Talk about granulosa cell tumors. I have no relevant disclosures. So I think I show horses and zebras because today we will talk about the zebra of granulosa cell tumors of the ovary. While they are uncommon, and in fact, sex cord stromal tumors represent 7% of ovarian cancers, granulosa cell tumors represent the largest portion of that 7%. And that's what we'll focus on today. Please keep in mind that there are other types of sex cord stromal tumors, including Sertoli-Leidig cell tumors. And I'm not going to discuss those today. We treat Sertoli-Leidig cell tumors just a bit differently. And perhaps we can revisit that at a different day. When we look at the incidence of different types of ovarian cancer, what you'll see is that stromal tumors, while uncommon, really peak in the 30s and 40s. So they're very different from epithelial tumors. And these tumors are different from the standard ovarian cancer. They arise from sex cord stromal tumors and their precursors, and specifically granulosa cell tumors come from the sex cords. Typically patients will come in with symptoms typical of a pelvic mass. So sometimes pain, bloating, abdominal fullness, but with granulosa cell tumors, you can see excess estrogen or androgen production. So many times the patients will be hirsute. Sometimes they can be virilized. If they're very young, because sometimes these tumors do occur in young women, you can see isosexual precocious puberty. For women in their 30s and 40s, we see menorrhagia or metrorrhagia, and sometimes amenorrhea, depending on the hormones produced. Sometimes granulosa cell tumors happen in postmenopausal women. And there we see evidence of estrogen, like breast enlargement or tenderness or postmenopausal bleeding, or even thickening of the vagina in a patient who would otherwise have atrophy. Like this patient, preoperatively, a lot of times we see large masses, as you can see. And this shows that in fact, a PET scan sometimes will show granulosa cell tumors to light up. In these patients, we have to think about the consequences of estrogen. So abnormal uterine bleeding can prompt, and it should prompt an endometrial biopsy or DNC, because we often see hyperplasia or even cancer in these patients with granulosa cell tumors because of the estrogen that they produce. As Dr. Welsh showed, we see elevated inhibits, both A and B, and anti-malarian hormone. Sometimes we also see elevations in CA-125. So when we think about surgery in these patients, most patients, because of the size of the tumors, will proceed to exploratory laparotomy. Minimally invasive surgery, even though I'm quite the proponent of minimally invasive surgery, with granulosa cell tumors, and we'll talk a little more about this, but we use these only in the setting of disease confined to the ovary or to determine resectability most times. We want to obtain the diagnosis and determine the stage, determine what we will need to do to achieve complete or optimal cider reduction, and really the goal, these are surgically treated tumors. We have to achieve maximal cider reduction with the goal of no visible disease. Occasionally, we can't get everything out, and at that point, that would be a suboptimal debulking with over one centimeters of tumor remaining. In that case, we want to relieve the symptoms and stop. However, granulosa cell tumors are not as responsive to chemotherapy as epithelial tumors, so we really want to do our very best to get all of the disease out because we cannot rely on effective chemotherapy. So sometimes we can use minimally invasive surgery, but the goal is really removing these without rupturing the tumor and obtaining the visualization that you need. So really, and I don't often speak to open surgery, but I do with granulosa cell tumors if they appear to be extensive as in this patient. If the tumor appears to be confined to the pelvis, we do standard staging. Keep in mind, and I'll show you why, but staging does not include lymphadenectomy for granulosa cell tumors. We can, in young patients as in this patient, initially perform just the unilateral salpingo-oophorectomy in order to preserve fertility. However, in patients who have completed childbearing, we proceed with hysterectomy and removal of both tubes and ovaries. If the patient has bulky disease, of course, we do not need to stage these patients because then the goal is simply leaving the patients with no visible residual disease for the primary surgery. You've seen Dr. Welsh's great slides. Here are some additional slides. You can see here, call exner bodies forming, and that tends to be seen in granulosa cell tumors. There are multiple forms, including these trabecular forms or just, as you can see, these uniform cells with grooved nuclei. Most adult granulosa cell tumors are unilateral at the initial presentation, but they can be quite hemorrhagic and 30% show up with hemoperitoneum. These can recur many years after initial treatment, as you've seen with this patient. Juvenile granulosa cell tumors are quite similar. Most occur in adolescents and teenagers and can be more aggressive than the adult type tumor. Here we see CD31 stain that stains the blood vessels within the tumor. And again, just showing that these tumors are quite vascular and they stain positive for inhibin, as is seen in this beautiful slide. So let's talk about some of the surgical decisions that we make. Fertility is very important, and so we wanna discuss this with our young patients preoperatively. Typically, we perform a unilateral salpingo-oophorectomy of the abnormal mass, because of course at the first surgery, we don't know that this is a granulosa cell tumor. So we send it to pathology to determine what it is. And sometimes that's very difficult to determine on frozen section. So often when we're faced with that, we preserve the uterus and the contralateral normal appearing tube and ovary in young women who want to maintain fertility. However, if childbearing is complete, we remove the uterus, cervix, both tubes and ovaries, and of course remove any additional disease with, I keep saying this, but it's really important, no visible residual disease. Minimally invasive surgery has historically not been an option, but that's changing. We know that fertility appears to be safe and does not lead to much in the way of infertility. There does appear to be some risk of early menopause. And now, of course, we have additional options for assisted reproductive technology in these young patients. Very important, fertility preservation does not refer to just a cystectomy. There are no data about this. And so we definitely remove the entire abnormal tube and ovary. This is reflected in the NCCN guidelines. And I mentioned before that we do not need to do lymphadenectomy, and this is why. We looked at this in 2013 and found 257 evaluable patients in our retrospective review. None of those patients in whom lymph nodes were removed had positive nodes. We determined that lymph node metastasis was extremely rare in sex cord stromal tumors, and so it may not be necessary to include routine lymphadenectomy in the staging of granulosa cell tumor patients. This has been confirmed by other authors and is now reflected in the NCCN guidelines. Briefly, we really want to avoid rupturing granulosa cell tumors because in other types of tumors that are very chemosensitive, you can get away with treating them with chemotherapy and reducing their risk to an unruptured case. However, that is not true in granulosa cell tumors. So the literature is a little bit variable, but the bottom line is you want to avoid rupture. In general, minimally invasive surgery is safe, but do what you need to do to do the adequate surgery without rupturing the tumor if possible. Now, in this patient, you see she's had multiple secondary cytoreductive surgeries and actually this is another view of her CT, and here's a mass that you see here that's recurrent granulosa cell tumor. We looked at this 10 years ago and found that of all of the secondary cytoreductive surgeries that we did at MD Anderson, 75% were considered optimal with a median progression-free survival of 33 months and an overall survival of 170 months from the time of that secondary surgery. Patients that led to a better outcome were a single site of disease and the progression-free survival for those patients was 46 months, whereas for multifocal disease, it was lower at 31 months. Two-thirds of patients had multiple cytoreductive surgeries just like this patient, but what we saw was that the median progression-free survival decreased with each subsequent surgery. So basically, patients did well for longer upfront and then with subsequent surgeries, that length to recurrence shortened. So the take-home points, fertility-sparing surgery is important for young patients. Preoperative counseling and oncofertility is important. We save the uterus and contralateral tube and ovary when we can. You do not need to do a lymphadenectomy which is an obviously visible abnormal node. We try to avoid rupture and minimally invasive surgery is safe in certain circumstances. When we look at adjuvant therapy, the original studies were tiny, as you see here, basically case reports of two patients, seven patients, two patients, all with platinum-based therapy. But what you see is the utility of platinum. Nicoletta Colombo looked at bleomycin, vincristine, and platinum and found nine of 11 responses, but severe toxicity. And this led Dr. Gershenson to look at bleomycin, etoposide, and cisplatin. In nine patients with advanced stromal tumors, he found an 83% response rate, but only one of seven patients had a durable remission. And this became the standard of care largely due to GOG-115. It looked at four cycles of BEP. The initial regimen yielded two fatalities based on bleomycin toxicity. So this was modified to the regimen that you see. So it's very important to use the amended regimen of bleomycin to avoid that toxicity. Here's one way of giving BEP chemotherapy, though there are multiple methods. We looked, therefore, at the activity of taxanes in these patients. And what we found was substantial activity both in upfront and recurrent disease. And we compared this with BEP and basically found no difference in progression-free survival or overall survival. There were equivalent findings in recurrent disease, but the presence of platinum was really important. And so that led us to just recently present GOG-264 at this year's IGCS. This was a trial of paclitaxel and carboplatin versus bleomycin, etoposide, and cisplatin in patients with either newly diagnosed or recurrent chemo-naive stromal ovarian cancers. Patients received either paclitaxel carboplatin or BEP with the primary objective of progression-free survival. 63 patients accrued at the interim futility analysis, evenly split between taxel carbo and BEP. 87% of these were granulosa cell tumors, so clearly we can apply this information to this patient. The DSMB closed this trial early for futility of paclitaxel and carboplatin. This was supported by 21 events on paclitaxel carboplatin versus 16 events on BEP with a hazard ratio of 1.12. What that means is that even if we continued the trial for the second half, there was no way that there was going to be a definitive superiority result. The arms were well-balanced, and what we found was that BEP showed a median progression-free survival of 19.7 months. Paclitaxel carboplatin showed a median progression-free survival of 27.7 months. And as you see, here's the hazard ratios from a stratified model, where the hazard ratio is 1.12, falling within that futility region. So even though it looks like paclitaxel carboplatin is almost better, you really can't say that. What you can say is paclitaxel and carboplatin failed to improve for progression-free survival in ovarian sex-scored stromal tumors compared to BEP, but it did show a more favorable side effect profile. And so what that means to me is that both of these regimens have activity and can be used. And so I think that the take-home from this is that it really, based on the side effect profile, defines paclitaxel and carboplatin as the upfront treatment that we would use, but BEP can be utilized for a second active regimen. Other regimens have been looked at as well. Burton published paclitaxel. It was initially an all-comers trial, but basically was used only for recurrent disease and paclitaxel does show activity. We looked at bevacizumab based on the angiogenic profile with overexpression of VEGF and very vascular tumors. And we initially anecdotally found activity of bevacizumab. Subsequently, we looked at GOG251 in recurrent sex-scored stromal tumors and in 36 patients found basically a clinical activity rate of over 90%. So this met criteria to declare this agent active. This was our progression-free survival and the median overall survival was not reached. There is a current trial looking at bevacizumab with paclitaxel in recurrent disease. As Stephanie mentioned, FOXL2 mutations do occur and are pathognomonic for granulosis cell tumors. And so our take-home messages, fertility-sparing surgery when desired, routine lymphadenectomy can be admitted, minimally invasive surgery is acceptable if you're not going to rupture the tumor and can remove it intact. The goal is to remove all visible disease and paclitaxel and carboplatin and BEP are both options, but paclitaxel and carboplatin is less toxic. We know that secondary tumor-reductive surgery is appropriate sometimes many times like this patient and that the chemotherapy options in both upfront and recurrent disease include paclitaxel, carboplatin, and BEP, but there are other systemic therapies that we can evaluate, including bevacizumab with or without paclitaxel, hormonal therapy, and radiation therapy. We can surveil our patients with inhibins, anti-malarian hormone, CA-125, and of course, pelvic examination and directed imaging. And that's all I have. Thank you very much. That was a phenomenal overview of granulose sultan. Thanks. We have just a minute or two for questions. Well, not much, but any thoughts or?

granulosa cell tumors

sex cord stromal tumors

ovarian cancers

surgery

chemotherapy