Skin Cancer: Melanoma, Basal Cell Carcinoma, and Squamous Cell Carcinoma

1. Introduction

Skin cancer represents the most common malignancy in many populations, with its incidence continuing to rise globally. The term encompasses a heterogeneous group of neoplasms arising from the skin’s cellular components, primarily the epidermis. The three principal types—melanoma, basal cell carcinoma (BCC), and cutaneous squamous cell carcinoma (cSCC)—differ fundamentally in their cells of origin, biological behavior, metastatic potential, and therapeutic approaches. While BCC and cSCC are collectively termed non-melanoma skin cancers (NMSCs) and are far more prevalent, melanoma is responsible for the majority of skin cancer-related mortality due to its aggressive nature and propensity for distant metastasis.

The historical understanding of skin cancer has evolved from early descriptive observations to a molecular-level comprehension of carcinogenesis. The link between ultraviolet (UV) radiation exposure and skin cancer, particularly NMSCs, was suggested in the late 19th century and has been robustly confirmed by epidemiological and molecular studies. The development of targeted therapies and immunotherapies for advanced melanoma, beginning in the 2010s, represents one of the most significant advances in modern oncology, transforming a once largely untreatable condition into a model for precision medicine.

For medical and pharmacy students, a thorough grasp of skin cancer is essential. Knowledge spans from primary prevention and early detection to the complex pharmacological management of advanced disease. The management of skin cancer is inherently multidisciplinary, involving dermatology, surgical oncology, medical oncology, radiation oncology, and pharmacy. Pharmacists play a critical role in managing systemic therapies, monitoring for adverse drug reactions, ensuring adherence, and counseling patients on sun-protective measures and self-examination.

Learning Objectives

• Differentiate the epidemiology, etiology, clinical presentation, and histopathological features of melanoma, basal cell carcinoma, and squamous cell carcinoma.
• Explain the molecular pathogenesis and key genetic alterations driving each major type of skin cancer.
• Describe the staging systems, diagnostic workup, and principles of local therapy for cutaneous malignancies.
• Analyze the mechanisms of action, clinical applications, and major toxicities of systemic pharmacological agents used in advanced or metastatic disease, including chemotherapy, targeted therapy, and immunotherapy.
• Integrate knowledge of risk factors and carcinogenesis to formulate evidence-based strategies for primary and secondary prevention.

2. Fundamental Principles

The fundamental principles of skin cancer revolve around the anatomy of the skin, the concept of carcinogenesis, and the classification of neoplasms. The skin is the body’s largest organ, consisting of three primary layers: the epidermis, dermis, and hypodermis. The epidermis, a stratified squamous epithelium, is the origin of most skin cancers. Its major cell types include keratinocytes, which constitute the majority, and melanocytes, which are pigment-producing cells located in the basal layer.

Core Concepts and Definitions

Carcinogenesis: The process by which normal cells are transformed into cancer cells. In skin cancer, this is predominantly a multistep process involving initiation (DNA damage), promotion (clonal expansion of initiated cells), and progression (acquisition of malignant phenotype). UV radiation acts as a complete carcinogen, capable of both initiating and promoting carcinogenesis.

Clonality: Skin cancers are monoclonal proliferations, meaning they arise from a single progenitor cell that has acquired genetic mutations conferring a selective growth advantage.

Field Cancerization: Particularly relevant to cSCC, this concept describes the presence of widespread, genetically altered cells across a region of skin chronically exposed to a carcinogen (e.g., UV light). This explains the high rate of local recurrence and development of multiple primary tumors in sun-exposed areas.

Tumor-Node-Metastasis (TNM) Staging: A standardized system managed by the American Joint Committee on Cancer (AJCC) used to classify the anatomical extent of cancer. Staging criteria differ significantly between melanoma and NMSCs, reflecting their differing metastatic risks.

Key Terminology

• Actinic Keratosis (AK): A precancerous lesion of keratinocytes, considered a direct precursor to some cSCCs.
• Breslow Thickness: A microscopic measurement, in millimeters, of the vertical depth of a melanoma from the granular layer of the epidermis to the deepest point of invasion. It is the single most important prognostic factor in primary melanoma.
• Clark Level: A histological scale describing the anatomical level of dermal invasion by melanoma (Level I-V).
• Lentigo Maligna: The melanoma in situ phase of lentigo maligna melanoma, appearing as a slowly enlarging, irregular macule on chronically sun-damaged skin.
• Mohs Micrographic Surgery: A specialized surgical technique involving the sequential removal and complete circumferential marginal histological examination of tumor tissue, allowing for maximal tissue preservation and high cure rates, especially for BCC and cSCC in cosmetically sensitive or high-risk locations.
• Nodular vs. Radial Growth Phase: Melanoma growth patterns. The radial growth phase is characterized by horizontal expansion within the epidermis and superficial dermis and is non-metastatic. The vertical growth phase involves invasion into the deeper dermis and carries metastatic potential.

3. Detailed Explanation

An in-depth exploration of each major skin cancer type requires separate consideration of their distinct pathological and molecular landscapes.

3.1. Basal Cell Carcinoma (BCC)

Basal cell carcinoma is the most common human malignancy, originating from the basal keratinocytes of the epidermis or the hair follicle. It is characterized by local invasiveness and destructiveness but an exceedingly low metastatic rate (<0.1%).

Epidemiology & Etiology: The incidence of BCC is strongly correlated with cumulative, intermittent UV exposure, particularly during childhood and adolescence. Other risk factors include fair skin (Fitzpatrick types I-II), light eye and hair color, immunosuppression, and genetic syndromes such as Gorlin syndrome (nevoid BCC syndrome), which is caused by mutations in the PTCH1 gene.

Molecular Pathogenesis: The hallmark molecular event in sporadic BCC is constitutive activation of the Hedgehog (Hh) signaling pathway. In approximately 90% of cases, this is due to inactivating mutations in the PTCH1 tumor suppressor gene or, less commonly, activating mutations in the SMO (Smoothened) gene. In the absence of Hh ligand, PTCH1 inhibits SMO. Mutation of PTCH1 releases this inhibition, allowing SMO to activate the GLI transcription factors, leading to uncontrolled expression of genes promoting cell proliferation and survival.

Clinical & Histopathological Subtypes:

• Nodular BCC: The most common subtype, presenting as a pearly, telangiectatic papule or nodule, often with central ulceration (“rodent ulcer”).
• Superficial BCC: Appears as a scaly, erythematous, slightly elevated patch, often mimicking eczema or psoriasis. It tends to occur on the trunk.
• Infiltrative/Morpheaform BCC: Presents as a sclerotic, scar-like, ill-defined plaque. This subtype is more aggressive, with a higher risk of subclinical extension and recurrence.

Histologically, BCC displays nests of basaloid cells with peripheral palisading, retraction artifact from the surrounding stroma, and variable degrees of keratinization.

3.2. Cutaneous Squamous Cell Carcinoma (cSCC)

Cutaneous squamous cell carcinoma arises from the malignant proliferation of keratinocytes in the epidermal spinous layer. It is the second most common skin cancer and possesses a higher metastatic potential than BCC, though this risk remains relatively low for most primary tumors (approximately 2-5%).

Epidemiology & Etiology: The primary etiological factor is chronic, cumulative UV exposure, leading to actinic damage. Other significant risk factors include immunosuppression (especially solid organ transplant recipients, who have a 65-250 fold increased risk), exposure to chemical carcinogens (e.g., arsenic), chronic inflammatory conditions (e.g., chronic ulcers, burns), and infection with high-risk human papillomavirus (HPV) types.

Molecular Pathogenesis: cSCC development follows a progression from actinic keratosis to carcinoma in situ (Bowen’s disease) and finally to invasive carcinoma. It is driven by the accumulation of mutations in a context of genomic instability. Key genetic alterations include:

• Inactivation of tumor suppressor genes TP53 (very common, often via UV-signature mutations) and CDKN2A (p16).
• Activation of oncogenic pathways such as the RAS-MAPK and PI3K-AKT pathways.
• Amplification of epidermal growth factor receptor (EGFR).
• Telomerase activation via TERT promoter mutations.

The concept of field cancerization is central, where a large area of sun-exposed skin contains clones of keratinocytes with TP53 mutations.

Clinical Features & Risk Stratification: cSCC typically presents as a firm, hyperkeratotic, erythematous papule, plaque, or nodule that may ulcerate. High-risk features that increase the potential for recurrence or metastasis include: diameter ≥2 cm, location on the ear or lip, depth of invasion >2 mm (or Clark level ≥IV), poor differentiation, perineural invasion, and occurrence in an immunosuppressed patient.

3.3. Melanoma

Melanoma originates from the malignant transformation of melanocytes. Although it accounts for only about 1% of skin cancers, it is responsible for the vast majority of skin cancer deaths due to its capacity for rapid metastasis.

Epidemiology & Etiology: Major risk factors include a history of severe, blistering sunburns (especially in childhood), intermittent intense UV exposure, the presence of numerous melanocytic nevi or atypical nevi, fair skin phenotype, family history, and genetic predisposition (e.g., mutations in CDKN2A). The use of tanning beds is a well-established risk factor.

Molecular Pathogenesis: Melanoma is a genetically heterogeneous disease. Oncogenic mutations are often driven by UV radiation, leading to a high mutational burden. Key driver pathways include:

• MAPK Pathway: Constitutively activated in approximately 90% of melanomas. The most common mutation is in the BRAF gene (≈50% of cases), with V600E being the predominant variant. Mutations in NRAS (≈20%) and NF1 (≈15%) are also frequent.
• Cell Cycle Regulation: Inactivation of CDKN2A (p16) is common in both familial and sporadic melanomas.
• Other pathways involving KIT (in acral and mucosal melanomas), GNAQ/GNA11 (in uveal melanoma), and the PI3K-AKT pathway are also implicated.

Clinical Subtypes:

Diagnostic ABCDE Criteria: A mnemonic to aid in the clinical identification of suspicious lesions: Asymmetry, Border irregularity, Color variation, Diameter >6 mm, and Evolving (changing in size, shape, color, or symptoms).

4. Clinical Significance

The clinical significance of skin cancer extends from its substantial public health burden to the paradigm-shifting advances in its systemic treatment, particularly for melanoma. Early detection and appropriate local management remain the cornerstone of cure for the majority of cases. However, the management of locally advanced, unresectable, or metastatic disease is a primary domain of pharmacological intervention.

4.1. Relevance to Drug Therapy

Pharmacotherapy for skin cancer is stratified by cancer type and stage.

Basal Cell Carcinoma: The vast majority of BCCs are cured with local therapies (surgical excision, Mohs surgery, cryotherapy, curettage and electrodesiccation). Systemic drug therapy is reserved for locally advanced or metastatic BCC, which is rare. In this setting, Hedgehog pathway inhibitors (HPIs) such as vismodegib and sonidegib are the standard of care. These agents target the SMO protein, inhibiting the constitutively active Hh pathway. Their use is limited by a high frequency of adverse effects, including muscle spasms, alopecia, dysgeusia, and weight loss, leading to significant discontinuation rates.

Cutaneous Squamous Cell Carcinoma: Most cSCCs are managed surgically. For locally advanced disease, radiation therapy may be employed. Systemic chemotherapy (e.g., platinum-based regimens) has historically been used for metastatic disease with modest efficacy. The landmark development has been the application of immune checkpoint inhibitors (ICIs). cSCC, especially in immunosuppressed patients or those with chronic UV damage, often exhibits a high tumor mutational burden, making it immunogenic. The programmed death-1 (PD-1) inhibitor cemiplimab is approved for metastatic or locally advanced cSCC, demonstrating significant response rates. Pembrolizumab is also used in this context.

Melanoma: The pharmacological landscape for advanced melanoma has been revolutionized over the past decade. Treatment is guided by molecular testing (e.g., for BRAF V600 mutations). Two broad, and sometimes sequential, categories of systemic therapy are used:

1. Targeted Therapy: For BRAF-mutant melanoma (≈50% of cases), combination therapy with a BRAF inhibitor (e.g., dabrafenib, vemurafenib) plus a MEK inhibitor (e.g., trametinib, cobimetinib) is standard. This dual blockade inhibits the MAPK pathway more effectively and reduces the risk of cutaneous toxicities and secondary resistance compared to BRAF inhibitor monotherapy. Response rates are high, but resistance typically develops within a year.
2. Immunotherapy: Immune checkpoint inhibitors, which block inhibitory receptors on T-cells or their ligands on tumor cells, have demonstrated durable responses in a subset of patients. Agents include:
   • Anti-CTLA-4: Ipilimumab.
   • Anti-PD-1: Nivolumab, pembrolizumab.
   • Combination Ipilimumab + Nivolumab: Higher response rates than monotherapy but with increased immune-related adverse events (irAEs).

   These therapies can induce long-term survival in a proportion of patients with metastatic disease, a previously unattainable goal with chemotherapy.

4.2. Pharmacological Prevention

Pharmacological agents also play a role in chemoprevention, particularly in high-risk populations. Nicotinamide (vitamin B3) has been shown in randomized trials to reduce the rate of new NMSCs in patients with a history of multiple skin cancers. Its proposed mechanism involves the correction of UV-induced cellular energy depletion and reduction of immunosuppression. For actinic keratoses, topical field-directed therapies such as 5-fluorouracil, imiquimod, ingenol mebutate, and diclofenac are used to treat visible lesions and subclinical damage, thereby reducing the risk of progression to cSCC.

5. Clinical Applications and Examples

5.1. Case Scenario 1: High-Risk Cutaneous Squamous Cell Carcinoma

A 68-year-old male, Fitzpatrick skin type II, with a 15-year history of renal transplantation maintained on tacrolimus and mycophenolate mofetil, presents with a 2.5 cm, indurated, ulcerated nodule on the left pinna. A shave biopsy reveals a moderately differentiated invasive squamous cell carcinoma with perineural invasion. Staging imaging with CT of the head/neck/chest shows no evidence of nodal or distant metastasis.

Problem-Solving Approach:

1. Risk Stratification: This tumor has multiple high-risk features: location on the ear, diameter >2 cm, perineural invasion, and occurrence in an immunocompromised host. This places him at a significantly elevated risk for local recurrence and nodal metastasis.
2. Local Management: Wide local excision with margin assessment (likely requiring Mohs micrographic surgery given the location and high-risk features) is the primary treatment. Given the perineural invasion, adjuvant radiation therapy to the primary site and potentially the draining nodal basin may be considered.
3. Systemic Considerations & Pharmacist’s Role: The patient’s immunosuppressive regimen is a major contributing factor. In consultation with the transplant team, a risk-benefit assessment regarding potential reduction of immunosuppression must be made, balancing the risk of skin cancer progression against the risk of graft rejection. The pharmacist would be involved in managing this complex medication regimen. Furthermore, the patient requires aggressive education on sun protection and regular skin surveillance, as the risk of developing additional NMSCs is extremely high.
4. Future Systemic Therapy: Should he develop locally advanced or metastatic disease not amenable to surgery or radiation, systemic therapy with a PD-1 inhibitor like cemiplimab would be a primary consideration. The pharmacist would be crucial in educating the patient about potential irAEs (e.g., colitis, pneumonitis, endocrinopathies) and the need for prompt reporting of symptoms.

5.2. Case Scenario 2: BRAF-Mutant Metastatic Melanoma

A 45-year-old female presents with a rapidly growing, pigmented nodule on her upper back. Excisional biopsy reveals a 3.2 mm thick, ulcerated, nodular melanoma, BRAF V600E mutation-positive. Sentinel lymph node biopsy is positive in one axillary node. A subsequent PET-CT scan reveals multiple pulmonary and hepatic metastases.

Problem-Solving Approach:

1. Staging and Prognosis: This is Stage IV (distant metastasis) melanoma (AJCC 8th Edition). The prognosis, while improved with modern therapies, remains guarded.
2. Therapeutic Decision-Making: Two first-line systemic options exist: combined BRAF/MEK inhibitor targeted therapy or immunotherapy with anti-PD-1 monotherapy or combination ipilimumab/nivolumab. The choice is influenced by:
   • Tumor Burden & Symptom Load: Targeted therapy (e.g., dabrafenib + trametinib) often induces rapid tumor regression (within 1-2 weeks), making it preferable for patients with high symptomatic burden or rapidly progressive disease.
   • Durability of Response: Immunotherapy, while slower to act, may offer more durable, long-term responses in a subset of patients.
   • Toxicity Profiles: BRAF/MEK inhibitors are associated with pyrexia, fatigue, arthralgias, cutaneous events (e.g., photosensitivity, squamous proliferations), and ocular toxicity. Immunotherapy can cause potentially severe irAEs affecting any organ system. The patient’s comorbidities and preferences must guide the choice.
3. Pharmacist’s Role in Management: For targeted therapy, the pharmacist ensures understanding of dosing schedules, counsels on sun avoidance and skin care, and monitors for and manages adverse effects like fever syndromes. For immunotherapy, the pharmacist plays a critical role in patient education about irAEs, emphasizing the necessity of early reporting of symptoms like diarrhea, cough, or rash to facilitate timely intervention with corticosteroids or other immunosuppressants.
4. Sequencing Therapy: Resistance to targeted therapy typically develops. Upon progression, switching to immunotherapy is a common strategy. The reverse sequence (immunotherapy followed by targeted therapy) may also be employed, though the efficacy of targeted therapy after immunotherapy failure may be reduced.

5.3. Application to Specific Drug Classes

Hedgehog Pathway Inhibitors (e.g., Vismodegib): Used in advanced BCC. The dosing regimen (150 mg orally daily) is continuous until progression or intolerable toxicity. A key pharmacological challenge is adherence due to the chronicity of treatment and the high prevalence of adverse effects that impact quality of life. Management strategies include proactive symptom management and dose interruptions rather than reductions, as the latter may compromise efficacy.

BRAF/MEK Inhibitors (e.g., Dabrafenib + Trametinib): A classic example of rational combination therapy to overcome resistance. BRAF inhibitor monotherapy leads to paradoxical activation of the MAPK pathway in wild-type BRAF cells and rapid feedback reactivation via MEK. Adding a MEK inhibitor blocks this escape mechanism. Dosing schedules differ (dabrafenib twice daily, trametinib once daily), requiring clear patient instruction. Drug interactions are significant, as both are primarily metabolized by CYP3A4, necessitating caution with concomitant inducers or inhibitors.

Immune Checkpoint Inhibitors (e.g., Pembrolizumab): These agents do not directly target the tumor but modulate the patient’s immune system. Their pharmacokinetics are characterized by long half-lives (≈3 weeks), allowing for dosing intervals of every 3 or 6 weeks. Their efficacy correlates with biomarkers such as PD-L1 expression and tumor mutational burden, but these are imperfect predictors. The management of irAEs is a core competency, requiring algorithms based on toxicity grade, often involving high-dose corticosteroids (e.g., prednisone 1-2 mg/kg/day) and potentially other immunosuppressants like infliximab for colitis.

6. Summary and Key Points

• Skin cancers are primarily categorized into melanoma (from melanocytes) and non-melanoma skin cancers (BCC and cSCC, from keratinocytes). Their incidence is strongly linked to ultraviolet radiation exposure.
• Basal Cell Carcinoma is the most common human cancer. It is locally destructive but rarely metastatic. Molecular pathogenesis centers on constitutive Hedgehog pathway activation (e.g., PTCH1 mutations). Management is primarily surgical; advanced disease is treated with Hedgehog pathway inhibitors (vismodegib, sonidegib).
• Cutaneous Squamous Cell Carcinoma has a higher metastatic potential than BCC. It arises from actinic damage (field cancerization) and is associated with TP53 mutations. High-risk features guide management. Metastatic disease is treated with immune checkpoint inhibitors (cemiplimab) or chemotherapy.
• Melanoma is the most lethal skin cancer due to its metastatic propensity. Prognosis of primary disease is determined by Breslow thickness, ulceration, and mitotic rate. Molecular drivers include BRAF (≈50%), NRAS, and NF1 mutations.
• Systemic Therapy for Advanced Melanoma is divided into:
  1. Targeted Therapy: BRAF + MEK inhibitor combinations (e.g., dabrafenib + trametinib) for BRAF-mutant disease. Characterized by high response rates but limited durability due to resistance.
  2. Immunotherapy: Immune checkpoint inhibitors (anti-PD-1: nivolumab, pembrolizumab; anti-CTLA-4: ipilimumab). Can induce durable, long-term responses but are associated with immune-related adverse events requiring vigilant management.
• Prevention through sun protection (sunscreen, protective clothing, avoidance) remains paramount. Nicotinamide may be used for chemoprevention in high-risk patients.
• Clinical Pearls:
  • The “ABCDE” criteria are a vital tool for the clinical detection of melanoma.
  • In transplant patients, the risk of cSCC is dramatically increased, and management involves a balance between oncological control and graft preservation.
  • Pharmacists are essential in managing complex oral targeted therapies, monitoring for and mitigating adverse effects of both targeted and immunotherapies, and ensuring patient adherence and education.
  • Resistance mechanisms to targeted therapies (e.g., secondary BRAF mutations, pathway reactivation) are an active area of research and future drug development.

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