Thank you very much again, Linus, for the kind invitation. It was very dynamic discussions and actually that case presentation falls exactly in my presentation and some of the issues that I will discuss how the patient presents is exactly similar to this case. So as Dr. Linus Chung said, this has been my interest and I have published about it and I have been following the literature in this topic and I would like to share with you some of my points and I appreciate your comments at the end. I do not have any disclosure regarding these topics, but some of the information that I will present comes from the fourth edition of our textbook and selling this textbook I get a small royalty. So the objectives of my talk is this morning to discuss with you briefly about an overview of endometriosis and ovarian cancer, a few slides about our understandings of pathogenesis of these malignant transformations, and I spend most of my time on the chemical implication of these malignant transformations and how we could use it in our practice. You all know endometriosis is a very common disease in women, approximately 10% of the women estimated to have endometriosis, a specific characteristic of this disease is that it is a chronic inflammatory estrogen-dependent disease and typically has a high chance of recurrences and also it could be a progressive disease. We all know the main problem with these patients are chronic pelvic pain in the form of dyspnoea, infertility, abnormal uterine bleeding, and also organ dysfunctions in form of the ovarian dysfunction or effecting GI or GU symptoms and causes problems in this system, and also we know there is a malignant transformation of this disease, which has been known for many years. There are a lot of epidemiological studies done in the literature that shows these associations and this is a systematic review of meta-analysis, which was published last year, that shows there is a positive association of the endometriosis and risk of ovarian cancer, a standard risk ratio of 1.9 to 3, and specifically higher with the cheliceric carcinoma, endometriate carcinoma, and interestingly enough for other types of cancer like thyroid and even breast cancers. So, for the ovaries, we know that these, besides epidemiological data, histological data and molecular studies have shown this association and the link between endometriosis and epithelial ovarian cancer, and mostly endometriate clear cell and low-grade serous carcinoma, and also really other types of the carcinoma like endometrial stroma, sarcoma, adenosarcoma, and even TFLMT, they have seen this association between endometriosis and those cancers. So, what is our understanding of pathogenesis of this malignant transformation, and essentially based on three things. One, we call it somatic genetic mutation, inflammation, and hormonal. Somatic mutation means that endometriosis cells, which appears benign under the microscope, already harbor some molecular defects that ovarian cancer may arise from these areas. For example, loss of the heterozygosity has seen in chromosome 10, and in 56% of the patients with endometriotic cysts, and 20% of deep-infiltrated endometriosis or ovarian endometriosis have somatic cancer-driver genes. Inflammation is the hallmark of endometriosis, and loss of the cell regulation has been suggested caused by the inflammation in different pathways. One of them is that endometriosis implant produces pro-inflammatory cytokines, and persistent exposure to these factors causes disruption of the hemostasis and genomic instability, and subsequently long-term could cause abnormal proliferation. Also, macro-environment of endometriotic cysts, due to increased free ion and increased lipid peroxidase, causes a state of oxidative stress, and this exposure in the long-term could help the malignant transformation of endometriosis cells. Also, high level of the estrogen. In the ovary, of course, we have high level of the estrogen, and endometriosis implant itself has shown to have high aromatase activity, and actually the level of the estrogen in the endometriotic cells are significantly higher than even the serum, and this high level of the estrogen, both in the ovary or endometriosis cells in the peritoneum, causes the changes in the physiological prospect of this disease, causes proliferation, and by the continuation of proliferation is a chance of the DNA damage and abnormality of the cells. So if you put all these three together, that is our understanding that these endometriosis cells become malignant, and I'd like you to keep this thing in mind when we come later on discussing about the prevention and treatment of these patients. So majority of the malignant transformation of endometriosis in GYN has been shown to be in the ovaries. Again, it makes more sense because there is more estrogen there, and however, any endometriosis anywhere in the body is a possibility of the malignant transformation, and that has been shown after the ovary, the most common areas in the pelvis, on the fallopian tube, on the bowel, the vaginal septum, and even on the skin. In the patient that has caesarean, post-caesarean C-section endometriosis on their skin, malignant transformation, we have seen it. The risk factor for this malignant transformation, first of all, we don't know, unfortunately, at the present time, which patient developed these cancers, and we don't know. That is a problem. We know the patient with a long history of endometriosis, patients that have large endometrioma, patients that have had prolonged exposure to endogenous or exogenous estrogen, all patients that they have had previous hysterectomy and BSO, and they have had endometriosis, and they have gone on hormonal replacement therapy in form of the estrogen, they have had possibility of the malignant transformation of the peritoneal endometriosis. And of course, patients with infertility also has shown to have higher chance of the this malignant transformation. So, after this introduction, what is the clinical implication of this data? So, again, as I mentioned, the majority of these endometriosis transformations are from the ovary, and we focus on the ovary mostly. So, if you look for this group, there is no need to explain these slides. We know the general population risk of ovarian cancer by age of 40, by age of 70 is 1.4%. Patients with BRCA1 or 2, and patients with Lynch syndrome, they have higher chance of this malignant transformation. And we have some sort of a strategy in this patient usually do a salpingo-ophorectomy after a certain age, after they have finished their childbearing. So, patients with endometriosis, the risk of malignant transformation is not as high as BRCA1 or 2 or Lynch syndrome. The risk is 2 to 3%, which is twice of the general population. So, we do not recommend doing salpingo-ophorectomy in patients with endometriosis because the risk is very low, and most of these patients are young, and we don't want to cast So, what else we could do? How could we use this information? Again, for this group, I don't have to mention about the ovarian cancer. It's the second most common necrological cancer in the U.S. We have approximately 22,000 new cases each year, and unfortunately, we lose about 14,000 women each year to this cancer. And the average age of these patients are 63. And again, we know most of these patients at the time of the presentation are high-grade serous carcinoma or advanced stages. And look more carefully. If 70% of the ovarian cancer are high-grade serous carcinoma, they have poor prognosis, and the 30% of them all at the time of diagnosis are stage 1 or 2. Interestingly, 50% of these patients have had unexpected diagnosis, and they require another surgeon. And why is that? Exactly like the case that you presented. We looked several years ago in 76 patients with stage 1 ovarian cancer that they were completely staged. We looked at the clinical and pathological presentation of these patients when I was in Mount Sinai Hospital doing my fellowship. And we found that these patients, of these 76 patients, only 22 of them they were high-grade serous carcinoma. And majority of them, they were endometriate or clear serous carcinoma or mixed endometriate and clear serous carcinoma. And although the patient with the serous carcinoma, most of them they were asymptomatic, patients with endometriate and clear serous carcinoma or mixed presented with a pelvic mass, pelvic pain or abnormal uterine bleeding, exactly like it is the case today. And also when we looked at the patients besides the cancer, we found that the majority of the patients with endometriate, clear serous carcinoma or mixed, either they had ovarian endometrioma or pelvic endometriosis. And interestingly enough, we found that the patient with endometriate carcinoma, one-third of them, they had either endometrial carcinoma or endometrial hyperplasia or PADI. So they had synchronous tumor. And we all know about the possibility of the synchronous endometrial cancer and endometriate ovarian carcinoma. So the result of our study showed that non-serous ovarian carcinoma consists of two-thirds of our patients. And the serous patients, there were only one-third of them and they were mostly symptomatic. And this group presented with pelvic pain, abnormal uterine bleeding, and one-third of them, they had endometrial pathology. So these are the patients that they came to us and they had symptoms and then they were evaluated. And a lot of these patients are operated by non-GYN oncologists, like similar to this case that we presented. And the patient, they were not, the physician and the patient were not prepared for staging and they required to have another surgery. So this is a slide that I think we all should remember. If you look at the ovarian cancer and you look at the cell origin and the histology, the 10% of them are sex-coordinated stromal tumor, Jameson tumor, or mixed type of tumor. And these are the only 10% of this group. All of them, they have ovarian masses, they have specific tumor markers. Most of them, they present early stage and we treat them and they respond to chemotherapy well. The epithelial type of tumors, now we know there are two types. Type 2, which is the most common one, are high-grade serous carcinoma and differentiated are carcino-sarcoma. The molecular alteration of this group are P53 and most of these tumors arising from the fumarate or fallopian tube, especially fumarated end. And these are the tumors, as we all know, they don't have any specific markers. The cells drop the peritoneal cavity and the patient comes with ascites and carcinomatosis later. Type 1 epithelial ovarian tumors are low-grade endometriate and carcinoma, other ones, and the background of endometriosis, and they have a specific molecular alteration like KRAS, BRAF, for the low-grade one, and ARIDA1 for the chelicer or endometriate, which is very different than P53. So, if we keep these things in mind, now we understand that we have type 1 that's coming from the endometriosis and type 2 that's coming from the fumarated end. And that is the reason that we have not been able to find a screening test at the present time, because CA125, which is elevated or could be elevated because of the endometriosis and ultrasound is not helpful because we want to find cancer in earlier stage and high-grade cell carcinoma coming from the fumarated end. So, we don't have any screening at the present time, not only for the general population with a high-risk group and also patients with endometriosis, we do not have any screening at the present time. And if we want to develop any screening for epithelial ovarian cancer, we have to look for a specific molecular alteration of each histology and develop a screening for that particular one. How about prevention? What can we do to how to prevent as much as possible ovarian cancer transformation in this patient? We published this paper several years ago and classified the ovarian endometrioma, and the ovarian endometrioma are essentially two types. A small number of them, we call it type 1. These are endometrioma or a small one. It is very difficult to remove and these are real endometriomas. The majority of ovarian endometrioma are consistent of the functional ovarian cysts, mostly purposed luteum, which has been invaded by cortical endometriosis or type 1 endometrioma or pelvic sidewall endometriosis. and gradually this endometriosis has affected the function of this functional cyst and will not allow that this functional cyst by the end of the month disappears. And gradually this forms adhesions to the pelvic sidewall and this endometriosis affects the lining of the corpus tuteum. And when we as a surgeon operating and we lift up this endometrioma from the pelvic sidewall ruptures and we think we have ruptured ourself, but it is not us, it is the way that this endometrioma has been formed. So what does it mean? It means that if we put the patient in any kind of suppressive therapy that prevents ovulation and the patient does not form endometrioma, she would not develop ovarian endometriate Achilles sarcoma. That has been our practice for many years and the data in the literature clearly shows hormonal suppressive therapy that suppress the ovulation decreases the ovarian endometrioma formation. And again, we all know that a combination of oral contraception pills in the literature has shown very well decreases the risk of the ovarian cancer because it's a relative risk of the ovarian cancer formation by numerous studies has shown that decreases the risk of the ovarian cancers. So that could be one of the mechanism of the decreasing the risk of the ovarian cancer. And also, as I will discuss later, because of decreasing the risk of the retrograde menstruation. What else can we do? When we believe that whenever endometriosis or endometrioma is diagnosed, at the present time, the best method is to resect the endometriosis and endometrioma. And the endometrioma, no matter how small it is, if it has chance of malignant transformations, the smallest endometrioma that I have seen is two and a half to three centimeters in a 29-year-old patient. So we believe endometriosis has to be treated and the patient should be put on suppressive therapy in young women. This is a very interesting study, which was published by Mellon from Sweden. And they looked at the effect of the hormonal and surgical treatment for endometriosis on the risk of the epithelial ovarian cancer. And they looked at all the women with the first-time discharge diagnosis of endometriosis between the year 1969 to 2007 in Sweden National Patient Registry. And they looked at all the women that they diagnosed with ovarian cancer at least one year after the diagnosis of endometriosis. And they found that one-sided oophorectomy, which is involved with endometriosis using multivariate analysis decreases the risk of the ovarian cancer by 81%. And also, if you remove the endometriotic lesion completely, decreases the risk of the ovarian cancer significantly. So if you remember when I told you about the pathogenesis of this malignant transformation includes estrogen and inflammatory process. So we know that if you remove the estrogen production of these implants or the ovary, you could decrease the risk of the epithelial ovarian cancer in these groups of patients. So the other thing that I want to pay your attention is these studies of looking at two study of nurse-health nurses-health studies, looking at the role of tubal ligation, hysterectomy, unilateral oophorectomy, and risk of the ovarian cancer. These are the two prospective largest study. One is more than 120,000 women that between age of 30 to 35, and the other one, more than 111,000 cases between age of 25 to 42. And they look at the hazard ratio risk of decreasing the ovarian cancer in these patients. And you could see tubal ligation decrease the risk of the ovarian cancer by 24%. And non-serous was more than serous tumor if it is done before age of 35. If you look for the hysterectomy, it decreased the risk by 20%. Again, non-serous, more than serous type. And I will explain to you why is that. And we do oophorectomy, unilateral oophorectomy, decrease the risk by 30%. And here non-serous is equal to serous type. So tubal ligation decrease the risk of the endometriic carcinoma by 38%, chelicer carcinoma by 52%, and high-grade serous carcinoma by 19%. And the reason is that we believe, if you believe that endometriosis is the background of the endometriic and chelicer carcinoma, by doing the hysterectomy or tubal ligation, you prevent retrograde menstruation or transportation of inflammation from the vagina to peritoneal cavity. And that is the reason tubal ligation or hysterectomy has shown decreases the risk of the non-serous carcinoma more than serous carcinoma. So if we do salpingectomy, in patients that they are candidate for salpingectomy, and we discuss it later, not only we have decreased the risk of the high-grade serous carcinoma, which is the cancer coming from the fumigated end, also we have decreased the risk of the endometriate and chelicer carcinoma. We published this paper last year, and we looked at a study of the patient that underwent laparoscopy, and we looked for the incidence of the fallopian tube endometriosis, which is not very well known in the literature. And we had 444 patients, and all of these group, 153 of them, they had histologically diagnosed to have endometriosis in the pelvic cavity. And when we looked at the incidence of the macroscopically endometriosis that we saw by laparoscopy, they had typical endometriosis implant with the fallopian tube, or underwent salpingectomy, because they had salpingo-ophorectomy, or had hysterectomy, and we removed the fallopian tubes, or they had endometriosis, and the tubes, they were severely damaged, and we removed them. And we found that 42.5% of them, they had macroscopically, they had endometriosis. So endometriosis of the fallopian tube, it is not rare. And majority of these patients, they had severe endometriosis. So our suggestion was that patient that they have endometriosis, and you are operating on them, and if the tube is severely damaged, or they have finished the childbearing, and they are going to have operation for whatever reason, and you find endometriosis, we highly recommend to remove the fallopian tubes in this group, because you are going to decrease the risk of the epithelial ovarian cancer in these groups of the patients. So in summary, right now, regarding the role of the salpingectomy, we have two types. We have opportunity salpingectomy, that we recommend to perform instead of the tubal sterilization. Even if you do salarian section, and you want to do tubal ligation, we recommend to do bilateral salpingectomy. If you are doing the hysterectomy, definitely we recommend to remove the fallopian tubes too. And even other operation, even if you do myomectomy, and the tubes are damaged, and the patient is going to have IVF, we recommend to remove the fallopian tubes. And planned risk of use of salpingectomies are patients that they have BRCA1 or 2 mutations. And these are the patients that you don't want to remove the ovaries before the age of 35 to 40 for BRCA1 mutation, and for BRCA2 mutation, right now we recommend to remove the ovaries before the age of 40 to 45. We recommend you want to keep the ovaries for cardiovascular and benefits, and do two stages procedure, do salpingectomy first, after they have finished the childbearing, or you do salpingectomy and the patient feeds her eggs, and then later on we do oophorectomy. So, how about diagnosis? What else could we do to diagnose the endometriosis or malignant transformation early? And again, it's exactly similar to the case that was presented. As I said, whenever you have endometrioma, we recommend to remove the endometrioma, no matter how small it is, we recommend to remove them because most of those patients that have endometriosis are somewhere else, and you put them in suppressive therapy. However, if you don't want to operate on them and you have an endometrioma, watch for two things. One is, if the endometrioma is like this, and later on develop a neural nodule like this, exactly like your case was presented, and if there is a neural nodule, or the endometrioma all of a sudden become very large, these are the two characteristics of the malignant transformation of endometrioma. And this is, for example, a patient which was referred to me, this is an office ultrasound, you could see she has this nodule, and when I spoke to the patient, I had this nodule from the ovary, and this was endometriate adenocarcinoma. So, sometimes this nodule, the ultrasound, could be a blood clot, and you cannot differentiate between the real nodule or blood clots. In this condition, MRI is more useful to differentiate between a solid component in the endometrioma versus a blood clot. This is, for example, endometrioma with a small nodule, that could be a blood clot, but if we do an MRI, and the MRI shows this nodule, these nodules are more characteristic of the solid nodules, and the data has shown clearly this could be high chance of being malignant. And the other one is rapid growth of the endometrioma. This is an endometrioma, you could see the size of it, and has a nodule here, and nine months later, you could see this endometrioma all of a sudden became very large, and has this nodule, and when she was referred to us, and I scoped the patient, and this was a nodule which was malignant, and that was clear cell carcinoma. So again, two characteristics, a neural nodule in the endometrioma and rapid growth are the alarming condition. And we had excellent discussion regarding the management of these patients. The surgical section and the staging, it should be the first step, and we highly recommend that if you operate the patient, and the patient has any endometriosis lesion, as it was mentioned with one of the colleagues, definitely has to be removed, because those lesions later on could become malignant. And hopefully we could do molecular profiling to maybe find an actionable target. Endometriosis carcinoma, fortunately, they respond to chemotherapy very well. However, clear cell carcinoma, in my opinion, are two types. Some of them, they do not respond to chemotherapy, and this patient that you presented, she had three cycles of the chemotherapy during her operation. Obviously, whoever operated, maybe they didn't pay attention to those small lesions, but they didn't respond to that chemotherapy, and radiation seems to work better for clear cell carcinoma, and that has been, in my experience, and hopefully by doing molecular profiling, you could find a better targeted therapy, a immunotherapy for this group of patients. So in summary, I think this is the way we believe that all the patients with endometriosis has to be identified, and these patients has to also be followed. Fortunately, the malignant transformation is not as high, however, it exists. Even in the patient post-menopausal, that they have had, they have gone to menopause, and they have history of endometriosis, and sometimes they present to the gynecologist, and they are ignored, and then later on develop cancer, and they come to us as a GYN oncologist, and they have malignant transformation. And we recommend that patients that they are diagnosed surgically endometriosis, endometriosis, if they could tolerate on hormonal suppressive therapy, if they want to get pregnant, you should encourage them to get pregnant. And if the patient has endometrioma, and you don't want to operate on them, you do not let them go. You watch them carefully. It is not unusual in my practice that the infertility physicians, they have followed the endometrioma, even they have IVF on some of those endometriomas, and they have retrieved the eggs, and they later on found to be malignant. And in young patients, we recommend to have fertility preservation, freeze the embryos, and also egg freezing, or ovarian tissue preservation, because endometriosis, unfortunately, is a progressive disease, a lot of time, and could decrease the function of the ovaries. And we recommend to complete surgical resection of all endometriosis lesions during the surgery. And even if the patient has endometrioma, the drainage of the endometrioma is not adequate. Always you should take an ovarian cystectomy to be sure there is no pre-malignant condition on the ovaries. And when it comes to oophorectomy and hysterectomy or self-injectomy, every case should be individualized. And based on the patient's risk for malignant transfer, for the malignancy, and his desire and age past his infertility, we should consider self-injecting or hysterectomy or oophorectomy, based on the patient's age and his desire. So, and hopefully in the future, by understanding better of molecular alteration of different types of the cells of different histology, we could find better screening for this group of the patients, and we have better treatment for them. And these are the list of some of our publications, in case you are interested. Thank you very much. That was really excellent, Professor Nidjar. That was outstanding. Thank you very much. That was really...

endometriosis

ovarian cancer

chronic inflammatory disease

malignant transformation

risk factors

surgical removal

hormonal suppressive therapy