Even areas not exposed to sunlight can develop melanoma, such as the vulvar region. Vulvar melanoma is common in older women, so self-examination with a hand-held mirror is important [23]. The ABCDE (asymmetry, border irregularity, colour variation, diameter, elevation/evolving) rule and the ugly duckling sign are the first steps to distinguish pigmented nevus, nevus, brown spot from melanoma [24].

“ABCDE rule” summarizes the early clinical symptoms of melanoma [23, 25, 26].

A: Asymmetry. When an axis is drawn through the centre of the pigmented spot, there is asymmetry of the pigmented spot across the axis.

B: Border irregularity. The pigmented spot has rough, notched or serrated edges, lacking a smooth round or oval outline as expected in a normal nevus.

C: Colour variation. Normal pigmentation spots are usually uniform monochromatic, while malignant melanomas are cloudy black, brown black, and brown, and may have blue, pink, red or even white patches.

D: Diameter. Melanomas are usually larger than normal moles, and caution should be exercised when the pigmented spots are larger than 5 to 6 mm in diameter or increase in size significantly in the short term. Biopsy evaluation is required for pigmented patches larger than 1 cm in diameter.

E: Elevation/evolving. The size, shape, colour and elevation of pigment spots is changing, or new symptoms such as itching, bleeding and scab have appeared.

From a histological perspective, the same rule can also be understood as the ABCDE(FG) rule, which refers specifically to A (Asymmetry); B (Buckshot scatter); C (Cytological atypia); D (Deep mitosis); E (Enclosing lymphocytes); F (Fibrosis) and G (Gainsaying (=no) maturation).

Ordinary moles tend to look similar, but the skin lesions of malignant melanoma are more unusual than those of the surrounding melanocytic moles. However, this does not apply to vulvar melanoma [24].

Vulvar melanoma can be diagnosed with dermoscopy. Early lesions, characterized by irregular dots, multiple colours, blue and white veils and atypical blood vessels, can be detected by dermoscopy [21]. Keratinocyte hyperpigmentation of the vulvar base is a benign lesion that appears dermoscopically brown (100%) and black (60%) in superficial structures. Vulvar melanoma and other vulvar atypical melanocytic lesions, in addition to brown or black, can also be blue, pink, grey or white, and other benign lesions rarely appear in the colour. This is because lesions, such as melanoma, penetrate deeply into the dermis. These colours are rarely seen in benign vulvar melanoma. These colours are often the result of lesions that have deeply invaded the dermis. In addition, blue‒white veils, white structures, and atypical vascular patterns (e.g., milky red areas and atypical vessels) are often observed in vulvar melanomas, even though the Breslow thickness is less than 1 mm. These features are absent in benign pigmented lesions of the vulva [27].

On a cytological level, melanoma cells can mainly be divided into epithelioid cells and spindle cells. An epithelioid cell is characterized by a large round cytoplasm, abundant eosinophilic granules, and a vesicular nucleus with rough, irregular chromatin. It is most commonly seen in nodular and superficial spreading melanomas [24]. Spindle melanoma cells have obvious spindle shapes, and the cells are arranged in bundles, swirls, braids or pseudoangioma-like structures. The nuclei are curled, and melanocytes are difficult to find. They are commonly seen in sarcomatoid melanomas. Mild proliferation of fibrous tissue and obvious proliferation of blood vessels are observed in the stroma of melanoma cells. Melanoma stroma can also show myxoid degeneration [28].

The diagnosis of vulvar melanoma depends mainly on histopathology. In tissue biopsy, it is best to completely remove the suspected pigmented lesions 0.1~0.3 cm away from the peripheral cutting edge [29]. Partial biopsy is feasible for large lesions that cannot be completely resected. For patients with large vulvar lesions, punch biopsy could also be considered. A Keyes biopsy device with a diameter of 4~6 mm has been used to completely obtain cylindrical epithelial tissue with a depth of approximately 4 mm [30]. Freezing the pathology is not recommended. Immunohistochemical (IHC) staining with melanocyte markers and proliferation markers is used for the diagnosis and differentiating melanoma. Histopathology is particularly important in the diagnosis of non-pigmented malignant melanoma.

IHC is a commonly used and economical histological examination to diagnosis melanoma. The ideal marker for vulvar melanoma should be both sensitive and specific and try to pinpoint the extent of the lesion without missing tumour cells. S-100 is a highly sensitive marker in the cytoplasm and nucleus of melanoma, with a sensitivity of approximately 97%–100%. However, the specificity of S-100 is low because it is expressed on adipocytes, chondrocytes, Langerhans cells and tumour cells associated with these cells [31]. HMB-45 is an antibody specific labelling melanoma black that recognizes melanocytic antigen GP100 (also called Pmel 17). HMB-45 is expressed in the cytoplasm, and its specificity is higher than that of S-100. Related studies have shown that HMB-45 is a sensitive melanoma marker, with a sensitivity of 69% to 93%. In primary melanoma tumours, the expression level of HMB-45 is elevated [32, 33]. Other melanocytic differentiation markers include tyrosinase, Melan-A/melanoma-associated antigen recognized by T cells (MART-1), microphthalmia transcription factor (MITF), and vimentin. For melanoma with reduced or even absent expression of melanocyte markers, such as spindle cell melanomas, preferentially expressed antigen in melanoma (PRAME) can be a relevant marker [34]. Compared with single marker staining, dual staining can provide a more accurate evaluation of melanocyte proliferation. For example, the combination of the cell proliferation marker Ki67 with melanocyte markers (HMB-45 or MART-1) can more accurately evaluate the proliferation of melanocytes; combining cytoplasmic markers like HMB-45 and MART-1 with markers located in the nucleus, such as PRAME, can also contribute significantly to differentiate nodal nevus from malignant melanoma [35].

Once a vulval melanoma is confirmed, it is recommended to use the AJCC cancer staging manual instead of the International Federation of Gynaecology and Obstetrics (FIGO) staging [13] because FIGO staging does not provide adjunctive treatment decisions and prognostic indicators. The 7th edition of the AJCC staging system, published in 2009, was the first to abandon the Clark classification [36]. The staging and classification of melanoma in the 8th edition of the AJCC staging system depend upon Breslow thickness to determine the depth of invasion, thus accurately assigning staging according to classical TNM scores [37].

Vulvar melanoma has a high tendency for local or distant metastasis, so imaging examination is needed to obtain relevant information to make accurate surgical plans. Inguinal lymph node ultrasound could assist in the diagnosis of inguinal lymph node metastasis (sensitivity 86%, specificity 96%). Ultrasound combined with fine needle aspiration biopsy (FNAB) has a sensitivity of 93% and a specificity of 100% in the evaluation of positive lymph nodes. Magnetic resonance imaging (MRI) plain scan and enhanced scan can clearly show the infiltration of the lesion and its surrounding tissues. Plain and contrast-enhanced computed tomography (CT), brain contrast-enhanced MRI, and positron emission tomography-computed tomography (PET-CT) can be used to evaluate the distant metastasis of vulvar melanoma [41, 42, 43].

The role of surgery in vulvar melanoma remains unshaken. When metastasis has not occurred, surgical margins can refer to cutaneous melanoma. The negative margin distance for melanoma in situ is 0.5–1 cm. For invasive melanoma lesions, the negative margin distance is correlated with the Breslow thickness: when the Breslow thickness is $\le$1 mm, the negative margin distance is 1 cm; when the Breslow thickness is 1.01–2 mm, the negative margin distance is 1–2 cm; when the Breslow thickness is $>$2 mm, the negative margin distance is 2 cm [44]. Depending on the particular location of vulvar melanoma, surgery may damage the urinary and sexual function of patients such that the postoperative quality of life of patients is greatly compromised. Last few years, an increasing number of clinical studies have proven that patients with vulvar melanoma undergoing radical vulvar resection have no significant difference in survival rate compared with patients undergoing more limited vulvar resection [19, 45]. Therefore, conservative surgery, such as local extended resection (WLE), is considered a better treatment option [19]. Regardless of the depth of tumour invasion, the minimum surgical margin required for WLE is 1 cm, and the margin can extend into the subcutaneous fascia through the subcutaneous fat.

Complete lymph node dissection (CLND) is performed when lymph node metastasis is indicated by physical examination or imaging examination [43]. Complete surgical resection includes resection of the involved lymph nodes and surrounding tissues. Inguinal lymphadenectomy includes superficial and deep inguinal lymph nodes, and at least 10 lymph nodes are removed. When 3 or more inguinal lymph nodes are positive or Cloquet lymph nodes are positive, further pelvic lymph node dissection should be considered [46]. CLND is not recommended for early-stage (stage I, II) vulvar melanoma because of the high incidence of complications such as wound rupture, infection, and oedema after inguinal lymphadenectomy [47].

SLNB is a minimally invasive surgical technique used to assist lymph node staging in patients with cutaneous melanoma by identifying sentinel lymph nodes (SLNs) preoperatively and predicting the status of the remainder of the draining lymph node pool based on their histopathologic status [48]. In brief, SLNs were identified by blue dye (methylene blue solution, isosulfan or patent blue) combined with radionuclide tracer (Tc-99) [49], dissected and separated, and serial sections were obtained for immunohistochemical staining. Hematoxylin-eosinstaining staining was performed, and markers such as HMB-45 antibody, S-100 antibody and melanoma-pan staining were performed. Patients with positive sentinel lymph nodes needed further inguinal lymph node dissection [50]. In patients with vulvar melanoma, SLNB is mostly carried out under the premise of clinical research. Current small-scale clinical studies show that SLNB is only suitable for patients with moderate Breslow thickness (1–4 mm). For patients with thin Breslow thickness (1 mm), SLNB should be considered only when there are adverse factors such as high mitotic rate, ulceration, age 40 years, microsatellite lesions, vascular infiltration or Clark level Ⅳ. SLNB conducted in thick tumours ($>$4 mm) may increase the risk of regional metastasis. In this case, radical vulvar resection combined with bilateral inguinal lymph node dissection should be performed directly [50, 51, 52].

Vulvar melanoma is considered to be a radioresistant tumour. High-dose radiation can improve the local response, achieving a complete response rate of 20%–30%, while carbon-ion radiotherapy (C-ion RT) can achieve a 3-year survival rate of 53% [53]. Radiotherapy is only suitable for inoperable advanced patients or patients with postoperative recurrence or metastasis, and the dose is usually 40–60 Gray (Gy). Adverse reactions to radiotherapy include desquamation, ulceration, genital fistula, lymphatic fistula, rectal stenosis, and lower limb oedema [54].

Chemotherapy used to be the only systemic treatment for recurrent and metastatic melanoma. Chemotherapy is currently considered only when cutaneous melanoma is resistant to immune checkpoint inhibitors (ICIs) and targeted therapies. Given the lack of ICIs and targeted therapy in mucosal melanoma, chemotherapy is still an important treatment for vulvar melanoma. Commonly used chemotherapeutic drugs include amenimide (dacarbazine, DTIC), temozolomide, formustine, vinblamide, cisplatin, paclitaxel, and carboplatin. The effectiveness of dacarbazine alone or in combination with chemotherapy is only 10% to 20%, and the complete response rate is only 5% to 12% [55, 56, 57]. Janco et al. [58] reported 2 cases of vulval and vaginal melanoma treated with neoadjuvant chemotherapy. The patients were treated with neoadjuvant chemotherapy of paclitaxel and carboplatin $\pm$ bevacizumab first and then underwent surgical treatment after the lesion was reduced and then treated with paclitaxel and carboplatin plus bevacizumab after surgery. The final relapse-free survival (RFS) was 2 and 5 years, respectively. However, due to the small number of samples in clinical trials, some studies have concluded that postoperative adjuvant chemotherapy is significant for prolonging progression-free survival (PFS) and overall survival (OS), while some research results show that postoperative adjuvant chemotherapy does not affect RFS and OS [58, 59, 60, 61]. Therefore, the actual effect of postoperative adjuvant chemotherapy is still under debate.

Immune checkpoints are molecules expressed on immune cells that regulate the degree of immune activation. Tumour cells can inhibit the immune function of the body by activating immune checkpoints to achieve escape. ICIs can relieve immune suppression by inhibiting the corresponding immune checkpoints and enhance the antitumour ability of T cells. Melanoma is a highly immunogenic tumour. ICI-based immunotherapy has been approved by the Food and Drug Administration (FDA) as the standard of care for patients with advanced or recurrent melanoma [62]. Multiple clinical studies have shown that PD-1 (Programmed death 1) and PD-L1 are highly expressed in patients with vulvar melanoma, which provides a theoretical basis for the application of ICIs in vulvar melanoma [16, 63, 64].

Vulvar melanoma is highly reactive to vascular endothelial growth factor (VEGF) inhibitors because of its rich blood supply [84]. Representative drugs are lenvatinib, bevacizumab and axitinib. Lenvatinib is a multireceptor tyrosine kinase inhibitor that primarily targets VEGF and fibroblast growth factor (FGF) receptors [85]. In a retrospective analysis, 12 patients with brain metastatic melanoma with extremely poor prognosis were treated with bevacizumab. All patients showed good tolerance to bevacizumab, 10 of whom received immunotherapy after bevacizumab treatment, 5 of whom survived for more than 6 months, with 1 patient remaining relapse-free 4 years after the end of treatment [86]. An animal experiment showed that lenvatinib could not only be used as a direct cytotoxic drug against tumour angiogenesis and proliferation but also achieve antitumour effects by enhancing the infiltration and activation of NK cells in the tumour microenvironment [87]. Axitinib is a potent second-generation tyrosine kinase inhibitor (TKI) that blocks signalling via vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3 (as well as platelet-derived growth factor receptor (PDGFR) and c-KIT/CD117) and has been used clinically as a monotherapy for a variety of cancers [88, 89]. Axitinib also inhibits tumour progression and controls distant metastasis when used as a single agent in patients with advanced melanoma [90]. Many animal and clinical experiments have shown that the combination of PD-1 antibody and antiangiogenic drugs can further enhance the antimelanoma effect [91, 92, 93].

Imiquimod is a synthetic Toll-like receptor 7 (TLR7) agonist with antiviral and antitumour activity. Imiquimod activates TLR7 on antigen-presenting cells (APCs), thereby inducing the secretion of proinflammatory cytokines, mainly Interferon $\alpha$, Interleukin 12, and tumor necrosis factor-$\alpha$. TLR7 activation also promotes the maturation and migration of dendritic cells [94]. Esther Fuchs reported a case of recurrent vulvar melanoma with urethral involvement that where the patient successfully completed imiquimote treatment and was relapse-free for 4 years after completion of treatment [95]. Lonsdale-Eccles reported successful treatment of patients with vulvar melanoma in situ with topical 5% imiquimot cream [96]. Sadownik published a report on the success of 5% imiquimod treatment in patients with recurrent vulval melanoma after surgical resection [97]. Lauren S Prescott reported on imiquimod 5% cream in a patient with recurrent vaginal melanoma. Pelvic examination after the completion of topical treatment showed complete remission of the tumour, and there was no recurrence 18 months after the completion of treatment [98].

Patients with superficial spreading vulvar melanoma had a relatively better prognosis, while patients with nodular vulvar melanoma had a worse prognosis [13].

Breslow thickness is a key prognostic factor for patients with vulvar melanoma. Thicker Breslow thickness often predicts poor prognosis [13, 101]. In a multicentre retrospective analysis involving 77 vulvar melanoma patients, Breslow thickness was associated with tumour recurrence [102]. In another retrospective study of 16 patients with primary vulvar melanoma, the median depth of patients without recurrence after surgery was 0.9 mm (range 0.1 to 1.75 mm), while the median depth of patients with recurrence was 4.6 mm (range 3 to 8 mm). Patients with a Breslow thickness $\le$1.75 mm had no recurrence, while patients with a lesion depth greater than 1.75 mm had recurrence [103].

Lymph node metastasis is a related prognostic factor in vulvar melanoma. Patients with vulvar melanoma with regional or distant metastases tend to have a worse prognosis. In one study of 1917 cases of vulvar melanoma, the five-year OS of patients with localized lesions, regional metastases, and distant metastases was 55.8%, 22.2%, and 5.1%, respectively [104]. Sugiyama et al. [105] analysed 644 vulvar melanoma patients, of whom 179 (27.8%) underwent lymphadenectomy and 58 (9%) developed lymph node metastases. The 5-year OS rates of patients with lymph node positive scores of 0, 1, and $\ge$2 were 68.3%, 29% and 19.5%, respectively [105].

According to the density and extent of tumour infiltrating lymphocytes, they were classified as none, present but inactive (focal distribution), and active (diffuse distribution). When there are fewer infiltrating lymphocytes, the prognosis of vulvar and vaginal melanoma is poor [64]. The pathological diagnosis of tumour-infiltrating lymphocytes can be made by immunohistochemical labelling of CD8+ cytotoxic T cells.

LDH can catalyse the conversion of pyruvate to lactate in the hypoxic tumour microenvironment. In the AJCC melanoma staging system, 8th edition, LDH can not only affect tumour staging but also be used as a clinical predictor of the prognosis of melanoma patients. Elevated LDH often indicates a poorer chance of survival [106, 107].

c-KIT mutation is common in patients with vulvar melanoma [108], and increased c-KIT expression has been identified as a strong negative predictor of disease-free survival (DFS) and a strong positive predictor of early recurrence [99, 105].

Satellite metastases refer to macroscopic metastases around the primary melanoma lesion (within 2 cm in diameter). Intermediate metastasis/transitional metastasis refers to macroscopic metastases located between the primary melanoma (2 cm in diameter) and the primary lymph node. LVSI means that at least one cluster of tumour cells is seen in the space surrounded by flattened endothelial cells. One study found that the presence of any of these high-risk pathological features (satellite metastasis, mid-course metastasis, LVSI, dermal mitosis) increased the risk of melanoma recurrence by five times [99].

Ki67 and PPH3, both proliferation markers, have been shown to provide some limited independent prognostic information for melanoma, and their use does not affect staging. Increased expression of Ki67 and PPH3 indicates that tumour cells are proliferating at a high speed and are more aggressive [99, 109].

The prognosis of patients with vulvar melanoma is also related to age, complications, race, economic conditions and other factors.