Latin, Greek, and a quick review of lymphangioma

I was putting together some thoughts about lymphangioma the other day, and I got to wondering where the name came from. I love it when there’s a Latin or Greek word root that makes sense…and I found more than I hoped for when I looked into lymphangioma. (more…)

Hereditary hemorrhagic telangiectasia, simplified.

Hereditary hemorrhagic telangiectasia is one of a handful of diseases that I could never really get into my head. I don’t know why, because the name is so descriptive – it tells you exactly what the distinctive features of the disease are.

Maybe it’s because my professors used the older name for this disease – Osler-Weber-Rendu disease – which is about as non-descriptive a name as you can get. Good thing we’re getting away from eponymous disease names. They’re charming, but they make life really hard for students.

Back to hereditary hemorrhagic telangiectasia. Let’s take a closer look at this name – because once you know what the words mean, you’ll understand the disease without having to use brute memorization.

We’ll look at the words out of order, so that the explanation makes sense.

Hereditary: This is an autosomal dominant disorder. For boards (I can’t imagine an exam question on this, but who knows?), you might want to know that the mutated genes in this disorder encode parts of the TGF-β signaling pathway.

Telangiectasia: This is a great name, because everything you need to know is right there in the name. Too bad we don’t have time to cover some simple Greek and Latin word roots in medical school, because once you know a few, you can easily figure out what words mean. Telangiectasia comes from three Greek words:

  • τέλος (telos): “end” (For example: telomeres are the little things on the ends of chromosomes.)

  • ἀγγεῖον (angeion): “vessel” (angio- is almost always used to indicate a blood vessel. For example: an angiogram is an imaging study that looks at blood vessels.)
  • ἐκτείνειν (ekteinein) “to extend” (any time you see ectasia or ectasis, it means an abnormal dilation of a tubular structure. For example: bronchiectasis means dilation of bronchi.)

So telangiectasias are abnormal dilations of the very ends (tiny capillaries or venules) of blood vessels. They often occur in the skin and mucous membranes, and sometimes they look like tiny little spiders, but sometimes they just look like red blotches (check out the image above). Telangiectasias can also occur in the respiratory, gastrointestinal, and urinary tracts. Telangiectasias are not neoplastic (there aren’t any new, neoplastic vessels); they’re just malformations of existing vessels.

Hemorrhagic: Sometimes telangiectasias can rupture, causing nosebleeds, GI bleeding or hematuria.

That’s it! Now you know 🙂

Fuscus, February.

Before I get to fuscus, I have to say that I have HAD it with this month. Normally I start complaining about February around mid-January, and continue on every day until people start avoiding me. This year, I thought I could rise above it. I tried thinking positively. I tried reading Jung and Frankl to address my existential crisis. Last night I was up late listening to Jordan Peterson, and I thought I was doing pretty well.

But this morning, after coming out to a car completely encased in ice (not exaggerating), after seeing the sky the same color as the ground (greyish white) YET AGAIN, and after some other crap that I won’t go on about, I’m done. February just sucks. It’s not me, it’s you, February.

So where did February come from?

Since I sat down intending to write about the very nice Latin word fuscus, I thought maybe I’d look up the origin of the word February and see if there was some Latin that could help make me feel better. And there was! So I’m sharing what I found in the hopes that it may help others who have February issues.

February is usually said to be derived from the Latin februum, meaning anything that purifies or consecrates. This doesn’t fit my view of this month, but whatever. According to a prominent Roman grammarian (what a cool job, seriously) named Censorinus, who wrote De Die Natali (The Birthday Book) in 238 AD, there were tons of februamenta (rites of purification) going on in Rome during this time of the calendar year. Part of the purification was agricultural (clearing away dead stuff and getting the fields ready for planting). But it wasn’t just fields – houses, material items, and even the Romans themselves were februa (purified) in different ways, using different rites.

Wait, why all the purification?

In Roman tradition, February was originally the last month of the year, and, according to Ovid, it was “consecrated to the shades of the dead.” So along with acts of propitiation (appeasement, I had to look it up too), there were acts of purification to protect the living from evil spirits and also to banish the spirits at the end of the year so that the new year could begin in purity.

The image above is a drawing of the month of February from a fourth century calendar. The caption describes how to placate the ghosts that roam the earth in February. Okay – keeping angry ghosts from haunting the living – now we’re getting somewhere.

There must be something better, though.

Yes, there is. Some sources suggest that February actually comes from feber, a word which the Romans used to describe lamentation. YES! That’s it. I KNEW there had to be something in the name of this miserable month that reflected its true nature. Okay, the Romans were lamenting their deceased. But still. It fits. For the rest of the month, I’m going to say Lamentation instead of February and see if anyone notices.

Okay, back to fuscus.

For those of you brave enough to read this far, here’s a happy thing to offset all the misery. As you may know, there are a bunch of pigments you can see sometimes in tissues. One of them is called lipofuscin. It’s known as the wear-and-tear pigment, because it accumulates with age. Lipofuscin is composed of a bunch of lipids and proteins and has a yellow-brown appearance. It has no clinical significance – but you need to know it exists so you don’t confuse it with something else yellow-brown, like hemosiderin.

Here’s the good part. The first half of lipofuscin makes sense, since it’s composed partly of lipids. The second half is derived from the Latin word fuscus, which means dingy, brown, or dark – great Latin word choice, since lipofuscin has a dingy, brown appearance. So that’s why “obfuscate” means “to make unclear or obscure.” And it may be where we got the word “dusk” (from Middle English dosk, which came from Old English dox, which probably came from our Latin hero fuscus).

This is the weird kind of thing that makes me happy. I have no idea why finding the Latin connection between two seemingly unrelated words should make me happy in such disproportionate measure – or happy at all – but it does.

In this month of Lamentation, I’ll take happiness where I can get it.

What’s the difference between an aortic dissection and a false aneurysm?

 

 

 

 

 

 

 

 

Q. I’m a little confused about the difference between an aortic dissection and a false aneurysm.

In diagrams of aortic dissection, it looks like all three layers of the vessel have been damaged and blood is leaking out of the vessel BUT still contained by connective tissue etc. Isn’t that what a false aneurysm is? So what’s the difference between the two?

A. I can see what you mean – diagrams of aortic dissections can be misleading!

Diagrams of aortic dissection (like this one above, from Wikipedia) often focus on the three types of dissections. The point of these diagrams is just to show the place in the aorta where the dissection begins (near the heart vs. more distally). They can be kind of misleading, though, if they don’t clearly depict how the blood tunnels through the wall of the aorta. Like you described, it can look more like the aorta has actually ruptured all the way through, and the blood is collecting outside the aorta.

So let’s quickly review the definitions of false aneurysm and dissection.

In a false aneurysm, all three walls of the vessel have been broken through, and blood collects just outside the vessel. It doesn’t tunnel down or up into the wall of the vessel at all. After some time, the blood organizes and becomes firm – kind of like a blood clot – and it prevents further blood from escaping the damaged vessel.

In a dissection, only the inner portion of the vessel wall is damaged. Blood enters into that damaged area, and tunnels up or down within the wall of the vessel. Unlike a false aneurysm, in which blood bursts through all three layers of the vessel, in a dissection, the outer layers of the vessel are still intact, and blood forms a channel within the vessel wall itself.

So you had the right idea! It was just the diagram that threw you off. In the diagram above, the arrangement of the two little white arrows incorrectly implies that blood is busting all the way through the aorta at a single point – but the rest of the aortic wall looks intact. To really show what’s happening in an aortic dissection, the wall of the aorta should be more clearly depicted, and the second arrow should point up or down within the wall itself, showing the path of blood as forms a tunnel within the vessel wall.

 

What does “differentiation” mean?


Q. I have Googled and YouTubed this thing to death, and I still can’t grasp the meaning of “differentiation.” It seems the opposite of its definition. To “differentiate” means to recognize what makes something different. But according to your post on tumor differentiation, well-differentiated tumors resemble (don’t look different from) their tissue of origin. I would think if something is well-differentiated, it would look very different from the thing it’s being compared to. Why is the use here opposite of its meaning?

A. I totally get where you’re coming from. It’s REALLY frustrating in pathology when things are described in terms that don’t seem to make sense. You are not alone in questioning the use of this term!

The problem is that the word in question – differentiation – has a specific meaning in the real world. You’re exactly right in your definition: to differentiate between two things means to recognize what’s different or unique.

So you’d think that “differentiation” in the pathology world would mean the same thing: the recognition of things that are unique, different, or not the same. By logical reasoning, then, a “differentiated” tumor would be one that looked different from its cell of origin. And you’d think a “well-differentiated” tumor would be one that looked very different from its cell of origin.

Unfortunately, “differentiation” doesn’t have the same definition in the pathology world. So we have to put aside our logic and knowledge of vocabulary for a moment, irritating as that may be, and learn a new definition for this word.

The definition of “differentiation” in pathology-speak.

When we’re talking about tumors, the definition of “differentiation” is simply this: the degree to which tumor cells resemble their cell of origin. A well-differentiated tumor is one in which the tumor cells look very much like their cell of origin. A poorly-differentiated tumor (like the poorly-differentiated squamous cell carcinoma shown above) is one in which the tumor cells barely resemble their cell of origin.

That’s it. Yes, it’s an annoying word choice, because it is used here in a way that seems counterintuitive. But maybe it’s not as far off as it seems.

Maybe this will help.

I think about it (okay, rationalize it) this way. When cells are really immature, they don’t have a lot of features that make them look different from other cells. Myeloblasts don’t look very different than lymphoblasts, for example. So we could say that these immature cells are undifferentiated; it’s hard to tell what kind of cell they really are, and hard to tell them apart from other cells.

The same thing is true of the cells in poorly-differentiated tumors! The cells show practically no features that give away their identity; it’s hard to even tell what kind of cells they are. They are, in effect, undifferentiated.

If you think about “differentiation” this way (undifferentiated cells lack identifying features; it’s hard to tell what kind of cell they are), then the concept of tumor differentiation is a little easier to swallow. A little.

Do all leukemias arise from hematopoietic stem cells?

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Q. I have a quick question on the cell of origin in leukemia. In our pharmacology class, we went through a section on cancer. There was a slide that said leukemia is a tumor of hematopoietic stem cells. But leukemia involves more than just hematopoietic stem cells, right? I think I remember from our pathology class that leukemia can also involve cells downstream of hematopoietic stem cells.

A. You’re absolutely right! Which means you really understood the heme part of our pathology class! Just to back up a bit: all leukemias arise from hematopoietic cells (either myeloid or lymphoid cells). But not all leukemias arise in hematopoietic stem cells. Let’s take a look.

Some leukemias arise in stem cells.

All of the chronic myeloproliferative disorders, for example, originate in stem cells. As a result, when you look in the blood and bone marrow, you see a proliferation of all different kinds of myeloid cells (red cells, neutrophils, and megakaryocytes) at all stages of maturation (neutrophils, myelocytes, metamyelocytes, etc.).

In most of the chronic myeloproliferative disorders, a particular myeloid cell line dominates (in chronic myeloid leukemia (CML), for example, most of the malignant cells are neutrophils and precursors) – but because of the stem cell origin, there are other malignant myeloid cells present as well.

Here’s a cool thing. You’d think that the stem cell of origin in these chronic myeloproliferative disorders would be a myeloid stem cell, right? I mean, these disorders are composed of all kinds of myeloid cells – so the origin should be a myeloid stem cell.

It turns out that the stem cell involved is actually a very young stem cell – it hasn’t even decided whether it wants to be myeloid or lymphoid! We know this because the characteristic genetic abnormality (for example, the Philadelphia chromosome in CML) is also present in lymphocytes. That explains why when CML evolves into blast crisis, the blasts may be either myeloid or lymphoid.

Other leukemias arise in non-stem cells that belong to a specific cell lineage.

Acute promonocytic leukemia, for example, originates in a promonocyte (a stage of development between monoblast and monocyte). This means that when you look at the blood and bone marrow, you see mostly promonocytes (the cells in the image above with the lovely tissue-paper-like nuclei). Cells of other myeloid cell lineages (like red cells or neutrophils) are not present. These types of leukemias are a lot more straightforward.

Heme mistakes like this are common!

This kind of mis-statement (“all leukemias arise from stem cells”) happens a lot when people talk about hematopoietic diseases. Even the names of diseases are often stated incorrectly (e.g., “acute lymphoid leukemia” or “acute lymphocytic leukemia” instead of “acute lymphoblastic leukemia”). Heme is an area that many people shy away from, for some reason. I love it and find it really straightforward, but depending on how it’s taught, it can seem really confusing.

If you’re struggling with heme, there are tons of heme-related posts here on Pathology Student. You might also find my Complete Hematopathology Guide useful; it covers all the main hemepath stuff in a straightforward, no-BS way.

Tumor invasion and metastasis: are they the same thing?

Here are a couple great questions from one of my lovely students regarding invasiveness and metastasis.

Q. I have a quick question on today’s lecture. There is a slide near the end that has a picture of non-invasive carcinoma. For a tumor to be malignant, should it not be invasive?

A. Great question! I think you may be referring to the image above, which shows a gland with either severe dysplasia or carcinoma in situ.

Cancers are usually invasive, as opposed to benign tumors, which grow with pushing borders and are typically encapsulated.

However, very early cancers are called “carcinoma in situ”, which means they have not broken through the basement membrane yet (and thus are non-invasive). Every cancer has to start somewhere!

The only really definitive quality of malignancy is metastasis. If a tumor has metastasized, that is definite evidence of malignancy.

Q. But is invasiveness different from metastasis? That is, can a cancer metastasize without first invading tissue? Or are we talking about a tumor that has the ability to metastasize, but has not yet metastasized?

A. I’ll answer your questions separately.

1. Yes – invasiveness is different than metastasis.

  • Invasiveness is the ability of a tumor to extend into the surrounding tissue, and it is almost always a sign of malignancy. Benign tumors (with very few exceptions), are encapsulated and grow simply by expanding and pushing the surrounding tissue aside. Malignant tumors (with very few exceptions), are unencapsulated and grow by reaching into the surrounding tissue.
  • Metastasis is the ability of the tumor to move to a different location in the body and set up shop (start growing) there. Benign tumors NEVER metastasize. Malignant tumors usually do, although if detected early, they may be removed before they have the chance.

2. No: a cancer cannot metastasize without first invading tissue. In order to metastasize, tumor cells must first invade tissue, then make their way into vessels (either blood vessels or lymphatics), and then make their way out of those vessels and into new tissue.

3. Yes, the image above shows a non-invasive malignancy (carcinoma in situ), which is a malignant tumor that has not yet metastasized (or even invaded) yet. Left to its own devices, carcinoma in situ almost always becomes invasive carcinoma. As the tumor grows, some cells will most certainly develop the ability to become metastatic. So it’s way better to detect a carcinoma when it is in the carcinoma in situ stage rather than the invasive stage.

What the H is HLH?

Hemophagocytic lymphohistiocytosis is not easy to pronounce. That’s why it is often abbreviated HLH, which is a lot kinder on both the tongue and the keyboard.

The “hemophagocytic” part of the name, which means “blood + eat + cell,” comes from the observation that the immune activation in HLH often results in hemophagocytosis, in which blood cells are engulfed by histiocytes (macrophages in the tissue) in a very cannibalistic way. Check out the histiocyte in the center of this image (can you see the red cells inside?).

This activation of macrophages is why the disease has also been called macrophage activation syndrome in the setting of juvenile rheumatoid arthritis. The “lympho” part comes from the increase in lymphocytes that happens in HLH. Even though this disease has a complicated name and several different triggers, the symptoms have one common cause: Cytokine Storm.

What causes HLH? Cytokines and hit men.

Cytokines are important molecules in inflammatory signaling in the body, and when not properly regulated they can cause a lot of destruction. if you want a mini-review on cytokines check out all about cytokines in less than 400 words.

HLH happens when something triggers an over-activation of cytotoxic T and natural killer (NK) cells, which are cells responsible for quickly recognizing and destroying cells which have been infected, usually by viruses. Cytotoxic T cells and NK cells are specialized lymphocytes which are kind of the hit men of the immune system. When they detect cells presenting viral antigens via major histocompatibility complexes, they release perforins to punch holes in the cells and cytokines to signal other inflammatory cells to rush in and finish the job.

This immune over-activation turns on lots and lots of cytokine-producing macrophages. The massive cytokine release causes fever. The huge numbers of activated macrophages end up “eating” or destroying the patient’s own blood cells as well as doing damage to many organs, such as the bone marrow, lungs, and liver. The damaged blood cells get trapped in the spleen, causing splenomegaly. HLH can also kick off other problems in blood regulation, such as disseminated intravascular coagulation (DIC).

Primary vs. Secondary HLH

HLH can be genetic (“primary”) or acquired (“secondary”). Genetic cases usually appear in early childhood and are associated with a mutation affecting cytotoxic cell function, or with an immunodeficiency state such as Chediak-Higashi syndrome. Acquired forms of HLH can occur at any age – but often affect adults (although some adults are later found to have a predisposing mutation). Adult cases are hard to recognize, because they happen in the setting of other serious illnesses and can present with non-specific symptoms.

Acquired HLH can be triggered by any event provoking an immune response. Usually, though, it occurs in the setting of infection or malignancy, when the immune system is already compromised. Infectious triggers are usually viral, most commonly Epstein-Barr virus (EBV) and human immunodeficiency virus (HIV). Exactly why adult HLH happens in these settings is still poorly understood, although it is thought that underlying genetic susceptibility could play a role in some cases.

Diagnosis

Despite the name of the disease, hemophagocytosis is not necessary to diagnose HLH. It can be helpful  – but it isn’t specific for HLH, and can be found in a lot of other inflammatory conditions. So to diagnose HLH, you need either an established molecular abnormality consistent with an HLH mutation, or 5 of the following clinical criteria:

    1. Fever
    2. Splenomegaly
    3. Cytopenias in at least 2 blood cell lineages (indicating that the blood cells are being eaten up)
    4. High triglycerides and/or low fibrinogen (the latter is involved in the clotting cascade
    5. Hemophagocytosis
    6. Low or absent NK-cell activity
    7. High ferritin (which transports iron and is also a marker of acute stress in the body)
    8. Elevated soluble CD25 (also called soluble IL-2 receptor alpha. Remember, IL-2 tells lymphocytes to proliferate and differentiate)

Treatment

It is very important to recognize HLH quickly so treatment can be started – but diagnosis can be tricky since many of the symptoms overlap with sepsis or malignancy. Treatment includes chemotherapy, immunosuppression, supportive care, and sometimes bone marrow transplant (mostly in genetic cases). Untreated, HLH is nearly universally fatal.

Bottom Line

The lesson here? Never underestimate the power of cytokines…and think about the possibility of HLH in a very sick patient with the appropriate clinical warning signs.

For more about HLH, read Robbins 9e., pages 585-586

Reference:
Jordan, M. B., Allen, C. E., Weitzman, S., Filipovich, A. H. & McClain, K. L. How I treat hemophagocytic lymphohistiocytosis. Blood 118, 4041–4052 (2011).

A huge thanks to Michelle Stoffel, MD PhD, PGY3 Pathology Resident at the University of Wisconsin, for yet another informative and fun post! Check out her other awesome posts here, here and here.