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Beyond Molecules and Robotics– the Future Treatment of Endometriosis - Ceana Nezhat, MD

Beyond Molecules and Robotics– the Future Treatment of Endometriosis - Ceana Nezhat, MD

Endometriosis Foundation of America
Endometriosis 2013 / Beyond Molecules and Robotics - the Future Treatment of endometriosis
Ceana Nezhat, MD

Thank you very much Mr. Chairman and thank you for all of you for staying here late in the afternoon. It is a beautiful day today. And, of course, thank you Dr. Seckin for the kind invitation to be here with you.

I am amongst a distinguished audience and it would very hard, especially being the last speaker, to come and summarize. But as I was sitting in the back and Sarper who is managing Twitter, he said about 300 people are following these meetings. So in addition to you being here there are about 300 people on-line following us.

To make that one including incorporating the questions and answers I would like you to look at these questions, endometriosis, adenomyosis, endosalpingiosis, suture granuloma and adenocarcinoma. I am going to show you this video and I want you to give me the diagnosis and tell me what you think. If you look here, this lady had pain. They told her she had uterine prolapse, so she had uterosacral ligament plication. This is a lesion here. As you see here when we do the excision this other suture material here is on the margins of the lesion being excised. Seizing the posterior cul-de-sac the rectum is here. This is the suture and these are the lesions. Going back to the question tell me which one you think it is; the ones who think this is endometriosis raise your hands, okay; adenomyosis; endosalpingiosis; suture granuloma, two, three, four, five; cancer, does anybody think it is cancer? We have a pathologist here and you had a beautiful pathological presentation by Dr. Ayhan. This was adenocarcinoma. So looks can be deceiving. Look here, you had these sutures were placed on the...of adenocarcinoma. Actually I did the frozen section when I did this surgery. It came back endometriosis.

Audience Member: Did you go underwater?

Ceana Nezhat: It was the final pathology that came back adenocarcinoma, so we cannot really always look at what we see here. There is an old saying, it says, "The eyes do not see what the mind does not see". This is another one, I would like you to give me the diagnosis. The same diagnosis, you look here we have the fuse ascities, we aspirate the ascities, these are the lesions, cystic lesion, epithelial lesion...this is the bowel and these are all the lesions you look down around here. What do you think these are? Going back to the same question, like Dan Martin you can have two diagnoses now; he said you can have two. Which one?

Audience member: The C and the E?

Ceana Nezhat: C and E and the salpingiosis and adenocarcinoma, anybody else? This was actually pure endometriosis and adhesion. Ascities everything typical like cancer, the other one, everything typical like suture... You have heard these phenomenal talks today and we have heard a lot of good data. But Sarper said there was no controversy, everything was following, so I am going to create a little controversy for us.

This is endometriosis and endometriosis is an enigmatic disease. It is not one disease. It is a process and it involves any part of the body. Practically if you look at this slide show this is the diaphragm. Practically any part of the body, this is the ureter that almost was choked and people have lost a kidney because of endometriosis.

I do work with different companies but mainly in education and product development. There is no financial relationship to my talk and my conflict.

You have heard about overview on endometriosis. What I would like to focus on is pelvic pain, infertility, malignancy and see where we go in the future. Two things we know for fact today, everything else is suggestion. Endometriosis is estrogen dependent, progesterone resistant and it is an inflammatory disorder. This is a fact. The other one unfortunately from the time of the first symptom to diagnosis it takes eight to 11 years. So we are behind in assessing endometriosis. You have heard all of this that it could be retrograde menstruation, colonic metaplasia, immune dysfunction, environmental triggers. We know for a fact dioxin, we know that of DES patients who have been exposed to DES that 80 percent have endometriosis. Congenital anomalies; one question, almost all women have retrograde menstruation sometime in their lives. But why do not all of them have endometriosis?

We credit Sampson for retrograde menstruation but actually Sampson is the one who opened our eyes for us that if you suspect endometriosis look for extragenital endometriosis.

Historically 236 years before Sampson, Ruysch described retrograde menstruation. So it goes way back.

This is a heart, these are the endometriotic lesion on the pericardium. This is the hemoperitoneum at the time of menstruation, this is the lung and you see the blood, you see the inflammation on the surface of the lung with the hemorrhage. So spontaneous pneumothorax or cyclic...is all related to the endometriosis from the lung. But actually it is extra tissue of the lung causes this. When we resect this portion of the lung we see that endometriosis from outside is invading the wall of the lung. In 1967 Kuchner said pneumothorax associated with endometriosis it could be because of the air going through the fallopian tubes, going through the diaphragmatic hernia. So we have theories all over.

If we look at all the symptoms cyclic pain is the most common symptom associated with endometriosis. Look at the history. All these paintings from the 17th century show the adolescent, the teenagers, the young women are disabled because of the pain. They were bedridden, either a prayer for them or a house call from the doctor.

Why does endometriosis cause pain? This slide looks busy but it is a summary of all the talks we have heard today. Androstendione is from the adrenal gland. It goes in the tissue because the aromatase converts to the tissue estradiol. So why did Dr. Einarsson say GnRH analogue does not work? Because GnRH analogue suppresses the ovarian estrogen but the actual tissue produces its own estrogen. Serdar Bulun was here, I mean he is the mastermind behind it. The mechanism of contribution to the pain is activation of the nociceptors in the tissue. The tissue of endometriosis produces estrogen and produces a nerve fiber of their own.

Historically, we have used many treatments. In the 18th century they were using materials like this herbal medicine. This is using the potion or block in here but they used bull's gall, opium or alcohol in the vagina to help the pain. It may sound funny but bull's gall was androgen, like Danazol. Opium blocks the nerve pathway. And alcohol, we use alcohol today to inject for a nerve block. So it goes back to the 18th century. The treatment that we use today - it goes way back.

Looking at the 20th century in 1934 this was an ad. So from 18th century to 19th to 20th century still you would see natural remedies and herbs and massage were used to treat endometriosis. Today we have acupuncture and physical therapy. When we look at the treatment and the summary of all these talks that you have heard, all the medical therapies and surgical therapies for removing and excision. Excision unfortunately is taken beyond the proper utilization. And then sequential therapy, the success rate for medical - it works for a little bit then it stops working. The side effects are high. Surgery - there is no cure for endometriosis. There is only a cure for endometriosis on the internet. We do not know what it is. We do not have a cure for it. Surgical excision in two to five years you have 50 percent recurrence. Why is that?

When we look at infertility endometriosis could affect all the factors that could contribute to the pregnancy; peritoneal factor, ovarian factor, tubal factor and endometrial factor. It is a toxic, inflammatory organ.

In the past getting pregnant was a treatment for endometriosis. They said if you do not get pregnant the uterus wanders around the abdomen and causes more trouble. This is an 18th century painting. Before, many thought that the sperm carried a fully formed miniature baby that just needed to "cook" inside the abdomen of the women. They thought that women had nothing to do with fertilization, it was the sperm. It takes about 200 million sperm to fertilize one egg. That is a contraceptive ad.

When we talk about endometriosis and treatment we cannot suppress them because then it would contradict it. But when looked at...had a nice meta-analysis and showed that if we just do straight ovarian stimulation the success rate in stage one to two is 15 percent and three to four is about eight percent. Even if we go directly to IVF, in the best hands, there is a maximum 30 percent success rate. So getting pregnant directly is not the answer.

We had a Cochrane review in 2003 by Jacobson that showed if we go diagnostic laparoscopy versus treatment of endometriosis in stage one to two we could actually double the pregnancy outcome. So definitely surgical treatment could improve fertility.

Then you have about adenomyosis, Dr. Isaacson addressed adenomyosis. This is the summary published by Philippe Koninckx, Jacques Donnez, Arnaud Wattiez, these are the European leaders when it comes to endometriosis last year. Last year they said we therefore suggest that deep endometriosis should be pathologically defined as adenomyosis. We were talking about adenomyosis involving the wall of the uterus. We are changing the definition of extra-genital endometriosis. As soon as we thought we had an answer we really are trapped again where we started.

In 2011 we had the World Symposium on Endometriosis in Atlanta. Fifty-five leaders of the world came. We talked about immunology, mechanical treatment but the conclusion was that at today's expertise the surgical resection, without compromising the function of the organ and restoration of the anatomy, is the answer. No answer is left behind.

We owe a lot with laparoscopy when it comes to the knowledge of endometriosis, not only on treatment, but diagnosis. If you look at even general surgery, urology, the way that we started treating endometriosis by laparoscopy expanded to the other disciplines.

It is obvious that instead of having an 18th century midline incision by Ephraim McDowell, Fanestil incision in 19th century by Fanestil from Kiel, Germany, now today we have a smaller incision. This is a fact. You were asking about the role of AAGL and endometriosis. The AAGL has been in the forefront of treating endometriosis. This is a 1985 postgraduate course...so-called Levinson and here is Harry Reich talking about treatment of endometrioma. Then Camran Nezhat, my brother, at that time talked about video laparoscopy treatment of endometriosis. And the AAGL has been a part of this.

In 1985 Camran, my brother, he said if you do video laser laparoscopy and you can treat a stage four endometriosis with a good outcome, practically you could do anything. The problem was laparoscopy before that did not take off because it was a one man, one eye, one hand procedure, attaching the video changed the whole operating room to an orchestra. And everybody in the OR became involved. Now we had devices developed, we had energy cam, laser, monopolar, we have scissors but the principle is the same. This is the bladder, this is the pelvic sidewall and this is the uterus. You can vaporize it. You can excise it. The whole thing is not to damage the tissue just eliminate the pathology. Excision, vaporization all of them will work.

This is a 1991 report of bladder endometriosis. This is a lesion cystoscopy inside the bladder. The reason I show you this is because we reported 16 cases of bladder endometriosis; one of them was adenocarcinoma. When you see a lesion like this it is important to remove it. Any device is fine. This video looks old because it is old. But the lesion is everted, excised and we could see better. When you see better you can perform better. We magnified the tissue, approached, see the ureters, see around here? Then the lesion was removed with a healthy margin, and it was repaired. So this is a no-brainer, it has been done for more than 20 years. The most invasive disease can be treated.

Now this is a case I would like you to pay attention, please. This is the right side, left side, the uterus is here look at the tiny, tiny spots of endometriosis. This is the uterus. You see this is what I describe as miliary type of endometriosis, the smallest spots all over the abdomen. Now, knowledge of anatomy and proper instrumentation are the key factors here. Dull scissors chewing, change to sharp scissors. But this is too aggressive of a dissection and makes a hole in the bladder finishing as a complication. Call the urologist, all the disease is left behind. So certain procedures like these were a setback to the advancement of minimally invasive surgery. Because something can be done does not necessarily mean it should be done.

Laparoscopy did not take off because if I focus on this lack of precision you are working with ruder instruments and poorer dynamics. You had to work in a counter-intuitive environment and that why the robot came in. The hope for the robot is to bridge the gap between laparotomy and laparoscopy. It did not come in to replace a good technique of laparoscopic surgery. The company made these things, this is origami and this is peeling the grape, this is the actual function of the arms. You have more articulation. You can precisely excise the lesion. Do you need it? No. But this is what it has been advocated for. That you could decrease the tremor or you could down regulate your movement. That was good.

To be the best hospital you had to have the robot or otherwise you were falling behind. Vogue magazine - to be in Vogue you had to have a robot. They called it Wizards of Oz. So really, anywhere you look, for each dot you could see about at least $2 million dollars. The robot has exponentially grown around the country. You ask why? I do not know why. I am going to show you. This is side by side, let me pause this. This is endometriosis it was done in 1990. This is a ureter. This is practically shaving the disease with laparoscopy off the ureter. That is the ureter I showed you in the beginning where the patient almost lost a kidney. If this lady had gone to the urologist they would have done resection and re-implantation. Practically we have been able to do a precise excision of endometriosis. Dr. Advincula reported to the AAGL a position statement and he said on endometriosis Nezhat reference was used. It is a retrospective paper, nothing much to say. Respectfully, I disagree. Sarper this is for you. I disagree with you. I am going to show you.

We have done this fine dissection of the ureter for endometriosis. This is the robotic that you can do. In experienced hands you do not need the robot. And actually today's robot in its form and shape is a setback because you do not have tactile feedback. True you could do a fine dissection. True there is no tremor. True you could use your electrosurgical devices but this ureter could be easily transected because there is no tactile feedback. So that is why we reported that for endometriosis today robots are not superior. It is the experience of the surgeon, the drawback of a robot. This is right pelvic sidewall. People say okay why then use...this is lack of knowledge of energy. The robot here not only makes a hole here I want you to watch here. This is a delayed injury. This was recognized, it was managed but as you go here this is an unrecognized injury to the external iliac artery. So the lack of knowledge of the robot device actually could cause trouble. That is why you see negative feedback. If you can do something fancy it can still be the wrong thing to do.

Pappas said, "Surgeons must progress beyond cutting and sewing". We have to change our thinking about the way we approach medicine. True, we have new energies coming but everything is focused on endometriosis. We have...who works on a blood vessel so precisely. It is not damaging it but again, it is a surgical mentality.

This is the favorite quote by my mentor Dan Martin. This is from Donna Vogel in the 1980s who was working at the NIH. She said, "Endometriosis is a difficult disease to live with and difficult to understand. It's like nailing jello to a tree". It just makes sense. We are here today and we think we are doing something about...endometriosis but I do not think we are. As Einstein said, "We cannot solve our problems with the same thinking we used". I think we can work toward building molecules that can stop growth of endometriosis. So maybe surgery is not the factor or giving talks in chemotherapy or radiation is not the factor. Maybe we should go towards the genes.

If I summarize all of this we do know that endometriosis affects millions of women. Prevention, diagnosis and treatment, this is a busy slide but look here if we could have targeted therapies and if we could have non-surgical diagnoses that would be the future. We are working at Emory looking at the blood and peritoneal fluid, endometrium and endometriosis. We are hoping to find strategies and simple blood tests to see if we can find patients at high risk for endometriosis. I am also working with a collaborative study with Shannon Hawkins at Baylor. We are looking at the micro RNA level. Hopefully we can have gene therapy for treatment of endometriosis.

I would like to invite all of you to the AAGL this year in Washington, DC of which the main focus is "How can we approach this enigmatic disease when it comes to prevention, diagnosis and treatment?"

Thank you for your attention.

C.Y. Liu, MD: That was an amazing, comprehensive review, articulate review of the literature. We have 15 minutes for questions and answers - ten minutes.

Ceana Nezhat, MD: About cancer, I did not show because you saw that beautiful, beautiful talk. The only thing, if I may add, when we looked at our surveys of the patients that are actually in the review of all the patients that we did it was published in Fertility and Sterility and is easily accessible. One thing to remember, patients with endometriosis have a risk of recurrence of 2.4 percent. But then if they have been treated for fertility it becomes 4.2 percent. So fertility treatment on the patients with endometriosis could increase the risk of ovarian cancer. That is one thing I would like to add.

Audience Member: Hello, I just have a quick question. If endometriosis is not a benign disease then would it be consider malignant? And why is it not considered cancerous since cancer is a disease that is manifest by multitudes of different disorders involved with it and it has the ability to have uncontrolled growth cells that goes from one part of the body to the other? It sounds as if you are describing endometriosis, so why is not endometriosis cancer?

Ceana Nezhat, MD: I would probably pass this on to a pathologist but one thing I can say. We are looking at endometriosis as one thing. It is not one thing, endometriosis is a process. Remember adenomyosis, the definition is changing? We have nerve production, estrogen production, some are...some are fibrotic, it is a process. Some of them are at higher risk for progress to cancer than the others. Go head, please.

Ayse Ayhan, MD: From the eye of a pathologist I could say even in eutopic endometrium we have proliferation and then menstruation. It proliferates every month during the reproductive period. No matter that it is outside of the uterus, outside of the endometrial cavity it may proliferate. We would rather call it implantation rather than metastasis. So, it is totally different from the properties of a neoplastic process.

Ceana Nezhat, MD: If you read this issue of Fertility and Sterility it came up a week ago. There are three good articles that relate to it; one is from Serdar Bulun and Fazleabas that they are working on the baboons. They create endometriosis in the baboons and then they use aromatase inhibitors and two conclusions; when you look at this specially they have beautiful slides you can look at it, the patients or the baboons who were not on the aromatase inhibitors they had 40 percent progress of the disease. For the patients who were put on the aromatase inhibitors not only the disease 43 percent, they had atrophy and disappearance, you could see on the histology that there was lack of stroma. So it completely changed the pathological aspect and histological aspect of the disease. That is number one. Serdar is not here but definitely his study of aromatase inhibitors deserves credit. It blocks the cytochrome P450.

The second paper is by Jacques Donnez that they took a piece of the uterus of the baboon and they implanted it in the cul-de-sac. They created nodular endometriosis, like infiltrative endometriosis. Then you look at it and it is myometrium, endometrium and the transformation zone. So, that may answer your question. Hopefully the baboon studies open our eyes for future diagnosis and knowing more about endometriosis.

C.Y. Liu, MD: Ceana, you mention that endometriosis is a process. I thought I would just mention about endometriosis progress, proliferation and that it can go all the way to cancer, there is a high incidence of it. I am always puzzled by the biological behaviour and actual patient symptomatic too. The superficial endometriosis and the deep infiltrating endometriosis seem to me, I do not know, to be the same disease with two different expressions, or is it totally two different diseases? I want your comment on that.

Ceana, Nezhat, MD: Great question! The best way to answer that question is the ureter. We looked at the histological evaluation on the patients with endometriosis of the ureter. Endometriosis of the ureter, if it is external, it could explain retrograde menstruation. But if the endometriosis grows from inside the ureter, intrinsic ureteral endometriosis, definitely grows from the coelomic metaplasia. But extrinsic could be iatrogenic, could be menstrually produced. The bladder endometriosis that I showed you, true it had adhesions between the uterus and the peritoneum but the actual fungating lesion was inside the mucosa and started from there. That is not retrograde menstruation. That is the coelomic metaplasia.

C.Y. Liu, MD: Are you saying superficial endometriosis, the origin of superficial endometriosis and deep infiltrating endometriosis is different?

Ceana Nezhart, MD: For sure.

C.Y. Liu, MD: So, it is two different diseases or the same disease with two different phenotypes?

Ceana Nezhart, MD: I told you in the beginning our knowledge is limited. We are looking at endometriosis as one disease. I look at endometriosis as a process. In the earliest stages cancer was a post-mortem diagnosis. People would die, they would do it and they would find all these lesions. Now we have a different type of cancer, we have endometrial cancer and fallopian tube cancer. Endometriosis will be just like this one day. We will have different types of the glandular stroma pattern of endometriosis. I should not answer that question. The pathologist, a professor of pathology should answer that question. But that is the future.

C.Y. Liu, MD: I think we are running late and we can carry on the discussion in the next years.

Ceana Nezhart, MD: Thank you very much.