Hormones Gone Mad in a Rare Type of Ovarian Cancer

Shannon Vits was 16 when her menstrual periods stopped in 2015. She wasn’t worried, attributing the problem to her athletic activity with the poms dance team, but after the season ended, her periods didn’t return.

She consulted her doctor; blood tests confirmed an elevated testosterone level and a pelvic ultrasound showed a small mass on her right ovary. Vits was referred to a gynecologic surgical oncologist, who ultimately removed the ovary after finding an 8.4-centimeter Sertoli-Leydig cell tumor (SLCT) there.

The condition, which is exceedingly rare, is thought to develop in hormone- releasing ovarian cells that build connective tissue (made up of different cells that can develop into more common ovarian cancer). Standard treatment is surgery, sometimes followed by chemotherapy.

“Short of a tertiary referral center (where specialists practice), any oncologist will see (just) a handful of malignant Sertoli-Leydig cell tumors,” says Dr. Steven A. Vasilev, a gynecologic oncologist in Santa Monica, California. “They will see many more benign (SLCTs), but those are still rather rare, too.”

After her surgery, Vits was monitored every four months with blood tests and ultrasounds. During a January 2018 follow-up, the doctor found a growth on her left ovary, along with a slightly elevated testosterone level. By March, the growth had almost doubled in size. The doctor removed it along with most of Vits’ left ovary, leaving enough of the reproductive organ to retrieve eggs for future in vitro fertilization.

“It was my first year in college, and I was getting used to being away from home — that threw me for a big loop,” Vits says. She missed five weeks of classes and returned just before final exams. The remainder of her left ovary was removed in July after two rounds of egg retrieval.

Those familiar with SLCT might have recognized the cessation of Vits’ periods as a symptom. Up to half of these tumors can stop menstruation by releasing testosterone. Elevated levels of the hormone can also sometimes cause the development of male characteristics, such as a deepening voice and facial hair.

Vits had something else in common with most others who develop SLCT: a young age. Unlike most ovarian tumors, SLCT is generally a young person’s disease, affecting women under 30. The fact that Vits’ mother had her left ovary removed in 1979 after receiving a diagnosis of a rare granulosa cell tumor might be meaningful, too: Both types of ovarian masses are stromal cell tumors that can be caused by an inherited mutation of the DICER1 gene.

A RARE BUT SERIOUS TYPE OF TUMOR

There are more than 30 types of ovarian cancer, classified by cell type. SLCTs likely arise from sex cord-stromal cells, which release hormones and build connective tissue for the ovarian structures. Both Sertoli and Leydig cells are typically found in the testes. Sertoli cells support sperm cells, and Leydig cells produce testosterone. Leydig cells are also found in the ovaries, where they rarely cause problems.

As a category, sex-cord stromal tumors make up 7% of all primary ovarian tumors. SLCTs represent just 0.5% of all ovarian tumors, making them a small percentage even of stromal tumors.

Almost all SLCTs — 98% — are found in just one ovary, and at surgery, 80% are considered stage 1 and have not spread. Patients with stage 1 SLCT tumors have a five-year survival rate of 92.3%, which drops to 33.3% at stage 2 or greater. Those with well-differentiated tumors — the cells in the mass look close to normal — have almost a 100% five-year survival rate compared with 77.8% for patients with moderately or poorly differentiated tumors, in which cells appear more abnormal and aggressive.

Women with tumors that are poorly differentiated or have heterologous elements (tissues from areas other than the cancer’s site of development, such as immature cartilage or skeletal muscle components) have a greater risk of relapse than those with well-differentiated tumors, who are usually cured with surgery alone, says Dr. David M. Gershenson, a professor of gynecologic oncology at The University of Texas MD Anderson Cancer Center in Houston. Tumors with a heterologous element have a relapse rate of around 20%, whereas poorly differentiated tumors — even early-stage ones — have a 50% to 60% risk of relapse. “The degree of differentiation is probably the most important factor in prognosis and risk of relapse,” he says.

Opinions differ as to whether an SLCT is cancer. The National Institutes of Health lists it as a cancer, and Gershenson agrees with that definition. “Essentially all SLCTs are malignant; none are benign,” he says — there are simply differences in their aggressiveness.

Dr. Kris Ann Schultz, a pediatric hematologist and oncologist and principal investigator and founder of the International Ovarian and Testicular Stromal Tumor (OTST) Registry at Children’s Minnesota, encourages patients to not think of SLCT in terms of cancer or not cancer but, instead, to consider any form of it to be serious.

THE DIFFICULTY OF DIAGNOSING AN SLCT

About 75% of SLCTs are diagnosed in women age 30 and younger. Between 30% and 50% of the tumors release testosterone, which in one-third of cases leads to symptoms of virilization, or the development of male characteristics — a deepening voice, enlarged clitoris, facial hair, decreased breast size and cessation of menstrual periods.

Some symptoms, such as hair growth and vocal changes, may reverse after treatment, but others, such as an enlarged clitoris and smaller breasts, may remain.

The tumor can also cause pelvic pain and swelling, fatigue and acne. “You don’t have to have all those symptoms, but if you have (any of) those symptoms and you see an ovarian mass, think of this,” Schultz says.

Jennifer Nickle, who was 43 when she received her diagnosis in 2015, did not fall into the expected age group. Perhaps that — along with the rarity of the tumor type — is why she received an initial misdiagnosis of early menopause, for which she was prescribed iron supplements for anemia.

She had already seen her doctor for a year because of mild pelvic pain, chronic diarrhea and fatigue, as well as her period ending. Unhappy with the continued symptoms, Nickle switched doctors in 2015. By that point, she felt a golf ball-size mass when she pressed on her abdominal area. Her new gynecologist could not see a mass on an ultrasound — it was blocked by what the doctor thought was a large fibroid — but it was visible on a CT scan. Surgery was scheduled to remove both ovaries and the uterus as a precaution.

Before surgery, Nickle’s doctor did a workup to learn more about the mass. She ordered a blood test to screen for elevated levels of a protein called cancer antigen 125, which can indicate ovarian cancer. Nickle’s levels were only slightly elevated, so her doctor ruled out that diagnosis. Patients like Nickle, who have symptoms of virilization, should also get their androgen and testosterone levels checked before and after surgery; rarely, estrogen may be elevated. “Even if they’re not displaying virilization, they still may have elevated levels,” Vasilev says. If an SLCT is not suspected before the operation but diagnosed afterward, hormone levels should then be checked to use as a baseline, he says; this must be done as soon as possible, before the patient leaves the hospital, because levels drop quickly after surgery.

During an operation, a surgeon may ask pathologists to analyze tumor tissue to help determine the type of disease. Even well-versed pathologists may not be comfortable making an SLCT diagnosis during surgery, but if they do suspect SLCT at that time, the surgeon can biopsy other areas or sample fluid to look for cell spread outside the ovarian mass; this staging process can affect the type of treatment a patient receives. It’s important that the tumor remain intact during removal, because rupture will advance its staging and require chemotherapy that may not otherwise have been needed, Vasilev says.

Unless a patient has a simple cyst, he recommends choosing a hospital over an outpatient surgicenter, which won’t be able to have a pathologist analyze tissue during surgery. Also, surgicenters have limited access to surgeons and pathologists who have experience with rare tumors.

Even in the hospital, not all gynecologists, OB/GYNs or oncologists have that experience. Gershenson recommends that patients see a surgeon who is a gynecologic oncologist for their tumor workup and removal, if possible, and get treatment from someone familiar with SLCT. “If somebody doesn’t have expertise in dealing with ovarian malignancies, a number of errors can be made with management of surgery,” he says. Not only can the tumor rupture, but an ill-informed surgeon may remove the remaining ovary and uterus even if it’s not involved in the illness, rather than perform fertility-sparing surgery, he adds.

SLCTs that some consider benign are often found incidentally, after treatment for some- thing else, Vasilev says. He estimates that in those cases, less than half of patients get the appropriate workup and staging. The concern in overlooking this, he says, is that a nonaggressive but larger SLCT could develop malignant features if left in place.

A GENETIC CONNECTION

Identifying any genetic mutations that contribute to an SLCT’s development and growth is important, according to Vasilev. In the near future, he says, a routine way to determine this may involve blood tests, done before surgery, to check levels of circulating tumor DNA. This kind of test, known as a liquid biopsy, analyzes the DNA shed into the bloodstream by tumor cells as they die, making it possible to identify mutations associated with the cancer. This testing is available now, and although it is not considered ready for routine use, its role is being evaluated.

In many cancer types, knowing which mutations are present can help doctors choose treatments that target those aberrations. These kinds of treatments are not yet available for SLCTs, but identifying a patient’s DICER1 gene mutation can help establish the diagnosis by process of elimination: “Gynandroblastoma is the only other ovarian tumor that is associated with this mutation at any significant frequency,” says Dr. Anthony N. Karnezis, a gynecologic pathologist and an associate professor at the University of California, Davis. Knowing that a patient has the mutation can also help advance research and show that family members should be screened with the help of a genetic counselor, he says.

An inherited DICER1 mutation, present in more than half of SLCT cases, is also associated with a higher chance of developing other kinds of tumors, including pleuropulmonary blastomas of the lung and masses in the thyroid, kidney brain and cervix. Because 80% of people born with the DICER1 mutation inherited it from their parents, Schultz says, other family members may also have the mutation. Screening protocols for various tumors are available to check family members with the DICER1 mutation, from childhood through adulthood. “For some, (the mutation) is an entry point into surveillance that can be lifesaving,” Schultz says.

For example, she says, one woman with a DICER1 mutation in the OTST Registry had her 3-month-old son tested. He was positive for the mutation and underwent lung imaging, which revealed a lung cyst. Surgeons found it was a type 1 pleuropulmonary blastoma and removed it before it could turn into a more dangerous type 2 or 3 solid tumor, requiring more treatment.

Nickle is negative for the DICER1 mutation, so her family did not need testing. Vits tested positive, as did her mother and maternal uncle.

Another recently identified mutation associated with SLCT is FOXL2, which does not appear in people who have the DICER1 mutation. Karnezis says that just two publications to date identified FOXL2 mutations in SLCT and more research is needed, but one study found the mutations in 19% of these tumors. People with this mutation receive SLCT diagnoses at a median age of 79.5, much later in life than those with DICER1 mutations.

In cases of SLCT, FOXL2 mutations are not inherited, so these patients do not need genetic counseling.

SLCT TREATMENT IS FINDING ITS WAY

In its clinical guidelines for treating SLCT, the National Comprehensive Cancer Network (NCCN) recommends fertility-sparing surgery in stages 1a to 1c and removal of the affected ovary in all other stages. If the risk of relapse is 20% or greater, Gershenson says, additional (adjuvant) treatment is considered. The NCCN suggests platinum-based chemotherapy after surgery in stages 2 to 4 and possibly stage 1 intermediate- or high-risk disease. Gershenson says there is no absolute standard, because no reported randomized clinical trials have been completed due to the extreme rarity of the condition.

Now, however, Dr. Jubilee Brown, professor and associate director of gynecologic oncology at Levine Cancer Institute in Charlotte, North Carolina, is enrolling women with newly diagnosed ovarian sex cord tumors in a study, GOG-0264, which will compare the effectiveness of various chemotherapy regimens, Schultz says.

The OTST Registry is also studying this tumor type, as is the International Pleuropulmonary Blastoma/DICER1 Registry. “The goals of both registries are to further understand what causes these tumors, how to detect them at the earliest possible time and how to treat them in the most effective way with the least toxicity,” Schultz says.

The most common chemotherapy regimens for SLCT are paclitaxel plus carboplatin and the regimen of bleomycin, etoposide and cisplatin, known as BEP. “In general, SLCTs are not that sensitive to chemotherapy. Chemotherapy is only moderately effective,” Gershenson says. A recent study in the Journal of Gynecologic Oncology showed that adjuvant chemotherapy for patients with SLCT had no clear benefit for early-stage disease but was associated with improved survival for those with advanced disease.

Patients whose disease relapses after primary treatment may get additional surgery followed by high-dose chemotherapy, although surgery may not be appropriate if the disease has spread widely. Clinical trials may also be options in those cases.

Radiation is not typically used instead of chemotherapy, Gershenson says, unless metastatic disease causes symptoms in a specific area and surgery isn’t an option. “We don’t have any meaningful information on immunotherapy for SLCT at this point,” he adds.

Based on her tumor’s characteristics and in-depth discussions with experts, Vits decided to forgo chemo- therapy. Although she had a second incidence of SLCT, it was not a recurrence but a new tumor, on which several pathologists weighed in. One said it was moderately differentiated, and another believed it was well differentiated. Her doctors recommended adjuvant chemotherapy, but Vits felt that because the tumor was completely removed, chemotherapy side effects were not worth the risk. She continues to get her blood and testosterone levels checked every four months and also undergoes pelvic and thyroid ultrasounds.

Nickle’s 12-centimeter tumor was poorly differentiated with heterologous elements, and she followed her doctors’ recommendations for three rounds of postsurgical BEP. She had a difficult time with the chemotherapy and has some continuing side effects that could be associated with that treatment, her surgery and/or menopause: chemo brain, swelling in her hands and feet, and elevated cholesterol and liver enzymes. She follows up with her local gynecologist every four to six months for lung and abdominal/pelvic CT scans and bloodwork.

Nickle said she’s learned not to ignore any symptoms, no matter how small. Her advice for those with a new SLCT diagnosis: Fully research chemotherapy before agreeing to it. She recognizes that the treatment may be why she hasn’t had a recurrence, and she does not necessarily regret receiving it, but she says, “I wish I had researched it a little more before jumping in. I was not fully aware of the side effects and problems I would have going through chemo.”