Vulvar melanoma

　　First, etiology

　　Vulvar malignant melanoma often originates from junctional nevus or combined nevus. Although there have been reports of family history of vulvar malignant melanoma, there is almost no material on familial vulvar malignant melanoma. The age of onset of vulvar malignant melanoma in those with a family history of skin melanoma is earlier than those without a family history, with ages of 44.8 years and 49.7 years respectively. Those with a family history may have multiple foci and a tendency towards good prognosis. Evidence related to pregnancy is suspected and has not been conclusively determined. Other factors such as sexual partners, hormonal influence, etc., have not shown to be related to the onset of vulvar melanoma.

　　Second, pathogenesis

　　1. Clinical and pathological growth forms of melanoma

　　According to the growth and development patterns of melanocytic tumors, general skin melanomas can be divided into three types: superficial spreading type, nodular type, and freckle type.

　　(1) Superficial spreading type: Sharp, with a curved edge, elevated and uneven surface, which may appear nodules. The appearance is mixed, composed of brown, brown, gray, black, pink, and white. Before invasion of the stroma, there is a relatively large radial growth stage, and once it enters the vertical growth and infiltration stage, the clinical progression of the disease is quite rapid. The superficial spreading type accounts for about 70% of skin melanomas, and 1/2 to 2/3 of vulvar melanomas manifest as superficial spreading type growth.

　　(2) Nodular type: There are two types, black and dark blue, with smooth or rough surfaces. This type only exists in the vertical infiltration growth stage, with a short history and deep stromal infiltration at the time of diagnosis. This type accounts for 10% to 15% of skin melanomas and 25% to 50% of vulvar melanomas.

　　(3) Freckle-type: Large coverage area with irregular edges, color ranging from light to dark brown, characterized by radial growth and deep infiltration, generally classified as advanced stage at the time of diagnosis. This type accounts for 0% to 10% of vulvar melanomas.

　　2. Gross appearance of vulvar melanoma

　　Commonly found in hairless areas, 65% to 70% originate from or involve the mucosal surface of the vulva, 25% only involve one side of the labium majus, 10% involve the clitoris, and about 20% of patients present with extensive lesions at the time of consultation. Clinically, local skin or mucosa may appear in a blue-black, dark brown, or unpigmented color, with unclear boundaries, and the lesions may be flat, protuberant, or polypoid, with possible changes such as ulcers, swelling, or formation of satellite nodules. The range of the lesion can be a few millimeters to several centimeters. 10% of melanomas are amelanotic.

　　3. The microscopic characteristics of vulvar melanoma

　　Melanoma is composed of epithelial cells, nevus cells, and spindle cells, with different degrees of melanin in these three types of cells. The tissue morphological changes are very large, which can be similar to tumors derived from epithelial or mesenchymal tissues, or can be similar to undifferentiated carcinoma. There is a significant difference in cell size, which can be round, polygonal, spindle-shaped, or polymorphic. Nuclear atypia is obvious, and multinucleated or giant cells can also be seen. There are often obvious nucleoli, and nuclear division is common. The tumor cells are mostly arranged in nests or diffuse distribution, and a few superficially growing tumor cells only infiltrate the epidermis.

　　4. The relationship between vulvar melanoma and vulvar melanocytic nevus

　　10% of vulvar melanomas originate from the malignant transformation of vulvar nevi. Pre-existing nevi are considered to be the precursor of melanoma. Rafnarsson-olding reported that 5.5% of vulvar melanomas were associated with pre-existing moles, all of which were located on the hairy skin of the labia. 71% were related to superficial spreading type growth, and 5 cases of superficially growing melanomas on the hairy skin of the labia were associated with pre-existing moles. Under the microscope, benign skin nevi, malignant melanoma, and atypical nevus cells are adjacent to each other, showing a transition process from benign to malignant melanoma. The authors believe that melanomas on the smooth skin of the vulva are newborn melanomas. Superficially growing melanomas on the hairy skin of the labia are most likely to originate from the malignant transformation of vulvar melanocytic nevi, like melanomas in other parts of the skin.

　　Common complications of vulvar melanoma: Vulvar ulceration and infection. Immunohistochemical staining. The combined histochemical staining of antigens such as Keratin, Vimentin, S-100, HMB-45 in melanoma cells is helpful for the diagnosis and differential diagnosis of melanoma. The melanoma without pigment can also be cultured to produce melanin. Histopathological examination. Monoclonal antibody HMB-45 has high sensitivity and specificity for melanoma, and immunohistochemical staining can assist in pathological diagnosis. Some normal tissue at the edges should be included when excising living tissue.

　　The symptoms of vulvar melanoma are similar to those of other vulvar malignant tumors. Although vulvar melanoma can be asymptomatic and discovered incidentally during physical examination, the most common complaint is a vulvar mass, followed by vulvar bleeding or itching, vulvar ulceration, difficulty in urination, pain, headache, and weight loss are less common. These symptoms often occur in patients with advanced disease. If the late stage of the disease causes swelling in the inguinal region due to tumor metastasis, some patients with pre-existing moles may experience changes such as mole enlargement, etc. Rafnarsson-Olding reported 198 cases of vulvar melanoma, 34.8% of which had symptoms of vulvar bleeding, 28.3% had a history of vulvar mass, 15.2% and 13.6% of patients respectively felt vulvar itching and burning sensation, discomfort in urination and vaginal discharge accounted for 12.1% and 10.6%, respectively, and the incidence rates of ulcers, pain, and local darkening were not more than 5%.

　　Staging of vulvar melanoma:

　　1. Clinical staging

　　The earliest and simplest staging system, stage I: tumor confined to the vulva, with or without satellite lesions within 2cm of the primary tumor, stage II: tumor spread to regional lymph nodes, including skin or subcutaneous nodules more than 2cm from the primary tumor, located within the regional lymphatic drainage area of the primary tumor, stage III: tumor metastasis beyond the regional lymph node range.

　　2. FIGO staging and TNM staging.

　　3. Microscopic staging

　　In 1969, Clark proposed 5 invasion grades according to the degree of invasion of the dermal papillary layer, reticular layer, and subcutaneous fat layer of malignant melanoma, and the prognosis of patients involved was different. In 1970, Breslow proposed to estimate the prognosis by multiplying the tumor thickness (measured on the section with the deepest invasion) by the longest diameter of the tumor, and the melanoma was also divided into 5 grades. That is, Clark graded according to the anatomical landmarks of the skin, and Breslow graded according to the thickness of tumor invasion, but due to the lack of a clearly defined dermal papilla in the vulvar labial skin, Chung et al. proposed the modified Breslow grading, Clark grading, Breslow grading, and Chung grading system.

　　One: Prevention

　　When female patients have vulvar itching, bleeding, increased range of pigmentation, and vulvar melanocytic nevus, early treatment and follow-up should be done.

　　Two: Prognosis:

　　1. General prognosis judgment The recurrence rate of vulvar melanoma is 51% to 93%, with the most common sites of recurrence being the vulva, vagina, followed by the inguinal region. 37% to 40% have distant metastasis, with the most common sites of metastasis being the lung, bone, liver, and brain. Among patients with recurrence, 29% have multiple foci. The average time to recurrence is 1 year, and most patients die of distant metastasis. The prognosis is poor after recurrence, with an average survival of 5.9 months and a 5-year survival rate of 5%.

　　(1) Age and prognosis: Age is a significant independent prognostic factor for the survival of vulvar melanoma patients. Older patients have worse prognosis, and the risk coefficient for the impact of age on survival is 1.4 per 10 years. The prospective study of GOG found that elderly patients will significantly increase the risk of disease recurrence, with an increase rate of 26% per 10 years. Patients with an average age of 67 years or older are more likely to have vascular invasion, surface ulceration, aneuploidy, and tumor thickness greater than 5mm.

　　(2) Lesion location and prognosis: Tumors located centrally have significantly worse prognosis than those located on the sides. Primary tumors in the central location have a higher risk of lymph node involvement and recurrence compared to adjacent tumors. The survival time of patients with tumor in the ipsilateral paraglandular area is significantly longer than that of patients with clitoris or multiple foci.

　　(3) Growth pattern and cell type and prognosis: The order of growth patterns with progressively worsening prognosis is superficial spreading, mixed, lentigo, nodular, and unclassified. The cell types with progressively worsening prognosis are cord-like, epithelioid, mixed, and pleomorphic.

　　(4) Mitotic rate and prognosis: A higher mitotic rate is associated with a shorter survival period.

　　(5) Lymphovascular invasion and prognosis: The survival rate is reduced in patients with lymphovascular invasion.

　　(6) Tumor size and prognosis: Tumors with a diameter greater than 2cm have a poor prognosis compared to those with a diameter of 5mm or less, and those over 67 years of age.

　　(8) FIGO staging and AJCC staging and prognosis: Patients with FIGO I and II stages have significantly better prognoses than those with stages III and IV. Scheistroen reported that the 5-year survival rates for stages I, II, III, and IV were 63.2%, 44.2%, 0, 0, respectively; and the 10-year survival rates were 51.6%, 35.4%, 0, 0, respectively. The GOG prospective study reported that the 5-year survival rate of AJCC I stage patients was 85%, 40% for stage II, and 25% for stage III, and believed that the AJCC staging system is related to the recurrence time of the disease, and the AJCC staging system is more accurate in predicting the outcome of the disease than the FIGO staging. AJCC staging can determine prognosis and select treatment, and it is recommended that vulvar melanoma adopt the AJCC staging. Recently, Verschraegen reported 51 cases of vulvar melanoma, with 29% in stage I, 50% in stage II, 16% in stage III, and 7% in stage IV, with a 5-year survival rate of 91% for stage I, and 31% for those with ≥IIA (P=0.0002). AJCC staging is a major prognostic indicator related to patient overall survival and tumor-free survival, with P=0.0001 and P≤0.0001, respectively.

　　(9) Tumor surface ulcer formation and prognosis: Ulcer formation represents rapid tumor progression and is an important prognostic indicator for tumor-free survival, long-term survival, and recurrence. The 5-year survival rate of patients with ulcer formation is 14.3% to 40.5%, and the 5-year survival rate of patients without ulcer formation is 20% to 62.7%.

　　(10) Tumor thickness and invasion depth: Chung and Clark staging represents the degree of tumor invasion, Breslow staging represents the thickness of the tumor, and clinical studies by many scholars have proven to varying degrees that these three microscopic staging systems are related to the prognosis of the tumor. Chung and Breslow staging are more accurate in predicting the prognosis of the disease than Clark staging. Trimble applied the Chung and Breslow microscopic staging system to analyze 65 cases of vulvar melanoma, of which 47 were consistent with the Chung staging, including 1 case in stage I, 12 cases in stage II, 8 cases in stage III, 20 cases in stage IV, and 6 cases in stage V. The 5-year survival rates of each stage were 100%, 81%, 87%, 4%, and 17%, respectively, and the 10-year survival rates were 100%, 81%, 87%, 11%, and 33%, respectively. 65 cases were consistent with the Breslow staging, including 12 cases in stage I, 10 cases in stage II, 9 cases in stages III and IV combined, and 34 cases in stage V, with corresponding 5-year survival rates of 48%, 79%, 56%, and 44%. Therefore, the authors believe that the Chung microscopic staging system can better reflect the survival, lymph node metastasis, and outcome of vulvar melanoma than the Breslow system. GOG believes that the AJCC system is the best system to reflect the outcome of vulvar melanoma, and in the absence of the ACJJ staging system, Breslow staging will be the best staging system.

　　2. Some molecular biological studies on melanoma may help in the judgment of prognosis: Flow cytometry karyotype detection: The DNA flow cytometry detection of skin malignant melanoma shows that aneuploidy is an indicator of poor disease prognosis. Scheistroen et al. used flow cytometry to perform karyotype detection on the paraffin-embedded tissue of 75 melanoma cases, and found that the 5-year survival rates of diploid, tetraploid, aneuploid, and patients who could not be evaluated were 60.9%, 44.4%, 32.5%, and 71.4%, respectively; the 10-year survival rates were 60.9%, 44.4%, 23.2%, and 42.0%, respectively. There was a significant difference in the survival rate statistics between karyotypes (P=0.0101). Multivariate analysis showed that in patients who underwent initial surgery, DNA ploidy was an independent prognostic factor for tumor-free disease and long-term survival. Among the prognostic indicators for tumor-free survival, the prediction of DNA ploidy is second to vascular invasion and age at diagnosis. In terms of predicting long-term survival, DNA ploidy is second only to the location of tumor growth. Euploid tumors have the best prognosis, and aneuploid tumors have a higher risk of recurrence and poorer prognosis.

　　1. Immunohistochemical staining

　　The combined immunohistochemical staining of melanoma cells with Keratin, Vimentin, S-100, HMB-45, and other antigens is helpful for the diagnosis and differential diagnosis of melanoma. Generally, Keratin shows negative staining, Vimentin and S-100 show complete positive reactions, and HMB-45 is a specific antibody for malignant melanoma. However, some malignant melanomas do not express pigment antigens, and literature reports that the expression rate of HMB-45 in malignant melanoma is 90.6%.

　　2. Tissue culture

　　Colorless melanoma can also be cultured to produce melanin.

　　The tissue pathology examination monoclonal antibody HMB-45 has high sensitivity and specificity for melanoma, which can be used for immunohistochemical staining to assist in pathological diagnosis. Some normal tissue edges should be included when removing living tissue.

　　One, Therapeutic diet for vulvar melanoma

　　1. Ginseng porridge 3g of ginseng powder (or 15g of codonopsis pilosula), appropriate amount of rock sugar, 100g of good rice, cooked as porridge and eaten regularly.

　　2. Astragalus porridge 50g of Astragalus membranaceus, boiled water to make juice as cooking water, 100g of good rice, appropriate amount of brown sugar, 3g of bran powder, cooked together as porridge.

　　3. Angelica sinensis and Astragalus chicken 20g of Angelica sinensis, 100g of Astragalus membranaceus, 1 hen, cooked together and served in portions.

　　4. Ginseng and jujube rice 3g of ginseng (or 15g of codonopsis pilosula), 20g of jujube, 250g of good rice, 50g of sugar. The ginseng and jujube are chopped and steamed together, the rice is cooked, and sugar is added and served in portions.

　　5. Atractylodes and jujube cake 30g of atractylodes macrocephala, 250g of jujube, chicken gizzards, dried ginger, flour, oil, salt, and other seasonings in appropriate amounts. The drugs are ground into powder or cut into very fine pieces, mixed with flour and seasonings, fried into cakes, and eaten in portions.

　　Two, Malignant melanoma patients often have kidney deficiency, for kidney and liver deficiency, the following diet can be chosen:

　　1. Cordyceps and goji berry 10g of Cordyceps sinensis, 20g of goji berries, 100g of lean pork, 250g of eggs, appropriate amount of seasoning, cooked and served in portions.

　　2. Goji berry porridge 30g of goji berries, 100g of good rice, cooked together as porridge.

　　3. Walnut duck 200g of walnut kernel, 100g of chicken meat, 150g of water chestnut, 1 old duck, a little cooking wine, appropriate amount of oil and salt, cooked together and served in portions.

　　Three, For the toxic and stasis symptoms in malignant melanoma patients, the following diet can be chosen:

　　1. Garlic porridge 30g of purple garlic, 100g of good rice, cooked together as porridge.

　　2. Asparagus and mushroom soup 200g of asparagus, 100g of mushrooms, simmered over low heat, can be seasoned with appropriate spices for eating.

　　3. Tapioca porridge 60g of tapioca powder, 100g of good rice, cooked together as porridge.

　　Four, What is good for the body when eating vulvar melanoma

　　1. Postoperative consumption of Qi and injury to blood, so it is advisable to eat more Qi-nourishing and blood-nourishing foods, such as jujube, longan, adzuki beans, glutinous rice, lychee, mushrooms, carrots, quail eggs, lotus root powder, and legumes.

　　2. Radiotherapy can consume Yin and damage body fluids, so it is advisable to eat more Yin-nourishing and fluid-nourishing foods, such as spinach, Chinese cabbage, lotus root, radish, watermelon, banana, grapes, sea cucumber, sugarcane, and lily.

　　3. Chemotherapy can lead to the loss of both Qi and blood, so it is advisable to eat foods that nourish Qi and blood, such as mushrooms, walnuts, lotus seeds, mung bean porridge, jujube, longan, sea cucumber, and so on.

　　4. Eat more foods rich in vitamin A and vitamin C, and consume more green vegetables and fruits.

　　5. Regularly eat foods that have inhibitory effects on carcinogenesis, such as turnips, cabbage, and shepherd's purse.

　　6. Consume more refined rice, whole wheat flakes, jujube sugar, corn flour, yellow rice, and legumes (soybeans, adzuki beans, mung beans, and green beans).

　　7. Regularly consume nutritious dried fruit and seed foods such as sunflower seeds, sesame seeds, pumpkin seeds, peanuts, dried grapes, and so on. These foods contain a variety of vitamins, minerals, fiber, protein, and unsaturated fatty acids.

　　Fifth, it is best to avoid eating certain foods for vulvar melanoma.

　　1. Eat less refined rice and flour; avoid salted and smoked foods, especially charred and carbonized foods.

　　2. Adhere to a low-fat diet; consume lean meat, eggs, and yogurt regularly.

　　3. Foods should be as fresh as possible; avoid moldy and deteriorated foods.

　　4. Maintain smooth defecation; patients with constipation should consume fiber-rich foods and drink some honey every day.

　　5. Avoid stimulants such as coffee.

　　6. Avoid spicy and irritant foods such as scallion, garlic, ginger, cinnamon, etc.

　　7. Avoid stimulants such as rooster, pork head meat, etc.

　　8. Avoid seafood.

　　9. Avoid warm foods such as mutton, dog meat, chive, pepper, etc.

　　10. Avoid smoking and drinking.

　　First, Treatment

　　1. Vulvar Pigmented Lesions

　　It is not necessary to remove all vulvar pigmented lesions, especially benign moles, but biopsy is necessary when there is clinical suspicion of malignancy or the presence of malignant tumors. All congenital moles, junctional moles, and atypical hyperplastic moles should be removed. Lesions with a diameter greater than 5 mm, irregular and unclear boundaries, and spots-like pigmented lesions should be considered for removal. In addition, pigmented lesions that increase in size, deepen in color, produce irritative symptoms, or show ulceration and bleeding should be removed. Atypical moles with a family history or history of melanoma and/or other similar medical histories should be followed up under the strict supervision of a dermatological oncologist.

　　2. Surgical Treatment

　　(1) Surgical Approach: The management of vulvar melanoma is a balance, aiming to achieve local disease control while reducing the cure rate; it is not necessarily better to have a larger surgical range. The conventional treatment method for vulvar melanoma is similar to that for vulvar squamous cell carcinoma, which involves the performance of radical vulvectomy along with bilateral inguinal lymph node and pelvic lymphadenectomy. With the trend of individualization in the treatment of vulvar squamous cell carcinoma and the shrinking of surgical ranges and more conservative treatment of melanoma in other skin sites, the surgical management concept of vulvar melanoma has also changed. In 1987, Davidson et al. reported on 32 cases of vulvar melanoma and vaginal melanoma patients, and there was no difference in therapeutic outcomes whether radical surgery, simple vulvectomy, or simple local resection was performed, or whether radiotherapy was used as an adjuvant. The radical surgery adopted by the authors included simple radical vulvectomy, radical vulvectomy with inguinal lymph node dissection, or anterior pelvic exenteration. Therefore, the authors suggested local resection. If there is clinical evidence of metastasis to the inguinal lymph nodes, then the inguinal lymph node dissection should be added. For giant vulvar lesions or those with extensive local recurrence, radical surgery should be considered. Subsequent multicenter clinical studies have also not confirmed that extensive surgery is superior to local resection with margins of 2 cm. Verschraegen and his colleagues summarized the treatment of 51 cases of vulvar melanoma admitted between 1970 and 1997 in 2001, and found that the surgical technique itself did not change the prognosis of the patients.

　　(2) Surgical margin: Whether the surgical margin is thorough is significantly related to the recurrence of the disease and the prognosis of the patient. Rose et al. found that among 6 patients undergoing conservative treatment, only 1 patient recurred with a 2cm margin. Trimble and his colleagues summarized the treatment effects of 80 cases of vulvar melanoma patients and found that compared with incomplete radical surgery, radical surgery does not seem to improve the prognosis of the patients. It is recommended that for thin lesions with Chung II stage and invasion depth ≤1mm, perform a local radical resection with a margin of 1-2cm. For thick lesions of Chung III and IV stages, the margin requirement is 3cm. For Chung I stage, simple resection and close follow-up are sufficient. To prevent recurrence, even

　　Based on the above research, thickness

　　(3) Treatment of regional lymph nodes: GOG analyzed 71 cases of vulvar melanoma and found that FIGO staging, tumor size, tumor location, involvement of capillary-lymphatic vessels, and Breslow's tumor invasion depth were significantly related to lymph node metastasis. Lymph node metastasis means that the prognosis of the patient is extremely poor. From a large-scale study of skin melanoma, it was found that patients with a depth of 4.0mm of skin lesions have a very high risk of lymph node metastasis and recurrence. Similarly, it is almost impossible to benefit from lymph node resection surgery. For patients with primary tumor depth of 0.76-4.0mm, they may benefit from selective lymph node resection. It is not necessary to perform selective lymph node resection for all vulvar melanoma patients. Chung believes that patients with Chung II stage (tumor thickness ≤1mm) do not need lymph node resection. Trimple and others suggest that patients with lesion thickness >0.76mm (Clark III) should undergo prophylactic lymph node resection because patients with positive lymph nodes can achieve long-term survival. For patients with micro-metastasis of lymph nodes, prophylactic lymph node resection and vulvar radical surgery can make the 10-year survival rate reach 31%. A prospective study by Phillips et al. on vulvar melanoma lymph node resection and types of surgery showed that compared with those who did not undergo lymph node resection, positive lymph node resection or negative lymph node resection did not show the advantages of lymph node resection treatment. In summary, for vulvar melanoma patients with invasion depth >0.76mm (Clark III), patients with lateral lesions should consider undergoing ipsilateral lymph node resection, and patients with central lesions should undergo bilateral lymph node resection. Removing clinically involved lymph nodes is always beneficial to vulvar melanoma patients.

　　3. Chemotherapy and radiotherapy

　　It was previously believed that melanoma was tolerant to chemotherapy and radiotherapy, but recent data shows that advanced patients respond well to chemotherapy and radiotherapy. Radiotherapy and chemotherapy alone have led to survival of some patients for more than 10 years in advanced patients. Common chemotherapy drugs include dacarbazine (thiotepa), lomustine (chloroethyl cyclohexyl nitrosourea), cisplatin (DDP), vinblastine sulfate (vincristine), and vincristine (VCR), among others. The most effective chemotherapy drug for melanoma is dacarbazine (DTIC), with a response rate of 15%-25%. Only 1%-2% of patients receiving dacarbazine (DTIC) treatment achieve long-term complete remission. Common regimens include DVP (dacarbazine, vincristine, cisplatin), CPD (lomustine, procarbazine, actinomycin D), BDPT (carmustine, dacarbazine, cisplatin, tamoxifen), and VCD regimen.

　　BDPT regimen:

　　Carmustine (BCNU): 150mg/㎡ intravenous infusion on the 1st day, once every 6-8 weeks.

　　Dacarbazine (DTIC): 200-220mg/㎡ intravenous infusion on the 1st to 3rd day, once every 3-4 weeks.

　　Cisplatin (DDP): 25mg/㎡ intravenous infusion on the 1st to 3rd day, once every 3-4 weeks.

　　Tamoxifen: 10mg, twice a day, orally, 6-8 weeks as a course.

　　Cisplatin (DDP): 20mg/㎡ intravenous infusion on days 1-4.

　　Vinblastine sulfate (VLB): 1.5mg/㎡ intravenous infusion on days 1-4.

　　Dacarbazine (DTIC): 200mg/㎡ intravenous infusion on days 1-4, or 800mg/㎡, intravenous infusion on day 1.

　　3-4 weeks constitute one course of treatment.

　　External irradiation can be used locally in the vulvar and inguinal regions. For patients with tumor involvement of the vagina or recurrence in the vagina, vaginal brachytherapy can be used. The radiation dose is 4000cGY to 5000cGY. For high-risk patients, the main purpose is to improve local control. Radiotherapy can also be used for distant metastases to the brain, bones, and internal organs, playing a role in palliative treatment. Whether used conventionally or as a means of palliative treatment, radiotherapy can only alleviate the symptoms of vulvar melanoma in advanced patients and cannot achieve a cure for the disease.

　　4. Immunotherapy

　　(1) Interferon α: ECOGG (Eastern Cooperative Oncology Group) evaluated 280 patients with stage IIIB or III or with regional lymph node metastasis, 137 cases as controls, and 143 cases received interferon treatment. The method is: interferon 20MU/(㎡·d), intravenous administration, 5 times a week, for 4 weeks, then changed to 10MU/(㎡·d), subcutaneous injection, 3 times a week, for a total of 48 weeks. The results showed that the survival time without recurrence and the overall survival time in the treatment group were significantly prolonged. The beneficiaries of interferon treatment are those patients with lymph node involvement. Further in-depth research by ECOG found that high-dose interferon can significantly prolong the survival time without tumor recurrence and the overall survival time for patients with high-risk melanoma after surgery, which is unparalleled by any other drug, cytokines, and other forms of vaccines.

　　(2) Vaccine: Melanoma is the most immunogenic tumor, and therefore melanoma is used as the main model for tumor vaccine treatment research. The IgM and IgG globulins in the serum of melanoma patients can produce heterologous reactions to autologous and allogeneic melanoma, about 1/3 of the patients have the phenomenon of lymph node concentration in the tumor nodules. The freeze-dried BCG (Bacillus Calmette-Guérin, tuberculin) has the effect of enhancing the phagocytic power of the reticuloendothelial system. The skin scratch method of freeze-dried BCG (BCG) can be used, with each dose of 75-150mg, an area of 7cm×8cm. China has reported 15 cases of the therapeutic effect of melanoma in the genital tract, and it was found that all patients who survived for more than 1 year underwent surgery, chemotherapy, and immunotherapy with freeze-dried BCG (BCG), with good results. With the development of molecular biology technology, some genes encoding specific melanoma antigens have been cloned, and specific antigen polypeptide molecules have been identified. Utilizing specific antigens can stimulate the body to produce specific active immune responses. A new type of specific anti-melanoma vaccine with strong specificity has been developed. In 1998, Piura reported a case of a 25-year-old patient with primary vulvar melanoma of Clark IV grade. After surgery, the patient received adjuvant treatment with allogeneic specific anti-melanoma vaccine, achieving long-term remission and survival for more than 5 years, opening up a new era for active immunotherapy of vulvar melanoma.

　　(3) Adalimumab (Interleukin-2): Currently, there is no consensus on the therapeutic dose and administration time for the use of interleukin-2 alone. Although treatment regimens combining interleukin with chemotherapy and/or interferon achieve a high rate of response, they cannot achieve good long-term survival.

　　Two, prognosis

　　1. General prognosis judgment The recurrence rate of vulvar melanoma is 51% to 93%, with the most common site of recurrence being the vulva, followed by the vagina, and then the inguinal area. 37% to 40% of cases show distant metastasis, with the most common sites of metastasis being the lung, bone, liver, brain. 29% of recurrent patients have multiple lesions, with an average recurrence time of 1 year. Most patients die from distant metastasis. The prognosis is poor after recurrence, with an average survival of 5.9 months and a 5-year survival rate of 5%.

　　(1) Age and prognosis: Age is a significant independent prognostic factor for the survival of patients with vulvar melanoma. Older patients have a worse prognosis, with a risk coefficient for the impact of age on survival of 1.4 per 10 years. The GOG prospective study found that elderly patients will significantly increase the risk of disease recurrence, with an increase rate of 26% per 10 years, and an average age of over 67 years, where tumors are more likely to show vascular invasion, surface ulceration, aneuploidy, and tumor thickness greater than 5mm.

　　(2) Lesion location and prognosis: Tumors located centrally have a significantly worse prognosis than those located on the sides. Primary tumors in the central location have a higher risk of lymph node involvement and recurrence compared to those on the lateral side, and the survival time of patients with tumors on the lateral side is significantly longer than those on the clitoris or with multiple lesions.

　　(3) Growth pattern and cell type and prognosis: The order of worsening prognosis by growth pattern is superficial spreading, mixed, lentigo, nodular, undifferentiated, and by cell type is fascicular, epithelial, mixed, and pleomorphic.

　　(4) Mitotic rate and prognosis: A higher mitotic rate is associated with a shorter survival period.

　　(5) Lymphovascular invasion and prognosis: The survival rate is reduced in patients with lymphovascular invasion.

　　(6) Tumor size and prognosis: The prognosis is worse for patients with a tumor diameter greater than 2cm.

　　(7) Lymph node metastasis and prognosis: The survival rate of patients with lymph node metastasis is significantly reduced, with a 5-year survival rate of 0 reported by Scheistroen, compared to 56% for those without metastasis. Lymph node metastasis is associated with tumor vascular invasion, surface ulceration, aneuploidy, thickness greater than 5mm, and age greater than 67 years.

　　(8) FIGO staging and AJCC staging and prognosis: Patients with FIGO I and II stages have significantly better prognoses than those with III and IV stages. Scheistroen reported that the 5-year survival rates for stages I, II, III, and IV were 63.2%, 44.2%, 0, and 0, respectively, and the 10-year survival rates were 51.6%, 35.4%, 0, and 0, respectively. The GOG prospective study reported that the 5-year survival rate of AJCC I stage patients was 85%, stage II was 40%, stage III was 25%, and it was believed that the AJCC staging system is related to the recurrence time of the disease. The AJCC staging system is more accurate in predicting the outcome of the disease than the FIGO staging system. The AJCC staging can determine prognosis and treatment selection. It is recommended that vulvar melanoma adopt the AJCC staging system. Recently, Verschraegen reported 51 cases of vulvar melanoma, with 29% in stage I, 50% in stage II, 16% in stage III, and 7% in stage IV. The 5-year survival rate of stage I was 91%, and ≥IIA was 31% (P=0.0002). The AJCC staging is a major prognostic indicator related to patient overall survival and tumor-free survival, with P=0.0001 and P≤0.0001, respectively.

　　(9) Tumor surface ulcer formation and prognosis: Ulcer formation represents rapid tumor progression and is an important prognostic indicator for tumor-free survival, long-term survival, and recurrence. The 5-year survival rate of patients with ulcer formation is 14.3% to 40.5%, while the 5-year survival rate of patients without ulcer formation is 20% to 62.7%.

　　(10) Tumor thickness and invasion depth: The Chung and Clark grading system represents the degree of tumor invasion, while the Breslow grading system represents the tumor thickness. Clinical studies by many scholars have proven to varying degrees that these three microscopic staging systems are all related to the prognosis of tumors. The Chung and Breslow grading systems are more accurate in predicting the prognosis of the disease than the Clark grading system. Trimble applied the Chung and Breslow microscopic grading system to analyze 65 cases of vulvar melanoma, of which 47 were consistent with the Chung staging, including 1 case in stage I, 12 cases in stage II, 8 cases in stage III, 20 cases in stage IV, and 6 cases in stage V. The 5-year survival rates of each stage were 100%, 81%, 87%, 4%, and 17%, respectively, and the 10-year survival rates were 100%, 81%, 87%, 11%, and 33%, respectively. 65 cases were consistent with the Breslow staging, including 12 cases in stage I, 10 cases in stage II, 9 cases in stages III and IV combined, and 34 cases in stage V. The corresponding 5-year survival rates were 48%, 79%, 56%, 44%, respectively. Therefore, the authors believe that the Chung microscopic staging system can better reflect the survival, lymph node metastasis, and outcome of vulvar melanoma than the Breslow system. The GOG believes that the AJCC system is the best system to reflect the outcome of vulvar melanoma. In the absence of the ACJJ staging system, the Breslow grading system will be the best grading system.

　　2. Some molecular biological studies on melanoma have shown that the flow cytometry karyotype detection of non-chromosome aneuploidy is an indicator of poor prognosis for the disease. Scheistroen et al. used flow cytometry to perform karyotype detection on the paraffin-embedded tissue of 75 melanoma cases, and found that the 5-year survival rates of diploid, tetraploid, aneuploid, and patients who could not be evaluated were 60.9%, 44.4%, 32.5%, and 71.4%, respectively; the 10-year survival rates were 60.9%, 44.4%, 23.2%, and 42.0%, respectively. There was a significant difference in the survival rate statistics between the chromosome aneuploidy (P=0.0101). Multivariate analysis showed that in the patients treated with surgery, DNA aneuploidy was an independent prognostic factor for tumor-free and long-term survival. Among the prognostic indicators for tumor-free survival, the prediction of DNA aneuploidy was inferior to vascular invasion and age at first visit. In terms of predicting long-term survival, DNA aneuploidy was second only to the location of tumor growth. Haploid tumors have the best prognosis, and aneuploid tumors have a higher risk of recurrence and poorer prognosis.