Skin Cancer

Introduction

The skin is the largest organ of the human body, serving in both a protective and aesthetic capacity. Skin cancer refers to several types of malignancies that can occur, including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and malignant melanoma. While the first two types of skin malignancies are usually more amenable to treatment and are often described together as nonmelanoma skin cancers (NMSC), melanoma is classified as a separate type of cancer with typically more aggressive behavior and worse prognosis.

The incidence of skin cancers as a group is on the rise and currently accounts for over one-third of all diagnosed malignancies worldwide and more than half of malignancies in the United States. [1] In fact, the incidence of melanoma over the past fifty years has increased at a higher rate than with almost any other cancer. NMSC cases increased 77% between 1994 and 2014. [2] This increase in incidence is thought to be largely related to increases in lifetime cumulative sun exposure and more intense diagnostic scrutiny, indicating the tremendous importance of preventative programs and early detection strategies to reduce the incidence and mortality of skin cancers. Please visit the University of Pennsylvania's OncoLink skin cancer section for general information and relevant National Cancer Institute literature.

Epidemiology and Etiology

• Incidence of more than 3 million new cases of NMSCs annually in the United States alone; the incidence of melanoma in the United States is estimated at 200,340 new cases annually, with rates 15-20 times higher in whites than in blacks or Asians. [3, 4] Melanoma is the fifth most common cancer among American males and females. [4] Incidence is higher among men than women. [5] Overall, 75-80% of newly diagnosed skin cancers are basal cell carcinomas, 15-20% are squamous cell carcinomas, 1% are invasive melanomas, and approximately less than 1% are such rare skin cancers as Kaposi's sarcoma, dermatofibrosarcoma protuberans, cutaneous T cell lymphoma, Merkel cell carcinoma, and microcystic adnexal carcinoma. [6]
• Mortality from BCC and SCC is approximately 2,820 people annually in the United States, while melanoma results in about 8,000 deaths each year. [6] Nearly two-thirds of all deaths attributed to melanoma occur in males [7, 8].
• Etiology is multifactorial and dependent on both constitutional/genetic factors (fair skin color, propensity to burn from sun exposure, tendency to freckle, red or blonde hair) as well as environmental factors (sun exposure).
• Hereditary factors include several familial melanoma or dysplastic nevi syndromes, a family history of malignant melanoma, and xeroderma pigmentosum (XP ), a rare congenital genetic defect in the repair of ultraviolet radiation-induced DNA damage. Patients with skin cancers associated with such hereditary factors often present at an earlier age of onset.
• Risk factors associated with the development of NMSC and malignant melanoma (MM) include the following [9, 10]:
  • Exposure to ultraviolet radiation, particularly UV-B radiation from sunlight
    • While BCC and SCC usually occur on chronically exposed areas of skin, MM, with the exception of the lentigo maligna melanoma subtype, is usually more dependent on intermittent sun exposure that results in blistering sunburns, especially during childhood
    • History of five blistering sunburns confers a significantly increased risk of malignant melanoma [4]
  • Light skin, hair, or eye coloring
  • Personal history of previous BCC, SCC, and/or MM lesions
  • Family history of skin cancer in a first-degree relative
  • Increasing age
  • Male gender
  • Geographically living at lower latitudes, closer to the equator
  • Northern European ancestry
  • Immunosuppression, organ transplantation (up to 100 times higher risk), or a history of prior hematologic malignancy [11]
  • Occupational or environmental exposures to radium, arsenic, tar, creosote, or pitch
  • Women under 30 who use tanning beds have a sixfold increased risk of melanoma [4]
  • History of previous superficial therapeutic radiation
  • Greater than 25 melanocytic nevi (benign moles) or atypical or dysplastic nevus increase the risk of developing MM
  • Presence of lesions called actinic keratoses (erythematous and scaly skin patches that usually result from chronic sun exposure) increases the risk of developing SSC
  • History of current or previous smoking increases the risk of developing SCC and, possibly, BCC

Prevention

• The American Cancer Society recommends the following [12]:
  • Avoid direct sun exposure between 10 am and 4 pm, since the ultraviolet rays from the sun are most intense during this time.
  • Avoid sunlamps and tanning beds, which are artificial sources of ultraviolet radiation.
  • Cover all sun-exposed skin with sunscreen lotion that has a sun protection factor (SPF) of at least 30.
  • Wear clothing that covers as much of the arms, legs, and torso as possible.
  • Wear hats with wide brims to shade the face, neck, eyes, and ears.

Screening Recommendations

• The American Academy of Dermatologists and the Centers for Disease Control and Prevention recommend regular skin self-examinations and focused evaluations of all suspicious skin lesions by primary care providers or dermatologists. High-risk patients may benefit from annual physician total skin examinations.
  • Given the high prevalence of NMSCs, routine total skin examinations and skin self-examinations could detect more malignancies than cancer screenings for any other organ.
  • The effectiveness of skin cancer screening programs is examiner-dependent, as skin cancer specialists and dermatologists receive much better training than primary care physicians in the diagnosis of skin malignancies. In fact, screening examinations conducted by dermatologists have a 49% sensitivity and 97.6% specificity for melanoma detection [13, 14, 15].
• Two common screening checklists include the American Cancer Society's ABCDE system (Asymmetry, Border irregularity, Color variegation, Diameter >6 mm, Enlargement/ Evolutionary change) and the Glasgow seven-point checklist [16].

Clinical Presentation

• History: NMSCs often present as a non-healing sore, ulcer, papule, or plaque. MMs usually present as either a new nevus or a change in the appearance of a preexisting mole or nevus.
• Physical exam: BCC = small, firm, well-demarcated, dome-shaped papule, ranging from pearly white to pink or red, with central ulceration and raised borders; SCC = hyperkeratotic raised, firm papule, nodule, or plaque; BCC or SCC = scaling red/pink patch, enlarging pink papule or nodule, or a new nodule with scaling, erosion, ulceration, or crusting; MM = new or old nevus that has irregular borders, dark or multiple pigmentations, or appears asymmetrical, elevated, eroded, crusted, or ulcerated. Upon the identification of any type of potentially malignant skin lesion, a total-body skin examination and lymph node evaluation should be conducted.
• Lab studies: no characteristic findings unless metastatic disease is present.
• Radiologic studies: depending on the type and size of the malignant lesion, a chest x-ray with CT scans, bone scans, PET scans, and MRIs may be warranted for metastatic workup.
• Diagnostic studies: biopsy is absolutely essential for diagnosis. Depending on the type and size of the lesions, biopsy techniques may include punch, shave, saucerization, and elliptical incision or excision biopsies. While punch or incisional biopsies are often used for large lesions or lesions in cosmetically sensitive locations, a complete excisional biopsy is typically preferred for smaller lesions. For suspected cases of melanoma, a biopsy of the full depth of the skin and underlying fat is necessary to determine the depth of invasion, which is the most important indicator of prognosis.

Natural Course and Pathology

• Basal cell carcinoma: malignant transformation of basal cells.
  • Universally contains both epidermal and dermal components with no keratinization.
  • Common sites of primary BCCs: face (65-70%), nose (25-30%), trunk (15%) [17].
  • Histopathologic subtypes
    • Nodular : 60-65% of all BCCs; usually presents on the face as a flesh-colored or pink papule with a pearly appearance and a telangiectatic vessel in the papule, with or without ulceration.
    • Superficial : 25-30% of BCCs; more common in men than women; usually presents on the trunk as a light red scaly plaque or papule.
    • Morpheaform (sclerosing) : 5-10% of BCCs; usually presents as smooth, flesh-colored atrophic and firm papules or plaques, often with ill-defined borders; highest rate of recurrence of BCCs.
  • Staging: clinical staging is completed through the inspection and palpation of lesions and involved lymph nodes; pathological staging is established by the examination of the resected specimen.
  • Prognosis: although tumors are typically slow-growing and nonmetastatic in nature, lesions can become bulky and invade locally.
    • The rate of metastasis is 0.1% and is usually seen in patients with deeply invasive or large lesions. [18] Metastatic lesions have one- and five-year actuarial survival probabilities under 20% and 10%, respectively. Overall, the mortality rate from BCC is between 0.02% and 0.05%. Morbidity and disfigurement from local invasion of these tumors may be significant [18, 19, 20].
    • Second primary malignancies: following a diagnosis of BCC, the 3-year cumulative risk of developing a second BCC lesion is ~44%. Additionally, there is about a 6% risk of developing SCC, a two- to four-fold increased risk of developing melanoma, and a one-and-a-half- to three-fold increased risk of developing noncutaneous malignancies [21, 22, 23, 24].
• Squamous cell carcinoma: malignant transformation of keratinocytes.
  • SCCs originate in the epidermis and may occur anywhere on the skin or mucous membranes where squamous epithelium is present.
  • Malignant SCC lesions may arise from actinic keratosis or Bowen's disease, which is commonly considered SCC in situ and usually presents as a red or pink epidermal plaque with variable hyperkeratosis.
  • Lesions can rapidly progress to epidermal filling, dermal invasion, and local tissue infiltration and destruction.
  • Staging: is the same as for BCC.
  • Prognosis: is worse for larger tumors, deeper lesions, recurrent tumors, lesions with ill-defined borders, and tumors originating on the dorsa of the hands or head and neck, especially near critical structures or cosmetically-sensitive areas.
    • Metastatic potential is largely dependent on tumor location, depth, and size. The rate of metastasis is 5%. [25] Overall, the five-year survival for patients with cutaneous SCCs is more than 90%  and 99% when diagnosed early [19, 26].
    • Second primary malignancies: following a diagnosis of SCC, the 3-year cumulative risk of developing a second SCC lesion is ~18%. Additionally, there is about a 40% risk of developing BCC, and a one-and-a-half- to three-fold increased risk of developing noncutaneous malignancies [21, 23].
• Malignant melanoma: malignant transformation of melanocytes.
  • Primary MM lesions usually appear cutaneously, but lesions can also present in the eye, anus and GI tract, meninges, ear, and oral or genital mucous membranes.
  • While the majority of cases occur in patients younger than age 70, the mean age at diagnosis is 66 years [9, 27].
    • Approximately 10% of cases are familial, and these patients typically present at younger ages.
  • Disease at presentation: 77% of patients with clinically localized disease, 10% with regional involvement, and 5% with metastatic disease [7, 27, 28].
  • Two growth phases: radial, which features outward (lateral) expansion and lasts for a variable period of time, and vertical, which usually follows a period of radial growth and features rapid cellular invasion through the dermis.
    • Radial growth phase cells typically do not metastasize, but vertical phase cells have a greater metastatic potential since they can access dermal lymphatics and blood vessels.
  • Histopathologic subtypes
    • Superficial spreading : 65-75% of all MMs; usually presents as a deeply pigmented macule, plaque, or nevus that grows radially prior to vertical invasion.
    • Nodular : 15-30% of MMs; often presents as a darkly pigmented discrete nodule with initial vertical growth without a radial growth phase.
    • Lentigo maligna : 5-10% of MMs; usually arises from in situ melanoma and occurs on the head and neck.
    • Acral lentiginous : 2-7% of MMs; most common subtype found in dark-skinned patients; usually presents on the palms, soles, and nail beds, and is associated with a poorer prognosis.
  • Staging: the American Joint Committee on Cancer TNM staging incorporates two systems: Clark's levels (I through V) describe the depth of tumor invasion qualitatively, via description of the skin layer into which it invades, and Breslow's thicknesses describe the depth of invasion quantitatively, in millimeters. While both systems correlate with prognosis, Breslow's thickness is better able to predict survival. [29]
  • Prognosis is worse in patients with: lesions on the trunk, back, and head and neck; positive lymph nodes or angiolymphatic invasion; acral lentiginous lesions; tumors with high mitotic rates; ulcerated lesions; and in patients over age 65. Stage, nodal involvement, and tumor thickness are the most important predictors of survival [9, 30].
    • Metastatic potential is directly correlated with tumor thickness. Metastasis typically progresses from local disease or recurrence to regional metastasis to distant spread.
    • Five-year survival rates are 99% for patients with localized disease, 74% for regionally advanced disease, and 35% for metastatic disease. [31] Overall, the 5-year survival rate for all patients diagnosed with cutaneous melanoma is 94%, improved from 81% thirty years ago [7, 27, 28].
    • Second primary malignancies: following a diagnosis of MM, there is a >10-fold increased risk of developing a second MM lesion. Additionally, there is a three-to-fourfold increased risk of developing an NMSC, and a one-to two-fold increased risk of developing non-cutaneous malignancies [32, 33].

Treatment

• Basal cell and Squamous cell carcinomas
  • Complete surgical excision and Mohs micrographic surgery are the mainstays of therapy for NMSCs. While standard surgical excision can achieve cure rates of 90%, Mohs surgery can be used for select lesions to better achieve tumor-free margins and produce a 95-99% cure rate. [34]
    • Mohs surgery with intraoperative frozen section margin evaluation is preferred over standard surgical excision for NMSCs >2 cm, lesions with poorly-defined borders, or high-risk lesions [35, 36, 37, 38].
  • Laser surgery, curettage, electrodessication, and cryosurgery result in less controlled treatment margins, but are rapid and cost-effective therapeutic modalities that may be used to treat superficial and small NMSCs, particularly BCCs.
  • Immunotherapy, specifically immune checkpoint inhibitors, have become a standard part of skin cancer treatment. Currently, the NCCN does recommend pembrolizumab alone in the refractory setting of advanced or metastatic squamous cell carcinomas.
  • Radiation therapy is the treatment of choice for select small lesions in locations that would be difficult to excise, such as the eyelid, ear pinna, nasolabial fold, and lips. These lesions have 90-95% cure rates.
  • Chemotherapy, such as imiquimod or topical 5-fluorouracil, is useful for treating small, superficial BCCs.
    • Retinoids are used in both the prevention and treatment of skin cancers, causing cancer regression in some cases by an unknown mechanism of action.
    • High-risk cutaneous SCCs may be treated with systemic therapy such as carboplatin, paclitaxel, or EGFR inhibitors. Advanced BCCs may be treated with systemic vismodegib or cemiplimab. [39]
  • Photodynamic therapy (PDT), which combines a photosensitizing drug with a specific type of light to kill localized cancer cells, can effectively treat actinic keratoses and superficial NMSCs [34, 40].
• Malignant melanoma
  • Surgical excision with disease-free margins can result in long-term survival for patients with solitary or limited lesions. [41]
    • Current surgical margin recommendations: 1 cm margin of normal tissue for lesions <1 mm in thickness, 2 cm margin for lesions 1-4 mm in thickness, and 2 cm margin for lesions >4 mm in thickness [9].
    • Lymph node dissection is controversial, as removal would eliminate the most likely source of metastasis, but 80-85% of patients with stage I and II disease have negative lymph nodes at the time of surgery [9, 42]. Sentinel node dissection should be offered to patients.
      • For patients with clinically positive or enlarged lymph nodes, a fine needle aspiration (FNA) should be performed. A complete lymphadenectomy should be conducted in patients with a positive tissue sample for metastasis.
      • For patients with clinically negative nodes, a sentinel lymph node biopsy is generally performed in patients with poor prognostic factors, MMs that are deeper than 1 mm, or lesions that invade to Clark's level IV or greater.
  • Chemotherapy has largely been supplanted by immunotherapies for melanoma. However, BRAF/MEK inhibitors are still often used in unresectable diseases that are positive for BRAF mutations. However, immunotherapy is still recommended as the first line. [43]
  • Radiation therapy may be the primary treatment of choice for select patients who are not surgical candidates, either because of the size or location of the lesion or other physical limitations. Radiation should also be considered postoperatively for patients who are at high risk of regional recurrence, who have gross extracapsular extension, or multiple involved lymph nodes.
  • Immunotherapy is a quickly evolving area of research for cutaneous malignancies. In fact, metastatic melanoma was the first FDA-approved indication for immune checkpoint inhibitors in 2011. [44] The approval of ipilimumab for metastatic melanoma was the first of many for immune checkpoint inhibitors. Today, these therapies are used widely in the setting of melanoma. The NCCN recommends pembrolizumab or durvalumab in the adjuvant setting even for early-stage disease. [41]