| disease | Malignant Melanoma |
Malignant melanoma is more common in Caucasians. Australia's QueenS-Land is one of the world's most notorious high-incidence regions for malignant melanoma. The incidence of malignant melanoma in China is relatively low, but due to insufficient awareness among doctors and patients regarding its severity, cases are often diagnosed too late, resulting in unsatisfactory treatment outcomes. This disease predominantly affects individuals aged 30 to 60. Rare cases of juvenile malignant melanoma have been reported, with Spity documenting 13 cases ranging from 1.5 to 12 years old. Younger patients generally exhibit lower malignancy levels, and surgical removal often yields better prognoses. There is almost no gender difference in the occurrence of the disease, but lesion location correlates with gender: lesions on the trunk are more common in males, while those on the limbs are more frequent in females, particularly facial freckle-type melanoma, which is predominantly seen in elderly women.
bubble_chart Etiology
The exact cause of malignant melanoma remains unclear. Recent studies suggest that second-degree sunburns (with blister formation) play a more significant role in its pathogenesis than general sun exposure. Other predisposing factors include: ① Fair skin, blue eyes, and light-colored hair—common in Caucasians, who are more susceptible. ② Rare in Black individuals or those with darker skin tones; when it occurs, it typically affects areas with lighter pigmentation, such as the soles of the feet or palms. ③ Many researchers believe that nearly half of malignant melanomas develop from pre-existing moles. ④ Dysplastic nevus syndrome, an autosomal dominant genetic disorder, causes individuals to have numerous large, flat, irregularly shaped, thin, and variably colored moles. One or more of these moles may develop into malignant melanoma in most patients. Even those without a hereditary predisposition but exhibiting this syndrome should be closely monitored for melanoma. ⑥ Large congenital nevi (over 2 cm in size) have an increased risk of malignant transformation.
bubble_chart Pathological Changes(1) Pathological Classification
1. Superficial spreading type. Accounts for about 70% and can occur anywhere on the body surface. Initially spreads outward along the superficial layers of the skin, and later extends vertically into the deeper layers, known as the "vertical growth phase."
2. Nodular type. Accounts for about 15% and can also occur anywhere on the body surface. Primarily grows vertically, invading subcutaneous tissues, and is more prone to lymphatic metastasis, making it more lethal.
3. Acral lentiginous type. Accounts for about 10%, mostly occurring on the palms, soles, nail beds, and mucous membranes.
4. Lentigo maligna type. Accounts for about 5%, arising from long-standing freckles on the faces of elderly individuals. This type grows horizontally, expanding 2–3 cm or more in all directions.
5. Malignant melanoma with radial growth, unclassified.
6. Malignant melanoma arising from giant hairy nevus.
7. Malignant melanoma originating from oral, vaginal, or anal mucous membranes.
8. Malignant melanoma with unknown primary site.
9. Malignant melanoma arising from blue nevus.
10. Visceral malignant melanoma.
11. Childhood malignant melanoma originating from intradermal nevus.
(2) Growth Patterns Based on the way tumor cells grow and spread, they can be divided into radial growth and vertical growth phases. When tumor cells spread centrifugally between the epidermal basal layer and the dermal papillary layer, it is called radial growth. This is commonly seen in the early stages of lentigo maligna, superficial spreading, and acral malignant melanomas and can persist for several years. During this phase, the primary lesion rarely metastasizes to the lymphatic system, so relatively simple surgical excision can yield good results. When the tumor infiltrates deeper into the dermis and subcutaneous tissues, it is called vertical growth. Nodular melanoma may bypass the radial growth phase and directly enter the vertical growth phase, during which lymph node metastasis is more likely.
(3) Depth of Invasion A true milestone in the study of malignant melanoma is the recognition that the risk of metastasis and prognosis are closely related to the thickness of the lesion and the depth of skin invasion. Measuring the thickness of malignant melanoma in millimeters is a more accurate and comparable standard among pathologists and has become a benchmark for assessing the risk of lymph node metastasis and predicting prognosis. Currently, some renowned diagnostic and treatment centers highly recommend the method proposed by Breslow in 1970, which uses an ocular micrometer to directly measure tumor thickness for prognosis estimation. Tumor thickness is categorized into ≤0.75 mm, 0.75–1.5 mm, and >1.5 mm. Some authors further subdivide the >1.5 mm category to better observe the relationship between tumor thickness and prognosis.bubble_chart Clinical Manifestations
To carefully examine skin lesions, good lighting and a handheld magnifying glass are essential. The following changes in pigmented skin lesions often suggest the possibility of early malignant melanoma: ① Color: Most malignant melanomas display an uneven mix of brown, black, red, white, or blue. Any color change in a mole should raise particular concern. ② Edge: The borders are often irregular and jagged, caused by tumor spread or spontaneous regression. ③ Surface: The surface is typically rough, scaly, or flaky, sometimes with oozing or bleeding, and the lesion may be raised above the skin. ④ Surrounding skin: Edema, loss of natural skin luster, or discoloration to white or gray may appear around the lesion. ⑤ Abnormal sensation: Local itching, burning pain, or tenderness is common. When these changes occur, they strongly indicate a suspicion of malignant melanoma. It is not an exaggeration to say that any change in a mole warrants excision and biopsy to rule out malignant melanoma.
bubble_chart Treatment Measures(1) Surgical Treatment
1. Biopsy Surgery: For suspected malignant melanoma, the lesion along with 0.5cm to 1cm of surrounding normal skin and subcutaneous fat should be completely excised for pathological examination. If confirmed as malignant melanoma, the need for additional wide excision is determined based on the depth of infiltration. Generally, incisional or punch biopsies are not performed unless the lesion has already ulcerated or is too large for a single excision without causing disfigurement or disability, necessitating prior pathological confirmation. However, incisional biopsy should be performed as close as possible to the definitive surgery. The WHO Collaborative Center for Evaluation of Methods of Diagnosis and Treatment of Melanoma found in a prospective analysis that excisional biopsy not only has no adverse effect on prognosis but also helps determine the depth and extent of infiltration, facilitating the formulation of a more reasonable and appropriate surgical plan.
2. Extent of Primary Lesion Excision: The outdated view advocating the inclusion of 5cm of normal skin in the excision has been abandoned. Most surgical oncologists now recommend excising 1cm of normal skin around the lesion for thin melanomas (≤1mm in thickness), and 3cm to 5cm for lesions thicker than 1mm. For acral malignant melanomas, amputation of the affected digit (toe or finger) is often required.
3. Regional Lymph Node Dissection
(1) Indications: In the United States, most surgical oncologists adopt the following approach: ① For lesions ≤1mm in thickness, the metastasis rate is very low, and prophylactic lymph node dissection cannot be expected to improve long-term prognosis; ② For lesions >3.5cm to 4mm in thickness, the likelihood of occult distant metastasis is high, and long-term survival rates are relatively low (20-30%). Even with prophylactic lymph node dissection, a significant improvement in survival is unlikely. Nevertheless, many advocate prophylactic lymph node dissection as long as no distant metastases are detected; ③ For lesions with thickness between these two categories, the occult lymph node metastasis rate is quite high, making them the best candidates for prophylactic lymph node dissection to potentially improve survival.
(2) Extent of Regional Lymph Node Dissection: For head and neck melanomas, cervical lymph node dissection should focus on the parotid region, submental, and submandibular triangles if the primary lesion is on the face. For occipital lesions, the posterior cervical triangle should be emphasized. Upper limb melanomas require axillary lymph node dissection, while lower limb melanomas necessitate inguinal or ilioinguinal lymph node dissection. For melanomas on the chest or abdomen, ipsilateral axillary or inguinal lymph node dissection is performed, respectively.
4. Palliative Resection: For extensive lesions with distant metastases unsuitable for curative surgery, debulking or palliative resection may be considered to relieve ulcer bleeding or pain, provided anatomical conditions permit.
(2) Radiation Therapy Except for certain very early freckle-type malignant melanomas, radiation therapy is generally ineffective for other primary lesions. Therefore, radiation is not typically used for primary lesions but is employed for metastatic sexually transmitted disease sites. Current common radiation doses are: ≥500cCy per session for superficial lymph nodes, soft tissues, and metastases in the chest, abdomen, or pelvis, twice weekly, totaling 2000-4000cCy. For bone metastases, 200-400cCy per session, totaling over 3000cCy.
(3) Chemotherapy
1. Single-Agent Therapy
(1) Nitrosoureas: These drugs have some efficacy against melanoma. Literature reviews report an 18% response rate for BCNU in 122 melanoma cases, 17% for MeCCNU in 108 cases, and 13% for CCNU in 133 cases.
(2) Dacarbazine (DTIC): The emergence of DTIC marked a significant advancement in the treatment of melanoma, making it the most widely used drug. GaiIanl reported that DTIC demonstrated the best efficacy, treating 28 cases of melanoma with a dose of 350mg/m2 per administration, administered for 6 consecutive days, with a 28-day treatment cycle, achieving an effective rate of 35%.
2. Combination therapy: Malignant melanoma is not highly sensitive to chemotherapy, but combination therapy can improve the response rate and reduce toxic reactions. Commonly used combination chemotherapy regimens are as follows:
(1) The DAV regimen (DTIC, ACNU, VCR) is the first-line chemotherapy regimen for melanoma. Administration method: DTIC 100–200mg, IV d1–5; ACNU 100mg, IV d1; VCR 2mg, IV d1, repeated every 21 days.
(2) DDBT regimen (DTIC, DDP, BCNU, TAM) Usage: DTIC 220mg/m2, IV d1–3/3w; DDP 25mg/m2, IV drip d1–3w; BCNU 150mg/m2, IV d1/6w; TAM 10mg PO, 2/d. Response rate: 52.5%.
(3) CBD regimen (CCNU, BLM, DDP) Usage: CCNU 80mg/m2, PO, d1/6w; BLM 15u/m2, IV d3–7/6w; DDP 40mg/m2, IV d8/6w. Response rate: 48%.
(4) Immunotherapy The spontaneous regression of malignant melanoma indicates its association with the body's immune function. Bacille Calmette-Guérin (BCG) can concentrate lymphocytes in melanoma patients within tumor nodules, stimulating a strong immune response to achieve therapeutic effects. BCG can be administered via skin scarification, intratumoral injection, or oral administration. For localized small lesions, intratumoral BCG injection achieves a response rate of 75–90%. In recent years, biological response modifiers such as interferon, interleukin-2 (IL-2), and lymphokine-activated killer (LAK) cells have shown some efficacy.
(1) Tumor infiltration depth Tumor thickness is closely related to prognosis. In a study by Balch et al. (1982) analyzing the outcomes of 1,442 cases of malignant melanoma, the 5-year survival rate was 89% for 357 cases with primary lesions ≤0.75 mm, but only 25% for those ≥4 mm.
(2) Lymph node metastasis A review of the literature shows that the 5-year survival rate for cases with 1–3 lymph node metastases ranges from 41% to 58%, while for those with 4 or more metastases, it drops to 8%–26%. Although both tumor thickness and lymph node metastasis are significant prognostic factors, the presence or absence of lymph node metastasis appears to have a greater impact on prognosis.
(3) Lesion location Clinical analyses indicate that the prognosis of malignant melanoma varies depending on the site of occurrence. Generally, lesions on the trunk have the worst prognosis, followed by those on the head and neck, while lesions on the limbs tend to have a better outcome.
(4) Surgical approach According to Morton’s criteria for wide excision margins, lesions ≤0.75 mm in thickness should be excised with a 2–3 cm margin, those >0.75 mm but ≤4 mm with a 3–4 cm margin, and those >4 mm with a 5 cm margin. This approach reduces the local recurrence rate. Inappropriate local excision can lead to a recurrence rate as high as 27%–57%, and even extensive re-excision may fail to control locally recurrent tumors. Similarly, inadequate regional lymph node dissection may promote systemic tumor dissemination.
(5) Age and gender Rare juvenile malignant melanoma has a relatively favorable prognosis. Patients under 45 years of age generally have better outcomes than older patients. In terms of gender, female patients have a significantly better prognosis than males.
Avoid sun exposure as much as possible; using sunshades is an important primary prevention measure, especially for high-risk groups. Strengthening education for the general public and professionals to enhance the "three earlies"—early detection, early diagnosis, and early treatment—is even more crucial.
