Endofound’s Sixth Annual Medical Conference: Ending Endometriosis Starts at the Beginning
Endofound Medical Conference 2015
The Black Hole: What we don’t see in endometriosis
Tamer Seckin, MD
Rob Taylor, MD: Good morning, I am Rob Taylor from Winston Salem and it is my pleasure actually to introduce our first speaker this morning. A man who actually requires very, very little introduction but I do want to say that Dr. Seckin has been practicing gynecology and fantastic endometriosis surgery here at this hospital, Lenox Hill, for over 30 years. He is well known to all of us. He is the co-founder of the Endometriosis Foundation of America. I am really excited that he is kicking off the lectures this morning with a cosmological perspective that I think a number of us have picked up on in the theme of this symposium, the Black Hole of Endometriosis. Tamer, please…
Tamer Seckin, MD: Thank you, good morning. Before that Lone has also put up the history of the Foundation and what we have done. I think I am just going to run a couple of slides of what we have done in the past.
Rhoda was actually a patient I could say now after so many years of Dr. Reich’s. That group was created by Dr. Reich who happens to be the man we honored, on the right hand side, at the first Blossom Ball. He did not know he was being honored; he was very touched that night. This was our first Blossom Ball. We decided that I had organized the Foundation, filed everything, but there was nothing happening. There was no way I could break my eggshell or barriers to make it known to people other than my little cohort of patients. Padma came to my circle and she was very touched with the cause. She said she would do everything and as she moved along we did the first ball with her.
It says the Foundation is a non-profit organization focused on fighting the devastating effects of a disease that affects millions of women and adolescent girls. Since then I have spotted the adolescent girls that are the main subjects of our interest. Through awareness, education, research and legislative advocacy Endofound is committed to improving affected individuals’ lives by early detection and treatment.
My position has not changed. I had this vision for a long time and yesterday you witnessed that a state senator was here and we are getting significant funds for a cause like this. For the first time in America this cause is getting attention and legislative advocacy. I think it is important to know that. It is also important that Fareed is a friend of mine through some connections and Whoopi is a friend of Padma’s, they joined the ball and then “mentionitis” and the PR started.
The next year the topic was advancing the” Art and Science of Endometriosis”; it was about stem cells and radical excision surgery. Linda came into our lives and we were very touched about what she was going through and was doing at MIT. Camran of course, after Harry, is a very well known name in endometriosis for what he had done, bringing video to the field. We honored Camran. We decided to honor one scientist and one surgeon. We are trying to go along like that but it does not always happen that way each time.
The third year we named this very provocatively with the help of Lone “Let’s Talk about Sex and Endometriosis”. The deep, deep disease, it is a subject that nobody talks about. We honored Caroline Gargett who is the lady of stem cells research from Australia. I have had my eye on stem cells since then, that was six years ago. I was very affected by the way it was run.
An interesting character – David Redwine! He is a visionary. He has described things that nobody ever did with his own words, very, very much affected with his way of describing things and his techniques. Susan Sarandon joined us. Dr. Oz joined us.
The next year we again got back a similar theme to this year, which was named “Tapping the Roots for the Next Generation”. Again we are focused on adolescents and youngsters. Hugh Taylor and Charles Koh: Hugh Taylor from Yale does incredible work with stem cells, he joined us. And Charles Koh with surgical techniques also has affected all of us and I think he was rightly honored.
The following year it was about “the American Perspective”. We honored Dr. Bulun and Dr. Martin. Serdar, like me, is of Turkish heritage and has done significant work on endometriosis lesions, how estrogen is produced separately. He is the godfather of a lot of molecular findings. Dan Martin is well known to us with his findings.
Finally, last year, we honored Linda Giudice and Dr. Mettler. We felt that women had to be recognized separately. We think that endometriosis is a public health priority as a reproductive right and their work was recognized under the topic of “Politics, Ethics and Controversies”. We brought in an equal rights lawyer from Washington, Byllye Avery and we brought some lawyers in to discuss women’s rights issues and how women should look after their rights.
I was handed this the other day. We have generated almost two billion media impressions on the internet or by the press. It is important I think for awareness and prevention. When Betty Ford came out for breast cancer nobody talked about breast cancer – nobody. And it is breast cancer, cervical cancer that early detection, early diagnosis is important, we have seen the effects over the years. Since the cervical pap smear was initiated the deaths for 100,000 women is less than two already. The same is true with mammograms. Five year survival for all stages now – in 1975 it was 75 percent, it now almost 90 percent. We have some goals to achieve and I believe it is possible with early detection.
The Black Hole: so things that we do not know about endometriosis. Endometriosis is more than what we see in laparoscopy. When you look at the sky at night what you see are the stars. This is the milky way. But what I see is the energy that changed its shape and became matter that was a million light years ago. What we do not see are black holes – the other anti-matter. When you look at endometriosis if you think of these stars as endometriosis lesions there are more happening around that that we are not seeing. And it does affect us as I will tell you today, with the other universe in the pelvis, the milky way of endometriosis and the black holes, as I said. It all has to do with energy in the pelvic peritoneum through angiogenesis. What you see is an actual budding of a vessel, popping out and I put the black hole there. We will go from here.
There are so many things we do not know. I am not going to touch all of it. I will go to my obsession about the visual recognition of endometriosis. I am not going to impress you with the fancy cases we do but you need to know that endometrioma is the biggest culprit, the biggest evil of pelvic peritoneum and endometriosis care. We are not paying attention to endometriomas enough. It is like a hand grenade that explodes inside and basically ruins everything over years. This is a little animation of how the pelvis gets closed. This becomes a rectal disease that you see on the side.
This is another extensive case. You see the bilateral hydronephrosis bilateral tubes. How did this little lesion get to be like that? In some women it does not. We do not know. This is the same woman, the same women – do you know what this is? Does anybody know what this is? It is a rectal stent! It is not a cardiac stent, it is a rectal stent! Why is it put there? Because this woman is obstructed and nobody dares to operate on her. Nobody wants to touch her. That is why the put in this rectal stent.
Another one – this woman has a sacroiliac plate. We operated on this patient also. It is from this hospital that the chief of neurosurgery called me to say, “Listen we put this in but this patient has really very bad endometriosis”. We learned later it was the same woman with an arcuate uterus with the pin down there and the sciatic lesion on the side.
I start every case with a hysteroscope. I look at the endometrial cavity. In my early years I never paid attention to a hysteroscope but I recognized over the year the importance of it. I see tons of endometrial pathologies, like in this case a polyp, which can cause retrograde bleeding and cause symptoms and these patients do not necessarily have extensive endometriosis. In this case for example, you see endometrioma but what you do not see is, interestingly, a congenital anomaly. If anyone can see on the right hand side there is rudimentary. I missed this, the MRI person missed it and I missed it too. But in the end we did diagnose her, one-sided uterus with no communication to the other side.
Cervical length, uterine cavity and contraction pattern of the uterine muscles do play a role, and we do see subtle variation in the uterine morphology as mid-line prominences and bilateral funneling.
Stem cells have been an obsession because it is the only concept that really explains the old Republican theory of Wolffian duct versus – it is like talking about politics, what causes endometriosis. I am really agnostic and I do not really belong to any party on this. Many people do not believe in retrograde bleeding, they believe in müllerianosis. I am really curious about what Dr. Blatt will talk about. I do not belong to any party but I do believe stem cells have obviously a significant effect in the origins of endometriosis.
This is retrograde bleeding. This is blood in the peritoneum cavity and I think it is retrograde. I know it is retrograde because I did the surgery on this patient. You know how old the patient was? Guess, just one person. This woman was 65 years old! I am not trying to distract you from adolescents, I am going backwards now. Sixty-five years old taking estrogen for 20 years, no bleeding for 20 years, this is the first bleeding she had. This is how her sidewall looked, not bad, just peritoneum, right? You think so? This is a technique that I use, blue dye to observe the peritoneal morphology. This is how it looks. I also push blue dye retroperitoneally – this is how this peritoneum looked. I cut this peritoneum using a special pinning technique. I learned this from my pathologist friend from Japan. I stretch the peritoneum. I submit these in slices to pathology. Nobody likes me in the pathology department because when I go there I demand every little thing, they run away when I go there. They do this extra work for me. I thank them for that.
This is a cut off that peritoneum. You see the gland? You see another gland up there? You do not see anything there, right, in the middle. When you bring this you see the stroma and the gland, typical description of endometriosis. But it is more than you see. This is meso trichrome stain. You see the smooth muscles, smooth muscles in that peritoneum! This is not muscle tissue. What the hell are smooth muscles doing there? We know this fact but nobody talks about it much. There is tons of inflammation, more than glands there is inflammation. There is neural tissue there, nerve tissue. So we go to the area in the middle now where there are no glands. Look at the peripheral nerves and how they are close right underneath the mesothelial layer. Let nobody dismiss these women who have pain, the nerves are there. What we do not know is when did those nerves get there? Did they come because of the inflammation? New nerves? Neuroangiogenesis new? Or were old nerves were pulled up? We do not know that. The same way that in this case the mesothelium is thickened. In some case the mesothelium is not thickened. In this case it is. But lots of inflammation is squeezing the nerves. The estrogen receptor is positive. Calretinin is very specific for the mesothelium as you see on the right hand side. You look at the thickening over there. This is the area probably where the stromal activity is defined. Look at the estrogen receptor positivity – same way. Are these stem cells changing morphology or function? Probably, we do not know. This is again with different stains I am showing how the nerves and how the fibrotic elastosis, how the collagen has reconstructed there. But the word is inflammation, inflammation, inflammation.
Unfortunately, this is a very young patient, 23 years old who had a hysterectomy at the age of 17. Seventeen! It gives me goose bumps, how did this woman end up with a hysterectomy at the age of 17? I did her surgery and this is how it looked. The mesothelium is very thin, sub-mesothelium reactivity is incredible, it’s wild. It is not cancer but it is as if sub-peritoneal tissue is mimicking or trying to be like the uterus, with all the glands, with all the fibrosis, smooth muscle nerves but it is not reorganizing to be a uterus. It is wild reorganization. That is why we think stem cells have a lot of fingers in endometriosis etiology. These are…cells trying to be like the uterus. This is nerves in the same patient.
This 17 year old – we see just terrible cases. Fourteen surgeries done by one doctor and there is not a single, like Dr. Reich says, not a single pathology. Not a single pathology fourteen surgeries, same person. Or, as I said yesterday, 12 year olds are on morphine patches for pain purposes.
This is a peritoneal disease, inflammation is the key. I have animations of these things I have really thought about it a lot. It shows how iron accumulation separates the mesothelial cells. How these vessels start to curve. Spiral and stem cell activity not only from the diseased vessels also from above, probably oxidative distress of this debris. It is like the peritoneum gets primed to become a different organ already and these vessels spike and finally the debris could be rescued from the signaling of these elements on supra mesothelial and underneath.
From just some pilot studies what we did last year. I have sent close to 2,000 specimens to the Department of Pathology at Lenox Hill Hospital. We pushed all the big organ removal cases out, we also took the other excisions out of the cul-de-sac and posterior and we end up with 1600 excisions and all of these 1372 were examined after you take 233, you have 1300 specimens, 17 specimens. We had almost 14 excisions per case. What we see in general in these cases 55 percent were pure endo, 29 percent pure inflammation and from the biopsy where I took the biopsy. The others were stromal endometriosis and fibrosis. We do not know if those are healed endo sites but pathology has just described it. In every pure endo stroma there is inflammation described by the pathologist. This is total. Wait till you see this – this is interesting. When I look at the pelvic sidewall the inflammation percentage swells and I did more biopsies, almost three times as many biopsies on the pelvic sidewall and pure endo decreases. In the cul-de-sac I have more endo, less inflammation to deal with but the amount of excision I had to do from the cul-de-sac was less. In other words, I recognized more pathology on the pelvic sidewall than cul-de-sac. But the cul-de-sac was all classic things – my percentages were high.
These are statistically significant. This is a pilot study – the bottom line is that overall I have removed three times as much specimen from both pelvic sidewall and many of those specimens that are removed from the sidewall were more inflammatory in reaction. This is interesting because the literature does not say this. The reason is I use my blue dye technique. I use this technique, I try to illuminate the light source, the bright red and yellow and eliminate that from the spectrum. I use blue as my screening color so under the water I examine, I take photographs and I push the blue dye retroperitoneally – this is what I see. That made me take more than one biopsy. These are the photos I got, like to take pictures inside. What you see here again is classical endo but look at this area. Buzzing or burning this is not going to help. This whole area is sick. You are going to see more interesting pictures now.
This is normal peritoneum. Normal peritoneum is transparent, shiny with a plain texture. I am showing the effect of light and how it can interfere. This is not a reflection this is what you are seeing through the blue water. We can really see and identify pathology up to 100 micron. This is 5 mm here you just have to get the scope very close and you have to know how to patiently work meticulously on the patient. Again, shiny peritoneum and this is where you put the water and get the pressure of the gas off and things start to swim – like this lesion, like these lesions you can see them. Also, there is light reflecting – you cut the light reflection. This is retro-peritoneum and this is the lymph node actually, positive for endo. Look at these buds and how they are swimming when you push the water. This is like mini-period…bleeding spots. These are fascinating to see. Again, same spots, early bleeding, look at this angiogenesis site. The camera is exceptionally close. On this side you see the lesion is floating, it is not really attached, only attached by small vessels to the side.
Look at these wonderful angiogenesis new vessel formations and they can come in every format – again little buds. These do bleed and leave marks and become like scar tissue. This is very interesting. You do not see anything on this patient. This is not an endo patient actually I had operated on her for a previous myomectomy and excised endo from this area. When I looked back I saw this area and I went there and you cannot see anything but you see these two lesions there? One of these lesions is swimming and one of them is flattened. I excised these areas meticulously and sent them to pathology. This is the area you see is swimming, two of them like two little ears and these are flattened lesions. I went there and this is the floating lesion up there. And under hematoxylin this is the lesion, how it is and how it houses like a papillary here. There was no gland on this; however it was positive for CD-10 without any glands, so this is stromal. The other one that was flattened when we excised there were glands in it. So this is the area where the action is happening where endo is popping out without us noticing. Same thing.
Again, there is no defect in this thing. When you inject retroperitoneal hydro blue dye distention all the defects pop out. This is reorganization of the sub-mesothelial collagen and fibular network. The other side is smooth and when you look at this stroma positivity shows up under the microscope with iron deposit inflammation and stroma positivity.
These are typical of how I am obsessed visualizing these micro lesions, how they bleed and then become fibrotic. Over the years I have taken these pictures. This is the way I really do it. When you look at the left side you do not see anything but endo there, but look what happens. We make a little nick on the pelvic sidewall, again, the same thing, right on top of the ureter, a very small lesion. You do not see anything more than two lesions. But when you go in and distend like this suddenly the whole architecture and texture of the peritoneum is different. This is not a disease of what you see, there is more damage than we appreciate.
This is the type of excision we do. In the end you really restore and desiccate all the anatomy in certain cases when the patient comes to you with their tenth surgery and…fibrotic tissue around.
This is the thickening of the peritoneum, and its depth and its extension down below. It is all there you just have to know and find it. I’m almost closing. This is a patient I typically show. She came to us from Mississippi. What you see is a bowel lesion here. We did a bowel resection. But also with a bowel resection – this is how I suspend – I use grainy needle, single site, different from other people. Single incision in and out, the ovaries are suspended. You see endo lesions all over – typical endo. I have nothing suspected here. I typically went under water again, looked around, took my photographs and moved in hydro-distended retroperitonium. I excised this patient’s every endo, I removed 15 specimens from her, from the right side and left side. This is all gone, this is all gone too.
When the pathologist called me he said, “Look, I’m not happy with this thing I am seeing”. This is what I call the ovarian cleft. Pay attention to this area. He said, “This area where you marked ovarian cleft doesn’t look right”. This is how it looks after excision. We go in and we coagulate very meticulously. The pathologist obviously came as you see on the side that is the bowel, five of the excisions are cancer.
The final point I am trying to make is that laparoscopic visualization and recognition has to be verified with excision. And it has to be done by another doctor who is not a surgeon, who is a specialist in recognizing this under the microscope. That is how we will make a difference. Honestly, we should really scream for pathological diagnosis and we should not promote any laser ablation or laser coagulation of these because many of the epithelial tumors, 90 percent are epithelial and we know 20 percent of them are endometriosis related and the other high grade serous tumors could be, we know that they are most likely, tubal in origin and that leaves very little behind. Tubal trafficking has something to do with ovarian cancer. I am really sure we are going to hear more about this in the future. Ninety-five percent of the tumors have to do with retrograde spillage. This is a recent article, just closing up.
I am going to close with – I saw this quote at Dr. Z. Ali from Johns Hopkins. He is a…professor of pathology. We are doing some work with him, I am not sure he is here today, but I really love this quote and I wanted to share with you, “What we observe is not nature itself, but nature exposed to our method of questioning” (Werner Heisenberg, Physics and Philosophy, 1958). Thank you.
Rob Taylor, MD: that was wonderful. I guess we have time for a few questions. That was great. Please if you have got questions in the audience raise your hand. I think we have someone who will run with a microphone.
Linda Griffith, PhD: Linda Griffith, MIT. How hard is it to take those little lesions out and actually prepare them for the pathologist? Because they are so small, what is involved in going from seeing them, excising them and actually getting them into a form that the pathologist can look at and makes sense of? It just seems when they are so small…
Tamer Seckin, MD: Are you asking about the last specimen where I took that floating thing?
Linda Griffith, PhD: Yes. Just technically, how hard is it?
Tamer Seckin, MD: It is very difficult, extremely difficult. I still use– Harry has an incredible forceps with…very fine tip, custom made. Basically, I still use that. Continually doing because people are selling it but the bottom line is it is very difficult and we are trying to find a micro-biopsy technique to do it. I like to get those angiogenic spots with the micro-biopsy thing and send it like that. You will see a lot of things I think. If stem cells – we can stain them we will see a lot of things. That is the war zone I believe. But things are changing and happening right there in that bud that I described.
Rob Taylor, MD: Tamer, if I could the interesting data about the sort of sidewall, pelvic sidewall versus cul-d-sac. I agree with you, I am not really so concerned about the different histogenic theories. They are interesting and we are going to hear a lot more about them and I am a little bit agnostic as well. But if you actually follow the development of the Müllerian ducts you are going to see them embryologically more separate, closer to the sidewalls, higher in the pelvis and closer to the cul-de-sac, lower in the pelvis. I am curious as to whether where were your sidewall lesions coming from versus the cul-de-sac? I think the more anterior you are the more likely those ducts will have left remnants if you believe in that type of hypothesis – laterally.
Tamer Seckin, MD: I agree with you. That was not a question, you just made a comment?
Rob Taylor, MD: Yes.
Tamer, you made a very good presentation. I just want to ask a question. Back in the 1920, in the United States, there were two pioneers; one is John Sampson from Albany, New York. He proposed the retrograde dissemination of endometrial tissue. The other was Thomas Collins from Hopkins. Again, in the 1920s he proposed there is a different type of endometriosis that he called adenomyosis of rectovaginal symptom. And their biological behaviors are totally different. Both Sampson and Collins were very well trained pathologists. Collins detected there were muscle tissue…that is the reason he called it adenomyosis of rectovaginal symptom. The behavior of the adenomyosis of rectovaginal symptom could invade directly with the surrounding tissue and also can have a distal spillage by means of an empathic or immunological means. And that is what we see, for example, I am going to talk about ureteral endometriosis. They have a …external which we can explain by Sampson’s theory. But in the end there is again you see endometriosis not much with peritoneum involvement but endometriosis goes direct to the muscularis of the ureter or the bowel or even distant, like the diaphragm, the lungs or even the brain. Those are by hematological or by hepatic spray.
What you are seeing here probably reconfirms what they were thinking. Back in 1920s, a hundred years ago and we are still making a circle around. Very, very interesting. I just wanted to make this comment.