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Nonmelanoma Skin Cancer

Daniel Knabel, MD

Allison Vidimos, MD

Published: October 2019

Introduction

Nonmelanoma skin cancer (NMSC), is the most common malignancy in humans. The incidence of NMSC is not consistently reported to cancer registries; however, an estimated 5.4 million cases of NMSC were diagnosed in the United States in 2012.1,2 The average treatment cost of NMSC in the United States from 2007 to 2011 was estimated to be $4.8 billion annually.3

Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the 2 most common subtypes of NMSC and are sometimes referred to as keratinocyte carcinoma (KC). While BCC has traditionally thought to be approximately 4 times more common than SCC, recent evidence suggests that BCC and SCC may have similar incidences, a trend that may be related to an aging population, in which SCC is more common.2

The etiology of NMSC is strongly tied to ultraviolet (UV) radiation.4,6 Given the overwhelming incidence and cost of NMSC each year, prevention has become a public health priority. The American Academy of Dermatology recommends use of broad spectrum (long wave UV [UVA], 315-400 nm and short wave UV [UVB], 280-315 nm) sunscreen with a sun protection factor (SPF) of 30 or greater, abstinence from indoor tanning, and covering exposed skin from harmful sunlight whenever possible.7

Although the number of NMSC is staggering, both BCC and SCC have a better than 95% cure rate if detected and treated early.

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Basal Cell Carcinoma

Definition

BCC is the single most common cutaneous malignancy in humans. Although BCCs grow slowly and rarely metastasize, they can cause extensive tissue destruction through direct extension, leading to significant patient morbidity if untreated.

Epidemiology and Risk Factors

Over 1 million BCCs were diagnosed in the United States Medicare population alone in 2012.2 Although the incidence of BCC increases with age, it is becoming more common in younger adults, especially women.9 Factors such as excessive, chronic sun exposure, indoor tanning, fair complexion, prior exposure to ionizing radiation, exposure to chemical carcinogens such as arsenic, and genetic determinants are significant risks factors. Because of the increasing incidence in younger populations, health campaigns aimed at education and sun avoidance have been initiated with promising results.10

Pathophysiology and Natural History

The pathophysiology of BCC is not completely understood. Recent investigations suggest that BCC may arise from the stem cells of the hair follicle bulge or interfollicular epidermis rather than basal keratinocytes.8

The most common causative factor of BCC is UV radiation. UVB radiation has been shown to induce characteristic DNA mutations in keratinocytes called dipyrimidine dimers and manifest as signature mutations in tumor protein 53 (TP53), an important tumor suppressor gene.11 TP53 is responsible for arresting the cell cycle so that induced mutations can be repaired. Mutated TP53 is nonfunctional and leads to dysregulation of the cell cycle, with resultant unlimited cell proliferation. Inactivation of TP53 is the second most frequently encountered mutation in BCC pathogenesis.12

Although the exact mechanism of BCC propagation remains unclear, it is believed to arise when mutations that control cell growth activate pluripotential stem cells in the epidermis. Patched 1 (PTCH1), a tumor suppressor gene that negatively regulates the hedgehog signaling pathway, is the most common mutation identified in BCC. Through a series of complex interactions, the hedgehog signaling cascade has a central role in activation and repression of an important transcription factor, glioma-associated oncogene. Dysregulation of this pathway results in the development and progression of numerous malignancies, including BCC.13 Other mutations less frequently associated with BCC involve ras oncogenes and smoothened (SMO).14

The natural progression of untreated BCC is persistent, slow growth with invasion and destruction of adjacent tissues. Metastasis is very rare in BCC, with an estimated incidence of 0.0028% to 0.55%.15 Risk factors for metastasis include increased size (3cm diameter is associated with 2% risk of metastasis),16 location on the face, longer duration, aggressive features on histology, perineural/perivascular involvement and recurrent tumors.17

When metastasis occurs, the face is most often the site of the primary lesion and regional lymph nodes are most often the site of tumor spread, followed by lung, bone, and skin. The average interval from the first signs of BCC to metastasis is approximately 9 years.15 Metastatic BCC traditionally has a poor prognosis, with a median survival of approximately 8 months to 3.6 years.15,18-19

Signs and Symptoms

BCCs primarily occur on the head and neck with the nose being the most common site. The typical lesion is a small, pearly (waxy) nodule with a central depression and rolled border containing dilated blood vessels. A history of ulceration, crusting, or bleeding is common. Over 20 different clinicopathologic subtypes of BCC have been reported though most major dermatology texts detail 4 or 5 major subtypes.20-21 Five clinicopathologic subtypes are described in this review: nodular-ulcerative, superficial, pigmented, diffuse (infiltrating, morpheaform and sclerosing) and fibroepithelial (also referred to as fibroepithelioma of Pinkus).

Nodular-Ulcerative

The nodular-ulcerative variant (Figure 1) is the most common type of BCC. It manifests as a small, pearly dome-shaped papule with surface telangiectasias and a typical rolled border. Over time, central ulceration with bleeding or crusting is often seen. Differential diagnosis of this lesion includes sebaceous hyperplasia, SCC, verruca vulgaris (wart), molluscum contagiosum, intradermal nevus, appendageal tumors (tumors of the hair follicle and sweat ducts), amelanotic melanoma, and stasis ulcers (when located on the shins).

Superficial

Superficial BCC (Figure 2) is the least aggressive subtype of BCC. They often manifest as several scaly, dry, round-to-oval erythematous plaques with a threadlike raised border on the trunk and extremities. If untreated, superficial BCCs can enlarge to 10 to 15 cm in diameter without ulceration. Differential diagnosis of superficial BCC includes eczema, psoriasis, seborrheic keratosis, and Bowen's disease (ie, SCC in situ).

Pigmented

Pigmented BCC (Figure 3) is seen more often in darker-skinned persons such as Latin Americans and Asians. This subtype has all the characteristics of the nodular-ulcerative variety plus brown or black pigmentation from melanin. A history of arsenic ingestion has been noted with pigmented and superficial BCCs.

Diffuse (Morpheaform, Sclerosing, Infiltrative)

An indurated yellow to white plaque with an indistinct border and an atrophic surface characterizes morpheaform or sclerosing BCC (Figure 4). Ulceration and crusting are usually absent. This variety has an aggressive growth pattern, and invasion of muscle, nerve, and bone may occur. Morpheaform BCC is particularly insidious because of its benign scar-like appearance. Differential diagnosis of morpheaform BCC includes scar, localized superficial scleroderma (morphea), sebaceous hyperplasia, dermatofibrosarcoma protuberans, and microcystic adnexal carcinoma.

Fibroepithelial (fibroepithelioma of Pinkus)

Fibroepithelial BCC is a rare and unusual variant of BCC. Clinically, they appear as skin colored to pink, smooth, pedunculated papules or nodules (Figure 5). The most common location is the trunk, especially the lower back and thigh. This entity often mimics various benign skin tumors and the differential diagnosis includes intradermal nevus, fibroepithelial polyp, acrochordon, and seborrheic keratosis.22 Some consider the fibroepithelial BCC to be a form of trichoblastoma.23

Related Syndromes

Multiple BCCs are features of several syndromes such as nevoid basal cell carcinoma syndrome (as called Gorlin-Goltz syndrome or Gorlin syndrome), Bazex–Dupré–Christol syndrome, and Rombo syndrome.

Gorlin syndrome is characterized by BCCs; odontogenic jaw cysts; pitted depression of the hands and feet; osseous anomalies of the ribs, spine, and skull; and characteristic facies (frontal bossing, hypoplastic maxilla, a broad nasal root, and true ocular hypertelorism).24 This genetic disorder occurs in an autosomal dominant pattern. There is a mutation of the PTCH1 tumor suppressor gene located on chromosome 9.25

Bazex–Dupré–Christol syndrome is a rare familial syndrome associated with the development of BCCs early in life. It is characterized by a triad of multiple BCCs, follicular atrophoderma of the extremities, and hypotrichosis.26 Other less common findings include milia, ichthyosis, hypohidrosis, and visceral malignancies. The inheritance pattern is X-linked dominant in most cases.

Rombo syndrome has similar features to Bazex–Dupré–Christol syndrome, but is inherited in an autosomal dominant pattern. Clinical characteristics include early onset BCCs, atrophoderma vermiculatum-like appearance on the cheeks, milia, hypotrichosis, trichoepitheliomas, telangiectases, and acral erythema.27

Diagnosis

Clinical diagnosis of BCC is confirmed by biopsy of the suspected lesion for histopathologic interpretation. Biopsy techniques include shave biopsy, punch biopsy, and excisional biopsy. The goal of the biopsy is to provide adequate tissue for accurate diagnosis. For the majority of BCC subtypes, a shave biopsy suffices. However, when the lesion is believed to be a morpheaform or infiltrative BCC, a deep shave, punch biopsy, or excisional biopsy is recommended to obtain a sufficient tissue sample for correct interpretation.28

Treatment

BCC can be effectively treated by a variety of therapeutic modalities. Among the clinical subtypes of BCC, superficial BCCs respond to most treatment options; large nodular, ulcerative or morpheaform lesions can require more aggressive therapy. No single treatment method is ideal or appropriate for all tumors. The treating physician should carefully evaluate each BCC on an individual basis and choose the modality that is most appropriate for the lesion's size, site, and histologic type, as well as the patient's age, functional status, and post-procedural expectations.28

Electrodesiccation and Curettage

Electrodesiccation and curettage (ED&C) is a commonly employed, relatively simple and cost effective method for treatment of BCC. A significant disadvantage of the ED&C is the lack of histological margin assessment. Current guidelines recommend ED&C as an appropriate treatment for primary, well defined lesions, measuring 1 to 2 cm on the trunk and extremities of relatively healthy, immunocompetent patients. Superficial and thin nodular BCCs are best treated by ED&C. ED&C is less effective in the cure of recurrent lesions, morpheaform or infiltrative type BCCs, and tumors of terminal hair bearing skin (due to the risk of follicular extension of malignant cells).28-29 Select low-risk lesions (ie, small, well defined primary lesions with nonaggressive histology not involving skin of the central face, ears, genitals, hands, and feet) can achieve 5-year cure rates of up to 97% when treated with ED&C.30

Primary nondiffuse type basal cell carcinomas are more friable than surrounding normal skin and are initially debulked with a curette. The stroma and surrounding dermis are then electrodesiccated. This process is usually repeated 2 additional times. The resulting wound heals with a hypopigmented scar over 2 to 6 weeks. The main disadvantage of this treatment is the absence of histologic margin control. Treatment of facial lesions with this modality is generally not advocated because of the risk of deep invasion in embryonal fusion planes, the difficulty of adequate curettage in the sebaceous skin of the nose, and poor cosmetic appearance.

Cryosurgery

Cryosurgery (also referred to as cryotherapy) may be considered in the treatment of low-risk BCC when other therapies are impractical or contraindicated.28 Like, ED&C, cryosurgery of BCC lacks histological margin assessment. Randomized trials comparing cryosurgery to alternative therapies for BCC have reported recurrence rates ranging as high as 15% to 39% within 5 years.31-33 Liquid nitrogen (temperature −196°C) produces tissue destruction by reducing the temperature of the skin cancer to tumoricidal levels. It is not indicated for tumors deeper than 3 mm or those with indistinct margins. The main disadvantages include a hypopigmented scar, prolonged healing, pain during the procedure, and risk of recurrence. Cosmetic results of excision are favored over cryosurgery.34

Surgical Excision

Recent guidelines recommend standard excision with a 4 mm peripheral margin to a depth of mid-subcutaneous adipose tissue for primary, low-risk BCC.28 This margin accounts for the characteristic subclinical extension of BCC and yields a clearance rate of 95% for BCC with a diameter of 2 cm or less.35 There is insufficient data to recommend standard excision margins for high-risk BCC. However if standard excision is chosen for the treatment of high-risk BCC, margins greater than 4 mm should be employed and higher recurrence rates should be expected.36 Following the procedure, surgical margins of the specimen are examined histologically for assessment of adequate tumor removal. The wound defect can be closed primarily with side-to-side (primary) closures, flaps, grafts, or it may be allowed to heal by secondary intention. A disadvantage of surgical excision is incomplete margin control. Because the routine vertical sectioning technique (“bread loafing and quartering” methods of margin assessment) only assess approximately 1% of the margin.37-38

Mohs Micrographic Surgery

Mohs micrographic surgery (MMS) is a surgical technique utilized for the removal and complete margin assessment of skin cancer. MMS is the treatment of choice for high-risk BCC according to the American Academy of Dermatology (AAD) and National Comprehensive Cancer Network (NCCN).28,36 Given the incidence of NMSC and the cost of MMS, 4 major dermatological societies jointly proposed appropriate use criteria for MMS in 2012. The criteria is based on evidence-based medicine, clinical experience, and expert opinion, and outlines a rating system for the appropriate use of MMS based on tumor characteristics (type, location, size, aggressiveness) and patient characteristics (immunosuppression or genetic predisposition for skin cancer).39

MMS consists of the removal of the tumor by scalpel in sequential horizontal layers. Each tissue specimen is mapped, frozen, stained, and microscopically examined. This procedure is especially suited for tumors in high-risk anatomical locations; recurrent, large or aggressive tumors; and in patients with risk for aggressive and recurrent tumors (Table 1).39

Table 1: Tumor Features Suited for Mohs Micrographic Surgery39
Location
  • Area H: “Mask areas” of face (central face, eyelids [including inner/outer canthi], eyebrows, nose, lips [cutaneous/mucosal/vermillion], chin, ear and periauricular skin/sulci, temple), genitalia (including perineal and perianal), hands, feet, nail units, ankles, and nipples/areola.
  • Area M: Cheeks, forehead, scalp, neck, jawline, pretibial surface.
  • Area L: Trunk and extremities (excluding pretibial surface, hands, feet, nail units, and ankles).
Patient characteristics
  • Immunocompromised: patient with HIV, organ transplant, hematologic malignancy, or pharmacologic immunosuppression.
  • Genetic syndromes: basal cell nevus syndrome, xeroderma pigmentosum, or other syndromes at high risk for skin cancer.
  • Healthy: no immunosuppression, prior radiation therapy, chronic infections, or genetic syndromes.
  • Prior radiated skin: patient has previously received therapeutic radiation in this area of the body.
  • Patient known to have high-risk tumors: patient without other known health risk factors but with a history of unexpectedly more aggressive tumors than suggested by clinical appearance.
Tumor characteristics
  • Positive margin on recent excision
  • Unexpected tumor involvement at lateral and/or deep edges after prior excision presumed to have been definitive.
  • Basal cell aggressive features
    1. Morpheaform/fibrosing/sclerosing
    2. Infiltrating
    3. Perineural
    4. Metatypical/keratotic
    5. Micronodular
    6. Squamous cell aggressive features
    7. Sclerosing
    8. Basosquamous (excluding keratotic basal cell carcinoma)
    9. Small cell
    10. Poorly differentiated or undifferentiated (characterized by a high degree of nuclear polymorphism, high mitotic rate, or low degree of keratinization)
    11. Perineural/perivascular
    12. Spindle cell
    13. Pagetoid
    14. Infiltrating
    15. Keratoacanthoma type: central facial
    16. Single cell
    17. Clear cell
    18. Lymphoepithelial
    19. Sarcomatoid
    20. Breslow depth 2 mm or greater
    21. Clark level IV or greater
Reprinted from the Journal of the American Academy of Dermatology, J Am Acad Dermatol, Vol 67/4), Connolly SM, Baker DR, Coldiron BM, Fazio MJ, et al, AAD/ACMS/ASDSA/ASMS 2012 appropriate use criteria for Mohs micrographic surgery: a report of the American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery, 536, 2012, with permission from the American Academy of Dermatology, Inc. and the American Society for Dermatologic Surgery, Inc.

The MMS procedure is predicated on histologically inspecting the entire perimeter and undersurface of the excised specimen to ensure a tumor-free margin. MMS has an extremely high cure rate. A randomized controlled trial in the Netherlands analyzed recurrence rates between MMS and standard excision in treatment of high-risk BCC of the face. A 10-year recurrence rate for primary facial BCC was 12.2% for standard excision and 4.4% for MMS. The 10-year recurrence rate for recurrent facial BCC was 13.5% for standard excision and 3.9% for MMS.40-41

Defects after MMS can be closed immediately or a delayed repair may be performed in select cases. Repair can be achieved with primary linear closure, adjacent tissue transfer (flap), skin grafting, or healing by second intention.

Radiation

Radiation may be considered for the treatment of BCC when surgical intervention is impractical, contraindicated, or if the patient prefers radiation therapy. Superficial high-dose x-rays are administered in multiple, divided doses over several weeks. Brachytherapy and electronic brachytherapy are newer techniques used to radiate the skin in treatment of BCC.28 Five-year recurrence rates for radiation therapy of BCC range from 4% to 16%.36 Radiation therapy is contraindicated in patients genetically predisposed to develop BCC (ie, basal cell nevus syndrome) and those with connective tissue disease.42 Adverse effects include radiation-related toxicity, alopecia, and increased risk for secondary malignancy.

Vismodegib and Sonidegib

Vismodegib and sonidegib are oral medications that inhibit the protein smoothened in the hedgehog signaling pathway, and function as novel therapy for the down-regulation of BCC tumorigenesis. Sonic hedgehog inhibitors (SHHi) are used in the treatment of locally advanced and metastatic BCC. Early studies show promising results in this previously difficult to treat population, with a recent meta-analysis suggesting that most patients receiving SHHi experience at least a partial response and nearly 95% have at least stable disease.43 Side effects can be severe and include muscle spasms, dysgeusia, alopecia, myalgia, nausea, and vomiting. A recent study identified a mechanism by which some BCC tumor cells are able to evade SHHi via transcriptional alterations that change cell identity.44 This mechanism may explain why some BCCs are not effectively treated with SHHi or rebound once treatment is discontinued.

Topical Therapy and Photodynamic Therapy

Topical imiquimod is an immunomodulating medication approved by the U.S. Food & Drug Administration for treatment of superficial BCC of the extremities, trunk, and neck. Treatment is once daily to several times weekly (the latter is preferred) for up to 16 weeks with clearance rates ranging from 60% to 80%.28 Side effects include local irritation and rare reports of systemic flu-like symptoms when used over larger surfaces. Topical 5-fluorouracil (5-FU) is an antimetabolite with less evidence for use in treatment of BCC. For low-risk tumors, twice-daily application for up to 6 weeks results in clearance of 50% to-90%.28 Side effects are similar to imiquimod.

Photodynamic therapy (PDT) involves application of a photosensitizing medication (5-aminolevulinic acid or methylaminolevulinate) followed by incubation with a light source leading to formation of reactive oxygen species and cytotoxic effects.45 In a study examining PDT treatment for nodular BCC, aggressive, repeated PDT treatments, after debulking with curettage, resulted in histological clearance rates of greater than 70% (nearly 90% clearance for tumors of the face) with good cosmetic results.46

Outcomes

Five-year recurrence rates after treatment of primary BCC are 1% for MMS, 7.5% for cryotherapy, 7.7% for ED&C, 8.7% for radiation therapy, and 10.1% for surgical excision.47 It is important to note that recurrence of primary BCC may occur greater than 5 years after treatment, highlighting the importance of long term follow-up.41 The primary goal in the treatment of BCC is using the most appropriate therapy for complete removal of the malignancy with the highest cure rate and least cosmetic disfigurement or functional impairment.

Prevention and Screening

Patients with a history of BCC have a higher propensity to develop new cutaneous malignancies, including melanoma.48-49 Long term follow-up and self- or family-examination in patients who have had a BCC are important methods for monitoring for recurrence and detecting new skin cancers. Sun protective behaviors include sun avoidance, wearing sun protective clothing, repeated sunscreen application, and avoiding tanning beds.28 Evidence from a recent randomized, controlled trial reported a 23% reduction in the rate of new NMSC in a high-risk population with use of oral nicotinamide 500 mg twice daily.50 Prevention, screening, and education are integral parts of the total care of a patient with BCC.

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Squamous Cell Carcinoma

Definition and Cause

Squamous cell carcinoma (SCC) is a malignant tumor arising from the keratinocytes of the epidermis or dermal appendages. SCC is the second most common cutaneous malignancy after basal cell carcinoma (BCC). Unlike BCC, cutaneous SCC is associated with a greater risk of metastasis.51 Like BCC, exposure to UV radiation is the most common cause of SCC in fair-skinned populations and immunosuppression is increasingly recognized as a risk factor.52

Prevalence and Risk Factors

An estimated 200,000 to 400,000 new cases of invasive cutaneous SCC occur in the United States annually.51 In 2012, as many as 12,000 nodal metastases and 8,500 deaths were associated with invasive cutaneous SCC.53 Compared with BCC, the incidence of SCC seems to be increasing more rapidly, with an estimated lifetime risk of 9% to 14% among men and 4% to 9% among women.51 The most significant risk factors for the development of SCC include sun exposure, fair skin, age, and immunosuppression.53-54

Pathophysiology and Natural History

Cumulative UV exposure is the primary etiological factor for SCC in fair-skinned individuals.55 Although UVB is mainly responsible, UVA also plays a role. As in the pathogenesis of BCC, UV radiation leads to the formation of dipyrimidine dimers and mutagenesis of the p53 tumor-suppressor gene. A nonfunctional p53 protein leads to dysregulation of the cell cycle, uncontrolled growth and proliferation of aberrant keratinocytes.11 Many other factors associated with the pathogenesis of SCC are detailed in Table 2.

Table 2: Risk Factors for Squamous Cell Carcinoma
UV exposure from sunlight
Other UV exposures
  • Photochemotherapy [eg, psoralen (methoxsalen) plus ultraviolet light of A wavelength (treatment)] for skin disorders such as psoriasis
  • Indoor tanning
  • Occupational exposures (ie, laboratory transilluminators, UV germicidal lamps)
Ionizing radiation (ie, X-rays, nuclear radiation, soil, cosmic sources at high altitudes [ie, airline pilots])
Thermal injury to the skin
Exposure to chemical carcinogens
Arsenic
Chromates
Mineral oil
Polycyclic aromatic hydrocarbons
Mechlorethamine (nitrogen mustard)
Tars
Tobacco smoke
Others
Human papillomavirus (HPV) infections, especially from HPV types 16, 18, 30, and 33
Previously injured or chronically diseased skin
Burn sites
Chronic ulcers
Chronic radiation dermatitis
Scars of various causes
  • Chronic inflammatory diseases of the skin (ie, discoid lupus, lichen planus, lichen sclerosis)
Fair skin – easily burns, never tans, freckling, red hair
Genetic determinants
  • Xeroderma pigmentosum
  • Oculocutaneous albinism
  • Dystrophic epidermolysis bullosa
  • Epidermodysplasia verruciformis
Immunosuppression
  • Organ transplantation
    Acquired immune deficiency syndrome (HIV/AIDS)
  • Chronic lymphocytic leukemia (CLL)
  • Iatrogenic immunosuppression (ie, chronic glucocorticoid or thiopurine use)

Signs and Symptoms

SCC can arise in any cutaneous epithelial site though sun exposed skin of the head and neck, dorsal hands, and dorsal forearms are the most common sites. Rates of metastatic SCC range from 4% to 16%, with tumor thickness (greater than 2 mm), localization to the ear and immunosuppression being key risk factors for metastasis.56 Tumors of the vermilion lip have a fivefold risk of nodal metastasis compared with tumors of the cutaneous lip. Tumors of the external ear are reported to have up to 10.5% occurrence of regional nodal metastasis.57-58

Actinic Keratosis

Actinic keratosis (AK) is a premalignant macule or papule, found on chronically sun exposed skin, chiefly the face, ears, dorsal hands, and forearms. AK growths vary in morphological appearance: they can be multiple, discrete, flat or raised, verrucous, keratotic, pigmented, erythematous or skin-colored. The surface is usually scaly (Figure 6).

AK is considered a precursor to SCC. The transformation rate to SCC is estimated to range from 0.25% to 20% a year for each AK.59-60 The transformation may be heralded by the development of erosion, induration, inflammation, tenderness or enlargement.

Clinically, and even histologically, it is difficult to differentiate low- and high-risk AK and treatment is recommended for any AK macule or papule.61 Options for treatment include cryosurgery, ED&C, topical 5-FU, photodynamic therapy, dermabrasion, chemical peel, and laser resurfacing. It has been estimated that there is a 10.2% chance of at least 1 AK on a given patient transforming into an SCC within 10 years.20 However, this rate might actually be much higher, especially in immunocompromised patients such as organ transplant recipients.

Bowen's Disease

Bowen’s disease, or SCC in situ, is characterized by well demarcated, erythematous, scaly, slowly enlarging plaques that can occur on any part of the body (Figure 7). It may initially be confused with psoriasis, nummular dermatitis, or tinea and treated unsuccessfully with topical corticosteroids or antifungals prior to diagnosis. When it occurs on the glans penis, it is referred to as erythroplasia of Queyrat. The development of ulceration or induration can portend transformation to invasive SCC, which occurs in at least 5% of cases.62 Bowen's disease affects mostly older white men. Chronic sun damage and arsenic exposure have been implicated in Bowen's disease. Treatment options include excision, ED&C, photodynamic therapy, cryosurgery, topical 5-FU (off-label), topical imiquimod (off-label), and MMS.

Keratoacanthoma

A rapidly growing tumor, the pathogenesis and natural history of keratoacanthoma (KA) this is poorly understood and presents both diagnostic and therapeutic challenges. KA is generally believed to be a low-grade SCC. It usually starts as a 1-mm flesh-colored macule or papule and grows to a 1 to 2 cm nodule with a keratin-filled crater within several weeks to several months (Figure 8). “Giant” KAs have been reported as large as 20 cm. In most cases, solitary keratoacanthomas involute over 2 to 6 months, often healing with scarring. Multiple KAs can arise sporadically or in genetically predisposed individuals (rare familial cases and those with genetic predispositions to carcinogenesis, ie, xeroderma pigmentosa).63 Keratoacanthomas are generally found on sun-exposed skin, although they can occur anywhere on the body including the mucosa. Although keratoacanthomas may ultimately involute, the duration of regression is unpredictable.

KAs may mimic invasive SCC with regard to rapid growth pattern and clinical characteristics. Histological diagnosis is highly dependent on the clinician’s biopsy technique. A method of removal that ensures adequate depth for histopathologic review is important. Management of KAs remains controversial. Options for therapy include observation (generally not recommended), surgical excision (preferred treatment), ED&C, cryosurgery, MMS, radiotherapy, photodynamic therapy, topical 5-FU, topical Imiquimod and intralesional, and injections of 5-FU, bleomycin, methotrexate, or interferon.63

Squamous Cell Carcinoma

SCC can arise on any skin surface including the mucous membranes. It most often occurs in fair-skinned, middle-aged to older adult males. The most common sites affected are the scalp, dorsal hands, ears, lower lip, neck, forearms, and legs. Clinically, SCC presents as an enlarging, indurated, erythematous papule, nodule, or plaque with overlying scale (Figure 9). Ulceration and crusting occur later, followed by possible invasion of underlying structures and development of regional lymphadenopathy. On the lower lip, SCC arises on the chronically sun-damaged skin of the vermilion border. Patients usually note the presence of a firm nodule growing either inward or outward with ulceration. Squamous cell carcinomas of the vermillion lip are important to recognize as they carry a fivefold increased risk of metastasis compared with SCC of the cutaneous lip.57

Verrucous Carcinoma

Verrucous carcinoma (VC) is considered a low-grade variant of well differentiated SCC. VC typically presents as an indolent, exophytic papule, nodule, or plaque that resembles a wart (Figure 10). The oral cavity, genital area, and plantar foot are most commonly involved.64 VC can be locally aggressive but rarely metastasizes. The most effective treatment is excision with MMS required in some cases.

Diagnosis

As with BCC, a total body skin examination is the only screening test available for cutaneous SCC. Findings associated with high-risk SCC include

  1. any lesion involving central face, eyelids, eyebrows, periorbital skin, nose, lips, chin, mandible, pre- and postauricular skin/sulci, temple, ear, genitals, hands, and feet
  2. lesions greater than 1 cm involving the cheeks, forehead, scalp, neck and pretibia; or lesions greater than 2 cm elsewhere on the trunk and extremities
  3. SCC in immunosuppressed patients or in areas of prior radiation or chronic inflammation
  4. any lesion that is clinically poorly defined, recurrent, rapidly growing or histologically poorly differentiated, has a histological depth of 2 mm or greater, or with any perineural, lymphatic, or vascular involvement.

A physical examination of patient with high-risk SCC should include thorough examination of the areas of lymphatic drainage. The clinical presence of lymphadenopathy necessitates exclusion of metastatic disease. Cutaneous lesions suspicious for SCC should be promptly biopsised. Biopsy methods include shave, punch and excisional biopsy. The goal of any biopsy is to provide adequate tissue for an accurate diagnosis. No single biopsy technique for SCC is recommended above another in the literature.51

Treatment

An exhaustive review of all treatment modalities for SCC is beyond the scope of this publication. However, the reader should know that many treatment modalities are available for SCCs and no single technique suites every tumor. Treatment can be customized depending on the characteristics of the SCC, patient characteristics/preferences, and the experience of the physician. Treatment techniques for SCC include: ED&C, excision, MMS, cryosurgery, photodynamic therapy, topical 5-FU, topical Imiquimod, carbon dioxide laser, and radiotherapy.65

Bowen’s Disease (Squamous Cell Carcinoma in situ)

Evidence based treatment recommendations for SCC are excluded from the 2018 AAD guidelines on SCC treatment. However, in the AAD 2006 guidelines for management of Bowen’s disease, the British Association of Dermatologists (BAD) identified ED&C, phototherapy, and excision as having an overall strength of recommendation “A-rating” for the treatment of SCCs.66 It should be noted that MMS has an important role in treatment of SCCs in high-risk locations but is not necessary or cost effective in all situations.

Invasive Squamous Cell Carcinoma

Electrodessication and Curettage (ED&C)

ED&C is a relatively simple and expeditious treatment of SCC that is regularly used by dermatologists in practice. According to current AAD guidelines, ED&C may be suitable for the treatment of small, low-risk, primary invasive SCC on sun-exposed skin.28 ED&C is discouraged for treatment of recurrent lesions that have associated scar tissue or tumors of terminal hair-bearing skin due to potential involvement of follicular keratinocytes.

This technique sequentially scrapes the tumor cells from the epidermis and dermis, followed by destruction of a margin of normal skin by electrodessication. While curettage is performed the physician is able to differentiate soft, friable tumor cells from firm, normal dermis. Curettage followed by electrodessication is generally performed in 3 cycles to maximize the possibility of complete removal. Recurrence of SCC following ED&C has been reported to be 1.7% in small, low-risk tumors.67

Limitations of ED&C include the lack of tissue available for histologic evaluation and possibly poor cosmetic outcomes. Because of this and potential for follicular extension, ED&C is not recommended for treating tumors of the face.

Cryosurgery

Cryosurgery, also called cryotherapy, utilizes the extremely cold (-196°Celsius) tumoricidal activity of liquid nitrogen to destroy a volume of tissue containing a cutaneous malignancy. A 3 mm to 4 mm margin of normal tissue should be included. Although the cost of cryosurgery is low and it is relatively simple to perform, limited data are available on the use of cryosurgery in the treatment of cutaneous SCC.

A meta-analysis of 8 studies identified an overall pooled average recurrence rate of 0.8% in 273 patients with SCC.67 These tumors were primarily small and low risk. Cosmetic outcomes were not included. A randomized controlled trial comparing treatment of SCC with either PDT, topical 5-FU, or cryosurgery, demonstrated inferior complete response rates at 12 months postintervention for lesions treated with cryosurgery compared with other modalities. Cosmetic outcomes were also inferior in patients treated with cryosurgery.68 Given the lack of margin analysis and notorious risk of subclinical extension of SCC, current AAD guidelines recommend use of cryosurgery for only low-risk SCC.51

Excision

As with BCC, surgical excision is a common and effective method to treat SCC. Excision involves making an elliptical incision around the SCC with a margin of 4 mm to 6 mm of normal appearing skin.69 The incision is taken down to mid-subcutaneous adipose tissue and removed at that plane. Histological margin assessment occurs following tissue fixation. A 2013 systematic review based on pooled analysis of 1,144 patients in 12 observational studies reported a local recurrence rate of 5.4% following excision of SCC with 2mm to 10 mm margins.67

According to recent AAD guidelines, low risk SCC may be treated by standard excision with a 4 mm to 6 mm margin of normal skin.51 Standard excision may be considered in high-risk tumors, however complete margin assessment is preferred due to the characteristic subclinical extension in these tumors.70 Overall, standard excision is a commonly utilized and effective treatment modality for SCC.

Mohs Micrographic Surgery

Dr. Frederic Mohs designed the “chemosurgery” procedure (ie, Mohs micrographic surgery) to account for subclinical extension of various cutaneous malignancies. The procedure initially involved in vivo fixation of tissue with zinc chloride followed by excision with conservative margins, then immediate and complete histological margin assessment.71 MMS is ideal for the complete removal of cutaneous malignancies while preserving as much normal surrounding tissue as possible.

A retrospective cohort study from the Netherlands compared the use of MMS with excision in the treatment of 579 patients with 672 SCCs (380 by MMS, 292 by excision). Risk of recurrence was 3% following MMS (median follow-up 4 to 9 years) compared with 8% following excision (median follow-up 5 to 7 years).72 In a meta-analysis by Lansbury, a five-year cure rate of 97.4% was reported after pooled analysis of 16 studies with 2,133 SCCs at all sites.67 A meta-analysis by Rowe of treatment for recurrent SCC reported a 5-year recurrence rate of 10% for MMS and 23.3% for excision.73

According to current AAD guidelines, MMS is recommended for the treatment of high risk SCC. Established criteria for appropriate use of MMS guide practitioners in clinical practice (Table 1).

Laser Surgery

Current AAD guidelines do not include the use of laser modalities for the treatment of SCC due to lack of evidence in the literature.51 Though evidence is limited, in practice ablative lasers may be considered for excision or destruction of SCC with excellent hemostasis. A recent, small prospective study examined the treatment of SCC in situ with a single pass of fractional CO2 laser treatment followed by application of 5-FU under occlusion. At 9 months post treatment, 92% of patients remained clear of tumor.74 While laser assisted delivery of topical chemotherapeutics may have a role in treatment of small, low-risk tumors in the future, use of ablative lasers alone for treatment of SCC in situ have not demonstrated promising results.75

Ionizing Radiation

Radiation therapy utilizes highly energized atomic and subatomic particles to kill cancer cells. Modalities used in treating cutaneous SCC include external radiotherapy and brachytherapy. These methods minimize the exposure of surrounding normal skin to ionizing radiation. Existing data on the use of radiation in the treatment of SCC is limited; however, it may be suitable for the primary treatment of SCC in situations where surgery is not possible or contraindicated. In a large study, recurrence rates of 6.4% and 5.2% were reported following external radiation and brachytherapy, respectively.67 Adjunctive radiotherapy may be used in high-risk SCC, perineural invasion, involvement of underlying muscle or bone, and nodal involvement.51,76 The most common adverse events include local erythema, desquamation, and alopecia.

Photodynamic Therapy

Photodynamic therapy (PDT) involves application of a photosensitizing topical medication (often 5-aminolevulinic acid) followed by irradiation of the area under a light source. This results in the production of reactive oxygen species within tumor cells. Evidence for the use of photodynamic therapy in treating SCC is limited. Like ED&C, cryotherapy, and radiation therapy, PDT does not allow for the histological confirmation of tumor clearance. Penetration of photosensitizing agents to adequate depths for complete tumor lysis appears to be a limiting factor.77 Pooled recurrence data from 8 studies with a total of 119 SCCs yielded a 26.4% odds of recurrence following PDT. Despite this, PDT may have an important future role in treatment of superficial SCC in patients unable to undergo surgery and research is ongoing. Current AAD guidelines do not advocate the use of PDT as a primary treatment for SCC.51

Evolving Treatments

Evolving therapies for treatment of SCC include continued investigation aimed at improving the efficacy of the treatments already discussed above, namely photodynamic therapy. Human papillomavirus (HPV) is known to have a role in SCC. HPV vaccination may have a role in prevention of SCC in certain patient populations.78 Treatment of metastatic SCC with epidermal growth factor receptor inhibitors (cetuximab, panitumumab) and immune check-point inhibitors (pembrolizumab) are currently being explored with promising results.51

Outcomes

Most patients with primary cutaneous SCC have a very good prognosis. However, patients with more advanced disease may have poor outcomes. Population-based SCC outcomes data is lacking in the United States; however, an estimated 3,932 to 8,791 Americans died from cutaneous SCC in 2012.79 Several large European population based studies indicate relative 5-year survival of 93.6% in Germany and 75% to 98% in Norway with 5-year survival for advanced SCC being as low as 51%.80-81

Prevention and Screening

With the increased incidence, associated morbidity, and cost of treating SCC in the United States, there has been increased interest in prevention and screening. The AAD recommends at least annual screening of patients diagnosed with SCC or BCC.51 This recommendation is based on studies that have identified an increased risk of additional NMSC as well as melanoma in individuals that have had at least 1 NMSCs.48-49 In fact, according to Wehner et al, patients with a history of 2 or more NMSC have an 82.0% risk of an additional NMSC at 5 years and a 91.2% risk of an additional NMSC at 10 years48

Screening consists of a full body skin exam as well as a lymph node exam in high-risk patients. Patients should be counseled on sun protection and self-examination (Table 3). More aggressive screening should be considered in patients with genetic predisposition to developing SCC and immunosuppressed populations (eg, organ transplant patients).

The AAD currently does not recommend routine use of topical or oral retinoids for the chemoprevention of SCC, with the exception of acitretin in solid organ transplant patients.51 Due to limited evidence, the AAD does not recommend use of oral nicotinamide, difluoromethylornithine, celecoxib, selenium or beta-carotene for the chemoprevention of SCC. Although not currently recommended, oral nicotinamide may be a safe an effective method for reducing risk of subsequent NMSC in certain populations.50 Additional randomized controlled trials investigating strategies for the prevention of NMSC are needed.

Table 3: Sun Protection and Skin Cancer Prevention Recommendations
Perform skin self-exams.
Notify your dermatologist of any growing, bleeding, or in any way changing findings on your skin.
Protect your skin from the sun.
Avoid tanning and never use a tanning bed or sun lamp
Wear sunscreen and lip balm daily, even in the winter, that provide:
  1. SPF 30 or higher
  2. Broad-spectrum (UVA/UVB) protection
  3. Water resistance
Apply sunscreen and lip balm to dry skin 15 minutes before going outdoors to every part of your body that will not be covered by clothing
Reapply sunscreen every 2 hours, especially after swimming or heavy perspiration
Whenever possible wear a wide-brimmed hat, long sleeves, and pants
Wear sunglasses to protect the skin around your eyes
Avoid outdoor activities when the sun is strongest between 10 am and 2 pm
Use condoms to prevent an HPV infection, which reduces the risk of squamous cell carcinoma of the genitals
Limit of alcohol consumption and do not smoke.
Drinking alcohol and smoking can increase the risk of squamous cell carcinoma in the mouth.
HPV = human papilloma virus; SPF = sun protection factor; UVA = ultraviolet A; UVB = ultraviolet B.; Adapted from AAD website.7

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Summary

  • Basal and squamous cell carcinomas are the most common cancer in humans.
  • Sun exposure is the primary etiological factor driving the development of nonmelanoma skin cancer.
  • Most nonmelanoma skin cancers have a high cure rate with early diagnosis and appropriate treatment.
  • Patients with a history of skin cancer should have a full skin examination on a regular basis, coupled with education about ultraviolet sun exposure and the regular use of sunscreen.
  • Immunosuppressed patients have a higher incidence of skin cancer, especially squamous cell carcinoma, which can be more aggressive with appreciable morbidity and mortality.

Acknowledgments

The authors wish to acknowledge the contributions of Rebecca Tung, MD, to a previous version of this chapter.

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