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. 

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How to tell apart promyelocytes and myelocytes

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

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

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

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

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

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

So for our cells above:

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