Endometriosis Foundation of America
Endometriosis 2013 / Endometriosis and Look Alike Lesions
Dan Martin, MD
EndoFound Scientific and Medical Director
Dr. Seckin, Dr. Liu, my mentors, Dr. Gomel, Dr. Frank Loffer, colleagues, friends thank you for the opportunity of being here today. This is going to be a presentation that Dr. Seckin guaranteed me that I would not have to worry too much about computers. He said if I just followed the instructions this thing would work. Now I got it when they gave me the instruction to press any key, somebody forgot to tell me what this any other key thing is. I practiced this for a while, and nothing went really right. The screen goes blue, you press it again and you hit return two or three times. You get the blue screen of death.
Now, you have to think like a geek. Remember in geek terms okay is bad. Okay? So, this is "press cancel if you don't want your system to go". We are supposed to have said cancel. Am I smart enough? No, I am going to press okay. So, we went and pressed, okay, and just nothing went right.
We are going to today talk about different things that have to do with appearances, what endometriosis looks like, where have we been with it, where we might go and why this is important particularly with respect to misdiagnosis. After we will talk about the ASRM or the AFS publication on different colors of lesions that lead a whole bunch of people to believe that all clear lesions were endometriosis. It is just not so. We will come back to that one.
Medical-legally, if you diagnose cancer as endometriosis that is a problem for your patients and for you.
No conflicts of interest.
For those of you who heard the talk yesterday, you realize there are lots and lots of definitions for endometriosis. We can talk about histologic tissue diagnosis, dark nodules, clear blisters, ground glass appearance on a sonogram, varying degrees of menstrual pain and what it responds to, abnormal immunology, symptom complexes, lots of different definitions. You are not going to get one definition that gives you everything.
Now, back in the back, if you focus on the middle of that is it moving on you? Yeah, good, I was not sure how that was going to project back in the back. But that thing has no motion. It is a perceptual problem that we cannot look at that sort of pattern and not have it move on us. So, let's go to some perceptual problems that may affect what we are doing. That is out test card. That is not. We are going to vote, what was on the test card? Anybody see dolphins on the test card? That was the second card that was not the test card. The first card was the test card. How many saw four of diamonds? Four of spades? Four of hearts? No four of hearts? That amazes me, sometimes people get a four of clubs. How about ET? Okay. We look for what we know, we see what we look for. That is a black four of hearts. It is not real; it is not anything that we normally see. That is ET it is not a real card.
To some degree, when we talk about histology we get into Ron Batts' definitions of grades of certainty, particularly in research. Because we are doing biopsies in research, and we get things that look like they might be endometriosis. We get glands with no stroma; we get stroma but no glands. Those things we have to know how we classify those in our research. If you are doing it clinically and you thought it was endometriosis, and you get endometrial glands I think you can feel perfectly safe believing that was what it was. If you get endometrial stroma, I think the same thing is true. When we start getting things that are grade one that Ron Batt says are residual of absorbed endometriosis, and if you look at Marsh's paper it may not be residual, it may be precursors related to induction theory then we have to know how we clarify those.
The American Society Reproductive Medicine came out with this poster in 1996 talking about the different appearances of endometriosis whereupon we have a whole generation of physicians in the Memphis area who began to believe that everything that was on that poster was always endometriosis. That is just not so. Even the bottom left one, which is that scarred black lesion. That was only endometriosis in more than 99 percent of patients that they never had surgery and only about 92 percent if they previously had surgery. Anybody who has previously had surgery, these can be formed by the giant cell reactions by scarring around it. All the rest of those were varying degrees. It is interesting in that four of those pictures, you look down there, those are mine. Those four are mine. If you want to go back and look at the original, this is the last thing that Harry Reich, David Redwine, Arnold Kresch, and I did together in the 1990s. If you want that just go to Memfert.com and click on the left-hand side 1990 Endo Color Atlas. That is all it takes to get to that for those of you who want it. It covers almost this entire talk in the last six or eight pages. It tells you everything that I said or most of what I am going to say today some years ago.
Ron Batt's grade one endometriosis, these little clear looking lesions on the side wall, that is all they look like. If we look at it that was Ron Batt's in 1989, Marsh and Laufer in 2005 and Cabana in California in 2010. All of these share in common that they have those grade one characteristics. No glands, no stroma and patients whose history fit endometriosis and based on Marsh and Laufer these may be precursors to endometriosis. It gets into induction theory so Ron Batt would call this residual endometriosis, Marsh and Laufer, their article I think was mistitled, I would think if they proved anything it may be induction theory, but I am not sure they got that far along. And if it is induction theory Marsh and Laufer's are all on pre-menarchal endometriosis you cannot say it is retrograde flow therefore it had to be some sort of primary peritonitis, STD, something. But it gets into induction theory. So, there is the Marsh and Laufer paper. How many of you have read Marsh and Laufer? Anybody read the pre-menarchal paper, pre-menarchal endometriosis? Oh, therefore the question will not work.
I have got five patients, five pre-menarchal patients. Of the five pre-menarchal patients how many of you think had glands and stroma? How many of you think all five of them have it? You know better than that don't you? How about four? I do not have any takers on four, or three or two or one. Zero, none had glands and stroma. All of their patients have grade one changes coming out of that little column a part of connective tissue, chronic inflammation all these non-specific inflammatory and pre-inflammatory changes and only in the post-menarchal stage did one of them develop glands and stroma. You get into these interesting things, and they can call that endometriosis in pre-menarchal girls. If I had been a pre-reviewer and I would have given it some title like, "Inflammatory Changes Predisposed to Endometriosis is just another form of Induction Theory".
So we go back to simpler things, powder burns. Now everybody gets to vote because it is a picture. Is the powder burn the one on the left or is the powder burn the one on the right? For those of us who trained on shotguns I know which one we would pick. How many of you think the one on the left is the powder burn? Two or three or four. How many think the one on the right? One or two or three or four. Except for Paolo Vercellini, no good definition of that. Paolo defines it as the one on the left. Dark scarred lesions that are nodules. I think he just left the last part off. What is the importance of that? If you are trying to do a histologic study and get biopsies on it, where do you biopsy the one on the left, where do you biopsy the one on the right? We have to know, well that was my question. This is my question for the end of the talk. We will back up to that one. That came in too early. On the dark scarred lesion - let me see the previous slide. You cannot see that that dark scarred lesion is sitting on top of the ureter right there but that is where the dark scarred lesion is so it has to do with the biopsy. It is a difficult lesion to biopsy because you are on top of the ureter. You do not biopsy it you just get in behind it and do like everybody else who tells you to excise them, excise the thing. It is easier to excise than just to biopsy that one. For those of you who want to say that excision is a biopsy I will spot you that one, okay. But if you look through there the old blood is the dark area, the white area is the scar, muscular tissue and stroma. Any part of that that you section is going to come out as endometriosis because the glands and stroma are in the mix in all of it. If you look at the little powder burns the dark is the marker. The dark is not endometriosis. That is iron staining and hemosiderin. Endometriosis is the blisters. The little clear vesicles are endometriosis. If you are trying to prove that is endometriosis you have to go for the vesicles. On the previous one, you can tell your pathologist that is endometriosis, and he will cut through it and he will find it. Over here, for the vesicular lesions, you need to tell him there are 1 mm vesicles, little 1 mm blisters because if you give them a 1 or 2 cm piece of tissue and tell them that you sent them endometriosis and they do not know they are looking for 1 mm lesions they just will not find it. If we look at that on the left, it is without iron stains and on the right is with iron stains. If you want to pick up the iron, they also have to be told to do iron stains. Tell them they have 1 mm blisters and please do iron stains. They have different histologic and biologic behavior. The one on the left has focal pain; the patients will point to it. They come in and tell you where things are. The one on the right is diffuse. They get diarrhea and nausea. They hurt all over. The one on the left all the prostaglandins are contained. The one on the right is open to the peritoneum.
We get into positivity. If we are going to do biopsies, we want to know what is our metric? How do we base what we are doing on what has been done in the literature? If we look at people's ability to have positivity, the recent studies by Walter, Mettler, and Pardanani are scattered all over the place. The Pardanani was probably the one I liked best because it looked at three different surgeons and where they were, and they were scattered all at Yale. So, people have different positivities.
One of the things that we did was look at how people use biopsies. Remember the literature, if you have a positive biopsy versus a negative biopsy and you made a diagnosis of endometriosis, the literature does not tell you how to treat those patients differently. The literature just says make the diagnosis; you made the diagnosis. Biopsies do not help you in using evidence-based data, it can be applied and that is because most things like Marcoux’s study, the Endocan study in 1997 had no confirmation. Frank Ling's study in 1999, no confirmation, Buchweitz study from Germany using the 5-ALA fluorescence that he uses, he confirmed it, but it is just a dye study. It was a study outcome confirmation it is not a clinical study. One of the few studies that actually looked at confirmation in patient outcomes in Jenkins' study showed that patients responded the same to Lupron whether the biopsies were positive or negative and whether they did or did not have a diagnosis of endometriosis. Lupron works for estrogen dependent conditions whether they are endometriosis or anything else. That was also in Frank Ling's study.
Then we come back to more recent studies, the Near study on polymorphism. This was all self-reported, it did not even require laparoscopy. And the last one, we required laparoscopy but no confirmation. So, our literature right now does not rely on biopsies to give us an idea of what to do clinically. Everything we do clinically utilizes biopsies and excisions is based upon our impression. Where literature is lacking you continue to do that because like most of the people in this room or many of the people in this room my impression is that patients respond better to excision than to coagulation. It is going to be hard for me to follow up a patient in a randomized, controlled trial, to go back and let me do something else. How many patients do we have here? One, two, three, you two get to vote, you get two votes. If I tried to sell you a randomized, controlled trial from coagulation versus excision would you go into a randomized trial that sits back and says we are going to split the point into the side whether we coagulate or excise you? [Audience response] "Absolutely not". Are you going to sign that permit? "Not knowing what I know now". Yeah. It is like the Marcoux Endocan study. I do not know how they recruited patients into that study. They told patients who they were thinking might have endometriosis that in one group they were going to look at it and do nothing and, in another group, they were going to treat them. We had a study like that in the United States 15 years ago. We had eight centers doing the study and we had two patients sign into the study, everybody else looked at us like we had lost our minds. The two patients who signed into the study were both by the same researcher and we did not think he was telling the patients the same thing we were telling them because we could not understand how we could get anybody to sign that.
This is one of those "what in the world is this slide". Forget most of the data, there are only about three or four points. Endometriosis confirmation, I began at 42 percent, excuse me, 62 percent the first year in this study, and this year we are just doing it clinically, as routine as what we are normally doing, we are not making any changes. We are developing CO2 technology, trying to make sure what it will and will not do. We are doing excisions with the CO2 laser, not vaporization, pure excisions. In the process of developing this, this is on the first 97 patients, the next time we saw patients we actually dropped the confirmation because we were restoring everything. Third year out we finally go up, it is in the fifth year and the study was 495 patients we were getting really good at this. It takes time and a research study to do this and as I am no longer in the research study, I am down to 88 percent with about a 15 percent false negative.
And this, if we are going into a research study, is what we do. So, if you really want to get good biopsies this would be my research protocol where you realize that everything in yellow is not STARD compatible. If you want a study that is going to be STARD compatible you have to knock out things like looking at the tissue yourself, talking to the cutters, talking to pathologists, telling them to re-cut it because they are wrong anyway. You cannot do that in a STARD study. STARD studies are designed to be applicable to general clinical use and this type of study something with that many steps are not in general clinical studies. It is not effective. It is too expensive. It takes forever to make it work. Remember that 495 patients. Our staff had 54 surgeons doing endometriosis at that time, with a mean of 3 cases, so the average physician on our staff to get 500 patients would have taken 125 years. You have to have large volumes to do that kind of research.
And that is the time positivity intervals. Stratton and Stegman at NIH increase over time. Dulemba's recent article he increases over time and the top one is mine, increases over time. Then after we quit the study ours dropped, Buchweitz in the (Is Buchweitz in Austria or Germany? Austria or Germany, okay one of those two.)
So, we got to those look-alike lesions. We are not going to talk much about those today except remember most of these are 1991 slides, 1980 slides. What was that one? For those of you who have to go, do you remember what that one was? That is psammoma bodies. This is a newer slide, what is the differential? Endometriosis, endosalpingiosis, psammoma bodies, mesothelial perforations, lymphoid aggregates, what do we worry about most? Low malignant potential tumor and cancer, this was low malignant potential tumor. If vesicles start clustering up, you have got to have biopsies on clusters. Anything that clusters you have your biopsies on. That one? Laser burn, carbon, just old carbon. Another low malignant potential tumor bordering on cancer. Endosalpingiosis; you can tell this is an old, old picture, it is a 1984 picture I have never seen again. All these old dark red bumps –hemangiomas. Watch out for hemangiomas.’ How about vesicles, blisters on the tube, what are these blisters on the tube, almost uniformly? They are Walthard rest. They have been there since they were born. Do not go biopsying tubes in someone who is an infertility patient. It is not good for them, more carbon, more laser burn. And the last one that we really do not like is white nodules. The uterus is there, see the white nodules? White nodules in my practice 80% are endosalpingiosis. What is the other 20 percent? Metastatic cancer, so we really do not like the white nodules. That is scary looking stuff.
Techniques that we talk about; I remember one day with Dr. Redwine, I just love David's curve, he goes from Anna Murphy's study up at the top where she was calling microscopic 800-micron lesions down to his where he was looking microscopic as 120-micron lesions. Remember, most of us now have laparoscopes that resolve at about 20 microns. In spite of that we still cannot see 180-micron lesion because of the color contrast. There is just not enough color contrast to see them in that situation. So, what we do is we take something like that and that is about the size you see through a laparoscope. There are lesions on the right here, it is not that lovely looking stuff on the left it is the ones on the right. We have blown it up big enough on the scopes so we can see that area on the right. We magnified some more and now we can see all these little blisters in there. Those are running somewhere between about 200 and 2000 microns, which we can see. When you look at that you tend to focus on what you can see. You miss the ones down in the bottom right-hand corner, which are the same thing - small, little lesions. Some of these, if you put them under solution and then go even further down, if you put them under solution, they will float for you. And this is just under saline and Ringers. This is a 150 by 800-micron polyp. Under water, you can see it float. It is just like dandelions in the water, dandelions in the field. Whose quote is that? They do not act like dandelions. That is David Redwine's. David and I always disagreed on that; they do act like dandelions. So, dandelions in the field.
This is under normal saline. Why do I no longer use normal saline? Anyone been trained in that one recently? Would a nephrologist let us put normal saline in the peritoneum who are doing dialysis. Not a chance because it burns the peritoneum. They tell us to put in any buffered solution. Buffered solutions like Ringers, phosphate buffered saline, anything to keep saline out of the peritoneum as a floatation solution. It may be okay as a lavage solution because it is in and out so quick it does not have that much time to damage the cells, but you do not want to leave saline behind.
Instead of all of that, if you are looking - sorry - back one more slide. When we look at some of these lesions if you get the light reflections the wrong way they are hard to see. We are going to come up with one of Tamer's slides in just a second. These are precursors to them. If you look at that - that is hard to see because of the light reflections are bouncing off the lesions. If you just change the angle you get to see them all, same area, different light reflections. If you do what Tamer - and then if you look at those they fit Batt grade four, remember those are lesions where glands and stroma are encapsulated in what looks like a little mini uterus.
Here we go, glands and stroma are integrated into a little mini uterus surrounded by fibromuscular metaplasia. Little stage four looks like a little baby uterus is there.
Tamer did a much more elegant thing than I did. I was floating all of mine under saline and Tamer was floating his in methylene blue. Tamer floats his under methylene blue, which I think would have made it better. He gets very similar pictures. These are lesions similar to what I did. When he puts them under blue dye they just kind of jump out at you. My guess is under blue dye those little dandelions I saw would jump out also. So, anything that we do increases the chance that we can see our lesions they aid us. And some of them are really simple. Methylene blue is just a simple solution to put in. What concentration do you use? (Dr. Seckin's response, "Just one ampule to a liter".) So, one and a half to a liter, so not very concentrated.
We get these non-specific lesions, uterus with little vesicles on the top. Where there are vesicles on top of the uterus, they are almost always going to either be endosalpingiosis or psammoma bodies. These will clearly tint on the bottom right-hand corner. If there is other associated endometriosis, then there is a good chance those are endometriosis. When we see those as isolated lesions then that cluster of diagnosis endosalpingiosis, endometriosis, psammoma bodies, mesothelial proliferation, lymphoid aggregates, non-specific inflammatory things, all those diagnoses that pathologists send to us come into play.
Small, clear, white lesions can be endometriosis, endosalpingiosis, psammoma bodies, lymphoid aggregates, non-specific inclusions, mesothelial proliferations. If they are clustered, we worry about clusters. You have to add low malignant potential tumor. If it is on the fallopian tube, what do we add from three or four minutes ago, Walthard rest. We look at different things, psammoma bodies, endosalpingiosis and low malignant potential tumor. What is this one that we have not even mentioned before? This is not cancerous. This is not anything I have said before, what is that? That is re-implanted ovary after somebody morcellated one at laparoscopy. That is just an ovarian remnant. Is that remnant big enough to create an ovarian cyst? How many here think it is? How many here think it is not? How many cells does it take to make an ovarian cyst - one cell. How many cells does it take to make each one of us in this room - one cell. Started with two, became the one and became us. I'll spot you on it, it takes two cursors. Two precursors to make one and then it will grow. So, one cell for that; those are just psammoma bodies at the top and remnant ovary at the bottom. Same thing over here endosalpingiosis across the top of the uterus, and the one we really do not like, low malignant potential tumor. Cancer looks the same way. Eighty percent of the time we see that pattern though it is still endosalpingiosis. Most of the time it is endosalpingiosis, but all our cancers and pre-malignant cancers have been that way.
You are going to hear more excision and coagulation and I am going to talk more than you ever want to hear today but I want to discuss something anyway. When you have a lesion on the uterosacral ligament, beneath the uterus and that is palpable in the office. It is about one centimeter in size in the office. For those of you who want to coagulate it remember, that is what it took to excise it. You see the rectum in the back, the vagina in front and that is our specimen. All the fat around here, that is our specimen. As long as we can find fat, we can cut into it. And that is the specimen. This is 7 to 8 mm deep. Coagulators were effective up to 2 mm; it would have taken off the top layers off it; you cannot coagulate that deep. For a lot of these deep lesions there is no way that I know to coagulate that deep and be safe. Bob Wheeler showed in the 1970s that that can be coagulated with a monopolar coagulation. What is the deepest depth of penetration that you have with monopolar? Anybody remember that study - five centimeters. One of the safety concepts is when someone doing a tubal coagulation and took out the ovary and the ureter, monopolar goes deep. Bipolar is capable of hitting 2 centimeters if you stay on it long enough. Even though there are coagulators that are capable of going that depth they do not do it with enough predictability to use them effectively.
This is my Harry Reich slide, and Harry is not even here. For those of you who read the AAGL endo blog, we blogged this one about - it is not a blog, what do we call it Frank? It is a Listserv. It is a precursor to a blog. Anyway, everybody gets in there and has their three cents worth. And the three cents worth that was going about three weeks ago was, here is the uterosacral ligament and ureter on this side, the left ureter is coming through here, the uterosacral is there and the closer you are to the cervix this thing diverges as it goes along. Up next to the cervix the ureter is closer to the uterosacral than it is mid position than it is out here. But if there is medial deviation in the right broad ligament fossa like this one, remember there is a fossa back in there. And for those of you who really persist in calling it the sciatica hernia, remember if it were a sciatic hernia, it would be here, not here. Whether you call this a fossa or a pocket or anything else you want to call it, you can call it that, but it is not a sciatic hernia. In these situations, the ureter is always the medial border. So, if you see the ovary hiding way back in there do not go looking for the ureter back in the broad ligaments it is going to be sitting right here. In that situation the ureter comes closer to the uterosacral and then diverges again. It converges into this point then diverges. In the study we have one patient where the ureter actually sits on top of the uterosacral.
On the Listserv, the debate was what do you do with uterosacral suspensions, McCall's Culdoplasty, and that kind of stuff and the general knowledge is the further up the uterosacral you go the safer you are but in this situation as you go up you put the ureter in more danger. You get a laparoscope in there and you can see that. If you do not you just have got to hope it is not there.
Our conclusions today - knowledge changes, concepts change, if we keep on doing what we have always done we will keep on doing what we have always done right, we will keep on doing what we have always done wrong. and we will be happy because we will never know the difference. While we are changing, because there is going to be change, keep an open mind about this but not so open that your brains fall out.
Thank you.
