Melanoma

Aka: Melanoma, Cutaneous Malignant Melanoma, CMM

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II. Epidemiology

  1. Incidence 2016 to 2020 U.S.
    1. Male: 27 per 100,000 (59,000 U.S. men in 2024)
    2. Female: 17 per 100,000 (41,000 U.S. women in 2024)
  2. Prevalanence U.S.
    1. U.S. Prevalence in 2021: 1.45 Million
    2. Lifetime Prevalence: 2.2%
  3. Incidence by Fitzpatrick Skin Type
    1. Males with Fitzpatrick Skin Types I and II: 38 per 100,000
    2. Females with Fitzpatrick Skin Types I and II: 25 per 100,000
    3. Fitzpatrick Skin Types V and VI: 1 per 100,000
      1. However, when Melanoma is diagnosed in darker skin, it is often advanced with worse outcome
  4. Age at diagnosis
    1. Overall Mean: 65 years (regardless of Fitzpatrick Skin Type)
    2. Women age 25 to 34 years old: 17 per 100,000 (twice the Incidence of men in this age group)
      1. Melanoma is among the top two cancers in U.S. women in this age group
  5. Deaths: 8200 per year in United States predicted 2024
    1. Melanoma mortality has dramatically fallen since 2000 (related to treatment)
    2. Melanoma represents only 1% of Skin Cancers, but accounts for 75% of deaths from Skin Cancers
  6. Increasing Incidence
    1. Melanoma doubled from 1982 to 2011, and again increased >30% between 2011 and 2019
    2. Incidence is higher despite Sunscreen use, and postulated causes include ozone depletion

III. Pathophysiology

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

IV. Risk Factors

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

V. Exam

  1. See Dysplastic Nevus
  2. See Skin Cancer in Skin of Color
  3. See Dermoscopy
  4. See Weighted Glasgow 7-point Checklist for Melanoma

VI. Diagnosis: Biopsy

  1. See Atypical Nevus for biopsy guidelines
  2. Biopsy all suspicious pigmented lesions (and take images for EMR prior to biopsy)
  3. Obtain full thickness sample with 1-3 mm margins (via Punch Biopsy, Fusiform Excision or deep saucerization)
    1. Allows for Breslow Depth measurement (maximal thickness of primary lesion rounded to nearest 0.1 mm)

VII. Classification

  1. Precaution: Melanoma is Melanoma (manage all types aggressively)
  2. Melanoma in Situ (Up to 50% of Melanomas)
    1. Malignant Melanocytes are confined to the Epidermis
    2. Excision is typically curative with 5 mm to 10 mm margins (with clear margins confirmed on pathology)
  3. Superficial spreading Melanoma (SSM, up to 70% of Melanomas)
    1. More common at age 30-50 years, often on the trunk in men, and legs in women
    2. Most common Melanoma in fair skin
    3. Initially brown to black lesions develop blue, red, white color variations
    4. Form irregular, unusual shapes
    5. Initially flat, >6 mm, with radial growth for months to years
      1. When >2.5 cm vertically grow into Nodules
  4. Nodular Melanoma (NM, 15-20% of Melanomas)
    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. Involves trunk, head or neck most often
    4. Firm, raised, dome shaped lesions which may itch or bleed more easily
    5. Colors vary from brown or black to red or purple
    6. May appear flesh colored (amelanotic nodular Melanoma) and appear more like Basal Cell Carcinoma
    7. Most frequently misdiagnosed Melanoma (see differential diagnosis below)
      1. May be misdiagnosed as acne, Furuncles, Skin Ulcers
  5. Lentigo maligna Melanoma (LMM, 5-15% of Melanomas)
    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
      3. Often delayed diagnosed with larger lesions (>1 cm), increased from a Macule into a patch
    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
  6. Amelanocytic Melanoma (<5% of Melanomas)
    1. Nonpigmented Melanoma (red or pink coloration)
    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 advanced stage with lower 5 year survival
  7. Acral Lentiginous Melanoma (ALM, 2-8% of Melanomas)
    1. Represents up to 75% of Melanomas in non-caucasian patients (black or asian ethnicity)
      1. Least related to UV radiation and more to shearing forces with increased cellular genetic mutations
    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
      2. Biopsy from most nodular lesion (most accurate, predictive breslow depth)
  8. Subungual Melanoma (up to 3.5% of Melanomas)
    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)
    4. Affects great toe or thumb in >90% of cases
    5. Most common Melanoma in black, asian and hispanic patients

VIII. Differential Diagnosis

  1. 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
  2. Nodular Melanoma
    1. Dermatofibroma (amelanotic)
    2. Basal Cell Cancer (amelanotic)
    3. Hemangioma
    4. Seborrheic Keratosis
    5. Pyogenic Granuloma

IX. Labs: Histology

  1. 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
  2. Five-year survival related to tumor depth
    1. Thin breslow thickness (=1.0 mm) has significantly better prognosis than thicker breslow >1.0
    2. Stephens (2024) J Surg Res 301:24-8 +PMID: 38908355 [PubMed]

X. Staging (AJCC)

  1. In-Situ
    1. Stage 0 (TisN0M0)
      1. Confined to Epidermis (99-100% five and ten year survival)
  2. Localized
    1. Stage IA
      1. Thickness <0.8 mm and not ulcerated (T1aN0M0)
      2. Survival: 99% five year survival and 98% ten year survival
    2. Stage IB
      1. Thickness <0.8 with ulceration or 0.8 to 1.0 mm with or without ulceration (T1bN0M0)
      2. Thickness 1.1 to 2 mm without ulceration (T2aN0M0)
      3. Survival: 97% five year survival and 94% ten year survival
    3. Stage IIA
      1. Thickness 1 to 2 mm and ulcerated (T2bN0M0) or 2.1 to 4 mm and not ulcerated (T3aN0M0)
      2. Survival: 94% five year survival and 88% ten year survival
    4. Stage IIB
      1. Thickness 2 to 4 mm and ulcerated (T3bN0M0) or >4 mm and not ulcerated (T4aN0M0)
      2. Survival: 87% five year survival and 82% ten year survival
    5. Stage IIC
      1. Thickness >4 mm and ulcerated (T4bN0M0)
      2. Survival: 82% five year survival and 75% ten year survival
  3. Metastatic
    1. Stage III: Regional node metastases (Any T, N>=1, M0)
      1. Stage IIIA - Survival: 93% five year survival and 88% ten year survival
      2. Stage IIIB - Survival: 83% five year survival and 77% ten year survival
      3. Stage IIIC - Survival: 69% five year survival and 60% ten year survival
      4. Stage IIID - Survival: 32% five year survival and 24% ten year survival
    2. Stage IV: Distant metastases (Any T, any N, M1)
      1. Survival: 32% five year survival and 10-15% ten year survival

XI. Evaluation: Melanoma Metastases

  1. Lymph Node exam
  2. Full skin exam
  3. Chest XRay
  4. Labs considered above stage IA (and in all cases of Stage III and IV)
    1. Complete Blood Count (CBC)
    2. Comprehensive Metabolic Panel (includes Electrolytes and hepatic panel)
    3. Lactate Dehydrogenase (LDH)
    4. Common genetic mutations (e.g. BRAF)
  5. Advanced imaging (indicated for stage III, IV)
    1. CT Head, chest and Abdomen and/or
    2. PET Scan (eyes to thighs)
    3. MRI Brain (Stage IV)

XII. Management: Surgical Excision

  1. Lesions <=0.8 mm Diameter: Local excision with clear margins
    1. Melanoma in situ: Margin 0.5 to 1.0 cm
    2. Breslow thickness <=1 mm: Margin 1 cm
    3. Breslow thickness >1 to 2 mm: Margin 1-2 cm
    4. Breslow thickness >2 mm: Margin 2 cm
  2. Lesions >0.8 mm Diameter: Refer
    1. Refer to surgery or surgical oncology for wide local excision
    2. Sentinel Node biopsy often performed at same time
  3. Lymph Node biopsy indicated if Breslow thickness >1mm
    1. Sentinel Node biopsy for staging when Breslow thickness >1 to 4 mm (consider for 0.8 to 1)
    2. Complete Lymph Node dissection is no longer recommended (does not improve survival)
  4. Mohs Micrographic Surgery indicated where surgical margins are difficult to detect
    1. Lentigo maligna
    2. Lentigo maligna Melanoma

XIII. Management: Neoadjuvant Chemotherapy and Immunotherapy

  1. General
    1. Targeted therapies are available for gene mutations BRAF and MEK
    2. Targeted neoadjuvant therapy has significantly improved relapse-free 5 year survival
  2. Immune Checkpoint Inhibitors (intravenous agents)
    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
  3. Tyrosine Kinase Inhibitors (oral agents)
    1. BRAF Inhibitors
      1. Vemurafenib (Zelboraf)
      2. Debrafenib (Tafinlar)
    2. MEK Inhibitors
      1. Trametinib (Mekinist)
      2. Cobimetinib (Cotellic)
  4. Interferon Alfa-2B (Intron A)
    1. Cytokine effective in increasing relapse-free survival
    2. Wheatley (2003) Cancer Treat Rev 29:241-52 [PubMed]
  5. Tumor-infiltrating Lymphocyte (TIL) Therapy
    1. Lifileucel (Amtagvi)
  6. Oncolytic Virus
    1. Indicated in nonresectable Melanoma
    2. Intralesional injection of virus Talimogene Laherparepvec (Imlygic)
  7. Immune Stimulators
    1. Topical Toll-Like Receptor Agonist
    2. Imiquimod (Aldara)

XIV. Precautions: Defusing Myths

  1. Hairy moles do NOT differentiate benign from malignant
  2. Do not prophylacticly biopsy benign appearing moles
  3. Incisional Biopsy into Melanoma does NOT spread tumor

XV. Prevention

  1. See Melanoma Prevention
  2. Follow-up Immediately for:
    1. Pruritic nevus
    2. Atypical Nevus Signs
  3. 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 with full skin check, recurrence evaluation every 3 to 12 months for 1 to 2 years
    2. Stage I: Thickness <1 mm and no Atypical Nevus syndrome or FHx
      1. Follow-up with full skin check, recurrence evaluation every 3 to 12 months for 2 years
    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 6-12 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 and other imaging as per oncology recommendations
        6. No further repeat imaging indicated after the first 3-5 years disease free
    4. Stage III: Regional Metastases
      1. Diagnostics
        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. No further repeat imaging indicated after the first 3-5 years disease free
      2. Follow-up
        1. Follow up every 3-6 months for first 2 years, then
        2. Follow up every 6-12 months for next 3 years, then
        3. 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 3-6 months for 2 years
      5. Next every 6 to 12 months for 3 years
      6. Next follow-up yearly
  4. References
    1. Carek (2024) Am Fam Physician 110(1): 37-44 [PubMed]
    2. Lauters (2024) Am Fam Physician 110(4): 367-77 [PubMed]
    3. Wilbur (2014) Am Fam Physician 91(1):29-36 [PubMed]

XVI. Prognosis

  1. See Histology and Staging above
  2. Survival rates are better in women
  3. 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

XVII. References

  1. Fauci (1998) Harrison's Medicine, 14th ed., McGraw-Hill
  2. Goldstein (2001) Am Fam Physician 63(7): 1359-68 [PubMed]
  3. Houghton (1998) Oncology 12:153-77 [PubMed]
  4. Landis (1999) CA Cancer J Clin 49:8-31 [PubMed]
  5. Lauters (2024) Am Fam Physician 110(4): 367-77 [PubMed]
  6. Rager (2005) Am Fam Physician 72:269-76 [PubMed]
  7. Shenenberger (2012) Am Fam Physician 85(2): 161-8 [PubMed]
  8. Wilbur (2014) Am Fam Physician 91(1):29-36 [PubMed]

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