patients with HIV.

Let's hit a couple more B cell types quickly.

Mantle cell lymphoma.

This arises from the mantle zone of the lymph node.

The area that's right next to the germinal center follicle.

And the translocation.

The translocation is T1114.

Again, it involves the heavy chain locus on 14.

This time it moves the cyclin D1 gene from chromosome 11 over.

And cyclin D1, what does that do?

Cyclin D1 is a protein that promotes the G1 to S phase transition in the cell cycle.

It's another way of pushing the cell to divide.

The notes mention a key distinction from CLL here.

Very important.

Mantle cell is CD5 positive, just like CLL.

But it is CD23 negative whereas CLL CD23 positive.

That's how you tell them apart on flow cytometry.

And marginal zone lymphoma or maltoma.

This one tells a fantastic story about the link between chronic inflammation and cancer.

It rises in mucosal tissues.

The malt mucosa associated lymphoid tissue.

Like the gut.

The gut, the salivary glands, the thyroid.

And it is strongly linked to chronic irritation or inflammation in those sites.

So for example.

The classic example is helicobacter pylori gastritis leading to a gastric meletoma.

Or Sjogren disease, an autoimmune disease attacking the salivary glands leading to a salivary meletoma.

So the inflammation actually triggers the cancer.

Yes.

It starts as a reactive polyclonal process in response to the bacteria or the autoimmune attack.

The body is just trying to fight it off.

But eventually a single clone of B cells acquires a mutation and becomes neoplastic.

The notes say something really incredible here.

It's remarkable.

If you catch a gastric meletoma that's caused by H.

pylori early enough, you can treat the patient with antibiotics to eradicate the bacteria.

And the lymphoma can actually regress.

You cure the cancer by curing the infection.

Exactly.

It's one of the few examples of that in oncology.

That is incredible.

Now we have to talk about a really big one.

Multiple myeloma.

This is a lymphoma in a node and it's not exactly a leukemia in the blood.

It's a plasma cell neoplasm.

Right.

Remember plasma cells are the end stage of B cell maturation.

They're the factories that produce our antibodies.

Okay.

In multiple myeloma, one clone of plasma cells goes malignant and takes over the bone marrow.

And because they are factories, they just churn out product.

They churn out massive amounts of a single monoclonal immunoglobulin, usually IgG or IgA.

And this shows up on a test called serum protein electrophoresis as a sharp narrow spike called the M spike.

And the symptoms.

The text uses the serum mnemonic, but let's detail what those letters actually mean for the patient physically.

It's a great mnemonic.

C is for calcium, hypercalcemia.

R is for renal disease.

A is for anemia.

And B is for bone lesions.

Okay.

Let's start with the bone.

Why do patients get these olytic punched out bone lesions?

The myeloma cells that are sitting in the bone marrow produce something we call osteoclast activating factor.

Specifically, they interact with the Arank ligand system.

So they're telling the osteoclasts, the bone breaking cells, to go into overdrive.

They're whipping them into a frenzy.

And these overactive osteoclasts just start chewing up bone, which plunges literal holes in the skeleton.

We call them the lytic lesions.

Which explains severe back pain and the fractures.

Severe bone pain and pathologic fractures are classic presentations.

And because you are dissolving all that bone, you release a ton of calcium into the blood.

Which gives you the C and C rab, hypercalcemia.

Right.

And that can cause confusion, weakness,

constipation, all sorts of problems.

And that leads to the R for renal issues.

The hypercalcemia is definitely hard on the kidneys.

But the main cause of renal damage is something called Ben's Jones proteins.

What are those?

These are free immunoglobulin light chains.

The tumor is making so much antibody that it often makes extra light chains that don't attach to anything.

They're small enough to get filtered by the kidney into the urine.

But they are directly toxic to the kidney tubules and can clog them up.

Causing what's called myelomachad nephropathy.

And the anemia, the A in C trab.

That one's more straightforward.

The bone marrow is physically packed with these malignant plasma cells.

The diagnostic criteria is more than 10 or 20 percent of the marrow volume.

They simply crowd out all the normal red blood cell precursors.

There's no room left.

And one last visual finding in the peripheral blood for myeloma?

Rouleau formation.

What does that look like?

Normally red blood cells have a negative charge on their surface.

So they repel each other.

But the massive amount of protein in the blood in myeloma neutralizes that charge.

So the RBCs get sticky and they stack up on top of each other like a roll of coins.

So a stack of coins.

Got it.

What if a patient has that M spike but they don't have any symptoms?

No C rab criteria.

That is a very common scenario.

We call that M G U S monoclonal gemopathy of undetermined significance.

It's actually quite common in the elderly.

You can think of it as a pre myeloma state.

There is a steady one, two percent risk per year of it transforming into active multiple myeloma.

So for now, we just watch and wait.

And finally, in this B cell section, Waldenstrom macroglobulinemia.

That's a mouthful.

It is.

You can think of this as a cross between multiple myeloma and a lymphoma.

But the absolute key here is the type of antibody being produced.

It's always IgM.

And why does the IgM matter so much?

IgM is a huge molecule.

It's a pentamer, which means it's five antibodies all stuck together into big star shape.

Because it is so large, it dramatically increases the viscosity of the blood.

It makes the blood thick.

It creates a hyper viscosity syndrome.

The blood becomes thick like syrup.

What does that do to the patient?

It causes all sorts of problems.

Patients can get retinal hemorrhages leading to blindness, headaches, confusion, and reno phenomena.

But unlike myeloma, there are typically no lytic bone lesions and no hypercalcemia.

It's all about the thick blood.

OK, that wraps up the B cells.

Let's shift gears to the T cells.

They seem a bit rarer in the notes.

They are significantly rarer than B cell neoplasms, but there are a few important ones to know.

Let's start with adult T cell leukemia lymphoma, or ATLO.

This is a disease caused by a virus,

HTLV1, the human T lymphotropic virus.

It's a retrovirus, kind of like HIV.

And where in the world do we see this?

It has a very specific geography.

It's endemic in parts of Japan, the Caribbean, and Central Africa.

So if a board question mentions a patient from one of these regions who presents with skin lesions, enlarged nodes, and high calcium.

You should be thinking ATLO.

You should definitely be thinking ATLO.

And the visual, what do the cells look like?

The classic description is flower cells.

The nuclei of the malignant T cells are hyperlobated and convoluted.

And they can look like a clover leaf or the petal of a flower.

Then there's mycosis fungoids, which sounds like a fungal infection, but it isn't.

Correct.

That name is a historical misnomer.

It is a neoplasm of mature CD4 plus T cells that have a particular love for the skin.

We call it a cutaneous T cell lymphoma.

How does it present?

It classically progresses through stages.

It starts as a rash -like patch, then it becomes raised into a plague, and then it can form large tumor nodules.

It can look like eczema or psoriasis for years before it's diagnosed.

And the biopsy shows patria micro abscesses.

Yes.

Those are aggregates of the neoplastic T cells that are trapped up in the epidermis, the top layer of the skin.

And if these cells break out of the skin and get into the blood?

Then the disease name changes.

We call it caesare syndrome.

And the malignant T cells circulating in the blood have these very distinct cerebriform nuclei.

They look wrinkled and folded like the gyri of a brain.

Okay, time for a heavy hitter.

Hodgkin lymphoma.

This is specifically set apart from everything we just talked about, which are all called non -Hodgkin lymphomas.

How do we differentiate them?

There are several key differences.

First, Hodgkin lymphoma typically spreads in a very orderly, contiguous fashion.

It moves from one lymph node group to the next closest group in a chain.

For example, from the neck to the mediastinum to the axilla, it rarely skips.

And non -Hodgkin is more random.

Non -Hodgkin is much more likely to be widespread and non -contiguous at diagnosis.

Second, Hodgkin almost always stays in the lymph nodes.

It doesn't usually present as a leukemia in the blood.

And clinically, it has a classic bimodal age distribution.

One peak in young adults, around their 20s, and another peak in older adults, over 50.

And the absolute star of the show, the cell you have to find to make the diagnosis is the Reed -Sternberg cell.

You cannot miss this cell.

If you see one, you'll never forget it.

It is a massive cell.

It has a bilob nucleus, two large nuclear lobes that are mirrored.

And inside each lobe is a prominent eosinophilic or pink nucleolus.

So it looks like a pair of owl eyes staring back at you.

That's the classic description, owl eyes.

What are these cells actually?

Where do they come from?

They are thought to be crippled germinal center B cells.

But here's what's interesting.

In classic Hodgkin lymphoma, they lose their expression of standard B cell markers like CD20.

Instead, they acquire new aberrant markers.

They are CD15 positive and CD30 positive.

Okay, so CD15 and CD30.

That's the fingerprint.

That's the key immunophenotype.

Now what's really fascinating about Hodgkin is that the tumor isn't mostly made of cancer cells, right?

Exactly, that's a critical point.

The malignant Reed -Sternberg cells are actually the minority of the cells in the tumor.

Sometimes they're very rare and hard to find.

So what's the rest of the lump?

The bulk of the tumor mass is actually reactive inflammatory cells, lymphocytes, eosinophils, macrophages, plasma cells.

The Reed -Sternberg cells are like the evil puppet managers, secreting cytokines like IL -5 to attract this whole entourage of reactive cells around them.

Hodgkin has several subtypes, which is the most common one.

By far the most common is nodular sclerosis.

This accounts for about 70 % of all cases in the developed world.

It's also the only subtype that is more common in women than in men.

And the morphology, what does nodular sclerosis mean?

It means the lymph node is divided up into nodules by broad bands of collagen or sclerosis.

And the Reed -Sternberg cells in this variant have a specific look.

They sit in these clear, empty spaces called lacunae, so we call them lacunar cells.

Okay, what are some of the other subtypes?

There is mixed cellularity.

As the name implies, it has a mixed background of inflammatory cells, but often with abundant eosinophils because the RS cells are secreting a lot of IL -5.

And there's lymphocyte -rich and lymphocyte -depleted.

Correct.

And those names tell you a lot about the prognosis.

Why does the lymphocyte count matter so much for prognosis?

Because the background lymphocytes represent the body's immune response,

its attempt to contain the tumor.

So if you have lots of lymphocytes, as in the lymphocyte -rich subtype, your immune system is putting up a good fight and the prognosis is better.

And if you have few lymphocytes?

If you have the lymphocyte -depleted subtype with very few reactive cells and tons of Reed -Sternberg cells, it means the tumor is winning and the prognosis is much worse.

Also, the presence of B symptoms matters a lot for prognosis, right?

Yes, absolutely.

B symptoms are a specific constellation of systemic symptoms, unexplained fevers, drenching night sweats, and significant unintentional weight loss.

If a patient has these, it indicates a higher cytokine load from the tumor and it generally means a more advanced stage and a worse prognosis.

Okay, we are leaving the lymph nodes and going straight to the bone marrow for the next section.

Acute leukemias.

This is where things get really urgent.

The word acute implies a sudden onset and a very aggressive clinical course.

And the definition hinges on one central concept,

the blast.

Define a blast for us.

What is that?

A blast is an immature precursor cell.

It's a baby cell.

Normally, blasts stay in the bone marrow.

They mature into adult cells like neutrophils or lymphocytes, and then they leave.

Right.

In acute leukemia, the blasts acquire a mutation that causes a maturation rest.

They lose the ability to mature.

So they just pile up in the bone marrow as useless, immortal baby cells.

And the diagnostic cutoff.

The diagnostic cutoff is finding more than 20 % blasts in the bone marrow.

Anything over that is, by definition, an acute leukemia.

And because the marrow is full of these useless blasts, it fails at its regular job.

Exactly.

The blasts crowd out all the normal hematopoietic elements.

This presents as the classic triad of bone marrow failure.

Anemia, from lack of red cells, which causes fatigue.

Frombocytopenia, from lack of platelets, which causes bleeding and bruising.

And neutropenia, from lack of mature neutrophils, which leads to infections.

Let's split this category now.

Lymphoblastic, AL versus myelogenous, AML.

Acute lymphoblastic leukemia, or ALL, is the cancer of kids.

It is the most common malignancy of childhood.

It involves the malignant proliferation of lymphoblasts from either the B cell or the T cell lineage.

And how do we tell BAL from TAL?

BAL is the classic childhood leukemia that presents with marrow failure.

TAL presents a bit differently.

It's often in adolescent males, and it characteristically presents as a large mediastinal mass.

Why a mediastinal mass?

Because the thymus is in the mediastinum, and the thymus is the school where T cells mature.

So a large thymic mass in a teenager causing shortness of breath is TAL until proven otherwise.

What about the markers?

How do we know they're lymphoblasts?

The key marker for a lymphoblast is that it is TDT positive.

TDT is a DNA polymerase that's found only in the nucleus of immature lymphocytes.

That tells you it's ALL.

And then to split B versus T.

Then you use other markers.

CD10 and CD19 are classic for B cells, whereas markers like CD2, CD3, and CD7 are for T cells.

And BAL has this specific issue with sanctuary sites.

What does that mean?

It's a very important clinical point.

Chemotherapy is great at clearing the leukemic cells from the blood and bone marrow.

But many chemo drugs cannot cross the blood -brain barrier or the blood -testis barrier.

So the tumor cells can hide out there.

Exactly.

They can hide in the central nervous system or in the testes.

That's why treatment for ALL always includes prophylactic chemotherapy injected directly into the spinal fluid, into the peduncle sac, and regular examination of the scrotum for any masses.

Okay, moving from the kids to the adults.

Acute myelogenous leukemia, AML.

This is disease of older adults with a median age around 50 to 60.

These are myeloid blasts, the precursors to neutrophils, monocytes, and so on.

And the hallmark visual finding here is the hour rod.

What is an hour rod?

It is a crystallized aggregate of granules, specifically myeloperoxidase, or MPO, in the cytoplasm of the blast.

It looks like a reddish pink needle or a small stick inside the cell.

Jay, if you see one.

If you see a single hour rod, it is AML.

Period.

Lymphoblasts never have hour rods.

It is pythognomonic.

There is one specific subtype of AML that is incredibly high yield because the treatment is so unique,

acute promulocytic leukemia, or APL.

This is defined by the T1517 translocation.

This creates a fusion gene between the PML gene and the RARA gene, the retinoic acid receptor alpha.

And what does that fusion protein do?

It acts as a transcriptional repressor and blocks the maturation of myeloid cells.

They get stuck at the promulocyte stage.

And the treatment isn't typical kill -everything chemotherapy.

No, it's one of the most fascinating stories in modern oncology.

The treatment is ATRA, all -transretinoic acid, which is essentially a derivative of vitamin A.

So vitamin A can treat leukemia.

In this specific case, yes.

The ATRA drug binds to the abnormal RRRA receptor and overcomes the block.

It forces the malignant cells to mature.

It pushes them past the arrest point.

No, they just become normal neutrophils.

They turn into mature neutrophils and then eventually die off naturally.

It's called differentiation therapy and it's incredibly effective.

But there's a major danger with APL before you can treat it.

Yes, a very high risk of DIC -disseminated intravascular coagulation.

The granules in these promyelocytes are loaded with tissue factor -like substances.

If the cells break open, they trigger massive widespread clotting and bleeding simultaneously.

It's a true medical emergency.

Before we leave acute leukemia, the text mentions myelodysplastic syndromes or MDS.

MDS is essentially pre -leukemia.

The hematopoietic stem cells have acquired mutations, but they aren't fully blocked from maturing yet.

However, the maturation they undergo is disordered and defective.

The cells are ugly and many of them die in the marrow before they even get out.

So you get low blood counts, cytopenias.

Yes, but the marrow itself is actually hypercellular.

It's working hard, but producing garbage.

The classic visual clue here is the Pelgar -Wayette anomaly.

What's that?

These are neutrophils where the nucleus fails to segment properly.

They end up with just two lobes connected by a thin strand of chromatin.

They look like aviator glasses or a pair of dumbbells.

And MDS has a high risk of transforming into - Into full -blown AML.

The blast count in the marrow rises above that magic number of 20%.

It's no longer MDS, it's now AML.

All right, section six.

Myeloproliferative neoplasms or MPNs.

This feels like the opposite of MDS.

It absolutely is.

In MDS, the marrow fails to make enough good cells.

In MPN, the marrow goes into overdrive.

It's hypercellular and emits way too much of everything.

But unlike acute leukemia, the cells do successfully mature.

So you have very high counts of functioning or mostly functioning cells in the peripheral blood.

Let's start with CML, chronic myelogenous leukemia.

This disease is defined by one thing, the Philadelphia chromosome, the T922 translocation.

Okay, we've talked about a few translocations.

What's moving here?

This translocation fuses the BCR gene on chromosome 22 with the ABL gene on chromosome nine.

And what does that BCR -ABL fusion protein do?

ABL is a tyrosine kinase, a signaling molecule that tells the cell to grow and divide.

Normally it has a tightly regulated off switch.

The fusion with BCR removes that switch.

It creates a protein with constitutive tyrosine kinase activity.

It is stuck in the on position, constantly telling the cell to proliferate.

And this changed the face of medicine because we developed a drug specifically for this molecular target.

Imotidib or Gleevec.

It was the first truly successful smart drug for cancer.

It's a small molecule that fits perfectly into the active site of that abnormal tyrosine kinase and just shuts it off.

And it turned a fatal disease into?

Into a mannichalchromic condition for most patients.

It was a revolution.

What are the clinical findings for CML?

Massive splenomegaly is classic.

The spleen can fill the entire left side of the abdomen and in the blood you see a complete spectrum of myeloid cells from a few blasts all the way up to mature neutrophils.

But the real unique clue, the buzzword, is basophilia.

A markedly increased basophil count is highly suggestive of CML.

Next, MPN.

Polycythemia vera or PV.

This is a disorder where the marrow goes crazy churning out way too many red blood cells.

The hematocrit is sky high.

The blood becomes very thick and viscous.

And patients look plethoric.

Yes, they have a reddy red face complexion.

And they're at very high risk for clots, DVTs, strokes, heart attacks, because the blood is basically like sludge.

And there's a classic symptom.

Severe itching after a hot shower.

Pruritus, yes.

It's thought to be because PV also involves increased basophils in mast cells.

The heat from the shower triggers them to degranulate and release histamine which causes intense itching.

There's a paradox here with erythropoietin or EPO.

Right.

Normally, if your red blood cell count is high, the kidneys detect the high oxygen levels and shut down EPO production.

And in PV, the EPO level is indeed very low.

It's suppressed.

But the marrow just keeps going.

The marrow just keeps producing red cells anyway.

It has become independent of EPO signaling, usually due to a mutation in a signaling molecule called JAK2.

Then there's essential thermosithemia.

Same idea, but with platelets.

Way too many platelets.

Puts patients at risk of both bleeding and clotting.

Also frequently has that JAK2 mutation.

And finally in this group, myelofibrosis.

This is often considered the spent phase of an MPN.

The marrow has been working in overdrive for so long that it essentially burns out.

What happens to it?

The massive proliferation of megakaryocytes leads to the release of growth factors, particularly PDGF or platelet -derived growth factor.

And PDGF causes fibroblasts to activate.

Yes.

They come in and lay down collagen.

The bone marrow becomes replaced by scar tissue or fibrosis.

Hematopoiesis can no longer happen effectively in the bones.

So where does the blood get made?

The body reverts to its fetal sites of blood production.

The spleen and the liver take over.

We call this extra medullary hematopoiesis.

And as a result, the spleen becomes absolutely massive.

And the visual clue in the blood.

Teardrop RBCs, which are called dacrocytes.

As the red cells try to squeeze their way out of the fibrotic scarred up marrow or the crowded spleen, they get physically pinched and deformed.

They look like teardrops.

That is a very poetic, but very sad image.

It signifies total marrow failure.

It does.

Okay, last section.

A few quick hits on histiocytes, the spleen and the thymus.

Let's start with Langerhans cell histiocytosis.

Langerhans cells are a type of dendritic cell, an antigen presenting cell normally found in the skin.

This is a neoplastic proliferation of those cells.

The key markers are that they are CD1A positive and S100 positive.

And the finding on electron microscopy is famous.

The Birbeck granules.

They look exactly like tiny tennis rackets inside the cytoplasm of the cell.

Tennis rackets, I will never forget that.

You won't.

And there are several variants of this disease, ranging from a benign solitary bone lesion called an eosinophilic granuloma, all the way to a fatal, rapidly progressive multi -system disease in infants called letter of sigh disease.

And briefly on the spleen, we've mentioned splenomegaly a lot today, but what about splenic dysfunction?

What happens if the spleen isn't working or it's been removed?

If you have a splenia or you've had a splenectomy, you lose the body's primary filter for the blood.

Specifically, you lose the ability to clear out old, damaged red blood cells and to remove nuclear remnants from them.

Which leads to howl -jolly bodies.

Yes, you see these small, dark purple dots inside the red blood cells.

Those are leftover bits of the nucleus that the spleen normally would have bitten out.

If you see them, it means the patient has no functional spleen.

And what is the major clinical risk for those patients?

They are exquisitely susceptible to infection with encapsulated bacteria.

Streptococcus pneumonia, hemophilus influenza,

nasarium meningititis, salmonella.

The spleen is the primary defense against these organisms.

So, splenic patients need to be aggressively vaccinated and treated with antibiotics immediately if they get a fever.

We have covered a massive amount of ground today from the parking garage of the neutrophils all the way to the starry sky of Burkitt lymphoma.

It's a journey from the body's normal reactive processes to the completely neoplastic and disordered ones.

So, let's wrap this up.

We've seen that the blood is a system in a very delicate balance.

A little stress causes a left shift.

A viral infection brings out these wild -looking atypical lymphocytes.

But one wrong genetic move, a nine swapping with a 22, an eight with a 14, and the entire machinery breaks, leading to these cascading, life -threatening pathologies.

Exactly, and that is the final thought I really wanna leave you with.

When you look at a slide, or when you look at a patient, you are seeing the phenotype.

You're seeing the what.

But the goal is to always ask why.

The mechanism.

The mechanism.

The translocation, the mutation, the cytokine environment, that is where the disease actually lives.

A diagnosis like Burkitt lymphoma isn't just a label.

It's a shorthand description for a specific molecular accident, the overexpression of CMYC, that results in a specific predictable behavior, which is rapid growth.

And understanding that connection is everything.

It's the key to mastering pathology.

And with that, we will close the book on Chapter 21.

Thank you for diving deep with the Last Knit Lecture team, and go look at those images in the notes.

The starry sky, the owl eyes, the tennis rackets, they will stick with you.

Until next time, keep questioning.

See you on the next deep dive.