Okay, so thank you for the case presentation that is related to this talk, so I would like to talk on the vaginal intraepithelial neoplasia review. So the talk will be based on this study. It's the European Society of Gynecological Oncology, the ISSVD, the European College for the Study of Bowel Disease and the European Federation of Corposcopy, consensus statement of the management of vaginal intraepithelial neoplasia. This one was published, I think, last year in 2023, and as from after this paper, I didn't see any other updated review after this. So the vaginal intraepithelial neoplasia is difficult to diagnose and manage and has substantial potential to evolve to invasive cancer. It is a rare disease, but as some patients are at increased risk, so knowledge of the epidemiology, natural history, diagnosis, and treatment of VAIN is highly important for prevention of invasive vaginal cancer. So the recommendation was from systematic review in the year 2000-2022 from 54 studies related. So in 2011, the first corposcopic terminology of the vagina was published, and although the use of corposcope is essential for the diagnosis of VAIN, and if you see the corposcopic terminology of CIN, we had it for a long time. But the first one for VAIN was in 2011, and it distinguished type 1 as minor and type 2 as major finding, a typical and fragile vessel and lesion with an irregular surface in isolation as suspicious for invasive cancer, and as from this publication. So from the corposcopic terminology in 2011, the reliability of the terminology and vaginal corposcopic terminology is between 70 and 82%, and to increase the reliability of the pre-biopsy corposcopic diagnosis, investigators proposed to add a microbacterial pattern category and negative glucose iodine solution test, or as we call, shearless iodine test, to the abnormal corposcopic findings. A course of local estrogen therapy is given to post-menopause women, as it may help to distinguish between the benign mimics of atrophy and the true pre-neoplastic changes. For consistency, in contrast to the cervical corposcopic terminology, pattern of VAIN and histopathology has been reported to be less accurate, I mean, compared to the cervix, and histopathology has been reported to be less accurate, with the vaginal histopathology frequency being worse than what was anticipated by the corposcopic inflation. So for epidemiology and etiology of the VAIN, actually, as we talked previously, that the VAIN is a rare entity, but for now we have the patient quite a lot, right? And the incident was 0.222 per 100,000 women per year, accounting for 0.4% of the female lower genital tract pre-malignant lesions. And compared to VAIN, it is 100 times less frequent than VAIN. The patient was increased risk a little bit until the age 70 to 79 years, and increased with the advancing age, until at this age, like 70 to 79, the incident was around 1.5 per 100,000. So as we know that the large majority of vaginal neoplasm are HPV-associated squamous cell carcinoma that develop through VAIN, and VAIN1 or vaginal lobe-glazed lesion associated with both low-risk and high-risk HPV genotype, and VAIN2 and 3 of vaginal high seal, the most common genotype involves HPV16, 33, and 45. So this is people who have higher risk for development of VAIN, like history of cervical cancer or cervical high-glazed lesion, history of hysterectomy for cervical high-glazed lesion, as we talked previously. This is one thing that we need to be concerned about, like in the past, some doctor would like to do hysterectomy when they find the patient with cervical high seal. And this is the thing that we need to keep in mind, that sometimes we do the hysterectomy, but when they still have their personal HPV infection, they will have the VAIN after that. So moreover, people with previous irradiation for gynecologic cancer, people with immunosuppressed postmenopausal, and also in the past that we use the DES or Diet-2-Stilbestrol, some people who have exposed for the DES will be at high risk. So for critical aspects, the VAIN is an underdiagnosed disease due to the absence of symptoms. For cytology, most vaginal lesions are diagnosed as a result from abnormal cervical screening tests or abnormal vaginal screening tests. Individuals who have a positive cytology in the absence of cervical pathology should be surveyed for the presence of vaginal lesions. Cytology is quite sensitive, like the sensitivity is around 67 to 76% and more reliable than corposcopy for detecting vaginal lesions. When combined with the high-risk HPV test, this can improve detection accuracy up to 95%. For corposcopic assessment, because often no cross-identifiable lesions in the vagina during visual inspection, therefore the examination of the vagina using a corposcope is essential. It requires not only the usual application of 5% acetic acid. It must include a complete visualization of the vaginal walls and pores. The vaginal pores may make it difficult to detect or suspicious areas. When undertaking an exam, it is important to rotate the speculum with the blade open through 360 degrees. Like in this picture for the posterior vaginal wall, sometimes there are many pores around this and the lesion may be inside the pores that we need to see clearly. Corposcopic assessment of the vagina is complicated by several problems. For example, the field to be examined is large because for the cervix, we will try to look only at the cervix and the transformation zone, but the vagina is like the whole of the area, so it may be large and hard to find a lesion. It is difficult to see most of the changes at the ankle after hysterectomy, and the corposcopic pattern can be less specific than in the cervix. Following hysterectomy, affected areas may not be readily visible at the oversized vaginal walls, including the lateral dog ears from hysterectomy after the hysterectomy. The pre-invasive disease is often multifocal, and it is important to differentiate low-grade lesions from truly pre-malignant lesions or high-grade lesions so that we can avoid overtreatment. This one is a cervical high-grade lesion extending to the anterior vaginal walls, and it may be a bit hard to see. Similar to other sites, atypical and fragile waste cell and lesions with an irregular surface and isolation are suspicious for invasive disease. This one is an invasive cancer at vaginal cuff after hysterectomy for cervical high-grade lesion. The application of glucose iodine solution or Shuler's test is important in the corposcopy of the vagina. I think maybe in Nepal, normally when you do the regular corposcopy, you use both acetic acid and glucose solution, right? But in many countries, like in my hospital, generally when they do the cervical corposcopy, we use only the acetic acid. We don't use the glucose iodine. So sometimes for corposcopy of the vagina, we need to use glucose iodine as well. Corposcopically, VAIN may present as iodine negative epithelium only, similar to what is observed on the cervix in some cases. In postmenopausal patients with a marked atrophy of the vaginal mucosa, the interpretation of Shuler's iodine test may be difficult. So sometimes we need to do the application of topical estrogen for up to three to four weeks before the exam is recommended for the postmenopausal women who has a very atrophic of the vagina. Histology obtained by the biopsy is the gold standard for the diagnosis. And this is the VAIN, or vaginal III, or vaginal high-glazed lesion. After application of acetic acid and after stain of the glucose solution, you can see this area of unstained glucose solution, we see it better than for the acetic acid. For management, actually there is no unanimous agreement on which is the best method of the treatment of VAIN. The choice of the treatment depends on the number one characteristic of the patient, right? Age, parity, immune status, sexual activity, the type of lesion, like severity and the site of lesion, extent of the disease, multi-centricity, and also previous treatment, like treatment of VAIN, hysterectomy for high-glazed lesion of the cervix or previous irradiation. The low-glazed or HPV changes, VAIN1, or for now in some study, they call it vaginal low-glazed lesion. It is low risk. Consider expression of HPV infection with a low risk of progression and a high potential for spontaneous regression. So spontaneous regress without any treatment is around 50% to 88% of the cases. Lesion not associated with high-glazed lesion of cervix or vulva tend to have higher spontaneous regression, right? Almost 90%, like around 90%. Then those associated with the cervical or vulva high seal, that will be around 67%, suggesting of the different biologic behavior. For high-glazed or what we call high-glazed lesion of VAIN2 or 3 or vaginal high seal, have pre-malignant potential and should be treated. The progression without any treatment, progression to invasive cancer, ranging from 9% to 50% of the cases, up to what study that they do. For modalities of the treatment, in the past, we always used traditional methods that, like, for example, vaginectomy and vaginal radiation therapy, and now they're used only in the highly selected cases of extensive and persistent disease, both treatments cause significant morbidity and greatly worsen the quality of life. So for now, more conservative options, such as local excision, laser ablation, and medical therapy with topical agents are useful as first-line treatment, especially in the young patients and for multifocal disease. Aim to maintain a functional anatomic structure, preserving the elasticity and extension of the vagina. Each treatment modality has advantages and disadvantages to be discussed with the individual patient. So for surgical intervention that we can use, this can be excision and ablative technique. For excision, while local excision is associated with the lowest risk of recurrence, but it is limited in applicability because the squamous intraepithelial lesion of the vagina is frequently multifocal. So the reported residual disease rate after excision ranges from 8% to around 20%. The success rate after surgical excision is high, ranging from between 66% to 80%. And partial upper vaginetomy is considered a treatment of choice in high-grade lesion at the apical part of the region of the vaginal calf scar. And in case of multifocal lesion, or those that involve the lower one-third of the vagina, in case we want to do, we may need to do upper vaginetomy and combine with a laser vaporization. For excision, for a total vaginetomy, it is not an advisable procedure because it makes sexual intercourse impossible, and thus it must be reserved for exceptional cases when the spread of recurrent lesion cannot otherwise be managed, or in case of a short vaginal processed rectomy. For the lip, it is not a treatment of choice for vaginal lesions due to the difficulty in controlling the depth of the excision, and it may cause injury to the adjacent organ. The major disadvantage for using for ablation, the major disadvantage for the treatment of VAN is the risk of missing and invasive cancer by the ablation because we don't get the tissue for diagnosis. Since they do not provide a tissue specimen, and occult invasive cancer has been reported in 2.6 to 30% of patients, special attention is needed in patients with prior hysterectomy for cervical high seal extending to the upper vaginal valve scar. In these cases, most of the time the bury of the residual lesion cannot be reached by the local abrasive treatment. For this lesion, abrasion should not be performed if the entire area of abnormal epithelium cannot be visualized, or if there is any suspicious of invasion on corposcopic assessment with multiple biopsy recommended before ablation to rule out of an invasion. For example, this one is the vaginal high seal that was inside with the vaginal scar. For ablation, an attempt should be made to achieve depth of destruction to include epithelium affected by VAN because it's directly related with the outcome of the treatment. There's a study found that the thickness of the lesion was generally less than one millimeter for patients of all ages, except in rare cases of visible lesion with papillary hyperplasia. The mean thickness of the epithelium involved was 0.4 millimeter, and it did not differ between the grade of VAN. The CO2 laser vaporization can be performed under local anesthesia. Epithelial destruction to a depth of 1 to 1.5 millimeter, including the zone of thermal necrosis, seemed to be sufficient to destroy the epithelium-containing SIL without damage to the underlying structure. There's a report of 65 patients who were treated by laser vaporization, and they found that the cure rate is between 73% and 86%. The disadvantages of laser vaporization include an inability to treat debris of the vaginal cup epithelium and a technical difficulty in applying the laser to the distal space with the vaginal folding. Electrocoagulation has also been used in some place in the therapy of the VAN. A diatomy can reach and control the desired depth of ablation of 1.5 millimeter. However, it is less precise than the laser. And yesterday I was just has a case or I just like to show some picture that this is like the laser that we connect to the corpuscopy, and we can do it through corpuscopy and it will be kind of like a bit burned in a version of the patient. So in Thailand, we do it under anesthesia. So for medical therapy, the one that we use the most is Imiquimod, but there's few data for other medicine. So for Imiquimod, it is an immune response modifier that induce cytokines, which stimulate the activity of natural killer cells, promote maturation and activity of Langerhans cells and increase the effectiveness of T-cell-mediated response. Being proved useful in the treatment of VAWA, intraepithelial neoplasia, so Imiquimod has recently gained much interest for the treatment of vaginal lesion. A very low dose regimen of 5% Imiquimod once a week for three weeks appear to be an effective and well-tolerated treatment for low-grade VAN. The most recent systematic review, including 28 patients of VAN 2 and 3 treated with Imiquimod report at around complete response rate of 76% and a response rate of 89%. For 5th review, there are a few studies that talk about this, and the study report lower kill rate at the kill rate is around 57% and 41%, but the bad part was that the local side effects, including vaginal discharge, burning, pain, or ulcer may be highly uncomfortable and reduce compliance. Approximately 16% of the patients treated with 5th review report a side effect that most commonly irritation and dyspareunia, so it's not a treatment of choice yet for the VAN. For estrogen, because the study reported that estrogen therapy can be a potential treatment modality for VAN, there's one study found that in a small group of the patient with VAN 1 to 3, this is from VAN 1 as well, so it's like the high range of both low-grade and high-grade. They found that 90% had regression of kill, and at the same time, compared with a patient who didn't get the estrogen cream, in the group that get the estrogen has a kill rate is around 81%, compared to 71% without the estrogen cream. For radiotherapy, brachytherapy is a good option, though it's usually not purposed as the first-line therapy because of the risk of long-term radiation effects. It also compromises the possibility for secondary surgery in case of recurrence and makes the corposcopic exam difficult. For recurrence, actually there's no consensus about the ideal treatment modality for VAN yet. The patients treated for VAN are at high risk of developed recurrence. This depends not only on the method used, but on several other factors such as grade of VAN, localization, previous treatment, age, immune status, and consequently, presence of the HPV infection. For progression, the invasive cancer after treatment of VAN was reported to be 3 to 5%, with a mean time interval from treatment to progression of 54 to 61 months. All patients were high-risk HPV-positive and all primarily had VAN 3. So in patients with VAN 3, the rate of progression to invasive disease was significantly higher when compared with the patients with VAN 2, 15 vs. 1.4%. For follow-up and surveillance protocol, because this is HPV-related, so it's similar to other HPV-related diseases, management of VAN requires the long-term follow-up. There is no consensus yet for follow-up of the vaginal low-grade lesion. Maybe co-testing at 12 months is recommended, but for VAN 2 and 3 or high-grade lesion, the recommendation is to follow-up by cytology and HPV at 6 and 12 months, and after that can be annual cytology or every 2 to 3 years of co-testing. And VAN may recur after several years, and therefore long-term follow-up is recommended. Thank you.

Vaginal Intraepithelial Neoplasia

HPV

Colposcopy

Imiquimod

Laser Ablation

European Society of Gynecological Oncology