Melanoma
Melanoma is a malignant neoplasm originating from melanocytes, the pigment-producing cells primarily located in the basal layer of the epidermis but also found in mucosal surfaces, uveal tract, and other sites. The pathogenesis of melanoma involves genetic and environmental factors, most notably ultraviolet (UV) radiation-induced DNA damage, which leads to mutations in key regulatory genes such as BRAF, NRAS, and CDKN2A. This genetic instability results in uncontrolled cellular proliferation, evasion of apoptosis, and metastatic potential. Melanoma is characterized by its aggressive clinical course, high metastatic propensity, and significant mortality if not detected and treated early. The health impacts of melanoma are profound, as advanced disease is associated with substantial morbidity, reduced quality of life, and high healthcare utilization. Early-stage melanoma is often curable with surgical excision, but advanced or metastatic disease poses significant therapeutic challenges.
Superficial spreading melanoma is the most common form, accounting for approximately 70% of cases. It typically arises on intermittently sun-exposed skin, such as the trunk in men and the legs in women. This type is characterized by a prolonged radial growth phase, during which malignant melanocytes proliferate horizontally within the epidermis before invading deeper dermal layers. Clinically, it presents as a flat or slightly elevated lesion with variegated pigmentation and irregular borders.
Nodular melanoma represents about 15-20% of melanomas and is distinguished by its rapid vertical growth phase, with early invasion into the dermis. It often appears as a uniformly pigmented, dome-shaped nodule that may ulcerate or bleed. This type is more aggressive and associated with a poorer prognosis due to its propensity for early metastasis.
Lentigo maligna melanoma arises predominantly in chronically sun-damaged skin of elderly individuals, particularly on the face and neck. It begins as lentigo maligna, an in situ lesion with a slow radial growth phase, and eventually progresses to invasive melanoma. Clinically, it appears as a flat, tan to dark brown patch with irregular borders and color variation.
Acral lentiginous melanoma is less common, accounting for 2-8% of cases, and occurs on the palms, soles, and subungual regions. It is the most frequent subtype in individuals with darker skin tones. This type is characterized by a slow radial growth phase followed by vertical invasion, and often presents as a darkly pigmented macule or patch with irregular borders.
Desmoplastic melanoma is a rare subtype, typically presenting as a non-pigmented, indurated plaque or nodule, often on sun-exposed areas of older adults. Histologically, it is characterized by spindle-shaped melanocytes within a dense fibrous stroma. This type may be locally aggressive but is less likely to metastasize to regional lymph nodes.
Melanoma incidence has been increasing globally over the past several decades, particularly in populations of European descent. The annual incidence rates vary by geographic region, with the highest rates observed in Australia and New Zealand, where age-standardized rates exceed 30 per 100,000 population. In the United States, melanoma is the fifth most common cancer among men and women, with an estimated 100,000 new cases diagnosed annually and approximately 7,000 deaths. Melanoma is more prevalent in men than women, particularly after the age of 50. Risk factors include fair skin, a history of sunburns, excessive UV exposure, presence of multiple or atypical nevi, family history of melanoma, and genetic predispositions such as mutations in CDKN2A. Although it accounts for less than 5% of all skin cancers, melanoma is responsible for the vast majority of skin cancer-related deaths due to its high metastatic potential. Survival rates are stage-dependent, with five-year survival exceeding 90% for localized disease but dropping below 30% for metastatic cases.
The diagnosis of melanoma involves a combination of clinical evaluation, dermoscopic assessment, histopathological examination, and, in some cases, molecular testing. Clinically, suspicion is raised by lesions demonstrating asymmetry, border irregularity, color variegation, diameter greater than 6 mm, and evolving characteristics ('ABCDE' criteria). Dermoscopy enhances diagnostic accuracy by revealing specific patterns such as atypical pigment networks, irregular streaks, and blue-white veils. Definitive diagnosis is established via excisional biopsy with narrow margins, allowing for assessment of tumor thickness (Breslow depth), ulceration, and mitotic rate. Histopathology confirms the diagnosis and provides critical prognostic information. For staging, sentinel lymph node biopsy is recommended for tumors with a Breslow thickness greater than 1 mm or with high-risk features. Imaging studies, including ultrasound, computed tomography (CT), positron emission tomography (PET), and magnetic resonance imaging (MRI), are utilized to assess regional and distant metastases in advanced disease. Molecular testing for mutations in genes such as BRAF and NRAS guides therapeutic decision-making in selected patients. The American Joint Committee on Cancer (AJCC) staging system is employed to stratify patients and inform management.
Lifileucel is utilized as an adoptive cell therapy involving tumor-infiltrating lymphocytes for the treatment of melanoma. Nivolumab and relatlimab-rmbw, a combination immunotherapy regimen, target immune checkpoint pathways to enhance anti-tumor immune responses in melanoma patients. Pucotenlimab is administered as an immune checkpoint inhibitor designed to promote immune-mediated tumor destruction. Toripalimab is a monoclonal antibody that targets the PD-1 receptor on T cells, thereby augmenting the immune system's ability to recognize and eliminate melanoma cells. Encorafenib is a small molecule inhibitor of BRAF kinase, used in the treatment of melanoma harboring BRAF mutations. Binimetinib acts as a MEK inhibitor, often used in combination with BRAF inhibitors for patients with BRAF-mutant melanoma. Atezolizumab is a monoclonal antibody against PD-L1, facilitating immune-mediated attack on melanoma cells. Cobimetinib is another MEK inhibitor, indicated for use in combination with BRAF inhibitors in BRAF-mutant melanoma cases. Talimogene laherparepvec is an oncolytic viral therapy designed for direct intratumoral injection, leading to tumor cell lysis and enhanced anti-tumor immunity. Lambrolizumab, also known as pembrolizumab, is a PD-1 blocking antibody that stimulates the immune system to target and destroy melanoma cells.
| Structure | Generic Name | CAS Registry Number | Molecular Formula | Molecular Weight |
|---|---|---|---|---|
| lifileucel (Rec INN; USAN) | 2306267-74-1 | |||
| nivolumab and relatlimab-rmbw; relatlimab/nivolumab | ||||
| pucotenlimab (Prop INN; Rec INN) | 2403647-03-8 | |||
| toripalimab (Rec INN; USAN) | 1924598-82-2 | |||
 | encorafenib (Rec INN; USAN) | 1269440-17-6 | C22 H27 Cl F N7 O4 S | 540.011 |
 | binimetinib (Rec INN; USAN) | 606143-89-9 | C17 H15 Br F2 N4 O3 | 441.227 |
| atezolizumab (Rec INN; USAN) | 1380723-44-3 | |||
 | cobimetinib (Rec INN; USAN) | 934660-93-2 | C21 H21 F3 I N3 O2 | 531.31 |
| talimogene laherparepvec (Prop INN; USAN) | 1187560-31-1 | |||
| lambrolizumab; pembrolizumab (Rec INN; USAN) | 1374853-91-4 |
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Melanoma
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