II. Epidemiology
- Deaths: 7700 per year in United States predicted 2005
- Sixth leading cause of death in United States
- Accounts for 75% of deaths from Skin Cancers
-
Incidence: 59,580 new U.S. cases estimated for 2005
- Accounts for only 3-5% of Skin Cancers
- Most common cancer in women age 25 to 29 years (and second most common cancer ages 30-35 years)
- Increasing Incidence
- Has doubled every 10 years (related to ozone deplete)
- One in 74 Americans develop Melanoma yearly
- Increasing risk with age
III. Pathophysiology
- Melanocyte malignant transformation
- BRAF Mutation (esp. V600) is found in 50% of cases
- Allows for specific targeted Immunotherapy (Ipilimumab, Nivolumab)
IV. Risk Factors
- See Melanoma Risk Factors
- Precursor Lesions
- Lentigo maligna
- Congenital neoplastic nevi
- Clark's melanocytic nevi (Dysplastic Nevus)
V. Classification
- Precaution: Melanoma is Melanoma (manage all types aggressively)
- Melanoma in Situ
- Malignant Melanocytes are confined to the Epidermis
- Excision is typically curative with 5 mm margins
- Superficial spreading Melanoma (SSM): 70% of Melanoma
- More common at age 30-50 years, often on the trunk, and in women often on the legs
- Initially brown to black lesions develop blue, red, white color variations
- Form irregular, unusual shapes
- Initially flat radial growth for months to years and when >2.5 cm vertically grow into Nodules
- Nodular Melanoma (NM): 15-20% of Melanoma
- More common at age 40-60 years and twice as common in men
- No horizontal growth phase and rapid vertical growth over weeks to months
- Colors vary from brown or black to red or purple
- May appear flesh colored (amelanotic nodular Melanoma) and appear more like Basal Cell Carcinoma
- Most frequently misdiagnosed Melanoma (see differential diagnosis below)
-
Lentigo maligna Melanoma (LMM): 5-15% of Melanoma
- More common at age 50-80 years, especially with sun-damaged skin
- Develops on the face in 90% of cases
- Develops from the precursor lesion Lentigo maligna (Hutchinson's Freckle)
- Tumors develop in center of Lentigo maligna
- Typically invades after >5 cm in diameter
- Invasion can not be determined by external skin exam
- Amelanocytic Melanoma: <5% of Melanoma
- Nonpigmented Melanoma
- Broad differential diagnosis: Eczema, fungal dermatitis, Basal Cell Carcinoma, Squamous Cell Carcinoma
- Delay in diagnosis is common and often diagnosed at a more advance stage
-
Acral Lentiginous Melanoma (ALM): 2-8% of Melanoma
- Represents up to 75% of Melanomas in non-caucasian patients (black or asian ethnicity)
- Occurs on acral surfaces
- Palms, soles, distal digits (knuckles, fingertips), elbows, knees, ears and mucous membranes
- Diagnosis often delayed (presenting at more advanced stage with worse outcomes)
- Include foot exam with skin exam, especially in non-caucasian patients
-
Subungual Melanoma: Up to 3.5% of Melanoma
- Hutchinson Sign is a pigmented longitudinal band under nail plate (Longitudinal Melanonychia)
- Very aggressive tumor with early metastases even from small lesions
- Biopsy of lesion including the nail matrix (typically by dermatology)
VI. Differential Diagnosis
- Melanoma look-alikes in general
- Seborrheic Keratosis
- Irritated nevus
- Pigmented Basal Cell Carcinoma
- Lentigo
- Blue Nevus
- Angiokeratoma (red to blue vascular lesions)
- Traumatic Hematoma
- Venous lake (Phlebectases: soft, blue purple lesions on face, especially lips and ears)
- Hemangioma
- Pigmented Actinic Keratosis
- Nodular Melanoma
- Dermatofibroma (amelanotic)
- Basal Cell Cancer (amelanotic)
- Hemangioma
- Seborrheic Keratosis
- Pyogenic Granuloma
VII. Lab: Histology
- Clark's Level
- Five-year survival related to tumor depth
- Survival 99%: Depth < 0.85mm
- Survival 80%: Depth 0.85 to 1.69mm
- Survival 70%: Depth 1.70 to 3.64mm
- Survival 40%: Depth > 3.65mm
VIII. Staging (AJCC)
- In-Situ
- Stage 0
- Confined to Epidermis (99-100% five and ten year survival)
- Stage 0
- Localized
- Stage IA
- Thickness <1 mm and not ulcerated
- Survival: 97% five year survival and 95% ten year survival
- Stage IB
- Thickness 1 mm and ulcerated or 1 to 2 mm and not ulcerated
- Survival: 92% five year survival and 86% ten year survival
- Stage IIA
- Thickness 1 to 2 mm and ulcerated or 2 to 4 mm and not ulcerated
- Survival: 81% five year survival and 67% ten year survival
- Stage IIB
- Thickness 2 to 4 mm and ulcerated or >4 mm and not ulcerated
- Survival: 70% five year survival and 57% ten year survival
- Stage IIC
- Thickness >4 mm and ulcerated
- Survival: 53% five year survival and 40% ten year survival
- Stage IA
- Metastatic
- Stage III: Regional node metastases
- Stage IIIA - Survival: 78% five year survival and 68% ten year survival
- Stage IIIB - Survival: 59% five year survival and 43% ten year survival
- Stage IIIC - Survival: 40% five year survival and 24% ten year survival
- Stage IV: Distant metastases
- Survival: 15-20% five year survival and 10-15% ten year survival
- Stage III: Regional node metastases
IX. Evaluation: Melanoma Metastases
- Lymph Node exam
- Full skin exam
- Chest XRay
- Labs considered above stage IA (and in all cases of Stage III and IV)
- Complete Blood Count (CBC)
- Liver Function Tests (LFT or hepatic panel)
- Lactate Dehydrogenase (LDH)
- Advanced imaging (indicated for stage III, IV)
X. Management: Surgical Excision
- Local excision with clear margins
- Melanoma in situ: Margin 0.5 cm
- Breslow thickness <2 mm: Margin 1 cm
- Breslow thickness >2 mm: Margin 2 cm
- Wide margins (>3 cm) no longer recommended
-
Lymph Node biopsy indicated if Breslow thickness >1mm
- Sentinel Node biopsy for Breslow thickness 1-4 mm
- Mohs Micrographic Surgery indicated where surgical margins are difficult to detect
XI. Management: Chemotherapy and Immunotherapy
-
Immune Checkpoint Inhibitors
- PD-1 Inhibitors
- PD-L1 inhibitors
- CTLA-4 inhibitors
- LAG-3 inhibitors
- Relatlimab
-
Interferon Alfa-2B (Intron A)
- Effective in increasing relapse-free survival
- Wheatley (2003) Cancer Treat Rev 29:241-52 [PubMed]
- Tumor-infiltrating Lymphocyte (TIL) Therapy
- Lifileucel (Amtagvi)
XII. Precautions: Defusing Myths
- Hairy moles do NOT differentiate benign from malignant
- Do not prophylacticly biopsy benign appearing moles
- Incisional Biopsy into Melanoma does NOT spread tumor
XIII. Prevention
- See Melanoma Prevention
- Follow-up Immediately for:
- Pruritic nevus
- Atypical Nevus Signs
- Frequent History and physicals (with comprehensive skin exams) for high risk or Melanoma history
- Stage 0: Melanoma in situ (confined to Epidermis)
- Follow-up yearly
- Stage I: Thickness <1 mm and no Atypical Nevus syndrome or FHx
- Follow-up every 6 to 12 months for 5 years, then yearly as indicated
- Stage II: Thickness >1 mm or Clark's Level IV
- For Stage IIa, follow-up as per Stage I
- For Stage IIb
- Follow up every 3-6 months for first 2 years, then
- Follow up every 3-12 months for next 3 years, then
- Follow-up annually as indicated
- CBC, chemistry panel, LDH every 6 months (or per oncology recommendations)
- Consider Chest XRay
- Stage III: Regional Metastases
- CBC, chemistry panel, LDH every 3-6 months (or per oncology recommendations)
- PET/CT Scan and/or CT Scan every 4 to 12 months (or per oncology recommendations)
- Consider yearly Brain MRI
- Follow up every 3-6 months for first 3 years, then
- Follow up every 4-12 months for next 2 years, then
- Follow-up annually
- Stage IV: Distant Metastases (or per oncology recommendations)
- Chest XRay, CBC, Liver Function Tests every 3 months (or per oncology recommendations)
- PET Scan and/or CT Scan every 2-4 months for first 5 years and then annually
- Consider yearly Brain MRI
- Follow-up every 3-4 months
- Stage 0: Melanoma in situ (confined to Epidermis)
- References
XIV. Prognosis
- See Histology and Staging above
- Survival rates are better in women
-
Relative Risk of developing a second primary tumor: 10
- Second primary cancer develops in 4-8% of Melanoma survivors
- Melanoma recurrence may occur more than 10-20 years after the initial Melanoma management
XV. References
- Fauci (1998) Harrison's Medicine, 14th ed., McGraw-Hill
- Goldstein (2001) Am Fam Physician 63(7): 1359-68 [PubMed]
- Houghton (1998) Oncology 12:153-77 [PubMed]
- Landis (1999) CA Cancer J Clin 49:8-31 [PubMed]
- Rager (2005) Am Fam Physician 72:269-76 [PubMed]
- Shenenberger (2012) Am Fam Physician 85(2): 161-8 [PubMed]
- Wilbur (2014) Am Fam Physician 91(1):29-36 [PubMed]