Is a Breakthrough in Ovarian Cancer Possible? Why Salpingectomy is not the solution.

The United States is a great country for research because funds from different sources periodically become available to solve difficult challenges. Regarding cancer, whenever money is available, studies of ovarian cancer are immediately awarded funds in an effort to improve the dismal prognosis of this disease. We saw this when the SPORE and the MOON SHOOT programs were rolled out. However, in spite of all the money invested, significant progress, directly related to these programs, has not been made in ovarian cancer. The new program is the Break Through Cancer. This program has an impressive list of a Board of Directors, and a Scientific Advisory Board. This is the usual structure for awarding funds; however, is it effective? With this approach, the SPORE and the MOON Shoot programs failed in ovarian cancer. What is the reason? We cannot fix a problem that we do not understand. Is ovarian cancer aggressive because it starts in a hidden place, and it is difficult to detect, or is because it is a different type of cancer. I believe that both statements are correct. We are all familiar with the first one but not with the second. In the book Fere Ex Nihilo, I present all the facts that lead me to believe that ovarian cancer is different from most epithelial types of cancer and that understanding this difference is key to making progress.

One of the projects awarded by the Break Through Cancer is: Intercepting ovarian cancer, which is based on opportunistic salpingectomy. There are several reasons why this project is not the best solution to improve ovarian cancer.

1. Salpingo-oophorectomy to prevent ovarian cancer has been tried 40 years ago in cases of familiar ovarian cancer. Since the ovaries were also resected, this approach should have been more effective than salpingectomy alone; however, this practice was abandoned because, in 3 to 5 years, up to 10% of the patients develop peritoneal carcinomatosis, even when there was no tumor in the ovaries or in the fallopian tube. Resecting only the fallopian tube the proportion of peritoneal carcinomatosis could be higher. In the studies where salpingo-oophorectomy was done 40 years ago there is no mention of the morbidity issues, that for sure was created by the removal of the ovaries. Studies of the benefits of RRS with a follow-up shorter than 5 years should not be published.

2. Salpingectomy has been proposed to prevent ovarian cancer without studies of the complications that this surgical operation might have.How safe is to resect an organ that does not have its own vascularity? To resect an organ, we need to cut the main vessel supplying blood to this organ; however, there is not fallopian tube artery, the fallopian tube receives the blood from the ovarian and uterine arteries, would it be possible to resect the fallopian tube without damaging the blood supply to the ovary? Some studies have shown that after RRS only, some of these patients appear to show menopause symptoms.

• These symptoms can be uncomfortable, but the associated metabolic abnormalities could be life threating. Studies with no information about the possible morbidities due to ovarian failure, after only RRS, should not be accepted. 3 3-The origin of ovarian cancer in the fallopian tube is a controversial issue. It was proposed and questioned by the same researcher. Opportunistic salpingectomy to remove the origin of ovarian serous cancer has been proposed based on the studiesof Dr. Crum who in 2006 reported that most high-grade serous carcinomas originated in a STIC. He hypothesized that Pathologists had not noticed this before because the fallopian tube had not been properly studied. However, after careful examination of additional cases, Dr Crum said in 2015 that STIC is only seen in 40% of the cases, and that, therefore, another explanation was needed for the origin of ovarian cancer because most cases could not have arisen from the fallopian tubes sine no lesion is found in them.

  
  

  4. Most high-grade serous carcinomas involving the ovary are seen mainly in the medulla, not on the surface. If they originated in the fallopian tube, how the tumor cells got inside the ovary? Since 2006, when this theory was proposed the ones defending this theory have not been able to show one image that suggests how the tumor got inside the ovary. Nice diagrams have been proposed but could have not been proved with real images.

  5. It has been shown that hysterectomy alone also has an effect on the development of ovarian cancer, oophorectomy is the most effective. Salpingectomy is also effective, not as good as oophorectomy but a little better than hysterectomy. However, none of them have a 100% prevention of subsequent peritoneal carcinomatosis.

  6. Probably, the most important pressing and challenging issue we face is to first understand the problem before proposing a solution.

  
  

  There are two very important concepts that are necessary for understanding serous ovarian cancer:

  1. Serous tumors of the ovary are a family of neoplasms; they are all related. Serous borderline tumors are seen in most cases of low-grade serous carcinoma, and cases of high-grade serous carcinoma can be seen associated with serous adenofibroma, low-grade serous carcinoma and even in cases of serous borderline tumors. A theory that explains how one serous neoplasm develops should also be able to explain how the other types of serous neoplasms develop.

  2. The second important concept is that ovarian serous neoplasms are, like most cancers, multifocal and multicentric diseases. Multicentricity in cancer is very important, and this is the reason why, in most cases of cancer, the entire organ is resected or, after the resection of the tumor, the rest of the organ is treated with radiotherapy. The problem with ovarian serous tumors is that they do not involve an organ; they involve a system, the Mullerian system, the primary and secondary systems, which include several organs. The primary Mullerian system includes the fallopian tubes and the uterus. The secondary Mullerian system includes all the parts of the body that derive from the mesenchyma of the celoma; these are the ovaries, and the peritoneum, including the submesothelial tissue, which is under the mesothelium in the abdominal and pelvic cavities, and it also forms the framework of the lymph nodes. To understand ovarian cancer, we need to consider the entire Mullerian system as equivalent to one organ. Then, applying the concept of multicentricity, it will be easy to understand why serous neoplasms can be primary in the ovary, or in any part of the Mullerian system, including the fallopian tubes, the peritoneum, or in some unusual cases in the lymph nodes. This explains why, in serous carcinomas it is difficult to find stage I cases, or why recurrences are frequently seen.

  
  

  It is easy to understand multicentricity in serous lesions when we review benign lesions, which cannot be metastatic, and therefore, multicentricity is the only explanation. The best example is endosalpingiosis. The most frequent site of involvement for endosalopingiosis is the ovary, but it can be found in all the different parts of the primary and secondary Mullerian systems.

  
  

  Once we accept this concept of multicentricity for endosalpingiosis, the same concept should apply to the implants of serous borderline tumors, and to the lesions of low and high-grade serous carcinomas. It is very interesting that, at least at the beginning, the sites of involvement of serous lesions are always the same. These are the ovaries, the omentum, the submesothelial space of the uterus, the fallopian tubes, the rectosigmoid, and the appendix.

  
  

  It is remarkable that these are also the most common sites of involvement of endometriosis and endosalpingiosis, and often these benign lesions are seen near areas of serous tumors in 96 % of serous borderline neoplasms, in 47 % of low-grade serous carcinoma, and in 25 % of high-grade serous carcinoma.

  
  

  STIC is seen in some cases of only high-grade serous carcinomas as an early lesion because the fallopian tube is the only part of the Mullerian system with a serous epithelium; it does not need the metaplasia necessary in other parts of the system.

  
  

  In the book Fere Ex Nihilo, chapter 7, Peritoneal Serous Tumors: Metastases vs Multicentricity, I have included 42 images that support multicentricity.