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Adenomyosis - Keith Isaacson, MD

Adenomyosis - Keith Isaacson, MD

Endometriosis Foundation of America
Endometriosis 2013 / Adenomyosis: What We Know and Don't Know
Keith Isaacson, MD

What a difference it has been over the last four or five years when Dr. Seckin and the group had just started. I was privileged to be here for some of the earlier programs and it has evolved into just a scientific powerhouse I think. It is very exciting to be here.

In my 15 minutes I am briefly going to go through adenomyosis and touch on what we know, which would be very little versus what we do not know. I think adenomyosis is so much more common than we actually give it credit for. It is very interesting that probably somewhere around 350,000 to 400,000 women a year have an endometrial ablation for abnormal uterine bleeding. All of those patients if they do not have fibroids essentially have their abnormal uterine bleeding from adenomyosis. Now, there can be extensive and non-extensive but that is a huge number. I think when we start to evaluate women with menorrhagia and dysmenorrhea more women than not you are going to find will have adenomyosis. I think we know so little about it and it is very interesting that we have so many conferences on endometriosis where there is just a little bit spoken about adenomyosis. One of my pleas today is for us to give it a great deal more thought particularly clinically as well as research.

The diagnosis of adenomyosis or the definition is, "Endometrial glands and stroma present within the uterine musculature with adjacent smooth muscle hyperplasia. It can be focal or diffuse." What we have found is up to 48 percent of our women who had a hysterectomy when you ask the pathologist to look for adenomyosis they actually found it. So it is incredibly prevalent if you look for it. However, if you just send your specimen off it is very likely that the pathologist will not do enough slices and not find it.

It was described by Rokitansky in 1860 as "cystosarcoma adenoid uterium" and as Dr. Martin said this morning but it is really a more recent disease. Bird in 1972 is actually the one who coined the current terminology of "adenomyosis". It is really something we have not given a lot of thought to except for the past 30 to 40 years.

One of the problems with diagnosing adenomyosis is that we do not really have a clear definition histologically. I am going to come back to this in just a little bit. There are different definitions for adenomyosis: "1) Endometrial glands within the myometrium greater than one low power field from the basalis layer of the endometrium". That is what I learned as a resident and it never made sense to me because I have gone a looked in a lower power field and it was very difficult to say how big is a low power field. It is like how big is a mini lap as well, it is whatever you do is a mini lap in your hands. Another definition is, "Endometrial foci being deeper than 25 percent of the myometrial thickness". This is a criteria used most often for diagnosis in postmenopausal women. And then there is, "Glandular extension anywhere from >1bmm up to 3mm below the endometrial layer or 2.5 mm below the basalis layer". When we do not have a clear definition it is understandable as to why we do not really know the true incidence or prevalence of the disease.

Now the clinical presentation is abnormal heavy uterine bleeding in approximately 50 percent of the women, dysmenorrhea at 30 percent. Infertility, it is interesting because we always made the diagnosis of adenomyosis by hysterectomy in the past. We do not really know what the impact of adenomyosis was on infertility. So now we are diagnosing it and I will show you that with ultrasound, with MRI and now we can go back and look and see really what the impact is on fertility. And 35 percent of woman who have hysterectomies for other causes actually had adenomyosis found incidentally.

When you again look at the clinical presentation of reduced fertility we are finding that if you are looking for it in your infertility population you actually will find it. It may impact implantation. We will go through a little bit about the immune response and the problem with saying that adenomyosis is a cause of infertility is that there is often concurrent pathology such as fibroids and endometriosis. We do not really know which one is actually causing the problem.

Diagnosing adenomyosis can be done histologically. It can be done hysteroscopically, and it can be done with radiologic imaging. Again, the histological diagnosis is how are you going to get this tissue without taking out the uterus? Again, if you are looking for adenomyosis most often you are going to find it in the posterior wall and you are going to find circumscribed nodular aggregates. Here are the definitions, the histologic criteria that you have been looking for, and we see that the incidence of 5 to 50 percent is due to the different classifications that we have. But when you see a histologic picture like this it is very obvious when you see your glands of stroma well below the basalis but this is an obvious diagnosis of adenomyosis.

But there have been other ways other than hysterectomy for diagnosing this. McCausland has used a 5mm loop electrode hysteroscopically to try to make the diagnosis. Rudy Campo developed this new hysteroscope called the TROPHY hysteroscope, which actually has a core biopsy needle with it in which he can take directed biopsies either by ultrasound guidance or directly, again, by looking through the hysteroscope. And then of course, you can do an ultrasound guided biopsy. I think the ability to diagnose this if you feel like you need a histologic confirmation is going to improve over the next few years.

When you look at this hysteroscopically, we are looking at irregular endometrium with defects, altered vascularity and some cystic hemorrhagic lesions. This is just a flexible hysteroscope. It takes less than one minute to perform; no anesthesia is necessary, no tenaculum is necessary. When you see this pitting of the endometrium going towards the myometrium that is considered to be diagnostic of adenomyosis, if you believe in that. But these are the defects that they are looking for.

This image just shows, it does not show it very well in this picture, but you can actually see areas here, again, pockets of deep endometrium going toward the myometrium. That would be suggestive of adenomyosis. When you are doing a loop electrode if you are doing a resection for patients who have menorrhagia it is not uncommon that you will find these kinds of deeper pockets of actually old blood of our adenomyosis, again, into the myometrium so when you are doing this type of resection you have to make sure you get below that and resect the entire lesion. This is why so many of the global ablation techniques which go approximately 5 to 7mm into the myometrium are ineffective because they just do not go deep enough to pick up these other pockets and that is why 35 percent of those patients end up with a hysterectomy.

Imaging studies to pick up adenomyosis - I encourage all of you to start looking if you do not do your own vaginal probe ultrasounds to start doing them if you have a patient in whom you suspect adenomyosis. Because you will see these myometrial cysts, you will see ill defined hyperechoic areas, asymmetric uterine enlargement so you see the posterior wall maybe two or three times thicker than the anterior wall. Here is an example of a simple vaginal probe ultrasound and when you look it is more obvious than what you can see on the picture here but here is the endometrium. Then you see this hyperechoic area and there is actually a cyst inside this myometrium, which again is consistent with adenomyosis.

Here is another area and this is a retroverted uterus so actually you are looking at the posterior wall here and this is a focal area of adenomyosis. What is interesting is that you can see this so much more clearly with the ultrasound than you can with the MRIs. What did the MRI look like? The MRI looks for a thickened junctional zone. It never made sense to me what a thickened junctional zone has anything to do with some focal adenomyosis. But if you send a patient for an MRI to the radiologist the only way they are going to come back with a diagnosis is if they have a thickened junctional zone. When you do these ultrasounds real time yourself you will find the adenomyosis.

This is just a great case of I borrowed from Olav Istre. It was an unusual case of adenomyosis, which you see this fairly large, it was about 2 cm and looked like an endometrioma within the muscle of the uterus. This just shows that using his technique with ultrasound guidance he was able to open up this endometrioma, drain it and treat it hysteroscopically without having to do a hysterectomy. This is not as uncommon if you are looking for it then you may think, "I have two patients now I'm following that have the same thing". They have a lot of pain, you open it up and there is actually endometrioma within the myometrium filled with old blood. That can be treated hysteroscopically.

Now, MRI - we are looking for a large asymmetric uterus, thickened junctional zone. I want to compare with you here the ultrasound with the MRI. So here is the ultrasound. What you see is this thickened myometrium in a patient that has menorrhagia, dysmenorrhea, does not have fibroids. That is diagnostic of adenomyosis if that patient ended up getting a hysterectomy. You see the same thing with the MRI. So I do not really think there is much of a place now for MRI diagnosis of adenomyosis. Having said that where MRI can be helpful is in a patient that has adenomyoma. You see something like this. This is where it has been shown that MRI is more diagnostic than ultrasound and differentiating routine fibroid from an adenomyoma.

So, what is the cause of adenomyosis? Well, again, we have no idea. It is very similar to what are the causes of endometriosis but there are lots of theories. There is invagination of the basalis endometrium. This may be due to tissue trauma causing some injury which allows for an inflammation. When you have the inflammation increased macrophages and cytokines may allow for tissue to migrate into the myometrium. There are other theories of stimulation of migratory tissue by high expression of the estrogen receptor. We have talked about these patients may have some type of progesterone resistance in their endometrium and that may be a reason why they get migration of the endometrium into the myometrium. Certainly the theories of lymphatic spread and stem cell theory have already been touched upon this morning. So the answer is we do not really know what causes it.

The risk factors have been found most commonly in the fourth and fifth decades of life but you know this is similar to patients when we first saw endometriosis only affect the patients who were 35 to 40 years old because those were the only ones getting laparoscopy initially. Now with adenomyosis if the only way you are diagnosed is by hysterectomy most likely you are not going to find it in a 20 year old. However, if you are looking for it in these young patients you are going to find it, it is there. You find it right now in 25 percent of the patients who had the diagnosis of less than 39, and actually 10 percent of patients with diagnosis are over 60.

Multiparity seems to increase the risk of adenomyosis maybe due to the invasive nature of the trophoblasts into the myometrium. The frequency of adenomyosis increases with the number of pregnancies and there is some debate whether uterine surgery increases the risk of adenomyosis or not. These are just two schools of thought. I am just showing you there is data on both sides showing the D&C pregnancy terminations by Levgur and Parazzini said it did not increase the risk of adenomyosis. However, there is just as much data to suggest that prior D&Cs do not increase the risk of adenomyosis the same with cesarean section.

Tamoxifen - there was an article that recently came out suggesting that tamoxifen increased the risk of adenomyosis but I do not think that is the case. I think tamoxifen being a weak estrogen can stimulate adenomyosis that was present in a menopausal patient but I do not think that is the cause.

The big question, and what I would love to spend most of the time on and I only have one more minute, is why is it if a patient has endometrial glands and stroma in a myometrium, why do they get menorrhagia? Why do they get dysmenorrhea? Why do they have reduced fertility? This is the whole idea of setting up this Center for Gynopathology Research like we are doing with endometriosis. It is to try and understand if the patient has endometriosis or adenomyosis what is it about the presence of this ectopic endometrium that leads to the symptoms that you get? There are lots of theories, again, about disruptive uterine contractility, enhanced expression of cytokines.

That is what I wanted to finish with. It is just to say when we start developing these new tools I encourage all of you. I am incredibly lucky to be in Boston and work with some brilliant people at M.I.T. and you have heard from them today. I present something to them, a clinical problem to them, and it is a problem in which, and I personally feel like we have not made a lot of progress in the last 25 years, so I presented to these physicists and mathematicians who take a clinical disease and apply a mathematical model to it. Ninety-nine percent of which I have no clue what they are talking about. But they come up with a unique perspective. And now, finally, because of that unique perspective we might have some new approaches to studying the disease and understanding the disease and following the disease longitudinally. I think what does not make sense to me is that we are following our reoperation rates as a sign of success whereas now when we have some type of mobile application, as you saw this morning, and you can actually follow the symptoms of these patients, it is going to redefine what we consider successful therapy for endometriosis and adenomyosis.

And I will stop with that - thank you.