Pathology Student

Systemic lupus erythematosus is one of a few diseases that have earned the name “the great imitator.” It is a chronic, systemic illness with many, many possible symptoms in many different organ systems, and widely varying disease courses in different patients. We’ll go through a short summary of lupus here and save the more detailed information for other posts.

The underlying cause of lupus is not known. To manifest the disease, you most likely need have two things: 1) a genetic predisposition, and 2) some environmental trigger (sun exposure, drugs, etc.). Whatever the underlying cause, patients with lupus all have autoantibodies against self antigens. All patients with lupus have anti-nuclear antibodies (antibodies against some part of the cell nucleus – like DNA, histones, RNA-bound proteins, or nucleoli). Some patients also have anti-RBC, anti-lymphocyte, anti-platelet and/or anti-phospholipid antibodies as well.

The autoantibodies cause damage by forming immune complexes with their corresponding antigens (in the case of anti-nuclear antibodies, there must be some type of cell destruction to expose the corresponding nuclear antigens!), and circulating around the body lodging in places they should not be (like glomeruli, skin, joints, the pericardium, etc.). Remember what type of hypersensitivity reaction this is? (See the bottom of the post for the answer. But try to remember before you look!)

Organ systems commonly affected (with common manifestations) are:
1. Renal system (wide variation in manifestations, from painless hematuria, to lupus nephritis, to end-stage renal failure. One histologic hallmark is membranous glomerulonephritis with a “wire-loop” appearance due to immune complex deposition.)
2. Skin (the classic manifestation is a malar, or “butterfly,” rash, but scaly patches, ulcers, and other skin lesions can occur)
3. Nervous system (headache, mood disorders, seizures, psychosis, focal neurologic deficits)
4. Musculoskeletal system (arthritis of small joints of hands, muscle pain)
5. Cardiovascular system (pericarditis, endocarditis (called Libman-Sacks endocarditis), atherosclerosis)
6. Hematopoietic system (anemia, thrombocytopenia, leukopenia, antiphospholipid antibody syndrome)

There are two main forms of lupus: discoid lupus and systemic lupus erythematosus. Patients with discoid lupus have only skin (not systemic) involvement, and they do not have anti-DS DNA antibodies (an antinuclear antibody frequently present in patients with systemic lupus). Systemic lupus erythematosus is just what the name says: a systemic form of the disease. It is the more common form, unfortunately.

The prognosis is difficult to predict for individual patients. Some patients have very few symptoms; rarely, the disease course is acute and rapid. Most patients suffer a relapsing and remitting course over a period of many years (the overall 10 year survival is 80%). Acute flare-ups can be treated with steroids – but as of now, there is no cure.

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The type of hypersensitivity reaction that is characterized by immune complex deposition is type III.

Photo credit: NIH (http://www.niehs.nih.gov/health/topics/conditions/lupus/index.cfm), under cc license.

I received this very good question by email yesterday. Please feel free to send in your questions, and I’ll post the answers here.

Q. When a squamous cell carcinoma is designated as “poorly differentiated”, what other parameters/tests are performed to determine the tissue of origin?

A. Differentiation, for those of you who have just joined us, is a quality of tumors that has to do with how  much the tumor cells resemble their tissue of origin. Well-differentiated tumors are composed of cells that closely resemble their tissue of origin, whereas poorly-differentiated tumors are composed of cells that have little resemblance to their tissue of origin. Anaplastic tumors are the least differentiated of all: they show no resemblance to their tissue of origin.

This concept is important for a couple reasons. First, the degree of differentiation of a tumor often has a bearing on prognosis. Well-differentiated tumors generally carry a better prognosis than poorly differentiated tumors. Second, when a tumor is totally undifferentiated (anaplastic), you have to resort to special tests in order to figure out its origin (is it a squamous cell carcinoma, an adenocarcinoma, a lymphoma, a sarcoma, etc.).

Back to our question: when you have a poorly-differentiated squamous cell carcinoma, how do you know it’s a squamous cell carcinoma (as opposed to an adenocarcinoma, for example)? If the tumor is poorly-differentiated, that means there are still some morphologic features (albeit few) that reveal the squamous nature of the tumor. If you look carefully, you should be able to find some of these features, which would then point you towards the diagnosis of squamous cell carcinoma.

Two clear-cut features of squamous cell carcinoma are intercellular bridging and keratin pearls (there are other, “softer” features indicating a squamous cell origin, but we’ll focus on the more definitive features). Intercellular bridging is a term describing the special connection between the epithelial cells of squamous epithelium (it’s not present in glandular epithelium). By light microscopy, you can see little horizontal hair-like connections between the epithelial cells in both normal squamous epithelium and in malignant squamous epithelium. Look closely between the epithelial cells in the above image of a squamous cell carcinoma. See the little connections between the cells (they look like little zippers connecting the cells)? Those are intercellular bridges.

Keratin pearls are whorl-shaped accumulations of keratin made by malignant squamous cells. In normal squamous epithelium, keratin lies in a nice flat layer on the epithelial surface. In malignant squamous epithelium, the tumor cells can grow in any direction they want, and so the keratin they produce often gets trapped inside the tumor, forming pink, glassy, spherical masses. There’s a nice keratin pearl at about 2 o’clock in the image above.

So, if you have a tumor that you think might be a squamous cell carcinoma, but the cells aren’t showing clear squamous cell differentiation, look closely for epithelial bridging and keratin pearls. If you find either of these, it’s a good bet that you’re dealing with a squamous cell carcinoma. There are other little clues that point towards other types of tumors (like adenocarcinoma, or melanoma, or sarcoma), but that’s for another post.

Sometimes, you’ll get a tumor that shows no defining morphologic features whatsoever – no interepithelial bridging, no keratin pearls, no signs of differentiation along any other cell line. In these tumors (which would be described as “anaplastic”), you need to use a secret weapon to figure out what the cells are: immunohistochemistry. In this technique, you use a reagent consisting of antibodies against specific components of cells (there are lots of these specific components: squamous cells have cytokeratin in them, muscle cells have actin in them, etc.). These antibodies are bound to a substance that appears brown under the microscope. The concept is simple: you apply the reagent to the tissue in question, allow it to bind to the cells, then wash off the excess reagent and look at it under the microscope. If the tumor cells appear brown, that means they possess whatever antigen the antibodies in your reagent are directed against, and that information can help you figure out what type of cells your tumor contains.

So, if you have an anaplastic tumor, you might choose to apply immunohistochemical stains for cytokeratin, actin, and CD45 (an antigen present on lymphoid cells). If the cytokeratin stain comes back positive (brown), and the actin and CD45 stains come back negative, the tumor is most likely a squamous cell carcinoma. There are tons of immunohistochemical stains for all different types of cells. Generally, these stains are pretty specific for one cell line, but it’s not always totally straightforward. Some tumors stain positive for markers from cell lines other than their cell of origin, and some tumors show only weak staining with the stains that are supposed to be nice and positive. So you really need to use a panel of a bunch of different stains to make the best diagnosis.

The bottom line, then, if you have an undifferentiated appearing tumor: look for little morphologic clues (like keratin pearls) first. If you see few or no clues, then your next step is immunohistochemical staining, which will almost always reveal the origin of the tumor. If that doesn’t work, there are still other tests you can do – like cytogenetics or molecular diagnostics – and we’ll talk about those in future posts.

Photo credit: AFIP
http://commons.wikimedia.org/wiki/File:Well_differentiated_squamous_cell_carcinoma.jpg

Here’s a good question that gets at a concept you should understand: tumor cell differentiation.

Q. I’m doing a clinical research project, and I’m supposed to record the differentiation of resected tumors per the pathology reports.  A specific report says, ” cell carcinoma with squamous differentiation.”  Is this a ‘well-differentiated’ tumor, or how do you define this in the commonly used descriptive terms?

A. There are three common types of skin cancer: basal cell carcinoma (in which the tumor cells resemble the basal layer of epithelium), squamous cell carcinoma (in which the tumor cells resemble the upper layers of epithelium), and melanoma (in which the tumor cells are trying to be melanocytes). In the image of a basal cell carcinoma above, even at this low power you can see the dark blue, palisading tumor cells that are trying their best to resemble their normal basal-layer epithelial cell counterparts.

“Basal cell carcinoma with squamous differentiation” means that you have a basal cell carcinoma in which areas of the tumor look more like the upper layers of epithelium rather than the basal layer. It sometimes happens that a tumor of one type can show “differentiation” along another cell line (e.g., a glandular tumor that shows squamous differentiation). It really doesn’t have anything to do with whether a tumor is well-differentiated or poorly-differentiated.

“Well-differentiated” and “poorly differentiated” are terms that refer to how much the tumor cells resemble their cell of origin (a well-differentiated basal cell carcinoma is composed of tumor cells that closely resemble basal cells, whereas a poorly-differentiated basal cell carcinoma is composed of tumor cells that don’t resemble basal cells very much at all). So, you could have a well-differentiated basal cell carcinoma that shows areas of squamous differentiation, or a poorly-differentiated basal cell carcinoma that shows areas of squamous differentiation. The areas of squamous differentiation are really a separate issue.

Photo credit: Wikimedia.

Ringworm is a superficial fungal infection of the skin, nails, or hair. The causative agent is not a worm, but a type of mold called a dermatophyte (“skin plant”). Dermatophytes love non-living and/or keratinized tissue, like the stratum corneum of the skin, the nails, and the hair. There are three genera, if you care: microsporum, trichophyton, and epidermophyton.

Most of the time, the dermatophytoses (a more official name than ringworm) are classified by their location. The word “tinea” (meaning, in this case, “dermatophytosis”) usually precedes the anatomic location. Here are some common dermatophytoses:

Tinea capitis (dermatophytosis involving the scalp)
Tinea barbae (dermatophytosis involving the beard area)
Tinea pedis (dermatophytosis involving the feet, commonly called “athlete’s foot”)
Tinea crurus (dermatophytosis involving the groin, commonly called “jock itch”)
Tinea corporis (dermatophytosis involving skin in any other anatomic location)
Tinea unguium (dermatophytosis involving the nails)

There are a couple unique kinds of dermatophytoses too, including tinea nigra (a tropical condition in which dark brown fungi cause brown/black macules on palms or soles) and piedra (a fungal infection of the hair shaft itself). 

Dermatophytoses affecting the skin have a characteristic ring-shaped lesion with a raised, red, sharply-demarcated border. This is probably where the worm idea came in – people thought the advancing borders of the lesion indicated the presence of a worm in the skin. These lesions are most common in warm, moist areas of the body, but they can occur anywhere, really. They are not dangerous – just bothersome.

Note: the nice picture of an athlete’s foot (perhaps with a ringworm infection between the first and second toes) was taken in the Capitolene Museum in Rome by Thrillho. It can be found at: http://www.flickr.com/photos/thrillho/916166760/.