Malignant Melanoma

Malignant melanoma is a type of cancer that begins in the cells that produce pigment in the skin, called melanocytes. Melanocytes are responsible for producing the pigment melanin that gives color to the skin, hair, and eyes, have an interesting developmental origin.

They are derived from neural crest cells, a group of embryonic cells that arise from the neural tube during early development and give rise to a diverse range of cell types in the body. Due to the fact that melanocytes are originated from neural crest cells, it is possible for melanomas, which are cancerous growths that arise from melanocytes, to develop in other locations beyond the skin.

This occurs in areas where neural crest cells migrate during development, such as the brain and the gastrointestinal tract. Melanoma is a relatively rare form of skin cancer but is fatal, accounting for most skin cancer deaths. It typically appears as a dark, irregularly shaped spot or lesion on the skin that may change in size, shape, or color over time.

Malignant melanoma is an increasingly common form of cancer worldwide, growing faster than any other cancer except for lung cancer in women. It is particularly prevalent among younger age groups and individuals of White ethnicity, compared to Blacks and Asians. In men, melanoma is the fifth most common cancer, while in women, it is the seventh.

It accounts for 5% of all new cancer cases in men and 4% in women. Melanoma is infamous for affecting young and middle-aged people, unlike other solid tumors that typically affect older adults. The average age at diagnosis is 57 years, and approximately 75% of patients are younger than 70. Melanoma is the third most fatal cancer, causing many deaths among all types of cancer, especially among patients under 55 years old.

Melanoma can be triggered by exposure to ultraviolet radiation from the sun or artificial sources like tanning beds. This radiation causes DNA damage in the skin cells, leading to mutations that allow the cells to grow uncontrollably. The transformed cells start to divide and multiply rapidly, leading to the development of a tumor.

Melanoma is also associated with genetic mutations in several genes, such as BRAF, NRAS, and TP53, which can promote the growth and spread of cancer cells. The immune system plays a crucial role in recognizing and eliminating cancer cells. However, melanoma cells can evade the immune system by producing substances that inhibit the immune response or by altering their surface antigens to avoid detection.

Melanoma is classified into four stages based on the extent of tumor growth and spread. In the early stages, the cancer is confined to the skin, while in advanced stages, it may have spread to other organs. Melanoma can develop in healthy skin or areas of the skin with previous precursor lesions. When a malignant melanoma develops in healthy skin, it is referred to as arising de novo without evidence of a precursor lesion.

However, solar irradiation is known to induce many cases of de novo melanomas. Melanomas can also occur in areas of the skin that are not typically exposed to sunlight, such as the soles, palms, and perineum. Certain types of nevi are considered to be precursor lesions of melanoma. These include common acquired nevi, dysplastic nevi, congenital nevi, and cellular blue nevi.

Melanomas typically have two growth phases, the vertical and radial growth phase. During the radial phase, malignant cells develop in a radial pattern in the epidermis. As time progresses, most melanomas continue to the vertical growth phase, where the malignant cells invade the dermis and develop the capability to metastasis.

Melanoma is caused by a variety of factors, including family history, personal characteristics, sun exposure, atypical mole syndrome, and socioeconomic status. Individuals with a positive family history of melanoma have a 2.2-fold higher risk of developing the disease, with 5% to 10% of patients having at least one affected relative. Those with specific personal characteristics, such as blue eyes, red hair, and a pale complexion, are also at increased risk.

Additionally, those who easily sunburn, or freckle, have many benign or dysplastic melanocytic nevi, or are immunosuppressed are more susceptible to melanoma. Sun exposure is a significant risk factor for melanoma. Exposure to high levels of UVA and UVB radiation over a lifetime, particularly in low latitudes, can increase the risk of developing the disease.

Those who have experienced more blistering sunburns or used tanning beds are also at higher risk. Recent evidence has shown that individuals who use sunscreen may still be at risk for melanoma if exposed to UVA radiation, mainly if they use sunscreen primarily to block UVB radiation. Atypical mole syndrome, familial atypical multiple mole melanoma, dysplastic nevus syndrome, is another risk factor for melanoma.

Those with this syndrome have a higher risk of developing melanoma over ten years, with a risk of 10.7%. The risk increases with the number of family members affected. Lower socioeconomic status is associated with more developed disease at the time of detection, as those with fewer resources may have less access to healthcare and may delay seeking treatment. Additionally, one survey found that low-SES individuals have reduced melanoma risk assessment and understanding of the disease, which may lead to delayed detection and treatment.

Various factors can impact the prognosis of cancer patients. Poor prognostic factors include tumor thickness, evidence of tumor in regional lymph nodes, a higher number of positive lymph nodes, distant metastasis, anatomic site, ulceration, and regression on histologic examination, and male sex. Additionally, the disease stage at diagnosis is a critical factor in determining prognosis.

Patients with stage I typically have a greater than 90% 5-year survival rate, while those with stage II disease have a survival rate ranging from 45% to 77%. The 5-year survival for patients with stage III disease varies from 27% to 70%. The prognosis for patients with metastatic disease is particularly grim, with a 5-year survival rate of less than 20%.

Clinical History

Melanoma has four major types classified based on their growth patterns. The most common type is superficial spreading melanoma, accounting for about 70% of melanomas. It usually appears as flat lesions that may become elevated and irregular later. These tumors typically have a variegated color with indentations, peripheral notches, or both. They have an average diameter of 2 cm.

The second most common type is nodular melanoma, accounting for 30% of melanoma diagnoses. It often appears as blue-black tumors, but in some cases, it may lack pigment. This type of melanoma proliferates and is usually diagnosed later than other types. Lentigo maligna melanoma is less common, representing 10% of melanomas.

This type of melanoma often appears as large, tan, flat lesions with marked notching of the borders. These tumors usually begin as freckle-like small lesions and can grow slowly over many years before turning into melanoma. Acral lentiginous melanoma is the least common type in Whites, accounting for only 2% to 8% of cases. However, it is more common in dark-skinned individuals, accounting for 35% to 60% of melanomas.

This type of melanoma may appear flat, tan, or brown stains with irregular borders on the palms and soles. Subungual lesions that occur under the nails can also be black or brown, with ulcerations in subsequent stages. It is essential to note that early detection of melanoma is crucial for successful treatment. Any new or changing moles or skin lesions should be evaluated promptly.

Physical Examination

Melanoma features are typically recognized by the abbreviation ABCDE. Asymmetry, boundary irregularity, color variations notably red, blue, and white tones in a black or brown lesion, Diameter more than 6mm, and Elevated surfaces.

Melanomas may also itch, ulcerate, bleed or form satellites. Individuals with metastatic disease or primary sites other than the skin exhibit signs and symptoms associated with the afflicted organ system.

Differential Diagnoses

Atypical fibroxanthoma
Basal cell carcinoma
Blue nevus
Epithelioid tumor
Halo nevus
Histiocytoid hemangioma
Mycosis fungoides
Pigmented spindle cell tumor
Sebaceous carcinoma

Early-stage melanoma is treated with surgery such as wide local excision with elective node dissection, sentinel lymph node biopsy, or both. Surgical margins are carefully considered during surgery, and skin grafting, or tissue transfers may be needed if primary closure is not feasible. Adjuvant therapy options include pegylated interferon, interferon alfa, granulocyte-macrophage colony-stimulating factor, and ipilimumab.

Advanced-stage (stage IV) melanoma may require different treatment options. Temozolomide, dacarbazine, interleukin-2, cisplatin, vinblastine, and dacarbazine (CVD), carmustine, tamoxifen, carboplatin, and paclitaxel are chemotherapy options. Ipilimumab, nivolumab, pembrolizumab, vemurafenib , trametinib, dabrafenib, and peginterferon alfa-2b are immunotherapy options. Treatment options will depend on the patient’s case and may require a combination of therapies.