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Melanoma & Cutaneous Malignancies

Nonmelanoma Skin Cancers (NMSC)

Overview

  • NMSC is the most common malignant neoplasm globally.
  • In the U.S., 1 in 5 Americans will develop NMSC during their lifetime.
  • 80% of cases are Basal Cell Carcinomas (BCCs), and 20% are Squamous Cell Carcinomas (SCCs).
  • Sun exposure is the predominant risk factor.
  • Patients with BCC or SCC have an increased risk of additional skin cancers, including melanoma.

Squamous Cell Carcinoma (SCC)

Presentation and Risk Factors

  • Risk factors:
    • Chronic sun exposure (cumulative UV radiation exposure is more critical than intermittent exposure).
    • Fair skin, light hair, and light eyes increase risk.
    • Environmental carcinogens: Arsenic, hydrocarbons, ionizing radiation, cigarette smoke.
    • Genetic disorders: Xeroderma pigmentosum, albinism.
    • Chronic inflammation: Burn scars (Marjolin ulcers), draining sinuses, and nonhealing ulcers.
    • Immunosuppression: Increased risk after solid organ transplantation (65x higher risk of SCC).
    • Human papillomavirus (HPV) infection.
    • BRAF inhibitors used for melanoma treatment.
  • Actinic keratoses (solar keratoses): Precursors to SCC, appear as scaling, erythematous lesions on chronically sun-damaged skin.
    • The risk of malignant transformation to SCC is 0.01%-0.6% per year, up to 2.5% over 4 years.
  • Bowen disease (SCC in situ): Appears as reddened areas that progress to plaques.

  • Invasive SCC:

    • Presents as palpable, scaling lesions with ulceration and firm edges.
    • Can spread horizontally and vertically, potentially invading underlying tissues.

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Treatment

  • SCC staging (T category): Based on the diameter of the lesion.
  • Local excision:
    • Most SCCs can be treated with 5-mm margins.
    • Mohs Micrographic Surgery (MMS) for cosmetically sensitive or high-risk areas.
    • 10-mm margins for higher-risk lesions.
  • Field therapies:
    • Radiation therapy, cryosurgery, photodynamic therapy.
    • Electrodessication and curettage, topical agents (e.g., imiquimod).
    • Cryotherapy is commonly used for small lesions and actinic keratoses.
  • Sentinel Lymph Node (SLN) biopsy:
    • May be indicated for high-risk SCC.
    • Occult lymph node metastases may occur in 7%-20% of cases.
  • Adjuvant radiation: Recommended for SCCs with perineural involvement or large nerve involvement.
  • Locally advanced or metastatic SCC:
    • Rare but difficult to treat.
    • Platinum-based chemotherapy and epidermal growth factor receptor inhibitors may be used.
    • PD-1 inhibitor (cemiplimab): Approved for advanced SCC, with a 50% response rate.

This summary highlights the presentation, risk factors, and treatment options for SCC, emphasizing its association with chronic sun exposure and immunosuppression and outlining both surgical and systemic treatments for advanced cases.

Basal Cell Carcinoma (BCC)

Presentation and Risk Factors

  • Most common type of nonmelanoma skin cancer (NMSC).
  • Typically found on sun-exposed areas of the head and neck.
  • Risk factors:
    • Intense, intermittent UV radiation exposure.
    • Hedgehog signaling pathway mutations:
      • Mutations in Patched or Smoothened (SMO) proteins.
      • Up to 90% of BCCs show mutations in the hedgehog pathway.
  • No precursor lesion for BCC (unlike SCC).
  • Lesions range from nodules to nonhealing sores with drainage and crusting.
  • Slow growth rate often delays diagnosis.
  • Rarely metastasizes, but when it does, survival is usually less than 1 year.

Histological Subtypes

  • Nodular BCC:
    • Well-defined, elevated, waxy lesion with pearly nodules at the margins.
    • Central depression with umbilication or ulceration and rolled edges.
    • Telangiectasia often visible on the lesion.
  • Cystic BCC:
    • Translucent with blue or gray appearance, can be mistaken for a blue nevus.
  • Superficial BCC:
    • Macular growth pattern, extending over the surface in a multicentric fashion.
    • May ulcerate with irregular margins.
    • Can resemble psoriasis, tinea, or eczema.
  • Micronodular BCC:
    • Pink or red lesions peppering the skin, with aggressive growth.
    • Lesions extend beyond visible changes and can invade deeper tissue.
  • Morpheaform BCC (white scarring type):
    • Among the most invasive subtypes, penetrating deep into the underlying subdermis.

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Treatment

  • Locally confined BCC:
    • Treatment involves margin-negative resection.
    • A 5-mm margin is generally sufficient for local control.
    • Mohs micrographic surgery (MMS) can be used for high-risk lesions.
    • Field therapies include:
      • Radiation therapy, cryosurgery, photodynamic therapy.
      • Electrodessication and curettage, and topical agents like imiquimod.
  • Systemic therapy (for locally advanced/metastatic BCC):
    • Hedgehog pathway inhibitors like:
      • Vismodegib: 30% response in locally advanced BCC, 43% response in metastatic BCC.
      • Sonidegib: Similar efficacy with a 30-40% response rate in metastatic or locally advanced cases.
    • Long-term responses:
      • Median duration of response: 15 months in metastatic patients, 26 months in locally advanced patients.

This summary provides an overview of Basal Cell Carcinoma (BCC), including its presentation, histological subtypes, risk factors, and the current treatment options, with a focus on surgical and systemic therapies for advanced cases.

Melanoma

Overview

  • Historical context: First described by Hippocrates and later by John Hunter and René Laennec.
  • Epidemiology: Primarily affects middle-aged adults, but occurs across all age groups. About 1 in 6 new cases are in individuals under 45 years.
  • Genetic risk factors:
    • High-risk skin types (Fitzpatrick types I and II).
    • Family history of melanoma.
    • Conditions like xeroderma pigmentosum.
    • Congenital nevi, dysplastic nevi, and melanocytic nevi increase risk.
  • Environmental risk factors:
    • Intense, intermittent UV exposure, especially causing blistering sunburns.
    • Immunosuppression and upper socioeconomic status.

UV Radiation and Melanoma

  • UVA:
    • Longer wavelength, penetrates deeper.
    • Found in tanning beds, associated with melanoma.
  • UVB:
    • Shorter wavelength, damages the epidermis.
    • Linked to melanoma oncogenes.
  • UV exposure contributes to mutations in over 90% of melanoma subtypes (per The Cancer Genome Atlas project).

Precursor Lesions

  • De novo melanoma: Arises in normal skin but can also develop in preexisting lesions (up to 40%), such as:
    • Dysplastic nevi
    • Congenital nevi
    • Spitz nevi
  • Dysplastic nevi:
    • 6-15 mm pigmented lesions with indistinct margins.
    • Require monitoring and, if suspicious, biopsy.
  • Spitz nevi:
    • Benign, rapidly growing skin lesions, common in children.
    • Atypical spitzoid melanomas in adults may need wide local excision (WLE) and sentinel lymph node biopsy.

Pathogenesis and Molecular Subtypes

  • Melanoma has the highest mutational burden of any malignancy.
  • The Cancer Genome Atlas identified four subtypes based on gene mutations:
    1. BRAF subtype (~50%)
    2. RAS subtype (~30%)
    3. NF1 subtype (~15%)
    4. Triple-wild-type (lacking BRAF, RAS, NF1 mutations, ~5%)
  • Key Pathways:
    1. MAPK pathway:
      • BRAF, RAS, and NF1 mutations drive signaling through the MAPK pathway, leading to unchecked cellular growth.
      • CDKN2A gene (tumor suppressor) inactivation also promotes tumor development.
    2. PI3/AKT pathway:
      • Commonly activated in melanomas, promoting proliferation.
      • PTEN loss (25%-50% of nonfamilial melanomas) leads to resistance to BRAF/MEK inhibitors.

Prevention and Screening

  • Primary prevention includes:
    • Avoiding sunbathing and tanning beds.
    • Using sun-protective clothing and sunscreen.
  • Public health measures:
    • Some countries ban indoor tanning beds for minors or entirely.

Initial Evaluation of Melanoma

Presentation

  • Melanoma often presents as an irregular pigmented lesion that has grown or changed over time.
  • The ABCDE criteria guide the assessment of suspicious lesions:
    1. Asymmetry
    2. Border irregularity
    3. Color variation
    4. Diameter greater than 6 mm
    5. Evolving size, shape, or color.

History and Physical Examination

  • Key elements in patient history:
    • Duration and changes in the lesion.
    • Symptoms: Itching, bleeding.
    • Risk factors:
      • Sun exposure, tanning bed use, immunosuppression.
      • Family history and previous skin cancers.
  • Physical examination:
    • Full skin examination to detect other suspicious lesions.
    • Palpation of cervical, axillary, and inguinal lymph nodes.
    • Ensure a complete skin exam as part of routine physical exams—takes only 1 minute.

Common Benign Lesions

  • Seborrheic keratoses: Common in elderly patients, appear as scaly, waxy, raised lesions that look "stuck on."
  • Amelanotic melanoma: Non-pigmented, pink or flesh-colored lesion, requiring high suspicion due to absence of pigmentation.

Advanced Disease Presentation

  • Most melanomas are diagnosed early, but:
    • 10% of patients present with regional lymphatic spread.
    • 5% may present with distant metastases (hematogenous spread).
    • In-transit melanoma: Tumor spreads within lymphatic channels, appearing as cutaneous/subcutaneous nodules between the primary tumor and lymph nodes.
  • Symptoms of metastatic disease:
    • Masses, neurologic symptoms, weight loss, bone pain, respiratory symptoms.

Biopsy of Melanoma

Types of Biopsy

  1. Excisional Biopsy:
    • Preferred for small lesions.
    • Removes the entire lesion with narrow margins.
    • Ensures full-thickness excision to subcutaneous fat, useful for accurate diagnosis.
  2. Incisional Biopsy (Punch Biopsy):
    • Larger lesions may require tissue diagnosis before complete excision.
    • A punch biopsy removes a 2-8 mm cylinder of tissue.
    • Punch biopsies should target the thickest or most suspicious area.
  3. Shave Biopsy:
    • Commonly performed by dermatologists.
    • Involves shaving the lesion after elevating it.
    • Drawback: Potential to truncate the lesion, affecting measurement of Breslow thickness.
    • Deep shave or saucerization biopsies can avoid this issue by removing tissue down to subcutaneous fat.

Biopsy Best Practices

  • Pathologic evaluation:
    • All pigmented lesions should be evaluated via fixation and permanent section.
    • Ablation techniques (cryotherapy, cautery, lasers) should be avoided to prevent delayed diagnosis.

Pathology of Melanoma

Biopsy Report and Diagnosis

  • The biopsy report is critical in evaluating a skin lesion and developing a treatment plan.
  • Pathologists may have a low threshold for classifying lesions as melanoma to avoid missing a diagnosis.
  • Equivocal lesions (severely dysplastic nevus to melanoma in situ) are often treated as early invasive melanoma with a 1-cm margin wide local excision (WLE).

Histological Subtypes

  1. Superficial Spreading Melanoma:
    • Most common type.
    • Usually on the trunk and proximal extremities.
    • Initially grows radially as a flat-pigmented lesion, often with asymmetry and irregular borders.
    • Untreated, it progresses to vertical growth, increasing depth and metastatic potential.
  2. Lentigo Maligna Melanoma:
    • Occurs on sun-exposed areas in older adults.
    • Presents as a flat, dark, slowly developing lesion with irregular borders.
    • Has a better prognosis due to its superficial nature but can be large and challenging to excise with clear margins.
  3. Acral Lentiginous Melanoma:
    • Develops in subungual areas, palms, and soles.
    • Common in nonwhite patients.
    • Frequently diagnosed at an advanced stage, leading to a poor prognosis.
    • Subungual melanomas may be mistaken for hematomas but do not migrate under the nail.
  4. Nodular Melanoma:
    • Raised papular lesions, often without the typical ABCDE criteria.
    • Can develop vertical growth early, leading to a poor prognosis.
    • Higher frequency of amelanotic lesions compared to other subtypes.
  5. Desmoplastic Melanoma:
    • Characterized by melanoma cells combined with stromal fibrosis.
    • Often amelanotic and challenging to diagnose.
    • Classified as pure or mixed based on the degree of desmoplasia.
    • Pure desmoplastic melanoma has a lower risk of lymph node metastasis, whereas mixed types have similar rates to other subtypes.

Growth Phases

  • Radial growth phase: Tumor cells proliferate in the epidermis and superficial dermis.
  • Vertical growth phase: Tumor invades deeper layers, allowing potential metastasis via blood vessels and lymphatics.

Depth Assessment

  • Breslow thickness (introduced by Dr. Alexander Breslow):
    • Measures vertical thickness from the top of the granular layer to the deepest tumor cell.
    • A more accurate predictor of prognosis compared to the Clark level of invasion.
  • Melanoma classification based on Breslow thickness:
    • Thin: <1 mm.
    • Intermediate: 1–4 mm.
    • Thick: >4 mm.
  • Prognosis worsens with increased thickness.

This summary outlines the key pathological features of melanoma, including its histological subtypes, growth patterns, and the use of Breslow thickness as a critical measure of prognosis.

Special Situations and Noncutaneous Melanoma

Unknown Primary Melanoma

  • Incidence: Less than 2% of all melanoma cases, 5% in metastatic cases.
  • Evaluation:
    • Comprehensive skin examination (including perianal, genital, scalp, nail beds, and external auditory canal).
    • Endoscopic evaluation: Oral cavity, nasopharynx, anus, and rectum for mucosal melanoma.
    • Pelvic examination for women.
    • Ophthalmology examination to rule out ocular melanoma.
    • Imaging: PET/CT and MRI of the brain to assess disease extent.
  • Hypotheses:
    • May originate from benign nevus cells trapped in lymph nodes.
    • Spontaneous regression of the primary tumor due to immune response is possible.
    • Prior history of a disappeared skin lesion or vitiligo should be explored.
  • Treatment: Treat like stage III melanoma.
    • Interestingly, patients with unknown primary melanoma have equivalent or better survival rates, possibly due to stronger immune responses.

Melanoma and Pregnancy

  • Incidence: Up to one-third of women diagnosed with melanoma are of childbearing age.
  • Risk association with pregnancy:
    • Early studies suggested hormonal influence, but current evidence does not support a direct link between pregnancy and melanoma development.
    • Prognosis of melanoma in pregnancy is similar to nonpregnant patients.
  • Treatment considerations:
    • Wide Local Excision (WLE) is safe under local anesthesia.
    • Sentinel Lymph Node (SLN) biopsy is safe but vital blue dye should be avoided.
    • Lymphoscintigraphy is considered safe with appropriate precautions.
    • Pregnancy termination has no therapeutic benefit.
    • Examine the placenta for metastasis.
    • Patients with poor prognostic factors should consider delaying the next pregnancy for 2-3 years due to higher recurrence risk during this period.

Noncutaneous Melanoma

Ocular Melanoma

  • Most common intraocular malignancy in adults.
  • Melanocytes found in the retina and uveal tract (iris, ciliary body, and choroid).
  • Primary treatments:
    • Enucleation or Iodine-125 brachytherapy.
    • Other options: Photocoagulation and partial resection.
  • Metastasis:
    • Occurs hematogenously, mainly to the liver.
    • Metastases often present with a diffuse pattern.
    • Dedicated liver imaging is necessary.
  • Immunotherapy response is lower in ocular melanoma, potentially due to lower mutational burden compared to cutaneous melanoma.

Mucosal Melanoma

  • Most common sites:
    • Head and neck (oral cavity, oropharynx, nasopharynx, paranasal sinuses).
    • Anal canal, rectum, and female genitalia.
  • Prognosis: Often presents at a more advanced stage and has a poor prognosis.
  • Treatment:
    • Aim for negative margin resection when possible.
    • Extensive local resections (e.g., abdominoperineal resection or pelvic exenteration) do not improve survival but may control local disease.
    • Radiation therapy: Can improve locoregional control.
    • SLN biopsy: Performed routinely for anal and mucosal melanomas when feasible.
  • Immunotherapy:
    • Response rates for mucosal melanoma are similar to cutaneous melanoma.
    • Consider immunotherapy in the adjuvant setting or for metastatic disease.

This summary highlights the unique challenges in diagnosing and treating noncutaneous melanomas, including unknown primary, pregnancy-associated, ocular, and mucosal melanomas, along with the distinct treatment strategies tailored for each subtype.