Endofound’s Sixth Annual Medical Conference: Ending Endometriosis Starts at the Beginning
Müllerianosis: Embryonic Endometriosis, Adenomyosis, Endosalpingiosis and Endocervicosis
Ronald Batt, MD
Lone Hummelshøj: He is my friend, a true pioneer in endometriosis and one of the two keynote speakers this morning, Dr. Ronald Batt who is the Professor of Gynecology at the University of Buffalo where he has been on the full-time faculty since 1993. In 2004 he received the Ortho-McNeil Fellowship from the ACOG in the History of American Obstetrics and Gynecology. This lead to the first scholarly history of endometriosis in 150 years, the book called “A History of Endometriosis”.
And now I am going to go to the infomercial; the proceeds of this book are donated to the World Endometriosis Society to pay for young medical students to go to the World Congresses on Endometriosis. Thank you for that.
Following years of research Dr. Batt and his colleagues published the theory of müllerianosis in 2007 and it is this topic that he is going to address this morning in his talk on the Theory of Müllerianosis: Odyssey of Discovery and Verification, Dr. Batt.
Thank you Lone. Ladies and gentlemen, I do not know why, but I am very nervous this morning. It is very hard to follow Dr. Seckin, believe me. As Lone said the theory of müllerianosis is, I want to present it as an Odyssey of Discovery and Verification and I want to tell it as a story but first of all I have to give you some background.
We define müllerianosis as an organoid structure, in other words it looks like an organ. I will try to show you that in slide illustrations as we go. It is an organoid structure of embryonic origin. In other words it is formed in the fetus during organogenesis. It is a choristoma. Choristoma was defined in about 1904 as normal tissue, which is incorporated within other normal organs during embryogenesis. It is completely normal tissue within another normal organ. In our case it would be normal endometrial tissue, normal endocervical tissue or normal endosalpingeal tissue singly or in combination incorporated within other organs as I said during organogenesis.
The Theory of Müllerianosis predicts that müllerian tissue, misplaced during organogenesis, results in the formation of four embryonic müllerian diseases. Again you would have because, you start with three tissues but you end up with four diseases: endometriosis, embryonic adenomyosis, embryonic endocervicosis and embryonic endosalpingiosis. This was our latest publication on that in 2013.
Now the theory of endometriosis, there is direct evidence supporting the existence of embryonic adenomyosis, endocervicosis and adenomyosis. But there is no direct
evidence yet for embryonic endosalpingiosis, it will get to that. However, there is strong circumstantial evidence to support the existence of all four of the embryonic müllerian diseases in human adults. This evidence explains the pathogenesis of rare müllerian lesions not explained by the classical and modern theories of pathogenesis as Dr. Seckin talked about earlier.
The Theory of Müllerianosis has clinical relevance. It identifies rare benign embryonic müllerian choristomas, which are congenital anomalies that are curable if they are completely excised. If completely excised they do not recur. It has scientific relevance because it opens a new field of comparative research between four embryonic müllerian diseases which complement the four acquired müllerian diseases with which we are all so familiar.
In essence, there are eight benign Müllerian diseases, four embryonic and four acquired. And you can see under the embryonic: endometriosis, adenomyosis, endocervicosis and endosalpingiosis. And the same under the acquired, so there are eight diseases and not four.
I would like to recognize at this point colleagues who contributed substantially over the years to the development of this theory. Charles Chapron and Dan Martin who was honored here recently. Germaine Buck Louis who I was associated with in Buffalo before she moved to NIH. John Yeh, my former chairman. Kunle Odunsi who is the chair of Gynecology at Roswell Park in Buffalo. Paulette Fauceglia who is the pathologist there. Philippe Koninckx, whom we all know. Richard Smith who is an MD, PhD. He had a PhD in anatomy with an emphasis on embryology and I will talk more about him later on. And Shashikant Lele, who is the former chair of the Gynecology at Roswell Park.
This Odyssey of Discovery began in 1984 when Donald Chatman from Chicago came one Tuesday evening to the Buffalo OBGyn Society and presented a paper on “Pelvic peritoneal defects and endometriosis”. If you look – it’s on the monitor but not on the screen yet – I will show you a slide in just a moment. He described openings in the floor of the Pouch of Douglas as defects. I went up to him afterwards and I said, “Don, I’ve seen these. They’re not defects they’re organoid structures”. And he said, “Well, to me they’re defects”. And I said, “Aye, aye sir, they are defects”. I then went back to surgery and since the term peritoneal defects implied a deficiency where there was none, we proposed a descriptive term “peritoneal pocket”; an organoid structure that descends from the Pouch of Douglas into the rectovaginal space. Here is a picture of one. And you will notice under the – you have the two uterosacral ligaments and sort of tucked under the uterosacral ligament is this opening. That opening descends into the rectovaginal space.
Here is a sagittal section showing that pocket. If you take an ovarian biopsy forceps and just slip it down into that pocket, grasp the base of the pocket you can invert it inside out like the wind socket in an airport. You have all seen them where they catch the wind direction. If you hold it up, and at the time I was doing surgery, I liked the lasers because they cut and were bloodless at the same time, you hold it up and you cut very, very carefully there and you have a nice specimen to send for histology. When we were doing this work the pathologist at our hospital was Professor Cornell Turpin who was the intended successor of the chair at Prague but came to Buffalo when I was a medical student and he did all my sections and he would serial section all my specimens.
Now the crux of the Odyssey is precisely 30 years ago this morning, honest to God this is a real coincidence and I was talking to Harry Reich earlier that this meeting was scheduled a little unusually that we are talking on a Sunday and then again on Monday and it happened to catch the 12th of April of 2015. But 30 years ago today I was in surgery and I saw bilateral peritoneal pockets in the Pouch of Douglas, not one on the left or one of the right, but bilateral. And the bilateral pattern plus the organoid structure suggested to me, I said, “This is a congenital anomaly”. That is when the idea struck and I remember that date precisely. I called down to Rich Smith who was in pathology in the basement and said, “Rich, come on up to surgery. Scrub up and come in, let’s take a look through the scope”. As I said, he was an embryologist also and he said, “I think you’re right. These are congenital anomalies”. And that insight stimulated 30 years of research.
Here is the photograph I had taken at surgery and John Nyquist, our illustrator, put it in and you can see on the left it is a small pocket. The one on the right actually has a septum in it. I will go on to the further part of this. Within a month, Jordan Phillips, who was president of the AAGL, called and said the keynote lecturer on endometriosis was too ill to travel to Beijing, China for the First Chinese International Congress on Obstetrics and Gynecology and could I fill in? You do not say no to Jordan Phillips. Kathleen and I got our act together and made up a lecture and we were off to Beijing.
On June 19, 1985, that was about two months after the insight I gave the keynote lecture in Beijing and its title was “Minimal Endometriosis Treatment and Relationship to Infertility”. At that time I said there were two types of minimal endometriosis; the congenital and acquired forms. This is from my notes of my lecture, “The human female may harbor endometriosis from embryonic life until death, the disease being active or inactive at various times. We view the histogenesis of endometriosis as a continuum starting with cases of congenital endometriosis originating in embryonic life, followed by cases of acquired endometriosis originating from the endometrium”. As you can gather for a long time I have been a rather firm believer of John Sampson.
In the audience was professor Maurice Bruhat who heard the presentation and came up to me afterwards and he said, “How would you like to come to France next year we’re going to have an international symposium on endometriosis is Clermont, France”. Rich smith and I travelled over there and presented our first presentation formally on “Duplications of the Müllerian System and Pelvic Endometriosis”. When we got back to Buffalo we really went at this in earnest and further study revealed many brim nodules on these peritoneal pockets in the pouch of Douglas.
A brim nodule, as I will illustrate in a minute, is a small 2 to 8 mm firm, tan nodule of almost cartilaginous consistency. And then there were spider nodules, which were in the floor of recesses in the broad ligament. The spider nodules are very rare. We had to hunt a long time to find a few cases of them. The brim nodules are more common as are the peritoneal pockets in the pouch of Douglas. The spider nodule is the center of the body of the spider is only 1 to 2 mm raised, again, a firm, tan nodule of almost cartilaginous consistency from which radiate four to six thick-walled blood vessels.
These are illustrations drawn from photographs in surgery. If you look over on the left side you see the left uterosacral ligament and then you see that recess and almost over touching the ovary you will see a little brim nodule and then in the floor of the recess is a spider. If you come over to the right this is a blow up of that lesion. There is about four blood vessels radiating from that spider and you can see the larger brim nodule on the edge.
Now the brim nodules and the spider nodules are unique and phenotypically specific embryonic müllerian lesions. I want to repeat this for emphasis. The brim and spider nodules are unique and phenotypically specific embryonic müllerian lesions. You see them nowhere else and none of the acquired forms of endometriosis will have this phenotype. Eighty-four to 90 percent of brim nodules contain endometrial glands and stroma. And about 90 percent of spider nodules have characteristic endometriotic glands and stroma. As you could see in the previous slide there are occasional brim nodules and spider nodules in the same recess in the broad ligament but the combination in the same recess is really, really, really rare!
Here is an unusual case of multiple spider nodules in the broad ligament. I want to introduce the idea of associated congenital anomalies with this disease. Note the uterosacral ligaments, they are thin, they are almost like knife edge, very, very thin lesions and you see the spider nodules several of them in the left broad ligament and one in the right. If we go to the inset at the right, this is a second case not the same, in the second case you notice the thin, very thin uterosacral ligament. But look at the ureter right next to it. There is your spider lesion in the recess.
As an aside, I want to tell you a little side bar story for a minute. My first professor and chairman of OBGYN at Buffalo was a revered man, Edward Winkler. In the last year he was alive he did a vaginal hysterectomy and got both ureters. He never got ureters. I watched him do surgery, he was a magnificent surgeon. I suspect what he had was a case where the ureter was medially displaced like this. If you are doing a vaginal hysterectomy just can imagine when you have a uterosacral and you put your clamp up there BANG you have got that ureter and there is no way you can miss it – but that aside, we get back to our story here.
We observed anomalies of the primary müllerian system in 15 percent of our patients with pelvic peritoneal pockets. In one case there was, Myer-Rokitansky-Küster-Hauser Syndrome and I wish, I have been out of practice now for 15 years and my records are gone, I wish I had that record again, but I do not have it. We also observed medial displacement of the ureter associated with large recesses in the broad ligament, recesses of sufficient capacity to envelope the entire ovary and in some cases the ovary and the fallopian tube on that side. In addition, we found significant medial displacement as I showed on the previous slide of one or both ureters in 26 percent of our patients in this initial series. Later on it was slightly less than that, probably closer to 19 or 20 percent.
This is a slide we took and if you look on the lower left you can see where the ovary is in this recess and again, the medial displacement of the ureter. We took a probe and lifted the tube out of the way so you can see the ovary. In the upper part you can see where the probe is holding the ovary up and the tube off to the side and you will see the large recess. In the floor of the recess, which is off to the right here, you can see two peritoneal pockets and those peritoneal pockets went down into the pararectal space. Again, if you take your little ovarian biopsy forceps that you are all familiar with, it looks like a clam shell with a couple of little needles on it, put that down into the floor of that pocket, grasp it and turn it inside out and excise it.
The slides that I have just shown, the illustrations, we published in two papers, the first was Rich Smith and I, “The Embryologic Theory of the Histogenesis of Endometriosis in Peritoneal Pockets”. The reason it happened to be in Obstetrics and Gynecology of North America is because back in 1986 when I was in Clermont, France John Rock was there and he said, “I’m going to be editor, a special editor, of a thing would you write a chapter? And the other was the case series and Germaine Buck was the one who did the organization and statistics in it, she is now Germain Buck-Lewis. This was “A case series study of peritoneal pockets and endometriosis: rudimentary duplications of the müllerian system”. Ironically we put this in the second issue of “Adolescent and Pediatric Gynecology” and the first two issues of this journal were never picked up by PubMed. If you do a PubMed search you will not come up with this article.
Then in 1989 also at the “Second International Symposium on Endometriosis” in Houston, Texas we published the first paper in which we use the term or the name müllerianosis. Just to stop for a moment, müllerianosis is a term that was used by John Sampson. John Sampson really wanted to use, I have read all of his articles, not read them I have studied them, and John Sampson really wanted to use müllerianosis instead of endometriosis. But the problem that he recognized and wrote about was that it implied an embryological origin. On the other hand endometriosis implied an acquired origin from the endometrium and so he chose and there was a long internal debate that he had, you can see it through his papers. He chose, even up to his last paper on the subject in 1940, he ended up of course choosing the term endometriosis. At that second international symposium we described the route of the pathogenesis of endometriosis associated with the peritoneal pockets.
Following that presentation in Houston was a 13-year drought. We went back home and we saw peritoneal pockets and all the things I have described but nothing new, nothing! It was totally frustrating. That drought was broken only by Young and Clement’s article: “Müllerianosis of the Urinary Bladder”. That was published in 1996, six years later. Young and Clement used müllerianosis as a pathological term or pathological diagnosis. We always used it as a pathogenesis, we were interested in the origin of things, they were interested in the pathologic descriptions of specimens that are delivered to them in pathology. Young and Clement suggested that müllerianosis was an appropriate pathological term to describe an admixture of two or all three types of müllerian epithelium.
In 2003 the drought ended for us. In May of 2003 one night Fertility and Sterility came and I read a case report by Tuech and his group from France on a solitary hepatic endometrioma located entirely within the parenchyma of the liver. There was no endometriosis anywhere else, not on the surface of the liver, the diaphragms, not in the abdominal cavity or in the pelvis, nowhere! That was a solitary lesion. They attributed this to coelomic metaplasia. I admit that I am biased towards Sampson quite heavily but if you go back in the literature coelomic metaplasia is a very, very old theory and there have been wonderful embryologists and pathologists who support it. But it is the default, automatic default pathogenesis on any lesion that the authors do not know what the pathogenesis is, they automatically say coelomic metaplasia. I looked at it and I said “How is coelomic metaplasia going to make a six and a half liter size, can you imagine a 6.5 liters of an endometrioma in the liver, when there is no endometriosis any place else? It does not make sense because the driver for coelomic metaplasia is the ovarian estrogen. Here is the ovary down in the pelvis and here is the liver up here. Why is there not endometriosis in between? I went to the library and started analyzing it.
Talking with my colleagues in a letter to the editor we postulated the theory of embryonic müllerian rests best explained the pathogenesis of the hepatic endometrioma as well as the absence of endometriosis in the spleen. We presented our argument of organogenesis of the liver, spleen and müllerian ducts begin, in that order, in the second month of fetal organogenesis. This offered an opportunity for a müllerian rest, an endometrial müllerian rest, to incorporate in the liver and the spleen.
The liver is the primary organ of hematopoiesis in the fetus. Vasculogenesis, Dr. Seckin talked about angiogenesis, angiogenesis is a term after birth for new blood vessel formation, vasculogenesis is a term for new blood vessel formation in the fetus. Vasculogenesis would explain the competence of a müllerian rest to menstruate over years and to adult life 6.5 liters of menstrual detritus to form this large, hepatic endometrioma. Vasculogenesis would also ensure survival of that intrahepatic müllerian rest all the way through embryogenesis and on into adolescence and adult life. It could maintain full functional potential of the müllerian rest during that long interval of hormonal deprivation between birth and the onset of estrogen stimulation at the thelarche. The absence of endometriosis in the spleen might be explained by the spleen presenting a hostile environment to the survival of endometrial müllerian rests. The spleen lacks such hematopoietic capacity during early embryogenesis besides which the spleen is just loaded with macrophages and it has a splenic culling process that would tend to destroy endometriotic müllerian rest.
We submitted that to Fertility and Sterility and the editor for letters at that time was Paul McDonough. We had no title on our article it was just to the editor. When it was published his title was “Isolated hepatic endometriosis: as rare as hens’ teeth, but sometimes you can learn a lot from a hen with teeth”. When I read that I thought “you dear man”, I said, “What a wonderful sense of humor and thank you”. With that unexpected encouragement we really started to analyze the literature for case reports of rare müllerian lesions and set out a little, minor subtle campaign of letters to the editor and were able to successfully argue that the theory of müllerianosis explained the pathogenesis in these rare lesions, and they were all müllerian embryonic lesions, better than any other theory that the authors had explained.
Then at 2006 this wonderful article was published, a case of spinal intradural müllerianosis at L2-L3 level. The histologic examination revealed all three of the tissues. Not one or two but all three. There was endocervical, endometrial and endosalpingeal tissues. That was Barresi and colleagues who published that in “Histology and Histopathology. So I wrote a letter and the editor came back and said, “We don’t accept letters please write a review”. So I said, “Fine”. I got Rich Smith and Germaine Buck-Louis, Dan Martin, Charles Chapron and Philippe Koninckx and at that time my chairman, John Yeh and through a series of emails and stuff we put our heads together and we wrote a review. In this review we defined müllerianosis as an organoid structure of embryonic origin, and you have heard this before, a choristoma composed of müllerian rests: normal endometrium, normal endosalpinx and normal endocervical tissue, singly or in combination, incorporated within other normal organs during organogenesis. In this case it was in the spinal cord.
Now to give you an idea of how rare these are there has only been, as far as I can find, five cases of müllerianosis of the spinal cord. These are rare lesions. One other lesion was from Dr. Kurman, professor of pathology from Johns Hopkins when he was a young man. He was I believe at Harvard at the time and he published a paper with endometrium and endosalpingeal tissue in the spinal cord and he had the paper checked before publication by a noted professor from England. This was a case where there were two tissues in a spinal lesion. But this one was wonderful, it had all three.
We studied and defined these müllerian choristomas always in complete clinical pathological context and such müllerian choristomas that I mention could have one, two or three müllerian components. These were formes fruste of the cervix, uterus or fallopian tubes respectively. They were really frustrated because these were during embryogenesis. Instead of that tissue going to form the cervix, uterus or the fallopian tubes it got displaced out into other areas.
In the course of our studies we identified müllerian choristomas in the pelvic cavity, the abdominal cavity and the thoracic cavities.
Based on Young and Clement’s 1996 article we postulated that suspected müllerian choristomas containing either two or three müllerian tissues constituted definitive evidence for the pathologic diagnosis of müllerianosis; and, suspected müllerian carcinomas containing two or three müllerian tissues constituted definitive evidence for the embryonic pathogenesis of the müllerian choristomas. You can see how much we were influenced by Clement and Young. Furthermore we postulated a single müllerian choristoma can be diagnosed with certainty when three conditions are met: no evidence of pelvic endometriosis elsewhere, no direct communication with the endocervix, endometrium or endosalpinx and no prior history of surgery on the reproductive organs.
During my research for my dissertation in history I read Robert Meyer’s autobiography. Meyer had identified embryonic adenomyosis in 1899 when he described an island of endometrium in the middle of the posterior wall of the fundus or a newborn girl. He also asked…for the uterus of an orangutan of six years old and he found adenomyosis in the posterior wall of the uterus in a young orangutan. That year he also identified embryonic endocervicosis in a fetus.
Now Robert Meyer, for those of you who are unfamiliar with his name was the distinguished German pathologist and embryologist and he had identified two of the four embryonic müllerian diseases over 100 years ago. That is his autobiography and that is the 1899 citation where he illustrated the adenomyotic lesion. I would have shown that to you this morning but I did not have the chance to clear it for copyright. German copyright is much longer than an American copyright.
In 2009 guided by our Theory of Müllerianosis Signorile and his group from Italy identified endometriosis in four human female fetuses between the gestational ages of 16 and 25 weeks. They stated, “Their ‘objective was to test the validity of the theory of müllerianosis’”. In so doing Signorile et al provided the first direct evidence in human female fetuses for the existence of embryonic endometriosis.
This is the article and their title of the article is “Ectopic endometrium in human fetuses is a common event and sustains the theory of müllerianosis in the pathogenesis of endometriosis, a disease that predisposes to cancer”. I think they put a little too much emphasis on the predisposal to cancer.