Melanoma, also known as malignant melanoma, is a type of malignant tumor that originates from melanocytes and is commonly found in the skin, as well as in the mucous membranes and the choroid of the eye. Melanoma is the most malignant type of skin tumor and is prone to distant metastasis. Early diagnosis and treatment are therefore particularly important.
Definition
Melanoma, also known as malignant melanoma, is a type of malignant tumor that originates from melanocytes and is commonly found in the skin, as well as in the mucous membranes and the choroid of the eye. Among Asians and people of color, melanoma originating from the skin accounts for 50% to 70% of all melanomas, and the most common primary sites are the extremities (about 50% of all melanomas), i.e., soles, toes, finger ends and under the nails, followed by mucosal melanomas (about 20%), while these two subtypes account for only 5% of all melanomas in European and American Caucasians. Melanoma is the most malignant type of skin tumor and is prone to distant metastasis. Early diagnosis and treatment are therefore particularly important.
Etiology
Excessive UV exposure in European and American Caucasians is a clear cause of the disease. UV light can cause skin burns and induce DNA mutations, which in turn induce melanoma development. In addition, photosensitive skin, the presence of a large number of common or abnormal developmental nevi, and a family history of skin cancer are high-risk groups. Extremity melanoma, which occurs mostly in Asia and Africa, has minimal exposure to UV light and the etiology remains unclear. Inappropriate treatment may induce malignancy and rapid growth of pigmented nevi, such as local irritation by cutting, strangulation, salt pickling, laser and freezing. It is not known whether endocrine, chemical, and physical factors have an effect on the development of melanoma.
Clinical manifestations
Signs of melanoma include changes in the morphology or color of existing skin pigmented nevi, bulges on the skin surface, itching of pigmented nevi, localized rupture and bleeding, and cracked finger (toe) nails. The early manifestations of pigmented nevus malignant change can be summarized as “ABCDE”.
A Asymmetry: One half of the pigmented nevus looks asymmetrical with the other half.
B Border irregularity: The edges are irregular or have cut marks or jagged teeth, unlike normal pigmented nevi that have smooth round or oval outlines.
C Color variation: Normal pigmented nevi are usually monochromatic, while melanoma is mainly a dirty black color, but can also have brown, brown, brown-black, blue, pink, black or even white.
D Diameter (diameter): Pay attention when the diameter of pigmented spots >5~6mm or pigmented spots grow significantly, melanoma is usually larger than normal moles, keep an eye on pigmented spots with diameter >5mm. For pigmented nevi >1cm in diameter, a biopsy is best for evaluation.
E Elevation: In some early melanomas, there is a slight elevation of the entire tumor.
The only shortcoming of ABCDE is that it does not take into account the rate of melanoma progression, such as the tendency for significant changes to occur within a few weeks or months.
Further progression of early cutaneous melanoma may present with satellite foci, ulcers, recurrent failure to heal, regional lymph node metastases, and metastatic metastases. Symptoms of advanced melanoma vary depending on the site of metastasis, with sites prone to metastasis being the lung, liver, bone, and brain. Melanoma of ocular and rectal origin is prone to liver metastases. Patients with metastatic melanoma may experience a range of nonspecific symptoms, including loss of appetite, nausea, vomiting, and malaise. In addition, melanoma metastases to different parts of the body may present with different symptoms, for example, bone metastases may present with bone pain, and lung metastases may present with cough and hemoptysis.
Diagnosis
(1) Physical examination
The diagnosis of melanoma is mainly based on visual examination. Irregular color or shape of pigmented nevus, recent enlargement or morphological changes of previous pigmented nevus should be noticed. We recommend regular self-examination of existing pigmented nevi using the “ABCDE” criteria mentioned above, or visiting a hospital for consultation.
(2) Biopsy
If the lesion is suspected to be melanoma after medical consultation, complete excisional biopsy of the lesion should be performed and sent for pathological examination after surgery to obtain accurate T-stage, with an incision margin of 0.3-0.5 cm, and the incision should be made in the direction of the skin line (e.g., the limb is usually chosen along the long axis of the incision). Direct extended excision is avoided to avoid altering the regional lymphatic return and affecting the quality of subsequent anterior lymph node biopsies. In lesions on the face, palms, soles, ears, fingers, toes or under the nails, or in huge lesions where complete excision is not possible, full skin lesion excision or puncture biopsy may be considered. If the tumor is huge and ruptured, or metastasis has clearly occurred, puncture or excisional biopsy of the lesion may be performed.
(3) Imaging examination
Imaging examination should be decided according to the actual local situation and patients’ economic condition. The mandatory items include ultrasound of regional lymph nodes (neck, axilla, groin, N fossa, etc.), chest X-ray or CT, ultrasound, CT or MRI of abdominopelvic region, whole body bone scan and cranial examination (CT or MRI). Whole-body PET-CT is feasible in patients with good financial situation, especially in patients with unknown primary foci.PET is an easier screening method to detect subclinical metastases. Most examiners believe that for early stage limited melanoma, the detection of metastatic lesions with PET is not sensitive and has a low benefit rate. For stage III patients, PET/CT scans are more useful to help identify lesions that cannot be clearly diagnosed with CT and areas that cannot be visualized with conventional CT scans (e.g., extremities).
(4) Laboratory tests
These include routine blood, liver and kidney function and LDH, which are mainly used to prepare for subsequent treatment and to understand the prognosis. Although LDH is not a sensitive indicator to detect metastasis, it can guide the prognosis. There are no specific serum tumor markers for melanoma
Treatment
(1) Surgical treatment
(1) Extended excision: Extended excision of primary foci should be done as soon as possible after biopsy confirmation of early melanoma. The safe margin of extended resection is determined by the depth of tumor infiltration in the pathology report: when the thickness of the lesion is ≤1.0mm, the safe margin is 1cm; when the thickness is 1.01-2mm, the safe margin is 1-2cm; when the thickness is >2mm, the safe margin is 2cm; when the thickness is >4mm, the latest evidence-based medical evidence supports a safe margin of 2cm.
②Sentinel lymph node biopsy (SLNB): SLNB can be considered for patients with a thickness of 1 mm, but given that the incidence of ulceration in cutaneous melanoma in China is more than 60%, and the prognosis of cutaneous melanoma with ulceration is poor, SLNB is recommended for patients with combined ulceration when biopsy techniques or pathological detection techniques are limited so that reliable depth of infiltration cannot be obtained.
(iii) Lymph node dissection: prophylactic lymph node dissection is not recommended. Patients with positive anterior lymph nodes or regional lymph node metastases judged by imaging and clinical examination (but no distant metastases in stage III patients) should undergo regional lymph node dissection based on extended resection.
④Management of limb metastasis: limb metastasis is manifested as extensive metastasis of skin, subcutaneous and soft tissues between the primary focus of one limb and regional lymph nodes, which is difficult to remove cleanly by surgery. This type is dominated internationally by isolated thermal perfusion chemotherapy (ILP) and isolated thermal infusion chemotherapy (ILI), which is a local treatment of anaerobic, low-flow infusion of chemotherapeutic agents, and the infusion of melphalan through an interventional arteriovenous cannula to establish chemotherapy access.
⑤ Stage IV patients who present with isolated metastases may also be considered for surgical excision.
(2) Adjuvant treatment of cutaneous melanoma.
The prognosis of postoperative patients varies according to risk factors. Based on risk factors such as depth of lesion infiltration, presence of ulceration, and lymph node metastasis, postoperative patients are generally classified into four categories: stage IA (low risk); stage IB-IIA (intermediate risk); stage IIB-IIIA (high risk); and stage IIIB-IV (very high risk). Low-risk patients have the potential for long-term survival, with a 5-year survival rate of about 95%. Intermediate-risk patients have a 5-year survival rate of about 80% after surgery, and high-risk and very high-risk patients have a 5-year survival rate ranging from 10% to 50%. Different adjuvant treatments should be selected for patients with different risk levels.
①Low-risk patients: there is no recommended adjuvant treatment option, preferring to prevent the appearance of new primary foci and focusing on observation.
②Patients at intermediate to high risk: adjuvant therapy with high-dose interferon may prolong recurrence-free survival, but the impact on overall survival needs to be continued to be explored. Clinical choices must be made in the context of the individual patient’s situation and willingness to treat.
(iii) Very high-risk patients: There is no standard treatment protocol, but high-dose interferon alpha-2b therapy remains the mainstay, as in the treatment of medium- and high-risk patients.
For mucosal melanoma, adjuvant chemotherapy is recommended, please refer to “Mucosal melanoma” for details.
(3) Adjuvant radiotherapy
Melanoma is generally considered to be insensitive to radiotherapy, but radiotherapy is still an important treatment tool in certain special cases. Adjuvant radiotherapy for melanoma is mainly used for lymph node dissection and postoperative complementary treatment of certain head and neck melanomas (especially nasal), which can further improve the local control rate.
(4) Systemic treatment of inoperable stage III or metastatic melanoma
Systemic therapy based on medical treatment is generally recommended for stage III or metastatic melanoma that cannot be surgically resected or recommended for clinical trials. Patients initially diagnosed are first recommended to undergo genetic testing, and treatment options are selected based on the results of the genetic mutation and the speed of disease progression, including PD-1 monoclonal antibody, CTLA-4 monoclonal antibody, BRAF V600 inhibitor, CKIT inhibitor, MEK inhibitor, high-dose IL-2 and chemotherapy. Specific treatment options need to be chosen by clinicians based on the patient’s condition.
Prognosis
Melanoma stage is significantly related to prognosis. The 5-year survival rates were 94%, 44%, 38%, and 4.6% for stage I, stage II, and stage III-IV, respectively; the median survival was 5, 4.25, 2.83, and 1.42 years, respectively. Primary foci thickness was significantly associated with prognosis, with 5-year survival rates of 92% and 43% for ≤1 mm versus >4 mm, respectively. A multifactorial analysis of the relationship between genetic variants and survival prognosis showed that mutations in both KIT and BRAF genes were independent prognostic factors for melanoma, and those with genetic mutations had a poor prognosis.