Malignant melanoma (MM) accounts for 90% of deaths due to cutaneous malignancies.1 Studies have confirmed that early diagnosis and standardized consultation and treatment processes are key factors in improving the prognosis of MM.
I. Clinical screening of MM
The 5-year survival rate of early MM can reach more than 80% after standardized diagnosis and treatment, so early and accurate detection of MM lesions is of great clinical significance. Clinical screening of MM mainly relies on the ABCDE differential diagnosis system2: A (Asymmetry), asymmetric lesions; B (Border), irregular borders; C (Color), uneven color; D (Diameter), more than 5mm in diameter; E (Elivation), enlargement or nodular growth, degenerative changes in the lesions. Among the above indicators, D is easier to determine objectively, A, B, and C need to be diagnosed with the aid of dermatoscopy if necessary, and E should be confirmed by medical history. In addition, the consensus is that congenital pigmented nevus with a diameter greater than 20 cm has a high rate of malignant transformation; acquired pigmented nevus with a diameter greater than 5 mm (black spot under the nail wider than 3 mm) should be alerted, and the older the patient is at the time of occurrence, the greater the possibility of malignant transformation; large black spots occurring in the distal end of the fingers, toe and plantar joints, and heel of Chinese patients should be investigated for extremity-type MM; if pigmented nevus occurs with size, color, symptoms and status (nodules occurring), it should be diagnosed as a nodule. If a pigmented nevus changes in size, color, symptoms and status (nodules or ulcers), it suggests the possibility of malignant transformation.
Biopsy pathological examination of MM
The diagnosis of MM must be based on biopsy pathological examination. Consensus suggests that if it is easier to directly close the suspicious lesion by excision, the lesion must be completely excised and sent for pathological diagnosis, because the state of MM invasion is different in different areas of the same tissue, and even some areas show benign manifestations, so one ring drill sampling may not be able to accurately diagnose MM, let alone fully reflect the state and extent of MM invasion.1,2,3,4,5,6,7 Of course, due to the location When it is difficult to remove the suspected lesion and close the defect directly due to its location or size, partial tissue sampling pathology can be used for diagnosis, and then complete excision and shaping repair can be performed after the diagnosis is confirmed. When using the sampling biopsy pathology method, it is important to take multiple points, such as in different color areas, in the area of nodules, ulcers are biopsied separately.
There are many requirements for pathology reporting in foreign MM diagnosis and treatment guidelines.1 Among the key elements that must be reported are: 1, the type of MM pathology; 2, Breslow depth; and 3, the presence or absence of ulcerative manifestations. In addition to HE staining, immunohistochemistry is needed to assist in the diagnosis if necessary. For example, positive S100, HMB45 and melan-A can confirm the black cell origin characteristics of the tumor, HMB45 suggests malignant features, and MIB-1 is a marker of active proliferation.
III. Breslow depth, a key indicator for MM diagnosis and treatment
The Breslow depth is the distance from the epidermal granular layer to the lowermost part of the tumor in the pathological section, usually measured in millimeters. The reason for emphasizing the reporting of Breslow depth is that this index directly determines the pathologic staging of MM, the need to perform an anterior lymph node biopsy, and the extent of surgery.1,2,3,4,5,6,7
IV. Exploration of lymph nodes and distant metastases
Once lymph node involvement is confirmed, the pathologic stage is determined to be stage III or higher, regardless of the depth of tumor invasion into the subcutis. If the enlarged superficial lymph nodes can be palpated clinically, they can be biopsied pathologically for diagnosis accordingly. If they cannot be palpated and the Breslow depth is more than 1 mm, an anterior sentinel lymph node biopsy is recommended1,2.
The sentinel lymph node is the first lymph node at the first station of lymphatic drainage from the MM lesion. The common techniques and steps of sentinel lymph node biopsy are: 1, applying lymph node scintigraphy to initially determine the location of the sentinel lymph node; 2, injecting isotope-labeled colloid or albumin at the MM lesion before surgery, and also injecting bioblue; 3, applying portable γ-ray detectors combined with the color of bioblue to specifically locate the lymph node; 4, excising the lymph node and ligating the lymphatic vessels; 5, excising the Half of the lymph nodes were subjected to routine pathology and immunohistochemistry, and the other half could be tested for tyrosine kinase mRNA. Finally, a comprehensive analysis of the presence of lymph node metastasis is performed. If tumor metastasis is confirmed in the sentinel lymph nodes, the tumor stage is directly classified as stage III. It is worth mentioning that the technology required for sentinel lymph node biopsy in China is still not complete so far, such as the commonly used patent blue and portable gamma ray detectors have not been officially introduced into the Chinese market, so reagents and technologies such as melanoma and B ultrasound are often used as substitutes.
The lymphatic drainage direction of MM in the hand and foot area is mainly in the axilla and inguinal or superficial femoral lymph nodes, but the lymphatic drainage direction of MM in the head, face and trunk area is more complicated, and there may even be multiple anterior lymph nodes, so caution is needed when exploring.
V. Pathological staging of MM
The pathological staging of MM is directly related to the patient’s prognosis and treatment, and is based on TNM (tumor, lymph node, distant metastasis) staging. Currently, the staging system of the American Cancer Center for melanoma is recommended.
Principles of surgery for MM
The most important treatment for MM is surgical excision of the skin lesions, in other words, the skin lesions that can be excised must be excised. The consensus is that the expansion of excision is not effective in improving survival, and the current emphasis is on the extent of excision based on the Breslow depth, with a maximum of 75 px. The specific recommendations for the extent of excision are detailed in Table 3.
Table 1 Excisional margins of melanoma1,2,3,4,5,6,7
Tumor thickness (Breslow)
Excision margin (cm)
In situ
0.5
≤1.0mm
1
1.01-2mm
1-2
2.01-4mm
2
>4mm
2-3
VII. Consensus and progress of drug treatment for MM
The most commonly used drug for the treatment of MM is high-dose interferon. In the past, a regimen of 3 to 5 million units three times a week was used, which has now been replaced by high-dose interferon therapy. In the Chinese guidelines for the diagnosis and treatment of MM, it is recommended to apply high-dose alpha-2b interferon therapy for 1 year (1500 wiu/m2d1-5X4w,900 wiu/m2 tiw X48w), or 1 month (1500 wiu/m2d1-5X4w). This recommended dose is slightly lower than the foreign 2000 wiu/m2.
The first-line chemotherapeutic agents for MM are dacarbazine and temozolomide.3 Dacarbazine is considered the “gold standard” of drug therapy for advanced melanoma, and no other chemotherapeutic agent has yet surpassed dacarbazine in terms of efficacy. Temozolomide, a derivative of dacarbazine, was found to have similar efficacy to dacarbazine in phase III trials, with the advantage of crossing the blood-brain barrier and being effective in reducing central nervous system recurrence.
Ipilimumab was approved by the US FDA in 2011 for the treatment of MM, and it is the first drug in nearly 30 years that has been confirmed to extend overall survival in patients with advanced MM. Its approval is also considered to be a new era of immune-targeted therapy8.
The BRAFV600 variant rate in Chinese MM cases is close to 26%. Phase I and II clinical trials have demonstrated that Vemurafenib can effectively inhibit BRAFV600 mutation with an efficiency of approximately 60-80%. In a multicenter phase III randomized controlled study comparing the efficacy of Vemurafenib and dacarbazine in patients with BRAFV600 mutations, Vemurafenib was 48.4% effective, while dacarbazine was only 5.5% surviving9.
Imatinib (KIT inhibitor) is being studied in patients with advanced melanoma with KIT gene mutations. Imatinib is effective up to 23.3%, with patients with exon 11 or 13 mutations being more sensitive to imatinib10,11.
VIII. Other treatments for MM
Adjuvant radiotherapy can be considered when the lesion cannot be resected or when distant organ metastases occur. However, it is important to mention that radiotherapy is palliative in most cases, and studies have confirmed that radiotherapy is particularly effective in relieving symptoms caused by brain and bone metastases3.
Palliative therapy with melphalan +/- α-TNF limb perfusion (ILP) or limb infusion (ILI) can also be used for extremity refractory MM. This therapy can achieve 20-50 times higher local drug concentrations than systemic chemotherapy with lower local toxicity3.
IX. Treatment options for each stage of MM
Early MM cases are common in dermatology and are predominantly of the limbic type. Usually, dermatologists can independently carry out local MM skin lesion enlargement excision and defect shaping repair, inguinal and axillary area sentinel lymph node biopsy, etc. Lymph node dissection can also be performed if conditions permit. Postoperative drug therapy must be supervised by experienced physicians.
In cases with MM pathologic stage in situ to stage Ia, simple enlarged excision of the lesion is sufficient, depending on the Breslow depth.
In cases with MM stage Ib to II, the primary treatment is also simple excision with additional postoperative interferon therapy recommended.
In cases with MM stage III pathology, local expanded resection with lymph node dissection and additional postoperative interferon therapy and ILP or ILI therapy are recommended.
In cases with stage IV MM pathology, the lesion is resected and the lymph nodes are cleared if possible. Genetic screening is recommended, and different targeted therapeutic agents are selected for patients with mutations, such as Vemurafenib for BRAF V600 mutations and Imatinib for KIT mutations. For patients without mutations, Ipilimumab, dacarbazine or temozolomide are recommended. Adjuvant radiotherapy can be used to relieve symptoms caused by metastases if necessary.