Vulvar intraepithelial neoplasia

　　1. Etiology of the Disease

　　1. Relationship with HPV (Human Papillomavirus) Infection: In VIN superficial cells, especially in VIN1 and VIN2, lesions caused by HPV infection are often visible, such as nuclear halo formation with nuclear displacement, thickened cell membrane, binucleation, and multinucleation. However, these viral changes are not the definitive evidence for VIN infection with HPV. Vulvar warts are often associated with HPV6, 11, and molecular biological techniques have proven that 80% of VIN are related to HPV16. Basta et al. found that in young patients with VIN and early vulvar cancer,

　　2. Relationship with Immune Deficiency: VIN incidence is significantly increased in patients with human immunodeficiency virus (HIV) infection, chronic lymphocytic leukemia, and long-term use of immunosuppressants (steroid hormones and tissue transplant inhibitors).

　　3. Relationship with Vulvar Nutritional Deficiency: Vulvar intraepithelial neoplasia is more common in lichen sclerosus et atrophicus than in hyperplastic nutritional deficiency.

　　4. Relationship with Changes in Sexual Behavior and Tobacco Use: Smoking is often associated with an increased risk of VIN grade III, and an increase in the number of sexual partners has also been found to be related to the occurrence of VIN grade III. Epidemiological studies have found that HPV infection is a sexually transmitted disease, and HPV infection is common in young VIN patients and is related to sexual history (including the number of sexual partners and age at first sexual intercourse).

　　5. Relationship with Cervical Lesions: Other studies have found that VIN is associated with cervical lesions due to shared risk factors, with approximately 15% of VIN patients having cervical lesions.

　　6. Relationship with Vulvar Cancer: The relationship between grade I vulvar intraepithelial neoplasia (VIN) and vulvar cancer has not been definitely established, but some epidemiological data suggest that such a connection exists. For example, the average age of VIN patients is 10 to 20 years younger than that of invasive cancer patients, and 95 to 18% of VIN patients have invasive cancer detected upon careful examination during treatment. Jones et al. followed up 5 VIN patients for 2 to 8 years and found that all 5 patients gradually developed invasive cancer. Other authors have reported that the incidence of VIN increased threefold from 1973 to 1977 to 1988 to 1992, with 3.4% progressing to invasive cancer. Conversely, some authors have reported that VIN can naturally regress. Others have reported that molecular DNA analysis can diagnose the malignancy of VIN lesions, and certain types of HPV play an important role in the etiology of VIN, especially in young patients. HPV6, 11, 16, and other subtypes can be isolated from VIN biopsy specimens, and PCR analysis shows that HPV16 is present in 80% of VIN lesions.

　　Second, pathogenesis

　　Vulvar intraepithelial neoplasia often shows pathological nuclear division, with more active mitosis in the middle and upper layers of the epithelium, an increased nuclear-cytoplasmic ratio, scattered multinucleated and immature cells, and also includes changes such as hyperkeratosis and incomplete keratosis, which are non-specific. According to the maturity of cells, nuclear atypia, cell arrangement structure, and mitotic activity, VIN can be classified into 1st grade (mild atypicality), 2nd grade (moderate atypicality), and 3rd grade (severe atypicality or in situ carcinoma).

　　The mild atypical hyperplasia epithelium has hyperplasia and changes in atypical cells, limited to the lower 1/3 of the epithelium.

　　The changes in the moderate atypical hyperplasia epithelial layer are in the upper 2/3 of the epithelium.

　　The changes in the重度不典型增生epithelial layer exceed 2/3, the atypical hyperplasia of in situ carcinoma involves the entire epithelial layer but does not penetrate the basement membrane.

　　The thickness of normal vulvar epithelium varies with the location: the vestibule is often

　　About 50% of VIN patients have epidermal intraepithelial neoplasia in other parts, most often associated with cervical intraepithelial neoplasia, 30% of vulvar intraepithelial neoplasia patients have concomitant cervical neoplasia, 4% have vaginal neoplasia, and 3% have concomitant cervical and vaginal neoplasia, which are more prominent in immunosuppressed and anorectal syndrome patients.

　　20% to 48% of patients are asymptomatic.

　　About 60% of vulvar intraepithelial neoplasia patients have the most common symptom of vulvar itching, discomfort, and burning sensation, which is more common in the labia majora and minora, followed by the clitoris, and less common around the urethral orifice.

　　About 17% of patients report the discovery of vulvar nodules.

　　Examination can reveal that 90% of patients have papules or spots on the local skin of the vulva, which can be gray, red, brown, brown or white, and can be single or multiple, fused or scattered. These lesions can occur at any part of the vulva, with the most common site being the bottom 8 points of the right and left labia minora, and white irregular lesions that are higher than the skin surface should be highly suspected of VIN. The doctor must carefully examine the perineum, including the vulva and rectum, anus, and single VIN mainly located near the navicular fossa and mucosa of the labia minora, occasionally seen at the posterior part of the perineum or around the clitoris, rarely occurring in areas with hair growth and clitoris glands, while multiple VIN can invade the prepuce of the clitoris, labia minora, navicular fossa, and perineum. About 1/3 of cases have infiltration of the labia majora and the posterior part of the perineum, and when the posterior part of the perineum is infiltrated, it often involves the anal canal and the inner groove of the buttocks, and the mucosa of the anal canal is often involved as well. Atypical hyperplastic lesions can develop upwards and extend to the squamous-columnar junction of the anal canal, the clitoris glands are rarely involved, and urinary tract infiltration is rare.

　　If patients have vulvar itching and discomfort, and appear rash-like changes, they should seek medical attention promptly and pay attention to keeping the vulvar area clean. As 80% of vulvar intraepithelial neoplasia lesions are associated with HPV (16 type) infection, timely diagnosis and treatment of HPV infection is necessary. Due to the risk factors such as anal-genital tract neoplastic lesions, immune suppression, and smoking, prevention and treatment of these risk factors are also particularly important. Prognosis: Vulvar intraepithelial neoplasia is a precancerous lesion. Literature reports that the incidence of malignant transformation in vulvar intraepithelial neoplasia after appropriate treatment is 3% to 7%. The overall recurrence rate of vulvar intraepithelial neoplasia is 30%, among which 50% of patients with negative surgical margins show persistent VIN or recurrence. Some scholars point out that the degree of vulvar intraepithelial neoplasia (i.e., grading) and the number of lesions directly affect the recurrence rate after treatment, that is, the higher the atypicality of the lesion, the more the number of lesions, the higher the recurrence rate. As for smoking, whether menopausal, and the choice of treatment method seems to have no significant correlation with the recurrence of vulvar intraepithelial neoplasia. After excluding invasive cancer, laser or surgical resection of recurrent lesions can be repeated. Patients over 60 years old or young patients with immune suppression may transform into invasive cancer.

　　For patients with vulvar intraepithelial neoplasia, anal genital tract examination should be performed, including:

　　1. Cervical cytology, anal cytology examination, cytology examination of keratinized epithelium

　　After softening the corneum with saline gauze, the superficial tissue is scraped off with a blade, and then the underlying epithelium is scraped for cytological examination. The depth of sampling should be determined according to the condition of the lesion, generally not reaching the subcutaneous fat layer. For anal cytological examination, a cell brush should be chosen. Although the cytological examination of keratinized epithelium cannot replace biopsy, in patients with recurrent, persistent HPV infection, due to the frequent presence of persistent, mild acetic white epithelium, this examination can reduce the number of repeated biopsies. If the cytological examination shows atypicality, biopsy should be performed, and biopsy should also be performed on suspicious lesion sites, and multiple sampling biopsies are required. Multiple biopsies can clearly define the depth of subepithelial spread to guide the depth of surgery. Lidocaine spray can be used locally before biopsy to reduce discomfort. If laser or other non-sampling treatment methods are used, excluding infiltration is particularly important.

　　2. Colposcopy and anoscopy

　　Colposcopy can improve the sensitivity of detecting lesions in adjacent tissues, and some studies have found that about 80% of VIN lesions are present around the primary lesion, mainly occurring in young patients. In women over 40 years old, about 35% of VIN lesions are present around the primary lesion. In addition, it is very important to thoroughly examine the entire vulva for some high-risk patients, especially young women.

　　Colposcopy can improve the sensitivity of detecting lesions in adjacent tissues, and some studies have found that about 80% of VIN lesions are present around the primary lesion, mainly occurring in young patients. In women over 40 years old, about 35% of VIN lesions are present around the primary lesion. In addition, it is very important to thoroughly examine the entire vulva for some high-risk patients, especially young women.

　　I. Dietary principles

　　1. Eat more foods with anti-vulvar tumor and leukoplakia effects, such as sesame, almond, wheat, barley, loofah, black chicken, cuttlefish, green snake, pork pancreas, chrysanthemum, umeboshi, peach, lychee, shepherd's purse, chicken blood, eel, abalone, crab, horseshoe crab, sardine, clam, tortoise shell.

　　2. Eat horseshoe crab, red, lobster, clam, sea cucumber, tiger fish, beetroot, mung bean, radish, chicken blood for pain.

　　3. Eat amaranth, cabbage, rapeseed, taro, kelp, seaweed, chicken blood, snake meat, pangolin, etc. for itching.

　　4. To enhance physical fitness and prevent metastasis, it is recommended to eat silver ear, black fungus, mushrooms, monkey head mushrooms, gizzard, sea cucumber, Job's tears, walnuts, crab, lizard, needlefish.

　　II. Dietary taboos

　　1. Avoid smoking, alcohol, and spicy刺激性 foods.

　　2. Avoid greasy, fried, moldy, and salted foods.

　　3. Avoid stimulants such as rooster and goose.

　　4. Avoid seafood and刺激性, allergenic foods when itching is severe.

　　5. Avoid warm foods such as mutton, chive, ginger, pepper, cassia, etc., if there is ulceration or bleeding.

　　Before treatment: a detailed understanding of the symptoms of the disease and related contraindications should be obtained.

　　The primary principle of treating vulvar intraepithelial neoplasia is correct diagnosis, which is helped by a systematic physical examination, colposcopy, and the use of 1% toluidine blue to improve the accuracy of pathological examination and exclude invasive cancer. The second principle is to accurately determine the extent of VIN lesions. Because VIN has a high propensity for multifocal onset, the extent of its lesions is often difficult to determine, especially in non-pigmented VIN lesions. Therefore, a thorough examination of the entire vulva should be conducted before treatment. Once VIN lesions are found, the vagina, cervix, and posterior perineum should be examined simultaneously. Many effective methods have been applied to VIN treatment, including surgical resection, electroresection, and laser therapy. The third principle is that the physician must clearly understand that VIN is a precancerous lesion, and once diagnosed, treatment should not be indefinitely delayed, although follow-up observation can still be carried out in some cases.

　　1. Drug treatment

　　5% fluorouracil ointment is applied to the vulvar lesions, once a day. The therapeutic effect varies, ranging from ineffective to 70% complete regression, but it is generally believed that the failure rate can reach 50%. Recently, there have been reports that 5% imiquimod (imiquimod) ointment can also be applied locally to the vulva, and interferon, vitamin A acid, and other local applications can be used. The advantage of drug treatment lies in its etiological treatment, which effectively maintains the integrity and function of the vulvar structure.

　　2. Surgical Treatment

　　For vulvar intraepithelial tumors that fail to respond to medication, have extensive lesions, or recur, surgical resection can be considered. The procedures include: local resection of the lesion, extensive local resection, simple vulvectomy, and vulvar skin excision (skinning vulvectomy) with thin skin grafting. The success of the surgery depends on the distance between the edge of the lesion and the edge of the surgical incision should be sufficient. Generally, it is required to excise normal skin more than 1cm.

　　3. Laser Therapy

　　The efficacy is good, especially suitable for lesions involving the minor labia. Carbon dioxide laser treatment has a local recurrence rate of about 1/3. Although the laser can vaporize tissue well, it cannot obtain tissue specimens for pathological diagnosis to exclude invasive cancer. Therefore, before laser treatment, VIN lesions should be re-examined by experienced physicians or technicians to avoid misdiagnosis. The advantages of laser treatment are minimal tissue damage and the ability to perform multi-site treatment. However, laser therapy is often misused at present.

　　4. Photodynamic Therapy

　　Apply 10% ALA gel to the surface of VIN and use a laser with a wavelength of 635nm and an intensity of 80-125J/cm2 after 2-4 hours for treatment. Studies have shown that PDT treatment leaves no local scars and has a short healing time, can maintain the appearance of the vulva, and has other advantages, but the efficacy of PDT is reduced in patients with HPV-positive, HLA-I deficiency, and increased CD4 (helper T cells) and CD68 (macrophages).

　　5. Other

　　Circumferential electroexcision and ultrasonic aspiration and cutting techniques can not only remove the lesion but also stop bleeding well and retain the specimen.

　　6. Expectant Therapy

　　When treating vulvar intraepithelial neoplasia, it is necessary to include the possibility of spontaneous regression in the treatment plan. Therefore, after a comprehensive systemic examination, 35-year-old patients without non-disomy VIN and without invasive cancer confirmed by clinical and tissue biopsy can undergo observation and follow-up, i.e., expectant therapy, especially for those who have recently been pregnant or have recently received treatment with androgenic steroids. As for how long the observation and follow-up should last, there is no consensus, with some scholars recommending 6 months to 2 years. Jones et al. reported that even in VIN2/3 young patients, VIN has a tendency to self-heal.