Melanoma


Pathogenesis and Diagnosis

  1. Epidemiology
    • Predominantly a disease of Caucasians
    • Risk factors include:
      • Fair complexion, blue eyes, blond or red hair
      • History of blistering sun burns
      • Atypical or Dysplastic nevi
      • Prior history of skin cancer
    • Median age at diagnosis is 50
    • Accounts for over 100,000 cases and 11,000 deaths annually in the United States

  2. Pathogenesis
    • Melanocytes originate from neural crest tissue
    • Melanoma can arise anywhere that melanocytes have migrated to during embryogenesis
    • Vast majority originate on the skin
    • Retina, anal canal, central nervous system, and gallbladder have also been reported as primary sites
    • 4% are discovered as metastases without an identifiable primary site
    • UVA and UVB radiation are considered key causative factors

  3. Precursor Lesions
    • Most melanomas develop from precursor lesions

    1. Nevi
      • Benign melanocytic neoplasms
      • Classified as junctional, compound, or dermal depending on the location of the nevus cells
      • Nevus cells accumulate in the epidermis (junctional), migrate partially into the dermis (compound), and finally rest completely in the dermis (dermal)
      • Atypical nevi are not precursor lesions, but rather are a marker for increased melanoma risk
      • Spitz nevi are benign lesions, usually seen in children, that may be difficult to distinguish from melanoma clinically and histologically

      Benign Nevus
    2. Dysplastic Nevi
      • 6 to 15 mm flat pigmented lesion with indistinct margins and variable color
      • Described as having mild, moderate, or severe dysplasia
      • Represents an intermediate stage between a benign nevus and malignant melanoma
      • 70% - 80% contain a BRAF mutation
      • Melanoma patients have significantly more nevi and dysplastic nevi than matched controls
      • Risk of developing melanoma increases with the number of dysplastic nevi

      Dysplastic Nevus
    3. Inherited Syndromes
      1. Dysplastic Nevus Syndrome
        • Autosomal dominant
        • Caused by a mutation in the CDKN2A gene
        • Associated with increased risk of pancreatic cancer
        • Screening for melanoma should begin at age 10
        • Only lesions suspicious for melanoma should be biopsied

      2. Giant Congenital Nevus
        • May reach 20 - 40 cm in size
        • Lifetime melanoma risk is 5% - 20%
        • Staged excision is appropriate

  4. Pathology
    • Initially, growth is radial in the plane of the epidermis and metastases do not occur
    • Transformed cells may enter a vertical growth phase
    • Cells in the vertical growth phase are morphologically and antigenically different than cells in the radial growth phase
    • Vertical growth phase gives tumor cells access to lymphatic and blood vessels

    1. Superficial Spreading
      • Most common type (70%)
      • Not necessarily associated with sun-exposed skin
      • Occurs anywhere except the hands and feet
      • Usually flat
      • May contain variations in color
      • Often contains areas of regression

      Superficial Spreading Melanoma
    2. Nodular
      • 15% of melanomas
      • Raised, blue-black in appearance
      • Often ulcerate
      • In the vertical growth phase at the time of diagnosis
      • Aggressive lesion, but prognosis is similar to a superficial spreading lesion of the same depth

      Ulcerated Nodular Melanoma
      Ulcerated Nodular Melanoma

    3. Lentigo Maligna
      • 10% of melanomas
      • Occur on the face and the back of hands of elderly people
      • Best prognosis because invasive growth occurs late
      • Lesions may be large and challenging to close
      • Histologic margins may extend well beyond the clinical borders of the lesion, making a negative margin excision difficult

      Lentigo Maligna Melanoma
    4. Acral Lentiginous
      • Occurs on the palms, soles, and subungual regions
      • Most common type of melanoma in black patients
      • Subungual melanomas are often mistaken for subungual hematomas, leading to a significant delay in diagnosis

      Acral Melanoma
  5. Prognostic Factors
    • Tumor thickness correlates with survival
    • Regional lymph node status is the most important prognostic factor predicting survival
    • Ulceration is another independent predictor of survival
    • Mitotic rate > 1/mm2 is a more recently validated prognostic factor
    • Older patients have a greater mortality than younger patients
    • Trunk and head and neck melanomas do worse than extremity melanomas

    1. Clark Levels
      • Based on the extent of invasion into the histologic layers of the skin
      • Prognosis worsens with increasing depth of invasion

      Clark Levels
    2. Breslow Thickness
      • Depth is measured directly using an ocular micrometer
      • More accurate predictor of survival than Clark’s levels

      Breslow Thickness
    3. Staging

      4. Melanoma Staging - AJCC 8th Edition
  6. Molecular Biology of Melanoma
    • Mitogen-activated protein kinase pathway (MAPK) is activated in most melanomas
    • In normal cells, binding between a growth factor receptor and its ligand are required to activate this pathway
    • RAS family of G-proteins are responsible for the initial transduction of the binding event signal

    MAPK Pathway
    1. NRAS Gene
      • NRAS mutations occur in ~ 20% - 30% of melanomas, leading to a NRAS protein which is always ‘on’
      • Result is continual activation of downstream kinases, which promote gene transcription leading to cell cycle progression, cellular transformation, and increased cell survival

    2. BRAF Gene
      • Activating mutation is present in 50% - 70% of melanomas
      • Function is to phosphorylate (activate) MEK, which in turn activates ERK, which is a critical step in the pathogenesis of many malignancies

    3. NF1 Gene
      • Tumor suppressor gene that acts to suppress NRAS signaling
      • Deactivating mutations are present in ~ 13% of cutaneous melanomas

    4. KIT Gene
      • Most frequently mutated gene in acral and mucosal melanomas

    5. MITF Gene
      • Microphthalmia transcription factor
      • Crucial to melanin production and melanocyte regulation
      • MITF amplification occurs in 20% of patients and is associated with poorer survival

  7. Diagnosis
    • Very challenging to distinguish benign pigmented lesions from early melanomas
    • Most melanomas display evidence of the ABCDEs

    ABCDE of Melanoma
    1. Biopsy
      • Suspicious lesions should undergo excisional biopsy with 1 mm margins
      • incisional biopsy or punch biopsy may be used for large lesions
        • Biopsy the most raised or ulcerated area
      • Incisions should be planned with the expectation that a definitive wide excision may be necessary, e.g. longitudinal orientation on the extremities
      • Shave biopsies underestimate tumor thickness and should be avoided
      • Ablation of pigmented lesions is contraindicated because it does not allow for pathologic examination of the specimen

Management

  1. Treatment of the Primary Lesion
    1. Wide Local Excision – Cutaneous Melanomas
      • In situ melanomas are excised with a 0.5 cm margin
      • Invasive melanomas are excised down to (but not including) the deep fascia
      • Melanomas ≤ 2 mm thick are excised with a 1 cm margin
      • Melanomas > 2 mm thick are excised with a 2 cm margin
      • Smaller margins may be acceptable in cosmetically sensitive areas as long as a negative margin can be achieved
      • Moh’s surgery is not standard for invasive melanoma

    2. Acral Melanomas
      • Occur on subungual sites and the palms/soles
      • Worse prognosis than cutaneous extremity melanomas of the same stage

      1. Subungual melanomas
        • Arise from the nail matrix
        • Subungual melanomas of the 2nd – 5th toes should be treated with an amputation at the metatarsal-phalangeal joint
        • Complete amputation of the 1st toe should be avoided if oncologically feasible because of the importance of the toe in balance
        • Subungual melanomas of the fingers should be resected at the distal interphalangeal joint to preserve function

        Subungal Melanoma and Amputation
      2. Palmar/Plantar melanomas
        • Can rarely be closed primarily because of the lack of surplus skin
        • Skin grafts are sufficient for non-weightbearing areas
        • Weight bearing areas may require rotation, advancement, or free flaps

  2. Treatment of Regional Nodes
    1. Clinically Negative Nodes
      1. Sentinel Node Biopsy
        • Relies on the fact that specific regions of the skin drain to a specific lymph node
        • SLN pathology accurately reflects the pathology of the remainder of the nodal basin
        • Single most important factor predicting prognosis in melanoma patients
        • Valuable in selecting patients who may benefit from adjuvant therapy or clinical trials

        1. Indications
          • Tumor thickness between 1 - 4 mm
          • Many centers routinely offer SLN biopsy for lesions ≥ 0.8 mm
          • Tumor thickness < 0.8 mm if ulceration is present, the mitotic index is greater than 1 mm2,or lymphovascular invasion is present (T1b)
          • Clark level 4 for melanomas < 0.8 mm thick
          • Tumor thickness > 4 mm if a positive SLN will change treatment

        2. Technique
          • Preoperative lymphoscintigraphy identifies all nodal basins at risk for metastatic disease – which might be in areas not anticipated
          • Radiotracer and blue dye must be injected intradermally
          • Pathologist makes a detailed examination of the SLN with multiple sections and immunohistochemical staining with melanoma-specific monoclonal antibodies: HMB-45, S-100, and Melan-A
          • Neurological injury is a concern, especially in the head and neck area (facial nerve branches, spinal accessory nerve)

      2. Management of a Positive Sentinel Node
        • Historically, patients with a positive SLN biopsy underwent completion lymph node dissection
        • Two recent randomized trials (multicenter selective lymphadenectomy trial I and II) have compared immediate completion node dissection with observation followed by node dissection for regional nodal recurrence
          • Patients who had immediate completion node dissection had a lower rate of regional node recurrence (8% vs 23%)
          • Melanoma-specific survival was the same in both groups
          • Rate of lymphedema was higher in patients who underwent immediate lymph node dissection

    2. Clinically Positive Nodes
      1. Therapeutic Node Dissection
        • Clinically suspicious nodes should be biopsied by FNA or excision
        • Metastatic workup – brain MRI, PET-CT scan – should be done prior to therapeutic node dissection
        • Long term survival and cure are possible, with prognosis depending on the extent of the nodal disease

        1. Axillary Node Dissection
          • Level 3 nodes should be removed, which requires division of the pectoralis minor muscle
          • Long-term complications include nerve injury (long thoracic nerve, thoracodorsal nerve), paresthesias (intercostal brachial nerve), and lymphedema

        2. Superficial Groin Dissection
          • May include the femoral nodes or the inguinal nodes
          • If the highest superficial node (Cloquet’s node) is positive, some surgeons will also do a deep ilioinguinal node dissection
          • It is not clear if adding the more extensive deep dissection improves survival, but it does increase the risk of lymphedema
          • Postoperatively, patients should wear compression stockings for at least 6 months

  3. Adjuvant Therapy
    • Patients with primary melanomas > 4 mm thick, ulcerated melanomas > 2 mm thick, in-transit lesions, and positive nodes are candidates for adjuvant immunotherapy
    • Patients with BRAF V600 mutations may benefit from targeted therapy rather than immunotherapy
    • Once distant metastases develop, median survival is only 6 to 9 months

    1. Interferon (IFN-α)
      • First drug to be FDA approved for the adjuvant treatment of high-risk melanomas
      • Treatment protocol uses a one month period of induction therapy (IV), followed by 11 months of subcutaneous therapy
      • Multiple studies suggest that high-dose interferon may prolong time to recurrence, but does not result in increased survival
      • Toxicity of therapy is significant, including moderate to severe flu-like symptoms, hematologic and hepatic dysfunction, and depression
      • Largely replaced by immunotherapy and targeted therapies

    2. Checkpoint Inhibitor Immunotherapy
      1. Nivolumab
        • Preferred agent because of longer relapse-free survival and decreased toxicity
        • Targets programmed cell death protein 1 (PD-1)

      2. Pembrolizumab
        • Targets PD-1
        • FDA approved for resected stage III disease

      3. Ipilimumab
        • Targets CTLA-4
        • Improved disease-free and overall survival when compared with interferon alpha
        • Replaced by the more effective and less toxic Nivolumab and Pembrolizumab

    3. Targeted Therapy
      • Targets the mitogen-activated protein kinase (MAPK) pathway with a combination of a BRAF inhibitor and MEK inhibitor
      • Patients selected for targeted therapy should have a BRAF V600 mutation
      • Dabrafenib and Trametinib are the approved drugs
      • Compared to placebo, this regimen improves relapse-free survival and overall survival

    4. Radiation
      • Not used routinely, since melanoma is considered a radiation-resistant tumor
      • Should be considered for high-risk head and neck melanomas, since the risk of local recurrence and in-transit disease is higher in these sites
      • May also reduce regional recurrence for patients with large palpable metastases (> 3 cm), more than 5 involved nodes, or extracapsular extension

  4. In-Transit Disease
    1. Definition
      • 8% of patients with melanomas > 1 mm thick will develop in-transit disease
      • Represents tumor emboli trapped within dermal and subdermal lymphatics
      • Occurs more than 2 cm from the primary tumor; satellite lesions occur within 2 cm of the primary tumor
      • Median time of development is 15 months
      • Often a harbinger of systemic disease

      Melanoma In-Transit Disease
    2. Treatment
      1. Local Therapy
        • Intralesional injection of BCG, IFN, IL-2
        • Excision for several small lesions
        • Talimogene Laherparepvec (T-VEC) is a genetically modified Herpes virus and is the first oncolytic virus therapy approved for advanced melanoma

      2. Hyperthermic Isolated Limb Perfusion (HILP)
        • Higher concentrations of chemotherapeutic drugs can be used regionally while minimizing system toxicity
        • Melphalan is the standard drug
        • Requires open cannulation of the artery and vein, a pump oxygenator and perfusion team, and tourniquet isolation of the extremity
        • Response rates are good but short-lived, with most recurring within one year
        • Limb complications rates are high: compartment syndrome, neuropathy, skin reactions, lymphedema
        • Isolated limb infusion (ILI) is a modification of the technique that uses percutaneous cannulation of the vessels and does not require a pump oxygenator or perfusion team

  5. Metastatic Disease
    • Most common sites are the brain, lung, liver
    • Median survival with stage 4 disease is 7 months

    1. Surgery
      • Most patients will have multiple sites of disease not amenable to resection
      • Some carefully selected patients have long-term survival after metastasectomy
      • Best treatment of melanoma at any stage of disease is complete resection of all disease

    2. Systemic Therapy
      • Dacarbazine (DTIC) and high-dose IL-2 are FDA approved for stage 4 disease
      • DTIC is not associated with increased survival
      • High-dose IL-2 has a complete response rate of 6%, but its use is limited by severe toxicity
      • Checkpoint inhibitors and targeted therapy can produce durable responses in 20% - 30% of patients
      • Vaccine therapies and T-cell adoptive therapies are available in clinical trials







References

  1. Sabiston, 20thh ed., pgs 724 - 747
  2. Cameron, 13th ed., pgs 820 - 824
  3. Oncology, Dec 2016, Vol. 30. pgs 1045 – 1052
  4. The Molecular Biology of Melanoma. Sullivan, Ryan and Fisher, David. UpToDate, May 2019. Pgs 1 -22
  5. Initial Surgical Management of Melanoma of the Skin and Unusual Sites. Stone, Michael. UpToDate, July 2019. Pgs 1 – 29
  6. Evaluation and Treatment of Regional Lymph Nodes in Melanoma. Stone, Michael. UpToDate, April 2019. Pgs 1 - 23
  7. Adjuvant Therapy for Cutaneous Melanoma. Sosman, Jeffrey. UpToDate, August 2019. Pgs 1 - 23