All right, so hopefully if someone could let me know if you see my first slide which is just the title. Yes. Yes. Okay. So today I'd just like to speak to the group a little bit about how we are managing our cases of advanced vulvar cancer here at the University of Maryland. So throughout this lecture, I was going to just briefly review for the fellows the epidemiology and pathophysiology in both the United States and globally for vulvar cancers, review staging prognosis. I'd like to share with you two cases currently in our practice that I think are very interesting with valuable learning points, provide an overview of what we have available to us for systemic therapy and touch a little bit on how we approach radiation, and then guidelines for surveillance. So in the United States, as of our calculations in 2017, vulvar cancer is actually the second least most common gynecologic malignancy, second only to vaginal cancers. That equates to about 6,000 new cases annually and over 1,000 deaths per year. Worldwide, as of 2020 estimates, at least 45,000 women are affected by vulvar cancer to provide an age standardized rate of just under one per 100,000. There is a recent geographic distribution of the age standardized rates with dark blue representing the highest and lighter blue lowest rates and white areas with no data. So what has been happening over the 10 years? For most regions, we're seeing an increase in vulvar cancer incidents among all women, all ages. The most common histology that you will encounter is generally a squamous cell carcinoma, and that's three quarters of all cases. We have both HPV-mediated and independent pathways, so your HPV-mediated disease is going to present with classic or warty appearance. HPV-independent pathways are often related to vulvar dystrophies, lichen sclerosis, differentiated VIN. And then some people consider verrucous carcinomas, which are a subset of squamous cell carcinomas, to be sort of HPV-equivocal. There's mixed data. These tumors are special in that they're highly amenable to surgical resection. They rarely metastasize. And a long time ago, we actually used to avoid radiation in this population because we believed that that could, one, not be effective and maybe even lead to an anaplastic transformation. I think that theory has fallen a little bit out of favor. Our second most common histology is actually going to be melanoma, counting for 2% and up to 10%. We have basal cell carcinomas, which, again, are usually also not associated with any lymphatic spread. Adenocarcinomas are a minority of our diseases. There's Bartholin's gland cancers, Paget's disease of the vulva, and then rarely we'll see sarcoma. For the fellows, just a reminder of what the role is for the HPV E7 and E6 proteins in the pathophysiology of malignancy. Currently, we believe that E7 binds phospho-RB, leading to a dissociation of the E2F transcription factor, which then prompts progression through the cell cycle, increased P16. The E6 protein is thought to inactivate the P53 tumor suppressor and target it for proteasomic degradation. So this is currently the FIGO 2021 staging scheme for carcinoma of the vulva. And our early stage disease is highly amenable to treatment with a simple partial vulvectomy. But once we start getting deeper stromal invasion, it is important to incorporate lymph node assessment. In our practice, we frequently have a sentinel lymph node mapping procedure in conjunction with the radical partial vulvectomy. And you're going to choose your decision for a ipsilateral or bilateral gland dissection based off of whether or not your primary tumor is lateralized at least two centimeters or greater from the midline. The patients that I'll present today have more extensive disease. And for those cases, multimodal therapy is generally most beneficial. And so I'll show you what we've done for some of our patients past surgery with some different regimens, including immunotherapy. The five-year overall survival based on some older data for even stage 1 tumors may be as low as 79%, and for stage 4 tumors may be as dismal as 13%. So here at University of Maryland, which is located in downtown Baltimore, we do see a variety of vulvar pathophysiologies. So we have both benign and malignant disease. So we have a lot of patients who present rather late to care with pretty impressive tumors that they've been living with for a while. So this is just an example of a completely benign process that was resected several years ago in this patient here on the left. And more recently, a teenager who had extensive vulvar involvement by Crohn's disease. And here you can see that we've resected that. She has a seating catheter in place, and hopefully she'll have good quality of life from her procedure. But as a tertiary medical center in an urban and underserved population, we are frequently treating advanced HPV-related cancers. At our center, we have a very large transplant program, and so these patients are immunosuppressed. We also have a fairly large dominance of HIV in our patient population as well. You can see here that Baltimore is a bit of a hotspot within Maryland for HIV, and our prevalence exceeds that of the whole southern region of our country and United States in general. And this is important because studies have shown that women who are living with HIV may present earlier than those without HIV. And in this particular study by Butt and colleagues that included more than 900 vulvar cancer patients, they deemed that 50% of women living with HIV who presented with vulvar cancer did present in an advanced stage. We also know that HPV and HIV interact in a meta-analysis, which included 29 studies in over 1,200 patients of anal, vulvar, and vaginal cancers. By DeVuste and colleagues, it showed that 40% of vulvar cancers, in fact, harbor HPV. Some of the most extensive disease that I've encountered in my career has occurred right here in Baltimore, even for patients who have access to care. And so this is just a snapshot of probably the worst case of cervical cancer that has come through my practice. This is a woman who didn't seek care because of any bleeding or perineal pain. She actually had a gangrenous lower extremity, and this is what we found on exam. We think that altered T cell function probably underlies the susceptibility of women living with HIV to HPV. But unfortunately, even though we think that highly active antiretroviral therapies can reconstitute the immune system, the benefit on HPV-related disease is still conflicting. So my first case that I'd like to talk about is patient AA. When I first met her, she was 33. She is immunosuppressed by HIV. She also has a history of multiple sclerosis with very few flares. This is an example of her condylomatous disease that we first identified in April of 2018. She was embarrassed by her condition, so did not seek attention for years. So she underwent a radical vulvectomy and inguinal femoral adenectomy. She did have foci of cancer within the specimen. She had close margins, received radiation, but unfortunately, it was lost to surveillance until she represented with a vulvar ulcer, went to a patient first, an urgent care center, and was given topicals for a period of time, and then finally did resume care. Fortunately, her office-based biopsy showed recurrence by micelle carcinoma. So she underwent a right vulvectomy biopsies, and unfortunately, after that procedure, she had rapid recurrence of her disease. At that time, a PET scan showed some uptake in her external iliac lymph node, but we were able to biopsy this, and it was negative. She was offered an exenteration, but declined. So she was dispositioned to re-irradiation, and we are fortunate enough to have access to protons. I chemosensitized her with cisplatin and dispositioned her to maintenance pembrolizumab. Unfortunately, just this month, she was admitted actually for what we think now is a pembrolizumab-induced sensory motor neuropathy. So she presented with exquisite pain involving her upper and lower extremities, was seen by neurology, and this diagnosis was confirmed by EMG. She has since been dispositioned to high-dose steroids. She did have an episode of sepsis while she was here. This is what her previously radiated site looked like upon initial examination prior to debridement. And in these photos, I'm just illustrating a concurrent cystoscopy. You can see how thin the tissues are subsequent to the radiation necrosis. So far, her biopsies at the time of wound debridement just show H cell. So bringing back some of the guidance from NCCN, these are the available options for systemic therapy. And you can see for this patient, we've currently employed cisplatin chemoradiation as well as pembrolizumab in her care. So what is the data for immunotherapy for vulvar squamous cell carcinomas? So the results from the vulvar cohort of Keynote 158 included 101 patients all previously treated with a median follow-up of 36 months. Patients were dispositioned to 200-milligram flat dosing every three weeks for up to two years. And in this particular cohort, the authors described a response rate of close to 11%. Oops, I have reversed that. It was higher in the PD-L1 positive group, but still it provided only a median progression-free survival of 2.1 months and overall survival of 6.2 months. So we still have areas where we can improve treatment for this disease. You might have noticed a few slides before that we also have Smipumab available to us. And really, this is extrapolated largely from the cervix data. So Tewari and colleagues in 2022 published their experience in a phase 3 comparison of this agent versus single-agent chemo in platinum-exposed patients. They allowed into the trial women regardless of their PD-L1 status and regardless of whether they were squamous or adenocarcinomas on histology. And we observed a 26% objective response rate, again, higher in the PD-L1 positive group. And notably, regardless of PD-L1 status, this was still favorable over standard single-agent chemotherapy where the response rate was as low as 6%. There was also statistically significant benefit in overall and progression-free survival compared to the single-agent chemotherapy group. So this was actually my first case of Pembrolizumab-induced neuropathy to this extent. So in looking at the data, Farouk and colleagues published a meta-analysis of over 23,000 patients across 38 trials looking at adverse events from chemotherapy versus immunotherapy. In this meta-analysis, Pembrolizumab-induced neuropathy was quite rare, less than 4%, but significantly lower than the neuropathy that we experienced from chemotherapy. Traditionally, the natural history of this is to present anywhere from weeks to months after exposure to Pembrolizumab. And like most immune-related adverse events, steroids underlie the mainstays of treatment. Right now, she's been on a moderately high dose of steroids for about two weeks and has had significant improvement. And then quickly, and I realize I made too many slides for you all, this is my second case that I wanted to use for teaching. This is patient EJ. She was 39 when I first met her, and she is similarly immunosuppressed, but with an undetectable viral load throughout the entire duration of her cancer journey. So I met her back in September of 2019 when she was referred to me from a benign GYN with a diagnosis of VIN or H-cell. She did have a history of anal cancer and received chemo-radiation for that in an outside institution. So she was treated in that immediate setting with laser ablation and subsequently amicromod topicals. By July of 2020, her vulva looked very unhealthy, but biopsies on the left showed only chronic ulceration, and on the right, we did have a focus of H-cell. Upon reexamination in October, she did have biopsy-proven squamous cell carcinoma on the left. She had some delays to the operating room, but was offered a radical vulvectomy. She had grossly positive lymph nodes bilaterally, so she had a bilateral lymph node dissection. Because of the size at that time, I did request the assistance of plastics for gracilis flap closure. Unfortunately, she did develop a lymphatic leak and required lipidial glue embolization, which was successful in controlling her inguinal femoral leak. She had close margins, received radiation with cisplatin, experienced radiation necrosis, completed a course of hyperbaric, and then with the extent of the radiation necrosis, she underwent diverting loop colostomy. By fall of 2021, she recurred with quite extensive disease, and as you can imagine, this is positive for squamous cell carcinoma. She also had radiation necrosis involving the sacral area, as well as biopsy-proven squamous cell carcinoma within this wound bed. She did have a pelvic exoneration. We converted her loop colostomy to an end colostomy and urology assisted in essentially implanting her ureters into the distal limb of what had been the loop colostomy. Unfortunately, she had an enterotomy during that case and her postoperatively anastomotic leak for which she returned to the operating room and had a diverting ileostomy, which left her with short gut syndrome. She is TPN dependent. And then she fistulized the stapled end of the, I guess, wet colostomy to her mesh, and she needed bilateral nephrostomies for palliation. Before she even left the hospital after exoneration, she had biopsy-proven recurrence. For her pain, she underwent a hypogastric nerve ablation. And since that time, she's been on a variety of Pembrolizumab, Weakly Taxol, or Lotnib. And she's actually doing quite well. This is a picture from the office. She complained to me of some additional pain. So this is the sacral coccygeal area, and she is currently declining office-based biopsy. So we are talking about next steps in management. So looking at NCCN, these are the agents that we have employed so far for this patient. And just a little blurb about Erlotinib, which may or may not be familiar to the group. So Tarsiva is an EGFR, tyrosine kinase inhibitor. It's an oral agent. It was explored by Horowitz and colleagues in a phase two study. It's given at 150 milligrams orally every day. And in this study, they deemed a cycle to be 28 days. Their overall objective response rate was close to 28%, which is quite nice for this disease site. Progression-free survival was also favorable at 13 months. The drug was well-tolerated. Most of the toxicities were grade one and consisted of things like fatigue. This is also a drug that causes acne-form rash, other dermatologic complications, and diarrhea. They did have, built into their study, a translational endpoint looking at EGFR status by IHC and other molecular techniques. But unfortunately, none of those correlated with response. So how effective is Taxol? So this is a nice chart that's actually embedded within the referenced article that compares some of the reported response rates and progression-free survivals for various regimens. So in my particular patient, I used weekly Taxol secondary to some of her performance status barriers. But in this particular study, it was given at three weekly with a response rate close to 14% and a progression-free survival of 10.4. So I don't think I need to tell this group that the access to radiation therapy really varies greatly across the world. And we are lucky here in Baltimore, though, we do encounter these advanced cases that we have access fairly easily to our radiation oncologists. This is just a quick geographic distribution illustrating the number of radiotherapy machines currently available as of 2024 per million. And we use radiation therapy sometimes as adjuvant therapy or in patients who have very bulky and unresectable disease as hopefully a definitive treatment. Your doses can go really up to 70 gray. So for the fellows, again, I'm running over time, but I'd like to remind you of the four R's of radiation. These together explain why fractionation is important and can determine the success or failure of any treatment. So we have repair, redistribution, reoxygenation, and repopulation. So repair refers to the fact that the lower the dose, the higher the likelihood of repair of the normal tissues exposed to radiation. Therefore, tumor is likely killed preferentially. Redistribution alludes to the fact that radiosensitivity varies throughout the cell cycle. So if you expose cancer cells at different times, you're likely to catch them in different phases and hopefully, if not exposed first in a radiosensitive portion of the cell cycle with subsequent treatments, you will capture that. Reoxygenation refers to the fact that oxygen is important for the generation of free radicals during radiation therapy. Large tumors are generally very hypoxic at diagnosis, but with repeated treatments, there's less respiration, less demand in the damaged cells, capillaries open, and tumor is reoxygenated, which may aid in the efficacy of radiation. Drawbacks. So we have to be mindful that big breaks in fractionation do detrimentally affect the outcome. So each cell repairs at a rate inherent to its own biology or histology, but you really want to make sure that your patient stays on track with the scheduled fractionations. This is just a graphical illustration of what should happen with normal cells versus cancer cells with repeated exposure to low-dose radiation. This is a nice review article that I think is very useful for our benign GYN colleagues or internists who might be helping us to take care of our patients. So this is a white paper by Salani and colleagues, and this is a table that just illustrates the recommended intervals of surveillance for patients with HPV-related diseases such as cervical, vulvar, and vaginal cancer. For your high-risk or advanced-stage patients, you want to probably be laying eyes on them every three months for the first two years of their therapy. So in summary, vulvar cancer is one of our less common GYN malignancies, but it really does have the potential for substantial morbidity. Squamous cell carcinoma of the vulva has several distinct pathways of pathogenesis. Patients with immunosuppression are at particular risk for HPV-mediated vulvar disease and multimodal approaches that consist of surgery, radiation, chemotherapy, targeted therapy, and now immunotherapy are really going to be beneficial for your advanced cases.

advanced vulvar cancer

multidisciplinary treatment

immunotherapy

Pembrolizumab

lymph node involvement

HIV