> Table of Contents > Squamous Cell Carcinoma, Cutaneous
Squamous Cell Carcinoma, Cutaneous
Mercedes E. Gonzalez, MD, FAAD
Herbert P. Goodheart, MD
image BASICS
  • Squamous cell carcinoma (SCC) is a malignant epithelial tumor arising from epidermal keratinocytes. Cutaneous (nonmucous membrane) SCC is the second most common form of skin cancer.
  • Lesions most frequently occur on sun-exposed sites of elderly, fair-skinned individuals. Most SCCs arise in actinic keratoses (solar keratoses). SCCs that develop from actinic keratoses are slow-growing, minimally invasive, and unaggressive. Thus, the prognosis of an SCC arising from an actinic keratosis is usually excellent because distant metastases are extremely rare.
  • An SCC may also appear de novo without a preceding actinic keratosis or emerge from a preexisting human papillomavirus (HPV) infection (verrucous carcinoma).
  • SCCs may develop from causes other than sun exposure such as within an old burn scar or on sites previously exposed to ionizing radiation.
  • Metastases are more likely to occur in thicker tumors >6-mm deep (1). Other risk factors for metastases include lesions that arise on the ears, the vermilion border of the lips, or on mucous membranes. An SCC located on sites that received ionizing radiation on the skin of organ transplant recipients, in chronic inflammatory lesions (e.g., discoid lupus erythematosus), in long-standing scars or cutaneous ulcers (e.g., venous stasis ulcers), or other nonhealing wounds, also have an increased rate of metastasis.
  • System(s) affected: skin/exocrine
  • Synonym(s): squamous cell carcinoma of the skin; epidermoid carcinoma; prickle cell carcinoma
EPIDEMIOLOGY
  • Predominant age: elderly population
  • Predominant sex: males >females
  • In the United States, >700,000 new cases each year
Incidence
  • The escalating incidence in the United States is due to an increase in sun exposure in the general population, aging of the population, earlier and more frequent diagnosis of SCC, and the increase of immunosuppressed patients.
  • The incidence is highest in Australia and in the Sun Belt of the United States.
ETIOLOGY AND PATHOPHYSIOLOGY
  • Exact mechanisms are not established; however, SCC is thought to arise from a multistep process that begins with a single mutated keratinocyte.
  • UV radiation damages skin cell nucleic acids (DNA), resulting in a mutant clone of the tumor suppressor gene, p53. This leads to an uncontrolled growth of skin cells containing a mutated p53 gene. Additional mutations in genes controlling cellular proliferation and/or death lead to squamous cell dysplasia, which then progresses to SCC in situ and later invasive SCC that has the potential for metastasis.
  • Cumulative UV radiation (including tanning salons, and psoralen-UV-A [PUVA] phototherapy) over a lifetime is the major etiologic factor in SCC (2)[A].
  • A high prevalence of HPV DNA from SCC tissue has been noted in immunocompromised as well as immunocompetent specimens of SCC tissue (3).
  • Other causative agents: ionizing radiation exposure, inorganic arsenic exposure, coal tar, and other oil derivatives
  • Immunosuppression by medications or disease such as HIV/AIDS
Genetics
  • Persons of Irish or Scottish ancestry have the highest prevalence of SCC.
  • Caucasians with the red hair/fair skin phenotype (associated with certain variant alleles of the human melanocortin-1 receptor [MC1R]) are predisposed to SCC.
  • SCC is rare in people of African and Asian descent, although it is the most common form of skin cancer in these populations.
RISK FACTORS
  • Older age
  • Male sex: However, incidence is increasing in females due to lifestyle changes (e.g., suntan parlors, shorter dresses).
  • Chronic sun exposure: SCC is noted more frequently in those with a greater degree of outdoor activity (e.g., farmers, sailors, gardeners).
  • Patients with multiple actinic keratoses
  • Personal or family history of skin cancer
  • Northern European descent
  • Fair complexion, fair hair, light eyes
  • Poor tanning ability, with tendency to burn
  • Organ transplant recipients, chronic immunosuppression
  • Exposure to chemical carcinogens (e.g., arsenic, tar) or ionizing radiation
  • Smoking (4)
  • Therapeutic UV and ionizing radiation exposure
  • Defects in cell-mediated immunity related to lymphoproliferative disorders (chronic lymphocytic leukemia [CLL], lymphoma)
  • HPV infection
  • Chronic scarring and inflammatory conditions
  • Specific genodermatoses (e.g., xeroderma pigmentosum, oculocutaneous albinism, and dystrophic epidermolysis bullosa)
GENERAL PREVENTION
Sun-avoidance measures: sunscreens, hats, clothing, and sunglasses with UV protection; tinted windshields and side windows in cars; sun-protective garments
COMMONLY ASSOCIATED CONDITIONS
  • Some investigators consider an actinic keratosis to be an early SCC, although relatively few ultimately are found to develop into an SCC.
  • Actinic cheilitis and leukoplakia of the mucous membranes of the lips
  • Cutaneous horn (see following discussion)
  • Xeroderma pigmentosum albinism
  • Immunosuppression
  • Chronic skin ulcers, preexisting scars, burns
image DIAGNOSIS
PHYSICAL EXAM
Lesions occur chiefly on chronically sun-exposed areas.
  • Face and backs of the forearms and hands
  • Bald areas of the scalp and top of ears in men
  • The sun-exposed “V” of the neck as well as the posterior neck below the occipital hairline
  • In elderly females, lesions tend to occur on the legs and other sun-exposed locations.
  • In African Americans, equal frequency in sunexposed and unexposed areas
  • Clinical appearance
    • Generally slow-growing, firm, hyperkeratotic papules, nodules, or plaques
    • Most SCCs are asymptomatic, although bleeding, pain, and tenderness may be noted.
    • Lesions may have a smooth, verrucous, or papillomatous surface.
    • Varying degrees of ulceration, erosion, crust, or scale
    • Color is often red to brown, tan, or pearly (indistinguishable from basal cell carcinoma).
  • Clinical variants of SCC
    • Bowen disease (SCC in situ): solitary lesion that resembles a scaly psoriatic plaque
    • Invasive SCC: often a raised, firm papule, nodule, or plaque. Lesions may be smooth, verrucous, or papillomatous, with varying degrees of ulceration, erosion, crust, or scale.
    • Cutaneous horn: SCC with an overlying cutaneous horn. A cutaneous horn represents a thick, hard, fingernail-like keratinization produced by the SCC. Bowen disease may also produce a cutaneous horn on its surface.
    • Erythroplasia of Queyrat refers to Bowen disease of the glans penis, which manifests as one or more velvety red plaques.
    • Subungual SCC appear as hyperkeratotic lesions under the nail plate or on surrounding periungual skin, often mimicking warts (5).
    • Marjolin ulcer: an SCC evolving from a new area of ulceration or elevation at site of a scar or ulcer
    • HPV-associated SCC: virally induced. An SCC most commonly seen as a new or enlarging warty growth on penis, vulva, perianal area, or periungual region
    • Verrucous carcinoma: subtype of SCC that is extremely well differentiated, can be locally destructive, but rarely metastasizes. Lesions are “cauliflower-like” verrucous nodules or plaques.
    • Basaloid SCC: less common than typical SCC; seen more often in men aged 40 to 70 years
DIFFERENTIAL DIAGNOSIS
  • Actinic keratosis: Early SCC lesions may be clinically difficult, if not impossible, to distinguish from a precursor actinic keratosis.
  • Basal cell carcinoma may be indistinguishable from an SCC, particularly if the lesion is ulcerated.
  • Keratoacanthoma: This lesion also may be clinically and histopathologically impossible to differentiate from an SCC; it is considered by some to be a lowgrade variant of an SCC.
  • Verruca vulgaris: The appearance of common warts is often similar to that of SCC lesions.
  • Seborrheic keratosis
  • Pyoderma gangrenosum
  • Venous stasis ulcer
  • Chemical or thermal burn
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • Surgical biopsy to ensure diagnosis: shave, punch, excisional, or incisional biopsy
  • P.987

  • Sentinel lymph node biopsy rarely is used to identify micrometastases in patients with high-risk SCC and clinically negative nodes. Whether the early detection of lymph node metastasis leads to enhanced survival in SCC is unknown.
  • Patients with lymphadenopathy should be evaluated for metastases with CT scanning, MRI, US, or PET.
Test Interpretation
  • Noninvasive SCC is characterized by an intraepidermal proliferation of atypical keratinocytes. Hyperkeratosis, acanthosis, and confluent parakeratosis are seen within the epidermis. Cellular atypia, including pleomorphism, hyperchromatic nuclei, and mitoses are prominent. Atypical keratinocytes may be found in the basal layer and often extend deeply down the hair follicles, but they do not invade the dermis.
  • In the in situ type of SCC (Bowen disease), atypia involves the full thickness of the epidermis but the basement membrane remains intact.
  • An invasive SCC penetrates through the basement membrane into the dermis. It has various levels of anaplasia and may manifest relatively few to multiple mitoses and display varying degrees of differentiation, such as keratinization.
  • Poorly differentiated tumors are clinically more aggressive. SCCs proliferate first by local invasion. Metastases, when they do occur, spread via local lymph ducts to local lymph nodes.
image TREATMENT
MEDICATION
First Line
  • Total excision: preferred method for SCCs, permitting histologic diagnosis of the tumor margins
  • Electrodesiccation and curettage (ED&C)
    • Best for small lesions (generally <1 cm) on flat surfaces (e.g., forehead, cheek) and SCC in situ (Bowen disease). ED&C may be used to treat superficially invasive SCCs that lack high-risk characteristics, but it is not appropriate for certain high-risk anatomic locations.
  • Cryosurgery with LN2 in selected lesions, such as SCC in situ
  • Micrographic (Mohs) surgery is a microscopically controlled method of removing skin cancers that allows for controlled excision and maximum preservation of normal tissue. It has the highest cure rate (94-99%) of all surgical treatments. Mohs surgery may be indicated for the following:
    • Large, recurrent or invasive SCCs (e.g., to bone or cartilage)
    • Lesions with a poorly delineated clinical border
    • Locations where preservation of normal tissue is extremely important (e.g., tip of the nose, eyelids, ala nasi, ears, lips, and glans penis)
  • Radiation therapy is a primary treatment option that is generally restricted to older patients who are physically debilitated or are unable to undergo or refuse to undergo excisional surgery.
Second Line
  • Immunotherapy with topical imiquimod (Aldara) 5% cream has been successfully used for the treatment of SCC in situ (Bowen disease), actinic keratoses, genital warts, and superficial basal cell carcinomas (6)[A].
  • Topical chemotherapy: topical formulations of 5-fluorouracil (5-FU) (6)[A]
  • Intralesional 5-FU and bleomycin has also been used successfully to treat SCCs.
  • Photodynamic therapy (PDT): PDT involves application of a photosensitizer (given topically or systemically) followed by exposure to a light source. Used primarily to treat large numbers of solar keratoses and is not recommended for treatment of invasive SCCs.
  • In patients with multiple or recurrent SCCs or those at high risk, such as organ transplant recipients, chemoprevention with systemic retinoids, such as acitretin, may be effective for reducing the number of new SCCs, treating existing SCCs, and reducing the risk of recurrence.
ADDITIONAL THERAPIES
For metastatic SCC, oral 5-FU has been used alone or in combination with SC interferon. More recently, epidermal growth factor receptor (EGFR) inhibitors, such as cetuximab (7)[C], are used in combination with systemic chemotherapy for metastatic disease.
SURGERY/OTHER PROCEDURES
  • Complete lymphadenectomy of the draining nodal basin for high-risk tumors
  • Metastatic disease requires aggressive management by a multidisciplinary team, involving plastic, ENT/maxillofacial, general and onchologic surgeons.
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
Skin exam every month for 3 months, 6 months after treatment, and then yearly
PATIENT EDUCATION
Skin self-exam: Encourage sun-avoidance techniques, protective clothing, sunscreens, and so forth. Artificial tanning devices should be avoided.
PROGNOSIS
  • For low-risk SCCs: a 90-95% cure rate with appropriate treatment
  • Overall, head and neck lesions have better prognosis; however, lip and ear lesions metastasize more frequently when compared with other sites.
  • The ability to produce scale (keratinization) indicates a tendency for a lesion to be more differentiated and less likely to metastasize.
  • Softer, nonkeratinizing lesions are not as well differentiated and thus are more likely to spread.
  • Lesions ≥2 cm are more likely to recur.
  • SCCs that arise in areas of non-sun-exposed skin or have a greater tendency to metastasize
  • An SCC arising on a mucous membrane or in a chronic ulcer should be regarded as potentially metastatic.
  • Recurrence rate and mortality is greater in immunosuppressed patients, especially solid-organ transplant recipients.
  • SCCs that are deeply invasive (≥6 mm in SC fat), or have perineural involvement, are more likely to metastasize.
  • When SCC does metastasize, it usually occurs within several years from the time of diagnosis and involves draining lymph nodes.
  • Once nodal metastasis of cutaneous SCC has occurred, the overall 5-year survival rate has historically been in the range of 25-35%.
REFERENCES
1. Brantsch KD, Meisner C, Schönfisch B, et al. Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study. Lancet Oncol. 2008;9(8):713-720.
2. Archier E, Devaux S, Castela E, et al. Carcinogenic risks of psoralen UV-A therapy and narrowband UV-B therapy in chronic plaque psoriasis: a systematic literature review. J Eur Acad Dermatol Venereol. 2012;26(Suppl 3):22-31.
3. Karagas MR, Nelson HH, Sehr P, et al. Human papillomavirus infection and incidence of squamous cell and basal cell carcinomas of the skin. J Natl Cancer Inst. 2006 Mar 15;98(6):389-95.
4. Leonardi-Bee J, Ellison T, Bath-Hextall F. Smoking and the risk of nonmelanoma skin cancer: systematic review and meta-analysis. Arch Dermatol. 2012;148(8):939-946.
5. Riddel C, Rashid R, Thomas V. Ungual and periungual human papillomavirus-associated squamous cell carcinoma: a review. J Am Acad Dermatol. 2011;64(6):1147-1153.
6. Micali G, Lacarrubba F, Nasca MR, et al. Topical pharmacotherapy for skin cancer: part II. Clinical applications. J Am Acad Dermatol. 2014;70(6):979. e1-979.e12.
7. Miller K, Sherman W, Ratner D. Complete clinical response to cetuximab in a patient with metastatic cutaneous squamous cell carcinoma. Dermatol Surg. 2010;36(12):2069-2074.
Additional Reading
&NA;
  • Martorell-Calatayud A, Sanmartín Jimenez O, Cruz Mojarrieta J, et al. Cutaneous squamous cell carcinoma: defining the high-risk variant [in English, Spanish]. Actas Dermosifiliogr. 2013;104(5):367-379.
  • Wang J, Aldabagh B, Yu J, et al. Role of human papillomavirus in cutaneous squamous cell carcinoma: a meta-analysis. J Am Acad Dermatol. 2014;70(4):621-629.
Codes
&NA;
ICD10
  • C44.92 Squamous cell carcinoma of skin, unspecified
  • C44.320 Squamous cell carcinoma of skin of unspecified parts of face
  • C44.42 Squamous cell carcinoma of skin of scalp and neck
Clinical Pearls
&NA;
  • SCCs that develop from actinic keratoses are generally unaggressive.
  • Unlike most basal cell carcinomas, SCCs of the skin are associated with a risk of metastasis, especially those arising on mucous membranes, chronic ulcers, or in immunocompromised patients.
  • A subungual SCC can easily be mistaken for a wart.