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A Study of the Omentum in Ovarian Cancer

Hackethal, Veronica

doi: 10.1097/01.COT.0000696440.28038.95
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ovarian cancer
ovarian cancer:
ovarian cancer

When Meg Wilkinson was diagnosed with stage II ovarian cancer in 2014, she had very mild symptoms. On ultrasound, her doctors thought she had a complex ovarian cyst. Her CA-125 was only slightly elevated. And, going into surgery, her oncologist told her she had strong odds of not having cancer. “I woke up from surgery to find out it was cancer. I was pretty devastated,” she said.

During surgery she underwent a complete omentectomy as part of the staging process, although her omentum was not found to harbor cancer. Since then, she has been plagued by digestive issues.

Her main symptoms include stomach distension, especially after eating salty meals or sitting for long periods of time. At points, her abdomen was swollen to the size of a 4-month pregnancy. She also has frequent bowel movements, about 6-9 times per day. Although she suffers from abdominal pain, she attributes it to scar tissue that constricts her GI tract and was formed after removal of her omentum.

“It can be quite miserable and very uncomfortable. It's like your whole inside middle is just wrong,” she said. “It's not like the 6 weeks after surgery swelling; it's a different type. I just don't feel good.”

When she first noticed symptoms, she visited her oncologist, who found no recurrence of cancer. When elimination diets and fasting failed to relieve her symptoms, she went to a gastroenterologist who prescribed IBS medications that made her feel worse. Finally, she found a second gastroenterologist and a lymphedema specialist who realized that her symptoms probably stem from removal of her omentum.

The Role of the Omentum

The omentum is a specialized fat tissue made of folds of peritoneum that appear to float on top of the intestines. It is subdivided into the greater omentum, which hangs down from the stomach, and the lesser omentum, which hangs down from the liver.

The word omentum comes from ancient Egypt, where priests examined it for signs of good or bad “omens” while embalming mummies. Hippocrates thought the omentum played a role in secreting and absorbing peritoneal fluids. And Aristotle called it a “fatty apron” that covers the intestines.

Even though the omentum has been known for nearly as long as recorded human history, it remains understudied. It took until the invention of the microscope in the late 1800s for scientists to realize that the omentum functions in protection (Gynecol Oncol 2013;131(3):780-783). The omentum can move around to surround and isolate damaged, infected, or inflamed areas of the abdomen. It can promote healing through angiogenesis, acting as a source of stem cells, and secreting fibrin or collagen (Oncogene 2019;38,2885-2898).

As a modulator of peritoneal homeostasis, the omentum plays a role in controlling fluid exchange. It also provides a storage place for lipids and a reservoir for immune cells. So-called milky spots within the omentum contain T and B lymphocytes, as well as macrophages and dendritic cells. As such, the omentum takes part in immunosurveillance of the peritoneal cavity and can either promote inflammation or tolerance to self-antigens (Oncogene 2019;38,2885-2898).

The Omentum in Ovarian Cancer

Physical proximity, lack of anatomical barriers around the primary tumor, and vascular and lymphatic connections all play a role in making the omentum the first site of metastasis for ovarian cancer, with a particular predilection for the milky spots.

That may make the omentum appear to be a risky organ when it comes to ovarian cancer, but some animal studies suggest the opposite. Some researchers think that the omentum “soaks” up tumor cells until it becomes overrun by them, and can no longer function in protection (Gynecol Oncol 2013;131(3):780-783). Others think of the omentum as a pre-metastatic niche. Ovarian cancer cells have a particular tropism for the omentum, they argue, and that plays a central role in promoting tumor metastasis (Oncogene 2019;38,2885-2898).

Various lines of research exist on the issue. Studies suggest that the fat cells in the omentum may provide a source of energy, angiogenic factors, and mesenteric stem cells that promote cancer growth and metastasis. In turn, ovarian cancer cells may re-program omental cells like adipocytes and fibroblasts, converting them into cancer-associated cells that promote tumor aggressiveness and metastasis. Another line of research concerns intraperitoneal macrophages, which may play a role in regulating tumor tropism for the omentum. The omental milky spots, in particular, appear to be a major source of intraperitoneal macrophages (Oncogene 2019;38,2885-2898).

Omentectomy in the Guidelines

Omentectomy for staging and possible therapeutic benefit has been included in ovarian cancer guidelines since the 1960s, after studies suggested that removal of the omentum was associated with improved outcomes.

Current updated 2020 NCCN Clinical Practice Guidelines in Oncology: Ovarian Cancer recommend omentectomy in newly diagnosed invasive epithelial ovarian cancer that appears to be confined to the ovaries or pelvis, along with lymph node dissection. They go on to recommend removal of all involved omentum in newly diagnosed invasive epithelial ovarian cancer involving the pelvis and upper abdomen (stage II and above), as well as resection of suspicious and/or involved lymph nodes.

However, the guidelines have not specified exactly how extensive removal of the omentum should be. While omentectomy remains routine in treating ovarian cancer, the extent of its removal may vary among providers.

Is Omentectomy Always Necessary?

Because removal of the omentum can result in surgical morbidity and longer-term problems with metabolism and peritoneal immunosurveillance, scientists are looking for ways to spare the omentum during treatment for ovarian cancer.

One thought is to investigate whether omentectomy is necessary in early-stage ovarian cancer. A recent study in China that included 245 women with early-stage malignant ovarian germ cell tumors (216 with stage I, 28 with stage II, and 1 with stage IIIA) found similar 10-year survival among patients with and without omentectomy (96.8% vs. 100%, p=0.340). Multivariate analysis controlling for potential prognostic factors showed that omentectomy and lymphadenectomy were not prognostic factors for survival, over a median follow-up of 6.5 years (Int J Gynecol Cancer 2019;29:398-403). However, germ cell tumors affect only a minority of women with ovarian cancer, up to 90 percent of which is epithelial in origin.

A review on epithelial ovarian cancer found that isolated omental metastases in early-stage disease are relatively rare. For women with early stage I epithelial ovarian cancer and grossly normal appearing omentum, the authors suggested that random omental biopsies rather than total removal probably suffice for staging. For women who are already planning chemotherapy, the benefit of removing normal appearing omentum is unclear, because these agents appear to be effective in treating microscopic omental disease (Gynecol Oncol 2013;131:784-790).

“Our literature review found that, at most, the risk of isolated metastases to the omentum ranges from 2 percent to 7 percent [in early stage I epithelial ovarian cancer]. Although low, this number is not 0 percent. It is notable that in cases of microscopic disease, chemotherapy seems to eradicate it. However, we fully acknowledge that given this data some practitioners would prefer to remove all tumor possible, even if it is microscopic,” wrote Alon Ben Arie, MD, and colleagues at Stanford University School of Medicine and Kaplan Medical Center in Rehovot, Israel.

The Omentum as a Therapeutic Target

Scientists are also trying to see if they can develop therapeutics that specifically target the omentum. The idea is that treating tumor cells that lie within the omentum could nip metastasis in the bud—and potentially spare the need for omentectomy.

“It's a promising area. If we choke it when it's just budding, we have a chance of success at controlling metastasis. We need to raise the attention of the scientific community about this line of research. Personally, I think it may be a good way of controlling metastasis,” said Xiaojing Ma, PhD, Professor of Microbiology and Immunology at Weill Cornell Medical College, with expertise in macrophages, tumor immunity, and metastasis.

Still, most research in this area consists of early-stage, proof-of-concept studies.

One recent study identified a unique subset of macrophages that lie within the omentum and may have therapeutic potential. In the study, researchers knocked out this subset of macrophages in a mouse model of ovarian cancer. Results showed that knocking out these macrophages greatly reduced metastasis, suggesting that they may have a causative role in ovarian cancer metastasis (J Exp Med 2020; https://doi.org/10.1084/jem.20191869).

The results provide fodder for the main therapeutic strategy in this area: targeting macrophages with vehicle molecules—particularly liposomes—that have been modified to deliver drugs that directly kill cancer cells, or molecules that elicit an immune response against them. The idea is that these vehicle molecules would be injected into the intraperitoneal space, where macrophages gobble them up and take them to the omentum, where they deliver their cargo.

“I think targeting the macrophages as a general strategy is really worth considering, although the key is how to be specific. You want to target only the local macrophages and not do it systemically. That's how we can control these cancer cells,” Ma noted.

For example, the subset of macrophages in this study express CD163+, which is found not only on macrophages within the omentum but also in macrophages in other tissues, especially atherosclerosis.

Another issue: about 70 percent of women with ovarian cancer present with more advanced disease, usually stage III. The above study did not look at distant metastases. Whether targeting macrophages can help women with advanced disease is a wide open question.

“This idea has not really been tried. Whether targeting tissue resident macrophages in the omentum can have a more distal impact at least in the peritoneal cavity—maybe even further—has not been looked at, but it should be,” Ma said.

Raising Awareness About the Omentum

Six years out from cancer treatment, Meg's numbers remain good. While her digestive symptoms have not resolved, she has learned to manage them. She controls her symptoms with the three Es: 1) Eat strategically (mostly low-salt meals cooked from scratch); 2) Exercise daily (and avoid sitting for long periods of time); and 3) Energize lymph flow (put your feet up at night, seek help from a lymphedema specialist).

In 2018, she founded the Omentum Project to raise awareness for other people living without an omentum. Ovarian cancer survivors who have had omentectomies could benefit from education, she thinks, particularly about their symptoms and how to manage them. A class and fact sheet provided at follow-up visits could be a start.

“I feel information empowers cancer survivors,” she said. “I think it's very important for oncologists to provide information to patients who have had their omentum removed.”

Veronica Hackethal is a contributing writer.

Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
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