Dan Martin & David Redwine - Great Debate on the ORIGINS of Endometriosis
Endometriosis Foundation of America
Medical Conference 2019
From Biomarkers to Precision Surgery
March 8-9, 2019 - Lenox Hill Hospital, NYC
I just want to publicly announce that I appreciate David's ... David gave me a call about Abbvie's ongoing advertisements and attaching our names. In fact, that was the case. However, the way I found this out through our previous executive director, Abbvie has approached to promote awareness and education that we stand for. We did not know this or Alisa was coming last year. They saw us as a very influential reach to the public, and we feel like we were duped into this,
Our communication director met with Abbvie last month in Boston. There was two $10,000 check which I assumed that was given for their participation now to our ball which, in fact, was given for educational support. We returned the checks. The checks are given. I will publically announce, and I'm publicly announcing that this relationship with Abbvie is due to two facts.
I have asked them to supply me with the real data from each center that they produce this or Orilissa result. Correct me if I'm wrong. Apparently, from what I have investigated, there are 46 centers. They produce 1600 patients, and I asked them how many of them were done outside of the United States. I did not get any answer. If there is Abbvie, any Abbvie representative in the room, if they can answer, I would greatly appreciate it, but that part really made me worry.
Also, obviously, we do not know how much they were rewarded for doing this research, this not being public also, in my opinion. Thank you for giving me this opportunity.
Origins of Endometriosis by Dan Martin. That's the end. I can't find the clicker. We're going to talk about the cell of origin, what Samson really said, and what's the difference between Mullerianosis which almost everybody believes and Mulleriosis. I have no current conflicts of interest. As of next month, I may be working with the CO2 laser company again.
If you really want to look at concepts and theories, my concepts and theories fall at that thing has 204 concepts and theories that you need to understand for this debate to really mean anything. If you want to read that, it's going to read like the papers you've listened to presented over the last two days. It's in-depth.
Now, this is only a theory. We're talking about David. Why do you want to destroy Samson? Samson doesn’t have much to do with this. Our problem is a delay in diagnosis, inappropriate planning, and treatment. We need to do more with those. For those of you who want to get excited about arguing with your doctors about treatment, remember what David said yesterday. You're not arguing with them about theory. It's more important to decide what you want in terms of treatment.
When you get it, severe pelvic pain as we heard this morning is not normal. Don't tell your daughters that having severe pain is normal. Basically, there are three divisions for the theories. The cell of origin, how the cell gets to where it's going, and how does it make the transition from a normal Mullerian cell to endometriosis.
If we look at the cell of origin, retrograde dissemination of menstrual endometrium, embryonic remnants, and uterus cervical extension are all three Mullerian. There's nothing magic about. Muller was pretty good at this thing. Now, David has taken those to do what he wants to do, and we'll talk about that as we go along, but it's like any time you see somebody disagreeing with these, there are at least four options.
Either I'm right and David's wrong David's right and I'm wrong, we're both right we just need to listen to each other more, or we're both wrong and we've got to start listening to this thing about stem cells, metaplasia, differentiation, all those other things that David and I don't usually talk about.
Remember, Mullerianosis is just simple ... Ron Batt did this two years ago, three years ago here. It's just basically what happens when Mullerian cells survive in places they're not supposed to survive. Ron Batt divides that into four different Mullerian diseases. They can either be congenital you can be born with them or you can acquire them later.
David's going to discuss what Mulleriosis is later. But if you go back into the 80s, Paul Domaleski sat back and decided like we heard this morning endometriosis is a systemic disease. It's more than just histology. Paul asked, "Is this really just the skin manifestation of systemic disease? Do we really have to worry about other things?" Do we worry about pain, infertility, mass, ovarian cysts, tumor in the pelvis? Do we worry about immunologic changes? Do we worry about all these other things that we see or do we just do like David and worry about histology because if all you worry about is histology and your whole definition is histology, then your answer is easy. When in doubt, cut it out. That is my theory today.
We're going to talk about Mullerianosis, is when in doubt, cut it out. David, I know you don't believe in immunocompetence, but it exists. The immune system is real. I know you don't. When we treat pain or endometriosis with pain medication, hormonal suppression, there's more going on than just pain relief. We're attacking at multiple levels.
I know the medicine will cure the disease, but the immune system is fully capable of doing it. We talked about science or surgery. John Samson in 1927 in presenting his retrograde thoughts and his coelomic metaplasia thoughts and his venous dissemination thoughts, was talking about scientific discovery.
David's theory is much easier. When in doubt, cut it out. David says no one gives him pictures. We've given him lots of pictures. These pictures that are coming are not for David. He's seen them all. He just wants to deny they exist. Let's go back to 1927. Samson's already published pictures of implantation where the implantation of endometriosis is similar. The inflammatory reaction is similar to what happens with the STDs and with cancer.
We've known this for years. Let's go to Craig Woods and Bob Shinken at the University of Texas, San Antonio. They start publishing in 1999. Immediately, the Europeans jump in with Michelle Nicolle, Jacques Donnez. They published their pictures not to be outdone. Craig Woods comes back in again in 2001. Now, he has color.
I like this color. We'll come up to better colors later, but those are some of my candidates for the best [inaudible 00:08:15]. I like some of the ones yesterday had even better pictures. Craig comes back again in 2003. Then, we get the conglomerate. Carolyn Jones from Manchester, England, the group from Padua, Italy, and the group from Chicago contribute to that one. The most recent one which is my candidate for the art of the day is from Dr. Kavoussi.
That's my candidate because his father and I trained together. He and his father are both in a reproductive endocrine practice together. That was with Dan Levovich. We've talked to earlier about how retrograde theory can go into the pelvis. It also could get to the bladder, the bowel, the appendix, the vagina infiltrates into the psychic nerve, hits the diaphragm. It can get to the pleura. It takes out the entire chest and the abdomen.
It doesn't explain the para-vertebral disease. It doesn't explain diseases in for distal sites, but it explains everything I saw in my practice. It gets into the pleura not by that, not by this but on one of those two routes. It either infiltrates straight through the diaphragm or goes to these little foramen that we see in the diaphragm all the time. If I can make my machine work. What am I doing wrong?
Here it goes. This little foramen up in here. For those who are in pediatrics, those are the same things that we get organ herniation through that [inaudible 00:09:51] when they need it. It's just that then they're larger. These are those smaller ones that we all get. There's plenty of exchange of fluid and women with those between the peritoneum and the pleura.
What Samson did say, so we don't misquote him, "Retrograde menstruation is not sufficient to explain all endometriosis." He knew that. His candidates were coelomic metaplasia and venous dissemination as the alternatives. He knew that endometriosis was different both in structure and in function than endometrium, that the fibromuscular histology was identical to that in adenomyosis, that both endometriosis and endometrium could coexist, and that you could see a transition between the two. He knew transition before we knew transition.
On the other hand, David wants to tell us that auto transplants don't change. Well, David, iatrogenic transplants change. If we look at iatrogenic transplants of either endometrium into the abdominal wall scar at the time of cesarean section or endometriosis into surgical scar sites at the time of surgery to remove it, both of those grow. They both change. They both have epigenetic and genetic changes. They have cancer-associated driver mutation changes. Why in the world you would tell me that auto transplantation has some magic difference that doesn't let it do all those changes? I don't know. I've never seen the data for it.
Maybe, David you can give me some data for why it doesn't exist rather than just saying it. Genetic support more than one theory. Even in men, we need both Mullerian and coelomic metaplasia theories to explain all the observations. Men aren't limited to that. Genetics may support all theories, any theories for you to try to claim that as part of your theory, it just means you're reaching.
We love Signorile. For those of you who've heard David talked about his 10% and 10%, that's the greatest false equivalence statement you'll hear today. The only other statements you heard from today when he sat back and tried to put estradiol levels at 100 to 350, for those of you who want to google that, the very first link says 15 to 350 from the Mayo Clinic. Google it. Estrogen [inaudible 00:12:26] milliliter. It's not hard to find. Here we go.
Not here. Not there. There. No. We're going to get there. There we go. Signorile found markers at the base of the vagina and the area of the pouch of Douglas. This is the rectovaginal area. What's missing from that, there's nothing up near the sigmoid. There's nothing near the appendix. There's nothing in the ovaries. Ovaries are quoted as being the source in up to 40% of patients. Rectovaginal is similar between 0.3 and 30%. This is the most common. This is the most uncommon.
Signorile suggests that his data will cover somewhere between 0.3 and 3% or 30%, if you want to look at it in selected groups, not the 10% that happens in all women's that happens to David. Signorile's group does not support the more common areas like the ovary. I wouldn't use that data to support 10% other than the fact it happened there, but it does support endometriosis in this area and the rectovaginal septum. I had to put one cartoon in there just for you
Now, let's look at what it really suggests to me because this is what we wrote in '92 about Mullerian remnants was when you look at a picture like this where there are no uterus cycles, the perineum is flat, but otherwise, the rectum and cervix are in the normal position. You already are suspicious that some Mullerian's going on here. This already looks like a congenital anomaly.
This is Philip Koninckx's paper when he dissects out this little 1 to 2-millimeter lesion that's right in here. If you don't find that on an exam before you do the surgery, you're not going to find it at surgery because [inaudible 00:14:31] pictures at surgery aren't going to tell you where it is. These are those things you either … Remember talked about yesterday you examine before surgery. You examine them during surgery. You examine on after surgery. This is one of those lesions. There we are, David. When it's younger stage, when in doubt, cut it out.
Now, Dr. [Budusku 00:14:54], Dr. Roman talk about bowel invisible microscopic endometriosis, and we're all ready for David to keep being consistent when in doubt, cut it out. Nope. David looks at these slides, realizes this slide from this morning that you've already seen. That is we have a big lesion here with really little satellite lesions. Even David knows that you can't chase that with a knife. We have a reversal and our whole thing. We're no longer going radically after margins. We are looking at risk benefit, when excision is good, when excision is not, when you want to do surgery.
I understand that this room worries more about Lupron than they worry about surgery, but for one of those people who has done surgery all of his life, I've been associated with five deaths in women having fairly minor procedures, two, I was on the resuscitation team who had to try to resuscitate them unsuccessfully, one, because I was part of the board of medical examiners for the state of Tennessee and the other two because we're doing quality assurance for a local hospital who within three months had two deaths from laparoscopies. Nothing is completely safe. Nothing gives you everything you want. I end.
I'm going to take down a vocal stance. Studying endometriosis is like nailing jello to a tree. It's hard to do. You can believe that or you can believe David. When in doubt, cut it out. Thank you. I forgot my last introduction. He's trying to push me off. I have one more slide. David, John Sampson died before you were born. He's old enough to ... If he's still alive, he's old enough to be your grandfather. Why do you want to destroy your grandfather?
I'm going to take the clicker so he can't [crosstalk 00:16:48]. Still lacking, I think, our robust evidence in humans of the two missing steps. I'm aware of the WIT study and other peritoneal and amniotic membrane studies. Studies in vitro like that aren't really in my opinion demonstrating what happens in vivo. You asked what's the difference between Mulleriosis and Mullerianosis.
I published my Mulleriosis paper in 1988. Endometriosis, as I said, happens to be the most common and most symptomatic of the Mullerian defects that occurred from the differentiation and migration problems during embryogenesis, but you can also, as I said in my paper, you can see endocervicosis, endosalpingiosis. You can see fimbria. There may be an ontological relationship with peritoneal pockets which are defects of formation of the peritoneum.
Mullerianosis, Batt published his paper in 1990. It talks about endometriosis, endocervicosis, endosalpingiosis and peritoneal pockets. I'm not sure there's much difference between the two other than mine was published two years earlier. That never mentioned my work in his papers or PhD thesis on Mullerianosis. Sampson started in the 1920s, perforating hemorrhagic chocolate cyst. There was a histology problem with that study though because of 23 patients, most did not have endometriomas.
This has had a big effect on theory and clinical associations. There was also a fertility problem because in that era, it was thought that all married couples should be able to get pregnant, and the fertility rate was less than 100% in his observation in his series. His conclusion was that endometriosis is prevented by pregnancy which has had untoward and overweighted effect throughout the years.
Here's another bit of Sampson evidence of attachment. These orderly cells that are lined up like soldiers on the peritoneum, none of which necessarily looks glandular. I don't know if you could call those stroma. There'll be an unusual arrangement of stroma to be like that. Here's attachment of a borderline tumor. You don't always see invasion of something when it's attached like that.
These are going to be examples of what people have said our attachment other than what we've just seen today earlier. This was another bit of evidence for attachment although it's just not clear to me where the attachment is occurring. It's not as clear-cut as the borderline tumor was. Here was something that was given to me by David Olive. This was supposed to show attachment of the endometrium and the lumen of the fallopian tube. Is that really attachment or did the particle of endometrium just kind of get stuck in the small diameter of the fallopian tube?
In a sense, you could ask is attachment real or are people who believe in attachment just seeing it and saying that that's what it is? In my own patients, I've looked at thousands of slides of endometriosis under the microscope. Here's a sample of one of the things I found was here's an area of glands and stroma. Here's a peritoneal surface. That's against it, I guess you could say, it's attached, but it's certainly not invading yet. The process of formation of endometriosis by Sampson's Theory requires not just attachment, but also proliferation and invasion.
Here's another fleshy lesion of the left broad ligament. Over on the right, you can see it looks like this. It's obviously glommed on to the peritoneum. It's attached in that way, but, again, no obvious invasion that I saw. Here's another little area of small glands and stroma. I'm wondering, like I said yesterday, in women without endometriosis, where's the evidence for the immunological warfare that is fighting off these reflux endometrial glands and stroma complexes. Is this evidence of the immune system rejecting an implant in a patient with a normal immune system? Well, no. Not really because that patient had endometriosis elsewhere.
Other people have found evidence of potential attachment, but again where is the evidence for proliferation and invasion? It's said that proliferation and invasion occur very rapidly and are over in 24 hours which is one reason why we don't have robust evidence for it. Well, enough biopsies have been taken by now that I would think that if proliferation and invasion occur, that we'd be seeing more robust evidence of that mitotic figures, invasion, what have you.
Yes, there is some apparent evidence for attachment both in my own experience and from what we've seen here and others, but where's the next step? Where's the next step? When I saw this work here, my heart dropped because this I thought looked like typical endometriosis. It represents admittedly a very strong argument for the question of the ability of these cells to attach and implant and grow.
Now, when you look at some of the photomicrographs, here's some of those cells. They don't have the fibromuscular metaplasia typically that you typically see with deep endometriosis. I don't know that they're invading or anything. That's one of the things that is kind of missing in the equation is what is the mechanism of attachment followed by proliferation and invasion. Why don't we have more pictures of all of these steps? Why don't we have clearer pictures so that I don't have to stand up here and be like eternal cynic about this Sampson's theory of reflux menstruation.
Here's another ... This is a mouse model of endometriosis induced by surgery. Again, you've got the peritoneum and the lesion, but there's no invasion. Without proliferation and invasion, our animal models really telling us all that we would like them to tell us. Well, probably not. They're limited obviously in what they can tell us.
Here is another ... I'm not sure why I'm showing this. This is just a laser vaporization failure showing that there's hemorrhagic adhesions and carbon left with endometriosis underneath. Is true recurrence possible or is it just disease that wasn't treated completely? I've found that cases of true recurrence, and I'll be showing you some of those in a second, one feature of some cases of true recurrence is that if you look at the area of the excision, in some patients, the recurrent disease or maybe it was persistent and just unrecognized, it's right around the rim like an arc of the area of excision.
Is this related to growth factors of surgical healing, inducing metaplasia of underlying substrate tracts of Mullerian tissue? I don't know. Or is incompletely excised deeper tracts of tissue? Here is a patient that had some areas of endometriosis at her initial surgery. You can see a little superficial areas here and here ... This is after excision. Then, there was no endometriosis at reoperation 1.2years later.
Here's another patient with initial surgery. Here's what it looked like. There was at 0.3 years later, there was a small superficial area of endometriosis at the right cul-de-sac although when you go back to the pictures, I'm not sure that I excised all the right cul-de-sac. Maybe, that was a lesion that just was missed.
Here is an area on the right side of the bladder. This is what it looks like after healing. There was no endometriosis in that area. Another before-and-after picture. This is another area of the bladder showing some hemosiderin deposition and some areas of endometriosis here and there. This is what it looks like after excision. Then, at reoperation later, there's some hemosiderin over here, but biopsies were negative.
Here's a little bit of endometriosis of the left cul-de-sac and just above the left uterosacral ligament. Here's what it looks like after excision. Then, about three-quarters of a year later, that's what it looks like in the healed version. There was no evidence of endometriosis there. Let's see. Here's another area of endometriosis of the bladder that was removed. Here's how it healed later. It was, I think, the same patient.
This lady had some endometriosis of her uterine fundus that I had not excised the first time, but nothing in the area. There are unresolved issues with Sampson theory and what we see as surgeons. This has been one of my kind of dichotomies over the years. I'm not a reproductive endocrinologist. I was trained as just a general OBGYN. I did obstetrics for nine and a half years and then began to develop my own laparoscopic techniques for treating endometriosis. Don't have a fellowship.
I didn't have a medical school affiliation. I didn't have a professorial title. Working out in rural Oregon, I was off the main track, I guess. Maybe that was part of my problem. I just was out in rural Oregon, but unresolved issues. Why are some women permanently cured by excision? Why in others that aren't cured, there isn't more and more disease as time goes by? We're getting some evidence of attachment. I'll agree to that, but where is the follow-up robust evidence for proliferation and invasion?
How do you explain the repetitive patterns that we see in patients with endometriosis? We see the same patterns in the bowel. We see the same patterns in the pelvis. We see the same patterns in the diaphragm. How does that occur? It doesn't appear to be random as you would expect by reflux menstruation. The surgical outcomes of the view of endometriosis through the lens of a surgeon, I think, needs to be taken into account as we consider where endometriosis comes from because surgery does something dramatic to the disease.
It's a filter. How the disease behaves after surgery is important. I think it would probably have a lot to say about the ultimate origin of the disease. I will claim victory with that statement. I hope you all have some questions for us later.
Thank you very much. It was a very exciting debate as expected. Do you have any questions for our two prestigious speakers?
I think this morning especially looking at the slides on the pictures we're talking about two different diseases, one is that I always treat it as deep fibrotic endometriosis, but what we were looking at now and questioning is microscopic endometriosis. I question as a retired longtime endometriosis surgeon, I question whether the microscopic endometriosis is of any of long-term effect in these patients.
Well, Phillip Koninckx thinks that it's not. He thinks that small little lesions like that don't make any difference. I think they're important because I've had patients who have only small little disease who get pain relief after their small little disease is removed. Whether small little disease advances to deep disease all the time [crosstalk 00:31:41].
After many years, a very close follow-up of all of our patients because we had a nurse practitioner in the office and surgical tech. They both communicated on a regular basis. My impression is that the microscopic disease does not cause pain. Like I said earlier, I call it bullshit endometriosis.
I think David had my voice tuned off. Remember in theory in terms of talking about microscopic and subtle endometriosis close to 100% of women have that at some time in their life. The normal immunosurveillance system probably clears it in 84 to 90%. What birth control pills, hormonal suppression do, nonsteroidal anti-inflammatory agents, heat was resolved. That's a different organization [inaudible 00:32:43] What those do is gives you bodies [inaudible 00:32:46] immuno system time to clear the disease. We hope that we will develop systems that can do what Harry and David implied. That is in a disease that may not be important, we want to stop it before it has time to develop into importance.
We're going to talk about this tomorrow. We don't want an average delay of 7.4 years. As stalls data shows, if you have infertility, it's going to be less than two years. If we put the money into it that infertility puts into it, we can make the diagnosis earlier or the emphasis. We want to go in early see if we can develop techniques to stop it before it ever develops to what we've seen up here. We don't want to see deep invasive endometriosis developed.
By that point in time, the only answer any of us have really have is excision.
Just one comment. I think I stand ... My position is with David on this issue very strongly because we have to make this for differentiate between microscopic disease than subtle disease. Microscopic disease is when human eye cannot ever see it's detected by pathologist under microscope. It's very clear. On the other hand, there's subtle endometriosis where human I cannot detect due to intensity of the laparoscopic light reflection of the peritoneum. There are many things happening in laparoscopy that obviates our detection.
There are disease that we oftenly miss actually. If we don't accept subtle endometriosis with them, you're calling all woman crazy who get very ill all in their head which is not the case. That's why we have huge group of women disagrees with doctors than they are all that down. 95% of the endometriosis is subtle disease that is there that's not detected. Endometriosis are primarily peritoneum disease before it is anything else.
What we treat is deep fibrotic endometriosis. That implies fibro-muscular tissue around what you call endometriosis. The fibromuscular tissue is a guide to the surgeon. We're using the scissors. You could always feel the difference between normal tissue and deep fibrotic tissue. If there's no deep fibrotic tissue, forget it. We're talking about a different disease which is probably possible two different diseases.
One thing about subtle disease is that there's no question that subtle disease can cause pain that has been scientifically proven by Chris Sutton's randomized control trial of sham surgery versus laser vaporization that he published in the 1990s. He had patients in two or three ASRM classification groups. The patients in group one in stage one had pain relief compared to the Sham controls. That tells me that so-called subtle disease that would be in stage one can cause pain.
Don't believe it.
Don’t believe science.
For once [crosstalk 00:36:21] I agree with David.
What? What you say? Who said that? [crosstalk 00:36:28].
I think that the major problem is that we have a very heterogeneous disease. I'm sure that many, fortunately, most of microscopic foci do not evaluate. However, in my experience of more than 300 colorectal resection, I have two recurrence on the staple line. Each time, I fully record all the procedure so I would had a look at the first procedure where the limit were macroscopically clean, but the pathologist found foci on the limit.
I'm sure that the recurrence on the stapled line could provide from this microscopic foci. Some of them may evaluate, but fortunately a majority of them, a large majority of them do not.
Let's go to lunch.
Thank you very much.