Melanoma

See Also

Epidemiology

Deaths: 7700 per year in United States predicted 2005
1. Sixth leading cause of death in United States
2. Accounts for 75% of deaths from Skin Cancers
Incidence: 59,580 new U.S. cases estimated for 2005
1. Accounts for only 3-5% of Skin Cancers
2. Most common cancer in women age 25 to 29 years (and second most common cancer ages 30-35 years)
Increasing Incidence
1. Has doubled every 10 years (related to ozone deplete)
2. One in 74 Americans develop Melanoma yearly
Increasing risk with age
1. Incidence in age under 14 years: 0.3%
2. Incidence in age under 20 years: 2%
3. Median age of diagnosis: 57 years old
4. Incidence increasing fastest in men over age 65 years

Pathophysiology

Melanocyte malignant transformation
BRAF Mutation (esp. V600) is found in 50% of cases
1. Allows for specific targeted Immunotherapy (Ipilimumab, Nivolumab)

Risk Factors

See Melanoma Risk Factors
Precursor Lesions
1. Lentigo maligna
2. Congenital neoplastic nevi
3. Clark's melanocytic nevi (Dysplastic Nevus)

Classification

Precaution: Melanoma is Melanoma (manage all types aggressively)
Melanoma in Situ
1. Malignant Melanocytes are confined to the Epidermis
2. Excision is typically curative with 5 mm margins
Superficial spreading Melanoma (SSM): 70% of Melanoma
1. More common at age 30-50 years, often on the trunk, and in women often on the legs
2. Initially brown to black lesions develop blue, red, white color variations
3. Form irregular, unusual shapes
4. Initially flat radial growth for months to years and when >2.5 cm vertically grow into Nodules
Nodular Melanoma (NM): 15-20% of Melanoma
1. More common at age 40-60 years and twice as common in men
2. No horizontal growth phase and rapid vertical growth over weeks to months
3. Colors vary from brown or black to red or purple
4. May appear flesh colored (amelanotic nodular Melanoma) and appear more like Basal Cell Carcinoma
5. Most frequently misdiagnosed Melanoma (see differential diagnosis below)
Lentigo maligna Melanoma (LMM): 5-15% of Melanoma
1. More common at age 50-80 years, especially with sun-damaged skin
2. Develops on the face in 90% of cases
3. Develops from the precursor lesion Lentigo maligna (Hutchinson's Freckle)
  1. Lentigo maligna is the in situ form of Lentigo maligna Melanoma
  2. Slowly grows over 5 to 15 years prior to shifting into the invasive Lentigo maligna Melanoma
4. Tumors develop in center of Lentigo maligna
  1. Typically invades after >5 cm in diameter
  2. Invasion can not be determined by external skin exam
Amelanocytic Melanoma: <5% of Melanoma
1. Nonpigmented Melanoma
2. Broad differential diagnosis: Eczema, fungal dermatitis, Basal Cell Carcinoma, Squamous Cell Carcinoma
3. Delay in diagnosis is common and often diagnosed at a more advance stage
Acral Lentiginous Melanoma (ALM): 2-8% of Melanoma
1. Represents up to 75% of Melanomas in non-caucasian patients (black or asian ethnicity)
2. Occurs on acral surfaces
  1. Palms, soles, distal digits (knuckles, fingertips), elbows, knees, ears and mucous membranes
3. Diagnosis often delayed (presenting at more advanced stage with worse outcomes)
  1. Include foot exam with skin exam, especially in non-caucasian patients
Subungual Melanoma: Up to 3.5% of Melanoma
1. Hutchinson Sign is a pigmented longitudinal band under nail plate (Longitudinal Melanonychia)
2. Very aggressive tumor with early metastases even from small lesions
3. Biopsy of lesion including the nail matrix (typically by dermatology)

Differential Diagnosis

Melanoma look-alikes in general
1. Seborrheic Keratosis
2. Irritated nevus
3. Pigmented Basal Cell Carcinoma
4. Lentigo
5. Blue Nevus
6. Angiokeratoma (red to blue vascular lesions)
7. Traumatic Hematoma
8. Venous lake (Phlebectases: soft, blue purple lesions on face, especially lips and ears)
9. Hemangioma
10. Pigmented Actinic Keratosis
Nodular Melanoma
1. Dermatofibroma (amelanotic)
2. Basal Cell Cancer (amelanotic)
3. Hemangioma
4. Seborrheic Keratosis
5. Pyogenic Granuloma

Lab
Histology

Clark's Level
1. Level 1: Epidermis
2. Level 2: Reaches papillary Dermis
3. Level 3: Fills papillary Dermis
4. Level 4: Enters reticular Dermis
5. Level 5: Penetrates subcutaneous fat
Five-year survival related to tumor depth
1. Survival 99%: Depth < 0.85mm
2. Survival 80%: Depth 0.85 to 1.69mm
3. Survival 70%: Depth 1.70 to 3.64mm
4. Survival 40%: Depth > 3.65mm

Staging (AJCC)

In-Situ
1. Stage 0
  1. Confined to Epidermis (99-100% five and ten year survival)
Localized
1. Stage IA
  1. Thickness <1 mm and not ulcerated
  2. Survival: 97% five year survival and 95% ten year survival
2. Stage IB
  1. Thickness 1 mm and ulcerated or 1 to 2 mm and not ulcerated
  2. Survival: 92% five year survival and 86% ten year survival
3. Stage IIA
  1. Thickness 1 to 2 mm and ulcerated or 2 to 4 mm and not ulcerated
  2. Survival: 81% five year survival and 67% ten year survival
4. Stage IIB
  1. Thickness 2 to 4 mm and ulcerated or >4 mm and not ulcerated
  2. Survival: 70% five year survival and 57% ten year survival
5. Stage IIC
  1. Thickness >4 mm and ulcerated
  2. Survival: 53% five year survival and 40% ten year survival
Metastatic
1. Stage III: Regional node metastases
  1. Stage IIIA - Survival: 78% five year survival and 68% ten year survival
  2. Stage IIIB - Survival: 59% five year survival and 43% ten year survival
  3. Stage IIIC - Survival: 40% five year survival and 24% ten year survival
2. Stage IV: Distant metastases
  1. Survival: 15-20% five year survival and 10-15% ten year survival

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)
1. Complete Blood Count (CBC)
2. Liver Function Tests (LFT or hepatic panel)
3. Lactate Dehydrogenase (LDH)
Advanced imaging (indicated for stage III, IV)
1. CT Head, chest and Abdomen and/or
2. PET Scan (eyes to thighs)

Management
Surgical Excision

Local excision with clear margins
1. Melanoma in situ: Margin 0.5 cm
2. Breslow thickness <2 mm: Margin 1 cm
3. Breslow thickness >2 mm: Margin 2 cm
4. Wide margins (>3 cm) no longer recommended
Lymph Node biopsy indicated if Breslow thickness >1mm
1. Sentinel Node biopsy for Breslow thickness 1-4 mm
Mohs Micrographic Surgery indicated where surgical margins are difficult to detect
1. Lentigo maligna
2. Lentigo maligna Melanoma

Management
Chemotherapy and Immunotherapy

Immune Checkpoint Inhibitors
1. PD-1 Inhibitors
  1. Nivolumab (Opdivo)
  2. Pembrolizumab (Keytruda)
2. PD-L1 inhibitors
  1. Atezolizumab (Tecentriq)
3. CTLA-4 inhibitors
  1. Ipilimumab (Yervoy)
4. LAG-3 inhibitors
  1. Relatlimab
Interferon Alfa-2B (Intron A)
1. Effective in increasing relapse-free survival
2. Wheatley (2003) Cancer Treat Rev 29:241-52 [PubMed]
Tumor-infiltrating Lymphocyte (TIL) Therapy
1. Lifileucel (Amtagvi)

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

Prevention

See Melanoma Prevention
Follow-up Immediately for:
1. Pruritic nevus
2. Atypical Nevus Signs
Frequent History and physicals (with comprehensive skin exams) for high risk or Melanoma history
1. Stage 0: Melanoma in situ (confined to Epidermis)
  1. Follow-up yearly
2. Stage I: Thickness <1 mm and no Atypical Nevus syndrome or FHx
  1. Follow-up every 6 to 12 months for 5 years, then yearly as indicated
3. Stage II: Thickness >1 mm or Clark's Level IV
  1. For Stage IIa, follow-up as per Stage I
  2. For Stage IIb
    1. Follow up every 3-6 months for first 2 years, then
    2. Follow up every 3-12 months for next 3 years, then
    3. Follow-up annually as indicated
    4. CBC, chemistry panel, LDH every 6 months (or per oncology recommendations)
    5. Consider Chest XRay
4. Stage III: Regional Metastases
  1. CBC, chemistry panel, LDH every 3-6 months (or per oncology recommendations)
  2. PET/CT Scan and/or CT Scan every 4 to 12 months (or per oncology recommendations)
  3. Consider yearly Brain MRI
  4. Follow up every 3-6 months for first 3 years, then
  5. Follow up every 4-12 months for next 2 years, then
  6. Follow-up annually
5. Stage IV: Distant Metastases (or per oncology recommendations)
  1. Chest XRay, CBC, Liver Function Tests every 3 months (or per oncology recommendations)
  2. PET Scan and/or CT Scan every 2-4 months for first 5 years and then annually
  3. Consider yearly Brain MRI
  4. Follow-up every 3-4 months
References
1. Carek (2024) Am Fam Physician 110(1): 37-44 [PubMed]
2. Wilbur (2014) Am Fam Physician 91(1):29-36 [PubMed]

Prognosis

See Histology and Staging above
Survival rates are better in women
Relative Risk of developing a second primary tumor: 10
1. Second primary cancer develops in 4-8% of Melanoma survivors
2. Melanoma recurrence may occur more than 10-20 years after the initial Melanoma management

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]