Cancer of the Skin¶
Chapter 81 | Part 4: Oncology and Hematology · Part 4 – Oncology: Solid Tumors · Chapter 81
Key Clinical Points¶
- Melanoma accounts for over half of deaths from skin cancer; incidence is increasing in the US.
- The ABCDEs rule (Asymmetry, Border irregularity, Color variegation, Diameter >6 mm, Evolving) is the primary screening tool.
- Breslow thickness is the most important clinical prognostic factor for recurrence and survival.
- CDKN2A germline mutations account for 20–40% of hereditary melanomas; BRAF V600E mutations are found in 40–50% of cutaneous melanomas.
- Sentinel lymph node biopsy (SLNB) is recommended for tumors >1 mm thick or ulcerated T1 tumors.
- Adjuvant anti-PD-1 immunotherapy significantly reduces recurrence risk (by 50%) in stage IIIB/C melanoma.
- Dark-skinned populations have 10–20× lower incidence but higher stage at diagnosis and worse outcomes.
- Non-sun-exposed melanomas (acral, mucosal) have different biology and poorer prognosis.
- Wide excision margins depend on Breslow thickness: 0.5–1.0 cm for MIS, 1 cm for T1, 1–2 cm for T2, and 2 cm for T3/T4.
- Dermoscopy is a critical tool for evaluating pigment patterns and lesion architecture.
1. DEFINITION & OVERVIEW¶
• Melanoma: ◦ Definition: An aggressive malignancy arising from melanocytes (pigment-producing cells derived from the neural crest). ◦ Noncutaneous Melanomas: Includes mucosal and ocular types; these possess distinct biology and poorer responses to immunotherapy. • Nonmelanoma Skin Cancers (NMSCs): ◦ Includes Basal Cell Carcinoma (BCC) and Squamous Cell Carcinoma (SCC). ◦ These are increasing in prevalence.
2. EPIDEMIOLOGY¶
• Risk by Skin Pigmentation: ◦ High-eumelanin populations: 1/100,000/year. ◦ Low-eumelanin populations: 27/100,000/year. • Demographics: ◦ Men are affected 1.4× more frequently than women. ◦ Median age at diagnosis: 66 years. • Trends: ◦ Mortality rates decreased by 5–7% annually post-2013 due to immunotherapy (e.g., ipilimumab, vemurafenib). • US Statistics (2024): ◦ Men: 59,170 cases (5th leading cancer). ◦ Women: 41,460 cases (6th leading cancer). • High-Risk Groups: ◦ Dark-skinned populations: 10–20× lower incidence but higher stage at diagnosis and worse outcomes. ◦ Non-sun-exposed melanomas (acral, mucosal): More common in nonwhite populations; carry poorer prognosis.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
• Genetic Susceptibility: ◦ CDKN2A germline mutations: 20–40% of hereditary melanomas. ◦ MC1R variants: Moderate-risk factor; reduce eumelanin production, increasing UV susceptibility. • Driver Mutations: ◦ BRAF V600E: Found in 40–50% of cutaneous melanoma (more common in younger patients with intermittent sun exposure). ◦ NRAS: ~20% prevalence. ◦ TERT promoter mutations: Correlate with poor prognosis and metastasis. • Pathways: ◦ UV-induced mutations in MAP kinase and PI3K/AKT pathways drive tumorigenesis. • Genomic Classification: ◦ BRAF/RAS/NF1-mutated vs. triple wild-type tumors have distinct prognostic profiles.
3.1 Genetic Susceptibility¶
• CDKN2A (chromosome 9p21): Encodes p16 and ARF; regulates cell cycle arrest and apoptosis. • Other Risk Genes: CDK4, MITF, BAP1, POT1, TERT (associated with familial melanoma syndromes).
4. CLINICAL FEATURES¶
• Screening Tools: ◦ ABCDE Rule: Primary tool for identifying suspicious lesions. ◦ "Ugly duckling" rule: Identifying atypical nevi compared to others on the same individual. • Diagnostic Aids: ◦ Dermoscopy: Used to evaluate pigment patterns and lesion architecture.
4.1 ABCDEs of Melanoma Detection¶
• Asymmetry: Benign lesions are usually symmetric. ◦ Border irregularity: Most nevi have clear borders. ◦ Color variegation: Benign lesions show uniform pigment. ◦ Diameter >6 mm: Size of a pencil eraser. ◦ Evolving: Changes in size, shape, color, or symptoms (bleeding, itching).
4.2 Types of Melanoma¶
• Superficial spreading melanoma: Most common subtype. ◦ Nodular melanoma: Aggressive; characterized by vertical growth phase. ◦ Acral lentiginous melanoma: Common in dark-skinned populations. ◦ Mucosal and ocular melanomas: Distinct biology, poor prognosis.
5. DIFFERENTIAL DIAGNOSIS¶
• Benign lesions: Symmetric, regular borders, uniform color. • NMSCs: ◦ BCC: Characterized by rolled edges and telangiectasia (see Figure 4). ◦ SCC: Often presents as an ulcerated, firm plaque. • Atypical nevi: Larger than 6 mm, irregular borders, multiple colors. • Melanoma in situ (MIS): Intraepidermal proliferation without dermal invasion.
6. INVESTIGATIONS & DIAGNOSIS¶
- Initial Examination: Perform full-body skin examination with bright lighting and dermoscopy.
- Biopsy: Obtain excisional biopsy with 1–3 mm margins for histologic assessment.
- Staging: ◦ Determine Breslow thickness (vertical depth) and ulceration status. ◦ Sentinel lymph node biopsy (SLNB): Perform if T1 is ulcerated or >1 mm thick.
- Imaging: ◦ CT/MRI: Used to evaluate for metastatic disease. ◦ PET-CT: Utilized for staging in advanced disease.
6.1 Biopsy & Pathology¶
• Procedure: Excisional biopsy preferred for diagnosis and margin assessment. ◦ Histologic Subtypes: Lentiginous, nodular, acral, mucosal. ◦ Immunohistochemistry: S100, HMB-45, Melan-A used for melanoma confirmation.
6.2 Staging & Imaging¶
• AJCC Staging: Based on T (thickness), N (lymph node involvement), and M (metastasis). ◦ SLNB Criteria: Recommended for T1 ulcerated or >1 mm tumors. ◦ Metastatic Workup: CT of chest/abdomen, brain MRI, PET-CT for advanced disease.
7. MANAGEMENT & TREATMENT¶
- Management of Clinically Localized Melanoma (Stage I, II): ◦ Wide Excision: Perform excision with margins based on Breslow thickness. ◦ 0.5–1.0 cm for MIS ◦ 1 cm for T1 ◦ 1–2 cm for T2 ◦ 2 cm for T3/T4
- Management of Regionally Metastatic Melanoma (Stage III): ◦ Sentinel Lymph Node Biopsy: Indicated for T1 ulcerated or >1 mm tumors. ◦ Adjuvant Therapy: Administer anti-PD-1 (e.g., pembrolizumab) to reduce recurrence risk by 50% in high-risk cases (IIIB/C).
- Treatment of Metastatic Melanoma (Stage IV): ◦ Targeted Therapy: Use BRAF/MEK inhibitors for patients with BRAF V600E mutations. ◦ Dabrafenib + Trametinib: 150 mg dabrafenib BID + 2 mg trametinib QD (Oral). ◦ Other options include vemurafenib, encorafenib (BRAF) and cobimetinib, binimetinib (MEK). ◦ Immunotherapy Monotherapy: ◦ Nivolumab: 360 mg IV every 3 weeks. ◦ Pembrolizumab: Alternative to nivolumab. ◦ Combination Immunotherapy: ◦ Ipilimumab + Nivolumab: 3 mg/kg ipilimumab + 1 mg/kg nivolumab IV every 3 weeks for 4 cycles. ◦ Other Options: T-cell engagers (e.g., Tebentafusp for uveal melanoma), Cytokine-based (High-dose IL-2), Oncolytic virus (Talimogene laherparepvec).
Treatment Regimens (Table 81-4)¶
• BRAF/MEK Inhibitors: Dabrafenib + Trametinib; Side effects: Cutaneous toxicity, fever. ◦ Anti-PD-1 Monotherapy: Nivolumab or Pembrolizumab; Response rates ~30–40%. ◦ Combination Therapy: Ipilimumab + Nivolumab; Higher response but higher toxicity (Colitis, hepatitis, hypophysitis). ◦ Other Options: T-cell engagers (Tebentafusp for uveal melanoma), Cytokine-based (High-dose IL-2), Oncolytic virus (Talimogene laherparepvec).
8. PROGNOSIS & COMPLICATIONS¶
• Prognostic Factors: Based on Breslow thickness, ulceration, and SLNB status. • 5-Year Survival Estimates (Table 81-3): ◦ Stage 0: >99% ◦ Stage IB: 94% ◦ Stage IIB: 81–83% ◦ Stage IIIA: 71–88% ◦ Stage IIIC: 44–60% ◦ Stage IV M1a: 50% at 5 years ◦ Stage IV M1c: ~25% at 5 years. • Complications: ◦ Local recurrence (1–2%). ◦ Distant metastasis (Stage IV). ◦ Treatment-related toxicity from immunotherapy.
9. SPECIAL CONSIDERATIONS¶
• Genetic Counseling: Indicated for patients with CDKN2A, BAP1, or POT1 mutations. • High-Risk Patients: Implement total-body photography and dermoscopy surveillance. • Non-sun-exposed Melanomas: These cases have poorer prognosis; consider genetic testing in familial cases.
10. KEY PEARLS & CLINICAL TRAPS¶
• Clinical Trap: Melanoma in situ (MIS) may mimic benign nevi but requires complete excision. • Pearl: BRAF testing guides targeted therapy in 40–50% of cutaneous melanomas. • Clinical Trap: Acral and mucosal melanomas often present at advanced stages with poor outcomes. • Risk Factor Highlight (Table 81-1): ◦ CDKN2A mutation carriers have a high relative risk of 14–28. ◦ Indoor tanning in women aged <30 has a relative risk of 6.0.
Reference Tables¶
TABLE 81-1 Melanoma Risk Factors and Relative Risk¶
Harrison's 22e, p.600
| RISK LEVEL | RISK FACTOR | RELATIVE RISK |
|---|---|---|
| detavelE | 1 atypical nevus versus 0 | 1.5 |
| Total common nevi, 16+ versus <15 | 1.5 | |
| Blue eye color versus dark | 1.5 | |
| Hazel eye color versus dark | 1.5 | |
| Green eye color versus dark | 1.6 | |
| Light brown hair versus dark | 1.6 | |
| Indoor tanning in any gender versus never | 1.7 | |
| Fitzpatrick skin type II versus IV | 1.8 | |
| Fitzpatrick skin type III versus IV | 1.8 | |
| History of sunburn versus no sunburn | 2.0 | |
| Blond hair versus dark | 2.0 | |
| 2 atypical nevi versus 0 | 2.1 | |
| Fitzpatrick skin type I versus IV | 2.1 | |
| High density of freckles versus none | 2.1 | |
| Total common nevi 41–60 versus <15 | 2.2 | |
| Family history of melanoma in 1 or more first-degree relatives |
||
| 3 atypical nevi versus 0 | ||
| Total common nevi 61–80 versus <15 | ||
| Red hair versus dark | ||
| Chronic lymphocytic leukemia | ||
| History of actinic keratoses and/or keratinocyte carcinoma versus not |
||
| Indoor tanning in women aged 30–39 versus never |
||
| 4 atypical nevi versus 0 | ||
| hgiH | Transplant recipient versus not | 2.2–4.6 |
| Indoor tanning in women aged <30 versus never |
6.0 | |
| 5 atypical nevi versus 0 | 6.4 | |
| Total common nevi 81–120 versus <15 | 6.9 | |
| Personal history of melanoma | 8.2–13.4 | |
| CDK2NA mutation carrier | 14–28 |
TABLE 81-2 Major Histologic Subtypes of Malignant Melanoma TYPE Lentigo maligna¶
Harrison's 22e, p.601
| TYPE | SITE | APPEARANCE | ASSOCIATED MUTATIONS |
|---|---|---|---|
| Lentigo maligna | Sun-exposed surfaces, particularly malar region and temple |
In flat portions, brown and tan predominate, but whitish gray sometimes present; in nodules, reddish brown, bluish gray, bluish black. |
BRAF 28% NRAS 15% PTEN |
| Any (more common on upper back and, in women, lower legs) |
Brown mixed with bluish red, bluish black, reddish brown, and often whitish pink. The lesion border is often visibly and/or palpably raised. |
||
| Nodular | Any | Reddish blue, purple, or bluish black; can be uniform or mixed with brown and black. |
BRAF 47% NRAS 33% |
| Palm, sole, nail bed, mucous membrane |
In flat portions, dark brown; in raised lesions (plaques), brown-black or blue-black. |
||
| Desmoplastic | Any (more common on head and neck) |
Highly variable; pigmentation is frequently absent. Can mimic nodular basal cell carcinoma. |
MAPK and PI3K 73% High tumor mutational burden, BRAF and NRAS uncommon |
| Choroid, ciliary body, iris | Dome or mushroom shaped. Display low internal reflectivity on ocular ultrasound. |
||
| Mucosal | Oral cavity, conjunctiva, sinuses, alimentary tract including rectum and anus, vulva |
Can display radial growth pattern with ABCDE features associated with cutaneous melanomas. Often present with advanced tumors infiltrating local tissues |
KIT, NRAS, KRAS or BRAF NF1 |
TABLE 81-3 Staging and Survival STAGE 0 IA IB¶
Harrison's 22e, p.603
| STAGE | TNM | 10-YEAR MELANOMA- SPECIFIC SURVIVAL ESTIMATE |
|---|---|---|
| 0 | TisN0M0 | >99% |
| T1aN0M0, T1bN0M0 | ||
| IB | T2aN0M0 | 94% |
| T2b-T3aN0M0 | ||
| IIB | T3b-T4aN0M0 | 81–83% |
| T4bN0M0 | ||
| IIIA | T1a-T2aN1a-2aM0 | 71–88% |
| T2b-T3aN1a-N2bM0 | ||
| IIIC | T3b-4bN1a-N3cM0 | 44–60% |
| T4bN3a-N3cM0 | ||
| IV M1a | Any T, any N, skin, soft tissue, or distant nodal sites |
50% at 5 years |
| Any T, any N, lung + any M1a sites | ||
| IV M1c | Any T, any N, skin, non-CNS visceral disease, any M1a or M1b sites |
~25% at 5 years |
| Any T, any N, CNS metastasis + any M1a,b,c sites |
TABLE 81-4 Treatment Options for Metastatic Melanoma Immunotherapy¶
Harrison's 22e, p.604
- Immunotherapy
Immune checkpoint blockade
Anti-PD-1: pembrolizumab or nivolumab
Anti-CTLA-4: ipilimumab
Combined ipilimumab and nivolumab
Combined relatlimab (anti-LAG-3) and nivolumab
T-cell engager
Tebentafusp (selected patients with uveal melanoma)
Cytokine-based immunotherapy
High-dose interleukin 2
Clinical trials investigating adoptive cellular therapy with tumor-infiltrating
lymphocytes for advanced disease and personalized vaccine targeting
neoantigens in high-risk resected melanoma
Oncolytic virus
Talimogene laherparepvec
Targeted therapies
BRAF inhibitors: vemurafenib, dabrafenib, encorafenib
MEK inhibitors: trametinib, cobimetinib, binimetinib
Local modalities
Surgery
Stereotactic radiation