Cancer of the Skin¶
Chapter 81 | Part 4: Oncology and Hematology
KEY CLINICAL POINTS¶
- Melanoma is the most lethal form of skin cancer, with incidence rates varying by ethnicity and UV exposure.
- Genetic factors like CDKN2A mutations and MC1R polymorphisms significantly increase melanoma risk.
- Early detection via ABCDE criteria and sentinel lymph node biopsy (SLNB) is critical for improving survival.
- Immunotherapy (e.g., anti-PD-1, anti-CTLA-4) and targeted therapy (BRAF/MEK inhibitors) have revolutionized advanced melanoma treatment.
- Nonmelanoma skin cancers (NMSCs) like basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are more common than melanoma.
1. DEFINITION & OVERVIEW¶
Melanoma is a malignant tumor of melanocytes, arising from neural crest-derived cells. Cutaneous melanoma accounts for ~50% of skin cancer deaths. Noncutaneous melanomas (e.g., uveal, mucosal) have distinct biology and poorer prognosis. Skin testing and tryptase levels help assess hypersensitivity reactions to chemotherapy.
Table 81-1 Melanoma Risk Factors and Relative Risk¶
| RISK LEVEL | RISK FACTOR | RELATIVE RISK |
|---|---|---|
| 1 | atypical nevus versus 0 | 1.5 |
| 1 | Total common nevi, 16+ versus <15 | 1.5 |
| 1 | Blue eye color versus dark | 1.5 |
| 1 | Hazel eye color versus dark | 1.5 |
| 1 | Green eye color versus dark | 1.6 |
| 1 | Light brown hair versus dark | 1.6 |
| 1 | Indoor tanning in any gender versus never | 1.7 |
| 1 | Fitzpatrick skin type II versus IV | 1.8 |
| 1 | Fitzpatrick skin type III versus IV | 1.8 |
| 1 | History of sunburn versus no sunburn | 2.0 |
| 1 | Blond hair versus dark | 2.0 |
| 2 | atypical nevi versus 0 | 2.1 |
| RISK LEVEL | RISK FACTOR | RELATIVE RISK |
|---|---|---|
| 2 | Fitzpatrick skin type I versus IV | 2.1 |
| 2 | High density of freckles versus none | 2.1 |
| 2 | Total common nevi 41–60 versus <15 | 2.2 |
| 2 | Family history of melanoma in 1 or more first-degree relatives | 1.7–3.0 |
| 3 | atypical nevi versus 0 | 3.0 |
| 3 | Total common nevi 61–80 versus <15 | 3.3 |
| 3 | Red hair versus dark | 3.6 |
| 3 | Chronic lymphocytic leukemia | 3.9 |
| 3 | History of actinic keratoses and/or keratinocyte carcinoma versus not | 4.3 |
| 3 | Indoor tanning in women aged 30–39 versus never | 4.3 |
| 4 | atypical nevi versus 0 | 4.4 |
| 4 | Transplant recipient versus not | 2.2–4.6 |
| 4 | Indoor tanning in women aged <30 versus never | 6.0 |
| 5 | atypical nevi versus 0 | 6.4 |
| 5 | Total common nevi 81–120 versus <15 | 6.9 |
| 5 | Personal history of melanoma | 8.2–13.4 |
| 5 | CDK2NA mutation carrier | 14–28 |
1.1 Subtopic¶
Melanoma is classified by histologic subtypes (e.g., superficial spreading, nodular, acral lentiginous) and genomic alterations (e.g., BRAF, NRAS mutations).
2. EPIDEMIOLOGY¶
Melanoma incidence is 1/100,000 in high eumelanin populations vs. 27/100,000 in low eumelanin populations. Men are slightly more affected (1.4:1). Median age at diagnosis is 66. Mortality rates are decreasing due to immunotherapy, but remain higher in older males. Nonwhite populations have lower incidence but higher mortality due to delayed diagnosis.
Table 81-2 Major Histologic Subtypes of Malignant Melanoma¶
| TYPE | SITE | APPEARANCE | ASSOCIATED MUTATIONS |
|---|---|---|---|
| Lentigo maligna | Sun-exposed surfaces | Brown/tan with whitish gray | BRAF 28%, NRAS 15%, PTEN |
| Superficial spreading | Upper back, lower legs | Brown mixed with bluish red | BRAF 57%, NRAS 18% |
| Nodular | Any | Reddish blue, purple | BRAF 47%, NRAS 33% |
| TYPE | SITE | APPEARANCE | ASSOCIATED MUTATIONS |
|---|---|---|---|
| Acral lentiginous | Palm, sole, nail bed | Dark brown | NRAS 25%, c-KIT 5-10% |
| Desmoplastic | Head/neck | Variable pigmentation | MAPK and PI3K 73% |
| Uveal | Choroid, ciliary body | Dome-shaped | BAP1, GNAQ, GNA11 |
| Mucosal | Oral cavity, conjunctiva | Radial growth pattern | KIT, NRAS, KRAS, BRAF, NF1 |
2.1 Subtopic¶
Global incidence is rising, with 324,635 cases in 2020. Dark-skinned populations have 10–20x lower incidence but worse outcomes due to delayed detection.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
UV radiation (UVR) is the primary cause, with DNA damage and impaired repair mechanisms. Genetic factors include CDKN2A mutations (70% of cutaneous melanomas) and MC1R polymorphisms. Non-UVR-related melanomas (e.g., acral, mucosal) have distinct molecular pathways.
3.1 Subtopic¶
Driver mutations include BRAF (50%), NRAS (10%), c-KIT (5-10%), and NF1 (48% of BRAF/ NRAS wild-type tumors). These mutations disrupt MAP kinase and PI3K/AKT pathways.
4. CLINICAL FEATURES¶
ABCDE criteria: asymmetry, border irregularity, color variegation, diameter >6 mm, evolving lesions. Cutaneous melanoma often presents as a pigmented lesion with ulceration. Noncutaneous melanomas (e.g., uveal, mucosal) may present with different clinical features.
4.1 Subtopic¶
Metastatic melanoma may present with skin nodules, lymphadenopathy, or visceral involvement. Elevated LDH correlates with poor prognosis.
5. DIFFERENTIAL DIAGNOSIS¶
Benign nevi, seborrheic keratoses, dermatofibromas, and other skin cancers (e.g., basal cell carcinoma, squamous cell carcinoma). Atypical nevi and melanoma may share similar features, requiring dermoscopy or biopsy for distinction.
6. INVESTIGATIONS & DIAGNOSIS¶
Clinical evaluation with ABCDE criteria, dermoscopy, and biopsy. Sentinel lymph node biopsy (SLNB) is used for staging. Molecular testing for BRAF, NRAS, and c-KIT mutations guides targeted therapy.
Table 81-3 Staging and Survival¶
| STAGE | TNM | 10-YEAR MELANOMA-SPECIFIC SURVIVAL ESTIMATE |
|---|---|---|
| 0 | TisN0M0 | >99% |
| IA | T1aN0M0, T1bN0M0 | 98% |
| STAGE | TNM | 10-YEAR MELANOMA-SPECIFIC SURVIVAL ESTIMATE |
|---|---|---|
| IB | T2aN0M0 | 94% |
| IIA | T2b-T3aN0M0 | 88% |
| IIB | T3b-T4aN0M0 | 81–83% |
| IIC | T4bN0M0 | 75% |
| IIIA | T1a-T2aN1a-2aM0 | 71–88% |
| IIIB | T2b-T3aN1a-N2bM0 | 60–77% |
| IIIC | T3b-4bN1a-N3cM0 | 44–60% |
| IID | T4bN3a-N3cM0 | 24–30% |
| IV M1a | Any T, any N, skin, soft tissue | 50% at 5 years |
| IV M1c | Any T, any N, non-CNS visceral | ~25% at 5 years |
| IV M1d | Any T, any N, CNS metastasis | <5% at 5 years |
6.1 Subtopic¶
Imaging (CT, MRI, PET) is used for staging and detecting metastases. TMB and GEPs may predict response to immunotherapy.
7. MANAGEMENT & TREATMENT¶
Surgical excision with margins (0.5–2 cm) is the primary treatment. Immunotherapy (anti-PD-1, anti-CTLA-4) and targeted therapy (BRAF/MEK inhibitors) are used for advanced disease. Mohs surgery is preferred for cosmetically sensitive areas.
Table 81-4 Treatment Options for Metastatic Melanoma¶
| IMMUNOTHERAPY | TARGETED THERAPIES | LOCAL MODALITIES |
|---|---|---|
| Anti-PD-1: pembrolizumab or nivolumab | BRAF inhibitors: vemurafenib, dabrafenib | Surgery |
| Anti-CTLA-4: ipilimumab | MEK inhibitors: trametinib, cobimetinib | Stereotactic radiation |
| Combined ipilimumab and nivolumab | Oncolytic virus: talimogene laherparepvec | Mohs surgery |
7.1 Subtopic¶
Adjuvant therapy includes immunotherapy (e.g., pembrolizumab, nivolumab) and targeted therapy (e.g., vemurafenib, trametinib) for high-risk stage III melanoma.
8. PROGNOSIS & COMPLICATIONS¶
Prognosis is determined by Breslow thickness, ulceration, and metastasis. Complications include metastatic spread to skin, lymph nodes, lungs, liver, or brain. Recurrence rates are higher in older males and those with high mitotic rates.
8.1 Subtopic¶
Patients with stage IV melanoma had <10% 15-year survival pre-2010; immunotherapy improved survival to ~50% for M1a disease.
9. SPECIAL CONSIDERATIONS¶
Pregnancy: Melanoma management is similar to nonpregnant patients, but surgery should avoid third trimester. Pediatrics: UV protection is critical. Elderly: Higher risk of delayed diagnosis and poorer outcomes. Immunocompromised: Increased risk of NMSC and aggressive melanoma.
9.1 Subtopic¶
Dark-skinned populations have higher mortality due to delayed diagnosis. HIV-positive patients have increased NMSC risk.
10. KEY POINTS & CLINICAL PEARLS¶
- Early detection with ABCDE criteria and SLNB improves survival.
- Immunotherapy and targeted therapy have transformed advanced melanoma treatment.
- NMSCs are more common than melanoma but have better prognoses.
- Genetic testing is critical for high-risk patients with multiple nevi or family history.
- UV protection and regular skin exams are essential for prevention.