What the heck is uniparental disomy?

We were talking about developmental pathology the other day in class – trisomies, sex chromosome numerical abnormalities, microdeletion syndromes etc. – and the term “uniparental disomy” came up.  (more…)

Happy New Year!

new year

Pathology Student is back after a nice long holiday hiatus. We will begin 2010 with a new series of real live questions from real live students. It is important to hear other students’ questions (and answers) because 1) you will probably learn or clarify something, and 2) it will hopefully encourage you to ask your own questions. So, without further ado, here are some questions and answers about female reproductive system pathology.

Q. In endometriosis, is the glandular tissue found outside of the uterus and not associated with it at all other than being of similar cellular makeup? In other words, is it essentially extra-uterine menses?
A. Endometriosis is extra-uterine endometrial tissue, not associated with the stuff inside the uterus at all – other than it is under the same hormonal control, so when the endometrial tissue inside the uterus undergoes cyclic changes, so will the endometrial tissue (endometriosis) outside the uterus.

Q. Is nulliparity a risk factor in endometrial hyperplasia?
A. Yes, actually, it is, although our textbook [Robbins Basic Pathology] doesn’t mention it. It falls into the category of things-that-increase-estrogen-exposure, so it’s a risk factor for any of the tumors related to estrogen excess.

Q. The risk factors for endometrial hyperplasia include exogenous hormone use. Is this the same thing as estrogen replacement therapy?
A. In this setting, yes, they are the same thing.  If you want to be complete about it, there are other kinds of exogenous hormones – like birth control pills – but when we’re talking about endometrial hyperplasia, the exogenous hormomes referred to are estrogen replacement therapy (birth control pills don’t have that effect on the endometrium).

Q. It seems like too much estrogen causes a bunch of issues. Do many of these pathologies arise simultaneously in the presence of excess estrogen?
A. No, not usually. The chances of any one tumor or lesion arising are relatively small (even though the risk is increased compared to the setting of normal estrogen), so the chances of two developing at the same time are very small.

Q. Can you give an example of what metrorrhagia is and when it might take place?
A. Metrorrhagia means there is bleeding outside the normal period time, for example: abnormally-timed bleeding during menopause, or bleeding from an intra-uterine tumor (which would not follow normal hormonal stimuli).

Q. Could a teratoma be an ectopic pregnancy?
A. No – a teratoma is a neoplasm; it is monoclonal. It arises from a germ cell that has gone bad and decided to develop into all three germ cell layers. The cells may grow to look like normal tissues, but they’re not under any embryologic organization or control (they just grow haphazardly). A pregnancy, whether it is intrauterine or extrauterine, is not monoclonal; the tissues are growing in response to embryologic signals, and if left alone, will organize into a human.

Q. What is peau d’orange?
A. Peau d’orange (French for “skin of the orange”) happens when you have a breast cancer that has infiltrated the lymphatics of the breast skin, making the skin edematous and orange-peel-looking. This change often happens in inflammatory breast cancer (so-named because the skin can look inflamed), in which the tumor preferentially involves lymphatics.

What is the prognosis in multiple sclerosis?

MS

Q. My 28 year old friend was just diagnosed with multiple sclerosis. What can he expect regarding prognosis?

A. MS is a demyelinating disease that is thought to be autoimmune in nature. It is not easy to predict an exact prognosis for an individual patient, but I think you can boil it down to the fact that while a small number of people with MS become unable to write, speak, or walk, the vast majority of patients are mildly affected by their disease. Let’s look at this in a little more detail.

Subtypes

There are several subtypes of MS, each with different symptoms and prognoses. Note that the frequencies of the different subtypes listed in different sources may not be comparable, because some sources refer to the frequency at diagnosis, while others refer to an overall frequency. It would be useful to know which subtype your friend fits into, because that may help determine his prognosis.

1. Benign MS
People with this type of MS have only rare attacks, and are minimally disabled 10 years after their diagnosis (therefore, you can’t make this diagnosis until 10 years have elapsed!).

2. Relapsing-Remitting
People with this type of MS attacks followed by partial or complete recovery periods free of disease progression. This is the most common type at diagnosis – but some patients move into one of the other types later on.

2. Primary-Progressive
People with this type of MS experience a slow but nearly continuous worsening of their disease from the onset, with no distinct relapses or remissions. This is an uncommon subtype.

3. Secondary-Progressive
People with this type of MS experience an initial period of relapsing-remitting MS, followed by a steadily worsening disease course. Many people with relapsing-remitting MS developed this form later on – but that was before new drugs for MS were introduced. This subtype may be less frequent now.

4. Progressive-Relapsing
People with this type of MS experience a steadily worsening disease from the onset but also have relapses, with or without recovery. In contrast to relapsing-remitting MS, the periods between relapses are characterized by continuing disease progression. This is an uncommon subtype.

Factors influencing prognosis

1. Factors associated with a better prognosis:

  • female gender
  • age of disease onset earlier than 40 years
  • a first attack consisting of optic neuritis or other sensory symptoms
  • lack of significant disability 5 years after onset
  • minor abnormalities on brain MRI scan at the time of diagnosis.

2. Factors associated with a less favorable prognosis:

  • male gender
  • age of onset at age 40 or later
  • a first attack consisting only of motor symptoms
  • difficulty walking or sustained impairment in coordination after resolution of first attack
  • large number of MRI lesions

All that being said.

It’s going to be hard to tell with a lot of certainty at this point what your friend’s prognosis is, because the diagnosis is new. Once he has had the disease a few years, then it will be important to see how it has progressed (or not progressed), because one of the more important predictors of one’s future MS course is one’s past MS course.

Here are some good web resources for learning more about MS:

1. The NIH
http://www.ninds.nih.gov/disorders/multiple_sclerosis/multiple_sclerosis.htm

2. The National Multiple Sclerosis Society
http://www.nationalmssociety.org/index.aspx

3. The University of California – San Francisco Multiple Sclerosis Center
http://www.ucsf.edu/msc/faq.htm#beyond

4. The Multiple Sclerosis International Federation
http://www.msif.org/en/about_ms/types_of_ms.html

The illustration above is from Joseph Babinski’s 1885 thesis, “Etude anatomique et clinique de la sclérose en plaques.”

Phospholipids, tissue factor and the platelet plug

plug

Q. I have a question about forming the platelet plug. Where are the phospholipids that get exposed, and how does platelet aggregation affect that? If this is in the subendothelium why weren’t they exposed upon ripping or whatever caused the endothelial damage? Also, what is tissue factor?

A. The phospholipids you’re referring to are part of the platelet cell membrane. The platelet membrane contains many different kinds of phospholipids on its surface. This is important because many of the coagulation factors (for example, the factor Xa-Va complex) require a phospholipid surface to exert their effects. During platelet aggregation, some of the phospholipids undergo important changes, making them more available to the coagulation factors.

Here is how a platelet plug is formed:

1. The endothelium gets ripped up, which exposes subendothelial proteins (like collagen) to the blood.

2. The platelets see these subendothelial proteins, and they stick to them using von Willebrand factor (this step is called platelet adhesion).

3. As the platelets adhese, they flatten out and release their granules (which have a lot of functions, one of which is to attract other platelets).

4. Other platelets come to the adhesion site, and they stick down onto the platelets that are already there (this step is called aggregation).

5. Now the platelet plug is formed. One cool thing about the platelet plug – in addition to its function of plugging the hole in the vessel – is that the platelet membrane provides a phospholipid surface which is essential for many of the coagulation factors. In fact, when platelets aggregate, certain phospholipids in their membranes become even more available to be used by the coagulation factors.

Tissue factor is a separate thing. It is the substance that initiates the whole coagulation cascade in vivo. It’s present in different areas of the body (in the subendothelium, in some inflammatory cells, and perhaps even in little locked-up microparticles in the blood). It is not present in active form in the blood until it’s needed for coagulation. So when the endothelium is ripped up (or when inflammatory cells decide to release it, or when the little microparticles get a signal to open up), tissue factor is exposed to the blood, and it binds to factor VIIa, and the cascade proceeds along the extrinsic pathway.

A different kind of plug: the image of Claes Oldenberg’s giant three-way plug at the Tate was taken by jovike (http://www.flickr.com/photos/49503078599@N01/54082836/), under cc license.