Chapter 25: The Skin: Pathology and Disease

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Welcome back to the Deep Dive.

We are shifting gears today.

Usually we take a broad look at a topic, maybe something from the news or a new tech trend, but today,

today is for the students.

Oh, yeah, the frantic students.

Exactly.

This is the Last Minute Lecture.

We know you're out there.

You've got a pathology exam tomorrow morning at 8 a .m.

Or, you know, maybe you're a medical student starting your dermatology rotation and you are just terrified of getting grilled by the attending.

Right.

You need the high yield stuff and you need it right now.

Yeah.

And even if you aren't a student, stick around because today we are diving deep into the skin.

And as it turns out, the skin is a lot more than just a wrapper.

It really is.

It's the largest organ in the body.

It is, right.

Yeah.

But historically, it hasn't really gotten the respect it deserves.

I mean, if you go back to the mid 19th century, you have Rudolf Virchow.

Now, Virchow is a titan.

He's literally the father of modern pathology.

But he had this view of the skin as just a mere protective covering.

Ouch.

Like it's just saran wrap for the important stuff.

Exactly.

He thought it was just a mechanical barrier to keep the body fluids in and the static shell.

But he was completely wrong.

Wow.

We now know the skin is this incredibly sophisticated sensory interface.

It's a massive immunologic organ.

It regulates your temperature.

It makes vitamins.

It is a vibrant, chaotic, complex ecosystem.

So our mission today is to decode that ecosystem.

We are walking strictly through chapter 25 of Robbins and Cotran, the absolute Bible of pathology.

We're going to translate the because looking at skin slides is, well, it's like reading a foreign language.

It really is.

If you don't know the vocabulary, if you can't tell the difference between hyperkeratosis and periceratosis, you're just looking at pink and purple blobs.

So we're going to break it down layer by layer, lesion by lesion.

Let's start with the architecture.

If we sliced a piece of skin right now and looked at it from the side like a layer cake, what are we seeing?

You're seeing three distinct zones.

The top layer, the part you can actually touch,

is the epidermis.

Think of this as the cellular shield.

It's made of keratinocytes, squamous cells that are glued tightly together.

Glued by what?

By junctions called desmosomes.

I really want you to remember that word.

Desmosomes.

Desmosomes.

Got it.

They are the molecular rivets holding the shield together.

If those rivets fail, you get blistering.

Okay.

So that's the shield.

What's underneath?

They're dermis.

This is the structural support.

It's tough.

It's made of collagen and elastin fibers.

It gives the skin its strength and its flexibility.

And buried inside the dermis, you have all the gadgets.

The gadgets.

Yeah, the anexa, the hair follicles, the sweat glands, the sebaceous glands.

They're all anchored down there in the dermis.

And then below all of that, you have the subcutus or the subcutaneous fat.

That's your insulation and your shock absorber.

Now, I assume the skin isn't empty.

It's not just bricks and mortar.

Who actually lives there?

Well, it's a busy neighborhood.

You have melanocytes living in the bottom layer of the epidermis.

Yeah.

They're basically the umbrella holders.

They produce melanin pigment to shield the DNA of the other cells from UV radiation.

The body is natural sunscreen.

Precisely.

Then you have the immune sentinels.

These are dendritic cells, specifically Langer hand cells.

They just hang out in the epidermis waiting to catch an antigen like a bacteria or a virus.

And then they run it to the lymph nodes to sound the alarm.

And I read something surprising in the chapter.

There are T cells actually living in the skin.

Yes.

This is a crucial concept.

There are T cells that are specifically programmed to live in the skin.

They possess a homing beacon, a molecule called CLA or cutaneous lymphocyte associated antigen.

So they have like a VIP pass that only lets them into the skin club.

That's a great way to put it.

Yeah.

They circulate in the blood, but they only exit into the skin.

This becomes incredibly important later when we talk about skin lymphomas.

Okay, let's get into the code.

Section one of our deep dive is the language of dermatology.

If you are a student, this is where you get pimped on rounds.

Doctor, is that a papule or a nodule?

And you better know the answer.

Let's simplify it.

Most of these terms are really just descriptors of size and texture.

Let's start with the flat things.

If you run your finger over the lesion and you can't feel it, it's just a color change.

It's either a macule or a patch.

What's the difference?

A ruler.

If it's small, less than one centimeter, it's a macule.

Think of a freckle.

If it's big, greater than one centimeter, it's a patch.

Think of a large birthmark or port wine stain.

Okay.

Macule small, patch big, both flat.

What if I can feel it?

What if it's raised?

Then you are dealing with a papule or a nodule.

Again, it's just size.

A papule is a small bump under one centimeter, like a pimple or a bug bite.

A nodule is a larger lump over one centimeter.

And then there's the plaque.

This one always confused me.

Think of a plateau.

A plaque is elevated.

You can feel it, but it's flat on top.

It's usually broad.

Psoriasis is the classic example here.

You get these raised, scaly plaque toes on the elbows.

That's a plaque.

Got it.

Now the wet stuff, blisters.

Same rule applies.

Small fluid -filled blisters are vesicles, like chickenpox or herpes.

Large fluid -filled blisters are boule, like a massive friction blister on your heel from breaking in new shoes.

Vesicle small, boule big.

Now those are the clinical terms, what you see with your naked eye.

But the pathologist is looking through a microscope.

They have their own secret language.

We need to decode that.

These are super high yield for exams.

First term is hyperkeratosis.

Sounds like too much keratin.

Exactly.

It's thickening of the stratum corneum, the outermost layer of dead skin cells.

If you play guitar and you have calluses on your fingertips, that is hyperkeratosis.

Okay.

What about parakeratosis?

That is hyperkeratosis with a twist.

Normally when skin cells die and reach the surface, they lose their nucleus.

They are just empty scales.

In parakeratosis, the cells at the surface retain their nuclei.

Why would they keep the nucleus?

It implies speed.

The skin is turning over so fast, producing cells so rapidly that they just don't have time to mature properly and lose the nucleus before they get pushed all the way to the surface.

We see this a lot in psoriasis.

Okay.

Next one.

Acanthesis.

That's just a fancy word for epidermal hyperplasia.

The living layer of the skin gets thick.

And finally, the one that sounds the coolest, spongiosis.

This is a very visual term.

It describes intercellular edema fluid building up right between the cells of the epidermis.

So the cells are being pushed apart.

Yes.

Normally keratinocytes are tightly packed, but when fluid rushes in, it pushes them apart, stretching those desmosomes we talked about earlier.

Under the microscope, the space between the cells looks clear and expanded, literally like a sponge.

This is the absolute hallmark of eczema.

Spongiosis equals eczema.

Got it.

Okay.

We have the vocab down.

Now let's start looking at the actual diseases.

We're going to start with color, disorders of pigmentation, and melanocytes.

This is a huge spectrum.

On one end, you have cute freckles.

On the other end, you have melanoma, which kills people.

Let's start with the freckle.

The fancy name is ephelus.

Right.

And here is a major misconception to clear up immediately.

A freckle is not an increase in the number of melanocyte cells.

It's not.

No.

If you biopsy a freckle, the number of melanocytes is totally normal.

But those melanocytes are overactive.

They were pumping out more pigment, more melanin, and donating it to the surrounding keratinocytes.

It's a functional change, not a growth of new cells.

That's exactly why they darken in the sun and fade in the winter.

Okay.

Contrast that with lentigo.

Lentigo is different.

In lentigo, you actually have hypoplasia of the melanocytes.

There are physically more of them.

They line up along the basement membrane in a linear spread.

Because there are actual extra cells, lentogens don't fade in the winter.

They are permanent.

Moving up the ladder of seriousness, we have the mole, the melanocytic nevus.

The common mole.

These are benign neoplasms.

And the pathogenesis here is fascinating.

In almost all moles, we find acquired mutations in growth signaling pathways, usually BRAF or RAS.

Wait, BRAF is an oncogene, right?

It tells cells to grow.

If moles have a mutation that says grow, why don't they just keep growing and become cancer?

Why did they stop it being a little mole?

That is the million dollar question in pathology.

It's a concept called oncogene -induced senescence.

The mutation turns on the grow signal, but the cell sort of senses that something is wrong.

It realizes, hey, I shouldn't be growing this fast.

So it triggers a permanent arrest mechanism.

It shuts itself down completely.

So the mole grows for a little bit, hits the brakes, and then just sits there forever.

Exactly.

It retires.

And it goes through a life cycle as it does this.

Walk us through the life of a mole.

It starts as a junctional nevus.

The nests of mole cells are right at the junction between the epidermis and dermis.

These look flat and dark.

Then what?

Over time, the cells grow down into the dermis.

This becomes a compound nevus.

It has components in both layers.

Clinically, the mole becomes raised.

The epidermal part eventually disappears.

You are left with nests only in the dermis.

This is an intradermal nevus.

These are those flesh -colored, soft, squishy bumps you often see on older adults' faces.

The cells there are completely senescent.

They are done.

But not all moles play by the rules.

We have to talk about the ugly ducklings.

The dysclastic neva.

Yes.

These are the troublemakers.

Dysclastic neva are usually larger, bigger than a pencil eraser, about 5 millimeters.

They have irregular borders.

The pigment isn't uniform at all.

It's very splotchy.

If I have one of these, is it automatically cancer?

Not necessarily, but they are big markers of risk.

Histologically, we see cytologic atypia.

The cells look weird and angular.

And we see linear fibrosis, where the dermis scars a bit around the reed ridges.

The most important thing is that if you have a lot of these familial dysplastic neva syndrome, your risk of melanoma is huge.

Which brings us right to the big one.

Melanoma.

We know the sun causes it.

Yes, UV radiation damages the DNA.

You get a stepwise accumulation of mutations.

You hit BRAF, then you hit TERT, then CDKN2A.

Eventually, the checks and completely fail, and the cells start growing uncontrollably.

There is a concept in the text about growth phases that seems really critical for prognosis.

Can you explain that?

This is definitely the most important concept to grasp for melanoma.

It usually starts in a radial growth phase.

Radial meaning sideways.

Yes.

The tumor cells spread horizontally within the epidermis.

They're just crawling sideways along the surface in situ.

At this stage, they absolutely cannot metastasize.

Why not?

Because there are no blood vessels or lymphatics up in the epidermis.

They are trapped.

If you catch a melanoma in the radial growth phase, you simply cut it out, and the patient is cured.

But eventually, it shifts.

It shifts to the vertical growth phase.

A subclone of cells develops the ability to invade downward.

They breach that basement membrane and dive deep into the dermis.

Once they are in the dermis, they can hit a blood vessel and boom, metastasis to the brain or the liver.

And this leads to the Breslau thickness.

Correct.

The prognosis is almost entirely determined by the Breslau thickness.

That is the distance measured in millimeters from the top of the granular layer down to the deepest tumor cell.

So depth matters way more than width.

Absolutely.

A wide flat melanoma is significantly better than a tiny deep one.

The deeper it goes, the worse the survival rate.

Visually, what are we looking for under the microscope?

Melanoma cells are the villains of dermatology.

They're large.

They have huge irregular nuclei, and often they have these prominent nucleoli that are cherry red.

We literally The text mentions some new targeted stuff.

This has been a massive revolution.

Since we know about the BRAF mutations now, we can use drugs that specifically inhibit that mutant BRAF protein.

And we use immune checkpoint inhibitors drugs targeting CTLA -4 PD -1 that take the breaks off the immune system so your own T cells can hunt down the melanoma.

Okay, let's move from the dark pigments to the lumps and bumps.

Section three, benign epithelial tumors.

These are the things look scary but usually aren't.

The absolute champion here is the seborrheic keratosis.

The stuck -on thing.

Yes.

These are incredibly common in older adults.

They look like waxy coin -shaped plaques.

They can be tan or very dark brown.

The description stuck on is perfect.

It looks like someone took a piece of brown candle wax and just pressed it onto the patient's back.

You can almost peel them off.

You can pick at them and they crumble a bit.

They're driven by mutations in the FGFR3 gene.

And under the microscope.

They are composed of sheets of small basaloid cells with a lot of hyperkeratosis.

But the key feature is the horn cyst.

You see these little circular cysts filled with keratin just trapped inside the tumor.

Now, usually these are harmless, but there is a sign, a specific clinical scenario where they mean something really bad.

The laser trelaw sign.

Sounds French and very ominous.

It is.

If a patient suddenly erupts with dozens or hundreds of seborrheic keratosis all at once, like an absolute explosion of them, that is a huge warning.

It's a perioplastic syndrome.

It suggests there is an underlying internal malignancy, usually a GI adenocarcinoma -like stomach cancer, that's pumping out growth factors like TGF -alpha, driving the skin to just grow wild.

So, sudden onset of waxy spots check the stomach.

What about acamthosis nigricans?

This is a condition where the skin, in the areas of the neck, the armpits, the groin, becomes thickened and hyperpigmented.

It looks like dirt, right?

Like you could scrub it off.

Patients often try to scrub it off.

Yeah, but you can't.

It feels like velvet.

And what does this tell us about the patient's health?

It's a window into their metabolic state.

The vast majority of the time, it's associated with obesity and diabetes.

High levels of insulin essentially stimulate the IGF -1 receptor on the skin cells, causing them to proliferate.

So velvet skin equals insulin resistance.

Usually.

But just like the seborrheic keratosis, it can also be a perineoplastic sign of GI cancer.

So you always have to keep that in the back of your mind.

Really quick on the nexal tumors before we move on.

Sure.

Cylindroma is the turban tumor on the scalp.

Serengomas are those little papules on the lower eyelids.

And sebaceous adenomas are crucial because they link to Myr -Torah syndrome, which is a variant of Lynch syndrome.

So again, an internal cancel link.

Wow.

Let's talk about the bad stuff again.

Section four, premalignant and malignant epidermal tumors.

Not melanoma this time, but the keratinocyte cancers.

Right.

These are the cancers of the skin cells themselves.

It starts with actinic keratosis, or AK.

Actinic means related to sunlight, right?

Yes.

These are sun -damaged premalignant lesions.

If you shake hands with an older golfer or a sailor, you might actually feel them.

They feel exactly like sandpaper, rough scaly spots on the face or the forearms.

And sometimes they grow weird structures.

The cutaneous horn.

Sometimes an AK produces so much keratin that it builds up into a literal conical horn sticking straight out of the forehead or ear.

It looks exactly like an animal horn, but it's entirely made of dead skin cells.

If we look at the cells in an AK, what do we see?

We see dysplasia abnormal, messy growth, but it is strictly confined to the lower parts of the epidermis.

It hasn't taken over the whole layer yet, and we see paracritosis, those retained nuclei in the stratum corneum, which is why it feels so rough.

If you leave an AK alone, does it become cancer?

It can.

It can clear up, or it can progress to squamous cell carcinoma, or SCC.

So let's talk SCC.

This is the second most common skin cancer.

If the dysplasia from the AK spreads to involve the entire thickness of the epidermis, we call it SCC in situ, or Bowen disease.

And when does it become invasive?

When it punches through the basement membrane and actually invades the dermis.

How do we recognize SCC on a slide?

You were looking for squamous differentiation.

The cells are trying to be skin cells, so they produce keratin,

but they do it in a very messy way.

You see squamous pearls, these beautiful swirling nests of pink keratin, trapped deep down in the tissue.

And if you look closely at high power, you can see intercellular bridges.

The bridges are the desmosomes.

Exactly.

Even though they are cancerous, they still try to hold hands.

You can see the little lines connecting the individual cells.

Who gets SCC?

People with chronic UV light exposure, people with p53 mutations, and very importantly, immunosuppressed patients.

Transplant patients are at huge risk for SCC because the immune system normally keeps these mutant cells in check.

Also patients with zero dermopigmentosam.

Contrast that with the most common cancer, BCC.

BCC is everywhere.

It's the most common invasive cancer in humans, period.

What does it look like?

It's usually a pearly papule.

It looks shiny or translucent, and you very often see tiny dilated blood vessels telangiectatious just running over the surface.

And the mechanism here is unique.

It involves the hedgehog pathway.

Yes.

Specifically, mutations in PTCH1.

This pathway is vital for embryonic development, but it usually shuts off in adults.

In BCC, it gets stuck in the on position, driving totally unchecked cell growth.

And histology is classic.

I remember this from my own studies.

The picket fence.

Peripheral palisading.

The tumor forms these nests of blue basaloid cells.

The cells on the very outer edge of the nest line up perfectly parallel to each other, like soldiers standing at a tension or a picket fence.

And there's a gap around the nest.

Yes.

Clefting.

The tumor nest shrinks a bit during lab processing, so it pulls away from the stroma, leaving a clear white gap.

If you see blue nests with picket fences and clefts, it's BCC.

Okay, we're going deeper.

Section five.

Dermal tumors.

These are tumors arising from the connective tissue itself.

Let's start with the dermatofibroma.

This is a benign, fibrous histiocytoma.

It's basically a funny scar.

It's a firm, tan bump, very often found on the lower legs of young women.

There's a test for this.

The dimple sign.

Right.

If you squeeze the end around the nodule, it doesn't pop up.

It actually dimples inward.

That's because the tumor is scarring the collagen down, literally tethering the skin to the deep tissue.

Under the microscope, you see swirling spindle cells wrapping around collagen bundles at the periphery.

We call it collagen trapping.

Now compare that to a tumor with a very similar name, but a much worse attitude.

DFSP.

Dermatofibrosarcoma pertubrans.

DFSP is a low -grade malignancy.

It goes slowly,

but it is extremely locally destructive.

It invades very deep.

The pattern here is famous.

The storiform pattern.

The spindle cells are arranged in tight, swirling cartwheels or ping -wheel shapes.

And how does it invade the fat?

The Swiss cheese pattern.

The tumor pushes down into the subcutaneous fat, wrapping around individual fat cells.

It looks just like a honey cone or Swiss cheese.

If you see that, you know you need to excise it with very wide margins because it has invisible tentacles.

Next up is a really confusing one.

Mycosis fungoids.

Seriously, the worst -named disease in all of dermatology.

It sounds exactly like a mushroom infection.

It totally does, but it is not a fungus.

It is a cutaneous T cell lymphoma.

So cancer of the T cells we talked about earlier, the ones with the VIP pass.

Exactly.

The CD4 positive T helper cells that have the CLA homing receptor become malignant.

They home to the skin and start proliferating there.

What does it look like clinically?

It's a very slow burn.

It starts as localized patches, red, scaly areas that look a lot like eczema.

Then they thicken into plaques.

Finally, they form large nodules or frank tumors.

It can take years, and patients are very often misdiagnosed with psoriasis or eczema for a long time.

When the pathologist finally catches it, what do they see?

They see lymphocytes invading the epidermis where they shouldn't be.

We see clusters of these typical cells called patria micro abscesses.

And the cells themselves look weird.

Highly abnormal.

Their nuclei are twisted and folded.

We call them cerebriform nuclei because the contour looks exactly like the folded surface of a brain.

Brain -like nuclei in the skin equals lymphoma.

Got it.

Last one in this section is mastocytosis.

This is an accumulation of mast cells.

In kids, it often presents as urticaria pigmentosa, these tan or salmon -colored spots.

And the sign.

The swells up and turns into a hive.

Why?

Because you are physically irritating the mast cells.

They degranulate on the spot, releasing a ton of histamine, which causes immediate swelling and redness.

This is a great parlor trick for a quick diagnosis.

Moving on to section six, disorders of epidermal maturation and acute inflammation.

Or as I call it, why is my skin red and itchy?

Let's start with ichthyosis.

The root ichthy means fish.

Like an ichthyosaur.

Exactly.

These patients have skin that literally looks like fish scales.

It's incredibly dry and cracked.

Is it because they are making too much skin?

You sure know.

It's because they can't shed it.

It's a defect in descomation.

The old dead cells just stick together way too tightly.

Instead of flaking off invisibly like they're supposed to, they build up into these compacted plates of stratum corneum.

Now let's talk about urticaria.

Hives.

This is the classic allergic reaction.

Type one hypersensitivity.

You eat a peanut or you take penicillin and boom.

Mast cells degranulate.

What actually causes the bump?

It's vascular permeability.

The histamine makes the blood vessels extremely leaky.

Fluid rushes out into the dermis, pushing the collagen fibers apart.

So if I biopsy a hive, what do I see?

Surprisingly little.

You see dermal edema, clear white spaces between the collagen bundles, and maybe a few scattered eosinophils.

But the it's a deep swelling.

Contrast that with eczema or acute eczematous dermatitis.

Eczema is completely different.

Whether it's poison ivy, which is contact dermatitis, or atopic dermatitis, or a drug reaction, the action is entirely in the epidermis.

This goes back to spongiosis.

Yes.

The inflammation causes fluid to accumulate within the epidermis.

The cells are stretched apart.

If the fluid pressure gets high enough, it actually breaks those desmosome bridges and you get a visible vesicle.

That's why poison ivy weeps.

Yes.

The weeping is literally intercellular edema fluid bursting out of the microscopic sponge.

And then there is erythema multiform.

This is a hypersensitivity reaction pattern, usually to an infection like herpes simplex, mycoplasma, or to certain drugs.

The lesion is incredibly famous.

The targetoid lesion.

It looks just like a bullseye.

A red center, a pale ring, and then a red outer ring.

What is happening at a cellular level to create that bullseye?

It's a cytotoxic attack.

CD8 positive T cells are actively attacking the basal keratinocytes.

They are killing the skin cells right at the junction.

And on the slide.

You see interface dermatitis.

That's a band of lymphocytes hugging the epidermal junction.

And you see necrotic keratinocytes, shrunken, intensely pink dying cells.

And this can get really bad, right?

It exists on a severe spectrum.

If the reaction is severe, covers a large surface area and involves the mucous membranes like the eyes and mouth, it progresses to Stevens -Johnson syndrome, or SJS, and then toxic epidermal necrolosis, or TEN.

In TEN, the entire epidermis basically dies and sloughs off.

It looks like a massive thermal burn.

It is an absolute medical emergency.

That is terrifying.

Let's shift to something chronic.

Section 7, chronic inflammatory dermatosis.

Psoriasis.

This affects one to two percent of the population.

It's a systemic disease, but it manifests heavily on the skin.

What is the classic presentation?

Salmon colored plaques covered with a very distinct silvery white scale.

Typically found on the elbows, the knees, and the scalp.

And the nails?

Nail changes are very common.

Pitting, discoloration, or these yellowish oil spots on the nails.

There are two famous signs associated with psoriasis.

First, the auspice sign.

If you pick off that silvery scale, you will see tiny pinpoint bleeding spots.

Why does it bleed like that?

Because in psoriasis, the dermal papillae, the finger -like projections of the dermis, are elongated and contain highly dilated blood vessels.

And the skin sitting right on top of them is very thin.

So when you peel the scale, you immediately unroof those vessels.

And the second sign?

The Cobner Phenomena.

This means that new lesions form at the exact sites of trauma.

If a psoriasis patient aggressively scratches their arm, a line of psoriasis will form right along the scratch mark.

Histologically, psoriasis is very busy.

It is.

The epidermis is vastly thickened, which is acanthosis.

The reet ridges extend downward uniformly, looking like test tubes in a rack.

The stratum granulosum is completely gone.

And you have neutrophils migrating all the way up into the stratum corneum.

Neutrophils in the scale?

Yes.

They form little collections called Monroe microabcesses.

If you see neutrophils in the horn, think psoriasis.

What about seborrheic dermatitis?

This is essentially severe dandruff.

It affects the seborrheic areas with lots of sebaceous glands.

So the scalp, the eyebrows, the nasolabial folds.

It's greasy and yellow scaly.

Is it just dry skin?

No.

It's actually inflammation driven by the malassezia fungus reacting with the excess sebum on the skin.

And the histology has a specific look right around the hair follicles.

Follicular lipping.

You see mounds of pericotosis specifically piling up around the opening of the hair follicle.

Next is lichen planus.

This is the one with the best mnemonic in all of pathology.

The six P's.

Pruritic, purple, polygonal, planar, papules, and plaques.

Pruritic meaning itchy.

Incredibly itchy.

These are purple flat topped bumps, very often on the wrists or ankles.

And if you look closely, they have a white pattern.

Yes.

Wickham striae.

It's a white lace -like network right on the surface of the papule.

What is the histology?

Like erythema multiform, it's an interface dermatitis.

The lymphocytes are attacking the basal layer.

But this chronic attack creates a sawtooth appearance of the reet ridges.

They become very pointed and jagged.

And the dead basal cells drop down into the dermis.

We call those civet bodies.

Section eight, blistering diseases.

This is my favorite part of the chapter because the mechanism is just so elegant.

It's all about what specific molecule is being destroyed.

Exactly.

We're mostly distinguishing between two big autoimmune players here, pemphigus and pemphigoid.

Let's start with pemphigus vulgaris.

In pemphigus, the body makes antibodies against desmoglines.

Remember the desmosomes from the very beginning, the glue holding the epidermal bricks together?

Great.

Pemphigus dissolves the glue.

This causes the keratinocytes to completely fall apart from each other.

We call this acantholysis.

So the cells are just floating loose.

Yes.

They round up and float away in the air.

Pemphigus vulgaris attacks desmoglane one in three.

DSG3 is located deep in the epidermis.

So the blister happens very low, just above the basal layer.

And what happens to the basal layer?

Well, the basal cells are attached to the basement membrane below them by hemidesmosomes, which are not attacked in this disease.

So the basal cells stay put on the floor.

They look like a row of tombstones sitting on the floor of the blister.

And because it attacks DSG3, it affects the mouth.

Yes.

Mucosal involvement is very common and painful because the blister roof is so thin.

These are flaccid blisters that rupture very easily.

The immunofluorescence pattern is famous here.

If you stain for IgG, you see a net -like or fishnet pattern outlining every single cell because the antigen is the glue between all the cells.

Now compare that to Pemphigus foliaceus.

Foliaceus is milder.

The antibody is only against desmoglane one, which is mostly in the superficial skin.

So the blister is very high up, right under the stratum corneum.

It usually doesn't even look like a blister.

It just looks like crusted scaly skin.

Okay.

Now the other heavyweight,

bolus pemphigoid.

Totally different mechanism.

Here, the antibodies are attacking the hemidesmosomes, specifically proteins called BPAG1 and BPHE.

Hemidesmosomes anchor the cells to the floor, right?

Exactly.

So the cells stick to each other just fine, but the entire epidermis unzips from the dermis.

So the roof of the blister is the whole thickness of the skin.

Correct.

That makes the blister very strong.

These are tense belay.

They don't rupture easily.

You can poke them and they stay intact.

And the immunofluorescence.

Since the target is the basement membrane, you see a linear IgG deposit right along the DE junction, which is a bright straight line.

Net -like is Pemphigus because it's the glue.

Linear is pemphigoid because it's the floor.

Got it.

Now one more blistering disease, dermatitis herpetiformis.

This is essentially the skin manifestation of celiac disease.

Wait, celiac is a gut issue, gluten sensitivity.

Yes, but patients produce IgA antibodies against gluten that cross -react with reticulin fibers in the skin.

Where do these antibodies attack?

They deposit at the very tips of the dermal papillae.

This recruits massive amounts of neutrophils to the tips.

You get neutrophilic micro abscesses at the tips of the papillae, which cause subepidermal blisters.

And clinically.

It is intensely itchy.

You see grooved vesicles that look a bit like hoopies, hence the name herpetiformis, but it's not a virus.

It's gluten.

Quick mention of non -inflammatory blistering.

Epidermolysis bullosa.

This is a group of inherited genetic diseases where structural proteins like keratins or collagen the 7th are defective.

The skin is so mechanically fragile that just minor friction causes severe blistering and porphyria defects in heme metabolism.

These get subidermal blisters in sun -exposed areas.

Histologically, the dermal papillae get very rigid and stick up, which we call festooning.

Section nine disorders of epidermal appendages.

Let's talk about the absolute bane of adolescence.

Acne vulgaris.

Acne is a perfect storm of four factors.

One, you have a keratin plug blocking the follicle outlet.

Two, you have excess sebum production, which is driven by androgens.

Three, propionic bacteria, acnes bacteria colonize that follicle.

And four,

massive inflammation.

Why does it get so inflamed?

The bacteria produce lipases that break down the sebum oils into free fatty acids.

Fatty acids are profoundly irritating to the surrounding tissue.

So we have comedones.

Right.

Those are non -inflammatory.

Open comedones are blackheads and the black color is actually oxidized melanin.

It's not dirt.

Closed comedones are whiteheads.

And then the inflammatory lesions are the pustules and deep nodules.

What about rosacea?

Rosacea affects older adults.

It causes persistent redness and flushing in the central face along with telangiectasias.

And in late stages, it can permanently change the shape of the nose.

Yes, rhinophyma.

The nasal skin gets very thickened and bulbous.

We think that pathogenesis involves high levels of catholicidin, which is an antimicrobial peptide that inadvertently drives extreme local inflammation.

Section 10, paniculitis.

We are way down in the fat now.

Paniculitis is inflammation of the subcutaneous fat.

We divide it based on geography.

Is the inflammation mostly in the septa, which are the connective tissue walls between the fat lobules, or is it in the lobules themselves?

Merythema nodosum.

This is the most common form.

It presents as very tender, red nodules, almost always on the anterior lower legs, the shins.

Is it septal or lobular?

It is a septal paniculitis.

The inflammation radically widens the connective tissue septa.

It's usually reactive, a delayed response to a strep throat infection, drugs like sulfa, or systemic diseases like sarcoidosis.

And erythema indurata.

So this is a lobular paniculitis.

The inflammation is deep inside the fat lobules themselves, often with vasculitis and necrosis.

Historically, this was heavily associated with tuberculosis.

Finally, section 11, infection.

The creepy crawlies.

Let's start with warts.

Boruco.

Caused by HPV, the human papilloma virus.

What does the virus actually do to this cell structure?

It causes verrucus epidermal hyperplasia, meaning undulating spiky waves of skin growth.

And it produces a very specific visual viral effect called choelocytosis.

What does a choelocyte look like?

It's a superficial squamous cell with a raisin -like dark shriveled nucleus surrounded by a prominent clear halo.

That halo is the defining viral effect.

Mulliscum contegiosum.

Apoxvirus.

Very common in kids.

It creates firm pink papules with a central dimple, which we call umbilicated.

And under the microscope, it's virtually impossible to miss.

It really is.

You see these massive homogenous pink cytoplasmic inclusions called mulliscum bodies.

The cells are just totally stuffed to the brim with virus.

Empedigo.

The classic honey -colored crust on the face of a child.

It's usually caused by staph aureus or strip.

There's a really fascinating connection here back to pemphigus, isn't there?

There is, and it's brilliant.

The staph bacteria produce a toxin exfoliato toxin A that specifically cleaves desmoglane 1.

Wait, desmoglane 1?

That's the exact same target in pemmigus foliaceus.

Exactly.

The bacteria have essentially evolved a biological pair of scissors that cuts the exact same protein that the autoimmune disease attacks.

So histologically, empedigo looks just like pemmigus foliaceus.

A sub corneal blister.

Nature is incredibly efficient.

Last one.

Fungal infections.

Tinea.

Ringworm.

Athlete's foot.

The fungus lives exclusively in the dead stratum corneum layer.

It causes mild spongiosis in the living layer below.

How do we see it if it's hiding in the dead skin?

Sometimes it's very hard to see on a standard H &E stain.

So we use a PAS stain.

It dyes the fungal carbohydrate walls bright magenta red.

You just look for red hyphae sandwiching themselves horizontally in the dead skin layer.

Wow.

We have traveled from the stratum corneum all the way down to the fat and from a simple acne spot to fatal melanoma.

It's quite a journey.

So to wrap this deep dive up, we've covered a huge amount of pathology.

If you had to give the listener, especially that exhausted student cramming right now, a final philosophical takeaway, what is it?

I would say this.

The skin is a window.

We started with Virta calling it a wrapper, but we've seen that it's actually a real -time dashboard.

When you see acanthocyst nigricans, you aren't just seeing thick velvet skin, you're seeing profound insulin resistance.

When you see dermatitis or pediformis, you're looking right at celiac disease in the gut.

When you see the laser trellis sign, you're detecting an invisible stomach cancer.

So don't just look at the skin, look through it.

Exactly.

If you learn to read the code, maculas, the papules, the microscopic patterns, you're essentially reading the internal state of the entire patient.

I really love that.

To everyone listening, take a second to look at your own skin check for that dimple sign.

Look at the intricate patterns in your fingerprints and just appreciate the sheer complexity protecting you right now.

Think about how altering the homing beacons on those T cells or modifying the skin microbiome might one day be the key to curing systemic diseases we haven't even cracked yet.

And if you are taking that exam tomorrow, remember, melanoma depth is Breslow, eczema is spongiosis, and psoriasis has Monroe micro abscesses.

You're going to crush it.

A huge warm thank you from the last minute lecture team.

Go get them.

Best of luck.

We'll see you in the next deep dive.