General Information About Skin Cancer

There are three main types of skin cancer:

• Basal cell carcinoma (BCC).
• Squamous cell carcinoma (SCC).
• Melanoma.

BCC and SCC are the most common forms of skin cancer and together are referred to as nonmelanoma skin cancers. This summary addresses the treatment of BCC and SCC of the skin and the related noninvasive lesion actinic keratosis. Refer to the PDQ summary on Melanoma Treatment for information about the treatment of melanoma.

Incidence and Mortality

Nonmelanoma skin cancer is the most common cancer in the United States. BCC is the more common type of nonmelanoma, accounting for about three-quarters of nonmelanoma skin cancers.[1] The incidence of nonmelanoma skin cancer appears to be increasing in some,[2] but not all,[3] areas of the United States. Overall U.S. incidence rates have likely been increasing for a number of years.[4] At least some of this increase may be attributable to increasing skin cancer awareness and the resulting examination and biopsy of skin lesions.

The total number and incidence rate of nonmelanoma skin cancers cannot be estimated precisely because reporting to cancer registries is not required. However, based on extrapolation of Medicare fee-for-service data to the U.S. population, it has been estimated that the total number of persons treated for nonmelanoma skin cancers in 2012 was about 3 million.[5,6] That number exceeds all other cases of cancer estimated by the American Cancer Society for that year, which totaled about 1.6 million.[7] Although nonmelanoma skin cancer is the most common of all malignancies, it accounts for less than 0.1% of patient deaths caused by cancer.

Anatomy

Anatomy of the skin showing the epidermis (including the squamous cell and basal cell layers), dermis, subcutaneous tissue, and other parts of the skin.

Risk Factors

Risk factors for nonmelanoma skin cancer include the following:

• Sun and UV radiation exposure (including tanning beds). Epidemiologic evidence suggests that cumulative exposure to UV radiation and the sensitivity of an individual’s skin to UV radiation are risk factors for skin cancer, though the type of exposure (i.e., high-intensity exposure and short-duration exposure vs. chronic exposure) and pattern of exposure (i.e., continuous pattern vs. intermittent pattern) may differ among the three main skin cancer types.[8,9,10] Skin cancers are more common in the southern latitudes of the Northern hemisphere.
• History of sunburns. People who have had sunburns are predisposed to the development of SCC.
• Light complexion and eye color. Individuals with a light complexion (fair skin that freckles and burns easily), light-colored eyes (blue, green, or other light-colored eyes), and light-colored hair (red or blond) who have had substantial exposure to sunlight are at increased risk of developing nonmelanoma skin cancer.
• Family history or personal history of BCC, SCC, actinic keratosis, familial dysplastic nevus syndrome, or atypical nevi.
• Chronic cutaneous inflammation. People with chronic cutaneous inflammation, as seen in long-standing skin ulcers, are predisposed to the development of SCC.
• Immune suppression. Organ transplant recipients receiving immunosuppressive drugs and individuals with immunosuppressive diseases are at an elevated risk of developing skin cancers, particularly SCC.[1]
• Other environmental exposure. Arsenic exposure and therapeutic radiation increase the risk of cutaneous SCC.[1]

Types of Skin Cancer

This evidence-based summary covers basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin and the related noninvasive lesion actinic keratosis (viewed by some pathologists as a variant of in situ SCC).[1] BCC and SCC are both of epithelial origin. Although BCC and SCC are by far the most frequent types of nonmelanoma skin cancers, approximately 82 types of skin malignancies, with a wide range of clinical behaviors, fall into the category of nonmelanoma skin cancer.[11]

Other types of malignant disease of the skin include the following:

• Melanoma. (Refer to the PDQ summary on Melanoma Treatment for more information.)
• Merkel cell carcinoma. (Refer to the PDQ summary on Merkel Cell Carcinoma Treatment for more information.)
• Cutaneous T-cell lymphomas (e.g., mycosis fungoides). (Refer to the PDQ summary on Mycosis Fungoides [Including Sézary Syndrome] Treatment for more information.)
• Kaposi sarcoma. (Refer to the PDQ summary on Kaposi Sarcoma Treatment for more information.)
• Extramammary Paget disease.
• Apocrine carcinoma of the skin.
• Metastatic malignancies from various primary sites.

Basal cell carcinoma

BCC is at least three times more common than SCC in nonimmunocompromised patients. It usually occurs on sun-exposed areas of skin, with the nose being the most common site. Although there are many different clinical presentations for BCC, the most characteristic type is the asymptomatic nodular or nodular ulcerative lesion that is elevated from the surrounding skin, has a pearly quality, and contains telangiectatic vessels.

BCCs are composed of nonkeratinizing cells derived from the basal cell layer of the epidermis. They are slow growing and rarely metastasize. BCC has a tendency to be locally destructive and can result in serious deforming damage if left untreated or if local recurrences cannot be completely excised. High-risk areas for tumor recurrence after initial treatment include the central face (e.g., periorbital region, eyelids, nasolabial fold, or nose-cheek angle), postauricular region, pinna, ear canal, forehead, and scalp.[12]

A specific subtype of BCC is the morpheaform type. This subtype typically appears as a scar-like, firm plaque. Because of indistinct clinical tumor margins, the morpheaform type is difficult to treat adequately with traditional treatments.[13]

BCCs often have a characteristic mutation in the patched 1 tumor suppressor gene (PTCH1), although the mechanism of carcinogenesis is not clear.[1]

Squamous cell carcinoma

People with chronic sun damage, history of sunburns, arsenic exposure, chronic cutaneous inflammation (as seen in long-standing skin ulcers), and previous radiation therapy are predisposed to the development of SCC. SCCs tend to occur on sun-exposed portions of the skin, such as the ears, lower lip, and dorsa of the hands. SCCs that develop from actinic keratosis on sun-exposed skin are less likely to metastasize and have a better prognosis than those that develop de novo, or on non–sun-exposed skin.[13]

SCCs are composed of keratinizing cells. These tumors are more aggressive than BCCs and have a range of growth, invasive, and metastatic potential. Prognosis is associated with the degree of differentiation, and tumor grade is reported as part of the staging system.[11] A four-grade system (G1–G4) is most common, but two- and three-grade systems may also be used.

Mutations in the PTCH1 tumor suppressor gene have been reported in SCCs removed from patients with a prior history of multiple BCCs.[14]

SCC in situ (also called Bowen disease) is a noninvasive lesion. Distinguishing SCC in situ pathologically from a benign inflammatory process may be difficult.[1] The risk of development into invasive SCC is low, reportedly in the range of 3% to 4%.[15]

Actinic keratosis

Actinic keratoses are potential precursors of SCC, but the rate of progression is extremely low, and the vast majority do not become SCCs. These typically red, scaly patches usually arise on areas of chronically sun-exposed skin and are likely to be found on the face and dorsal aspects of the hand.

Diagnostic and Staging Evaluation

BCC and SCC are usually diagnosed on the basis of routine histopathology obtained from a shave, punch, incisional, or excisional biopsy.[1]

Other tests and procedures may be incorporated into the diagnosis and staging of BCC and SCC of the skin when appropriate and include the following:

• Physical examination, including skin examination and history.
• Chest x-ray.
• Computed tomography (CT) scan or positron emission tomography (PET)–CT scan of the head and neck or chest.
• Ultrasonography of the regional lymph nodes.
• Lymph node biopsy.

Ophthalmic examination or evaluation is performed for the diagnosis and staging of eyelid carcinoma.

Related Summaries

Other PDQ summaries containing information related to nonmelanoma skin cancer include the following:

• Genetics of Skin Cancer
• Skin Cancer Prevention
• Skin Cancer Screening
• Unusual Cancers of Childhood Treatment (skin cancer in children)

References:

1. Reszko A, Aasi SZ, Wilson LD, et al.: Cancer of the skin. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1610-33.
2. Athas WF, Hunt WC, Key CR: Changes in nonmelanoma skin cancer incidence between 1977-1978 and 1998-1999 in Northcentral New Mexico. Cancer Epidemiol Biomarkers Prev 12 (10): 1105-8, 2003.
3. Harris RB, Griffith K, Moon TE: Trends in the incidence of nonmelanoma skin cancers in southeastern Arizona, 1985-1996. J Am Acad Dermatol 45 (4): 528-36, 2001.
4. Rogers HW, Weinstock MA, Harris AR, et al.: Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol 146 (3): 283-7, 2010.
5. Rogers HW, Weinstock MA, Feldman SR, et al.: Incidence Estimate of Nonmelanoma Skin Cancer (Keratinocyte Carcinomas) in the U.S. Population, 2012. JAMA Dermatol 151 (10): 1081-6, 2015.
6. American Cancer Society: Cancer Facts and Figures 2016. Atlanta, Ga: American Cancer Society, 2016. Available online. Last accessed March 22, 2019.
7. American Cancer Society: Cancer Facts and Figures 2012. Atlanta, Ga: American Cancer Society, 2012. Available online. Last accessed April 4, 2019.
8. Koh HK: Cutaneous melanoma. N Engl J Med 325 (3): 171-82, 1991.
9. Preston DS, Stern RS: Nonmelanoma cancers of the skin. N Engl J Med 327 (23): 1649-62, 1992.
10. English DR, Armstrong BK, Kricker A, et al.: Case-control study of sun exposure and squamous cell carcinoma of the skin. Int J Cancer 77 (3): 347-53, 1998.
11. Cutaneous carcinoma of the head and neck. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 171–81.
12. Dubin N, Kopf AW: Multivariate risk score for recurrence of cutaneous basal cell carcinomas. Arch Dermatol 119 (5): 373-7, 1983.
13. Wagner RF, Casciato DA: Skin cancers. In: Casciato DA, Lowitz BB, eds.: Manual of Clinical Oncology. 4th ed. Philadelphia, Pa: Lippincott, Williams, and Wilkins, 2000, pp 336-373.
14. Ping XL, Ratner D, Zhang H, et al.: PTCH mutations in squamous cell carcinoma of the skin. J Invest Dermatol 116 (4): 614-6, 2001.
15. Kao GF: Carcinoma arising in Bowen’s disease. Arch Dermatol 122 (10): 1124-6, 1986.

Stage Information for Skin Cancer

There are separate staging systems in the 8th edition of the American Joint Committee on Cancer’s (AJCC’s) AJCC Cancer Staging Manual for carcinoma of the eyelid and for cutaneous carcinoma of the head and neck. The cutaneous carcinoma staging system addresses cutaneous squamous cell carcinoma (SCC) and cutaneous basal cell carcinoma (BCC).[1,2] The staging system for carcinomas of the eyelid addresses carcinomas of all histologies.

Regional lymph nodes should be routinely examined in all cases of SCC, especially for the following:

• High-risk tumors appearing on the lips, on the ears, and in the perianal and perigenital regions.
• High-risk areas of the hand.
• Sites of chronic ulceration or inflammation, or burn scars.
• Sites of previous radiation therapy treatment.

BCC rarely metastasizes, so a metastatic workup is usually not necessary.

There are several factors that correlate with poor prognosis for recurrence and metastasis. They apply primarily to patients with SCC and an aggressive subset of nonmelanoma skin carcinoma, but rarely to patients with BCC, and include the following:[1]

• Extranodal extension.
• Tumor diameter.
• Depth of tumor.
• Anatomic site.
• Perineural invasion.
• Histopathologic grade or differentiation and desmoplasia.
• Extension to bony structures.
• Nodal disease.
• Immunosuppression and advanced disease.
• Overall health.
• Comorbidity.
• Lifestyle factors.
• Tobacco use.

Even with relatively small tumor sizes, SCCs that occur in immunosuppressed patients tend to behave more aggressively than do SCCs in nonimmunosuppressed patients. Although immunosuppression is not a formal part of the AJCC staging system, it is recommended that centers prospectively studying SCC record the presence and type of immunosuppression.

Staging for Cutaneous Carcinoma of the Head and Neck (Excluding Carcinomas of the Eyelid)

The AJCC has designated staging by TNM (tumor, node, metastasis) classification for cutaneous carcinoma of the head and neck, excluding carcinomas of the eyelid.[1]

Table 1. Definitions of Primary Tumor (T) for Cutaneous Carcinoma of the Head and Neck^a

T Category	T Criteria
a Reprinted with permission from AJCC: Cutaneous carcinoma of the head and neck. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 171–81.
b Deep invasion is defined as invasion beyond the subcutaneous fat or >6 mm (as measured from the granular layer of adjacent normal epidermis to the base of the tumor); perineural invasion for T3 classification is defined as tumor cells within the nerve sheath of a nerve lying deeper than the dermis or measuring ≥0.1 mm in caliber, or presenting with clinical or radiographic involvement of named nerves without skull base invasion or transgression.
TX	Primary tumor cannot be identified.
Tis	Carcinomain situ.
T1	Tumor ≤2 cm in greatest dimension.
T2	Tumor >2 cm, but ≤4 cm in greatest dimension.
T3	Tumor >4 cm in maximum dimension or minor bone erosion or perineural invasion or deep invasion.b
T4	Tumor with gross cortical bone/marrow, skull base invasion and/or skull base foramen invasion.
–T4a	Tumor with gross cortical bone/marrow invasion.
–T4b	Tumor with skull base invasion and/or skull base foramen involvement.

Table 2. Definitions of Pathological Regional Lymph Nodes (pN) for Cutaneous Carcinoma of the Head and Neck^a,b

N Category	N Criteria
ENE = extranodal extension.
a Reprinted with permission from AJCC: Cutaneous carcinoma of the head and neck. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 171–81.
b A designation of “U” or “L” may be used for any N category to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L). Similarly, clinical and pathological ENE should be recorded as ENE negative or ENE positive.
NX	Regional lymph nodes cannot be assessed.
N0	No regional lymph node metastasis.
N1	Metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE negative.
N2	Metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE positive;or>3 cm but ≤6 cm in greatest dimension and ENE negative;or metastases in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension and ENE negative;or in bilateral or contralateral lymph node(s), none >6 cm in greatest dimension, ENE negative.
–N2a	Metastasis in single ipsilateral node ≤3 cm in greatest dimension and ENE positive;or a single ipsilateral node >3 cm but ≤6 cm in greatest dimension and ENE negative.
–N2b	Metastasis in multiple ipsilateral nodes, none >6 cm in greatest dimension and ENE negative.
–N2c	Metastasis in bilateral or contralateral lymph node(s), none >6 cm in greatest dimension and ENE negative.
N3	Metastasis in a lymph node >6 cm in greatest dimension and ENE negative;or in a single ipsilateral node >3 cm in greatest dimension and ENE positive;or multiple ipsilateral, contralateral, or bilateral nodes, any with ENE-positive status;or a single contralateral node of any size and ENE positive.
–N3a	Metastasis in a lymph node >6 cm in greatest dimension and ENE negative.
–N3b	Metastasis in a single ipsilateral node >3 cm in greatest dimension and ENE positive;or multiple ipsilateral, contralateral, or bilateral nodes, any with ENE-positive status;or a single contralateral node of any size and ENE positive.

Table 3. Definitions of Clinical Regional Lymph Nodes (cN) for Cutaneous Carcinoma of the Head and Neck^a,b

N Category	N Criteria
ENE = extranodal extension.
a Reprinted with permission from AJCC: Cutaneous carcinoma of the head and neck. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 171–81.
b A designation of “U” or “L” may be used for any N category to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L). Similarly, clinical and pathological ENE should be recorded as ENE negative or ENE positive.
NX	Regional lymph nodes cannot be assessed.
N0	No regional lymph node metastasis.
N1	Metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE negative.
N2	Metastasis in a single ipsilateral node >3 cm but ≤6 cm in greatest dimension and ENE negative;or metastases in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension and ENE negative;or in bilateral and contralateral lymph nodes, none >6 cm in greatest dimension and ENE negative.
–N2a	Metastasis in a single ipsilateral node >3 cm but ≤6 cm in greatest dimension and ENE negative.
–N2b	Metastasis in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension and ENE negative.
–N2c	Metastasis in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension and ENE negative.
N3	Metastasis in a lymph node >6 cm in greatest dimension and ENE negative;or metastasis in any node(s) and clinically overt ENE (ENE positive).
–N3a	Metastasis in a lymph node >6 cm in greatest dimension and ENE negative.
–N3b	Metastasis in any node(s) and ENE positive.

Table 4. Distant Metastasis (M) for Cutaneous Carcinoma of the Head and Neck^a

M Category	M Criteria
a Reprinted with permission from AJCC: Cutaneous carcinoma of the head and neck. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 171–81.
M0	No distant metastasis.
M1	Distant metastasis.

Table 5. AJCC Prognostic Stage Groups for Cutaneous Carcinoma of the Head and Neck^a

Stage	T	N	M
M = distant metastasis; N = regional lymph nodes; T = primary tumor.
a Reprinted with permission from AJCC: Cutaneous carcinoma of the head and neck. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 171–81.
0	Tis	N0	M0
I	T1	N0	M0
II	T2	N0	M0
III	T1	N1	M0
	T2	N1	M0
	T3	N0	M0
	T3	N1	M0
IV	T1	N2	M0
	T2	N2	M0
	T3	N2	M0
	T4	Any N	M0
	Any T	N3	M0
	Any T	Any N	M1

Staging for Carcinomas of the Eyelid

The AJCC has designated staging by TNM classification.[3] The TNM classification is used to stage all cell types of eyelid carcinomas, except melanoma.

Table 6. Definitions of Primary Tumor (T) for Eyelid Carcinoma^a

T Category	T Criteria
a Reprinted with permission from AJCC: Eyelid carcinoma. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 779–85.
TX	Primary tumor cannot be assessed.
T0	No evidence of primary tumor.
Tis	Carcinomain situ.
T1	Tumor ≤10 mm in greatest dimension.
–T1a	Tumor does not invade the tarsal plate or eyelid margin.
–T1b	Tumor invades the tarsal plate or eyelid margin.
–T1c	Tumor involves full thickness of the eyelid.
T2	Tumor >10 mm but ≤20 mm in greatest dimension.
–T2a	Tumor does not invade the tarsal plate or eyelid margin.
–T2b	Tumor invades the tarsal plate or eyelid margin.
–T2c	Tumor involves full thickness of the eyelid.
T3	Tumor >20 mm but ≤30 mm in greatest dimension.
–T3a	Tumor does not invade the tarsal plate or eyelid margin.
–T3b	Tumor invades the tarsal plate or eyelid margin.
–T3c	Tumor involves full thickness of the eyelid.
T4	Any eyelid tumor that invades adjacent ocular, orbital, or facial structures.
–T4a	Tumor invades ocular or intraorbital structures.
–T4b	Tumor invades (or erodes through) the bony walls of the orbit or extends to the paranasal sinuses or invades the lacrimal sac/nasolacrimal duct or brain.

Table 7. Definitions of Regional Lymph Node (N) for Eyelid Carcinoma^a

N Category	N Criteria
a Reprinted with permission from AJCC: Eyelid carcinoma. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 779–85.
NX	Regional lymph nodes cannot be assessed.
N0	No evidence of lymph node involvement.
N1	Metastasis in a single ipsilateral regional lymph node, ≤3 cm in greatest dimension.
–N1a	Metastasis in a single ipsilateral lymph node based on clinical evaluation or imaging findings.
–N1b	Metastasis in a single ipsilateral lymph node based on lymph node biopsy.
N2	Metastasis in a single ipsilateral lymph node, >3 cm in greatest dimension;or in bilateral or contralateral lymph nodes.
–N2a	Metastasis documented based on clinical evaluation or imaging findings.
–N2b	Metastasis documented based on microscopic findings on lymph node biopsy.

Table 8. Definitions of Distant Metastasis (M) for Eyelid Carcinoma^a

M Category	M Criteria
a Reprinted with permission from AJCC: Eyelid carcinoma. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 779–85.
M0	No distant metastasis.
M1	Distant metastasis.

Table 9. AJCC Prognostic Stage Groups for Eyelid Carcinoma^a

Stage	T	N	M
M = distant metastasis; N = regional lymph nodes; T = primary tumor.
a Reprinted with permission from AJCC: Eyelid carcinoma. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 779–85.
0	Tis	N0	M0
IA	T1	N0	M0
IB	T2a	N0	M0
IIA	T2b–c	N0	M0
	T3	N0	M0
IIB	T4	N0	M0
IIIA	Any T	N1	M0
IIIB	Any T	N2	M0
IV	Any T	Any N	M1

References:

1. Cutaneous carcinoma of the head and neck. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 171–81.
2. Esmaeli B, Dutton JJ, Graue GF, et al.: Eyelid carcinoma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 779-85.
3. Carcinoma of the Eyelid. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 523-6.

Treatment Option Overview

Treatments for squamous cell carcinoma and basal cell carcinoma of the skin are described in Table 10.

Table 10. Treatment Option Overview for Nonmelanoma Skin Cancer

Stage ( American Joint Committee on Cancer Staging Criteria)		Treatment Options
Basal cell carcinoma	Localized disease	Surgical excision with margin evaluation
		Mohs micrographic surgery
		Radiation therapy
		Curettage and electrodesiccation
		Cryosurgery
		Photodynamic therapy
		Topical fluorouracil (5-FU)
		Imiquimod topical therapy
		Carbon dioxide laser
	Metastatic or locally advanced disease untreatable by local modalities	Hedgehog pathway inhibitors
	Recurrent nonmetastatic disease	Surgical excision
		Mohs micrographic surgery
Squamous cell carcinoma	Localized disease	Surgical excision with margin evaluation
		Mohs micrographic surgery
		Radiation therapy
		Curettage and electrodesiccation
		Cryosurgery
	Metastatic or locally advanced disease untreatable by local modalities	Chemotherapy
		Isotretinoin plus interferon alpha-2a
	Recurrent nonmetastatic disease	Surgical excision
		Mohs micrographic surgery
		Radiation therapy
Actinic keratosis	Localized disease	Topical agents
		Chemical peels
		Surgery
		Photodynamic therapy
		Laser therapy

Basal Cell Carcinoma of the Skin Treatment

There is a wide range of approaches for treating basal cell carcinoma (BCC) of the skin, including excision, radiation therapy, cryosurgery, electrodesiccation and curettage, photodynamic or laser-beam light exposure, and topical therapies. Each of these approaches is useful in specific clinical situations. Depending on case selection, these approaches have recurrence-free rates ranging from 85% to 95%.[1,2,3,4,5,6,7,8,9]

A systematic review of 27 randomized controlled trials comparing various treatments for BCC has been published.[10] Eighteen of the studies were published in full, and nine were published in abstract form only. Only 19 of the 27 trials were analyzed by intention-to-treat criteria. Because the case fatality rate of BCC is so low, the primary endpoint of most trials is complete response and/or recurrence rate after treatment. Most of the identified studies were not of high quality and had short follow-up periods, which will lead to overestimates of tumor control; only one study had a follow-up period of as long as 4 years. A literature review of recurrence rates in case series with long-term follow-up after treatment of BCCs indicated that only 50% of recurrences occurred within the first 2 years, 66% after 3 years, and 18% after 5 years.[11] A common finding was that the 10-year recurrence rates were about double the 2-year recurrence rates.

Treatment for Basal Cell Carcinoma of the Skin (Localized Disease)

Treatment options for BCC of the skin (localized disease) include the following:

1. Surgical excision with margin evaluation.
2. Mohs micrographic surgery.
3. Radiation therapy.
4. Curettage and electrodesiccation.
5. Cryosurgery.
6. Photodynamic therapy.
7. Topical fluorouracil (5-FU).
8. Imiquimod topical therapy.
9. Carbon dioxide laser.

Surgical excision with margin evaluation

A traditional surgical treatment, surgical excision with margin evaluation usually relies on surgical margins ranging from 3 mm to 10 mm, depending on the diameter of the tumor. Re-excision may be required if the surgical margin is found to be inadequate on permanent sectioning. In one trial, 35 of 199 primary BCCs (18%) were incompletely excised by the initial surgery and underwent a re-excision.[12] In addition, many laboratories examine only a small fraction of the total tumor margin pathologically. Therefore, the declaration of tumor-free margins can be subject to sampling error.[13]

In randomized trials, excision has been compared with radiation therapy, Mohs micrographic surgery, photodynamic therapy (PDT), and cryosurgery.

Evidence (surgical excision with margin evaluation):

1. In a single-center trial, 360 patients with facial BCCs smaller than 4 cm in diameter were randomly assigned to undergo either surgical excision or radiation therapy (55% interstitial brachytherapy, 33% contact radiation therapy, and 12% conventional external-beam radiation therapy [EBRT]).[14][Level of evidence: 1iiDii] Excisional margins, assessed by frozen section during the procedure in 91% of cases, had to be at least 2 mm, with re-excision if necessary. Thirteen patients were not treated and were dropped from the analysis.
   • At 4 years (mean follow-up of 41 months), the actuarial failure rates (confirmed persistent or recurrent tumor) were 0.7% in the surgery arm and 7.5% in the radiation therapy arm (P = .003).[15][Level of evidence: 1iiDii]
   • The cosmetic results were also rated as better after surgery by both patients and dermatologists, and also by three independent professionals. At 4 years, 87% of surgery patients rated cosmesis as good, versus 69% of radiation therapy patients.[15]
2. In a two-center, intent-to-treat analysis, 374 patients with 408 primary facial BCCs were randomly assigned to undergo either surgical excision or Mohs micrographic surgery with at least a 3-mm margin around the visible tumor until there were no positive margins in either case.[12][Level of evidence 1iiDii]
   • After 30 months of follow-up, the recurrence rate was 5 out of 171 tumors (3%) in the excision group and 3 out of 160 (2%) in the Mohs micrographic surgery group (absolute difference = 1%; 95% confidence interval [CI], -2.5% to +3.7%; P = .724). There was no difference in complication rates, and overall cosmetic outcomes were similar.[12][Level of evidence 1iiDii]
   • Total operative costs were nearly twice as high in the Mohs group (405.79 Euros vs. 216.86 Euros; P < .001).
3. In a multicenter, randomized trial, 101 adults with previously untreated nodular skin BCCs, excluding lesions of the midface, orbital areas, and ears, were treated with either excision (at least 5-mm margins) or PDT using topical methyl aminolevulinate cream (160 mg/g) followed by red-light exposure (wavelength 570–670 nm, 75 J/cm²) twice, 7 days apart.[16][Level of evidence: 1iiDiv] A per-protocol/per-lesion analysis was performed on the 97 patients who had an excision or at least one cycle of PDT.
   • At 3 months, the complete response (CR) rate in the surgery group was 98% (51 of 52) of lesions versus 91% (48 of 53) of lesions in the PDT group (P = .25). CR rates assessed at 12 months were 96% for the surgery group versus 83% for the PDT group (P = .15).[16][Level of evidence: 1iiDiv] The investigators interpreted the results as noninferiority of PDT, but the study may have been underpowered.
   • Both the investigators and the patients rated the cosmetic results as either excellent or good in a higher proportion of PDT treatments at each time point of follow-up. At 12 months, patient ratings of excellent or good were 98% in the PDT group versus 84% in the surgery group (P = .03), and investigator ratings were 79% versus 38% (P = .001).
4. In a randomized, single-center trial, 96 primary BCCs (patient number unclear) smaller than 2 cm in diameter involving the head and neck area were randomly assigned to either excision with a 3-mm safe margin or cryosurgery (i.e., curettage plus two freeze-thaw cycles by liquid nitrogen spray gun).[17][Level of evidence 1iiDiv]
   • At 1 year, there were no recurrences in the excision group versus three recurrences in the cryosurgery group (P = NS), but this is a very short follow-up time.[17][Level of evidence 1iiDiv]
   • Patients and five independent professionals who were blinded to the treatment arm rated the cosmetic outcomes. Their overall assessments favored excision.

Mohs micrographic surgery

Mohs micrographic surgery is a form of tumor excision that involves progressive radial sectioning and real-time examination of the resection margins until adequate uninvolved margins have been achieved, avoiding wider margins than needed. It is a specialized technique used to achieve the narrowest margins necessary to avoid tumor recurrence while maximally preserving cosmesis. The tumor is microscopically delineated, with serial radial resection, until it is completely removed as assessed with real-time frozen sections. Noncontrolled case series suggested that the disease control rates were superior to other treatment methods for BCC.[18,19,20] However, as noted in the section on excision, the disease control rate was not clearly better when it was directly compared with the disease control rate for surgical excision of facial BCCs in a randomized trial of primary BCCs.[12]
Mohs surgery. A surgical procedure to remove skin cancer in several steps. First, a thin layer of cancerous tissue is removed. Then, a second thin layer of tissue is removed and viewed under a microscope to check for cancer cells. More layers are removed one at a time until the tissue viewed under a microscope shows no remaining cancer. This type of surgery is used to remove as little normal tissue as possible and is often used to remove skin cancer on the face.

This surgery is best suited to the management of tumors that have recurred after initial incision or of tumors in cosmetically sensitive areas (e.g., eyelid periorbital area, nasolabial fold, nose-cheek angle, posterior cheek sulcus, pinna, ear canal, forehead, scalp, fingers, and genitalia).[19,21] It is also used to treat tumors with poorly defined clinical borders.

Radiation therapy

Radiation therapy is particularly useful in the management of patients with primary lesions that would otherwise require difficult or extensive surgery (e.g., lesions on the nose or ears).[22] Radiation therapy eliminates the need for skin grafting when surgery would result in an extensive defect. Cosmetic results are generally good, with a small amount of hypopigmentation or telangiectasia in the treatment port. Radiation therapy can also be used for lesions that recur after a primary surgical approach.[23]

Radiation therapy is avoided in patients with conditions that predispose them to radiation-induced cancers, such as xeroderma pigmentosum or basal cell nevus syndrome.

Evidence (radiation therapy):

1. As noted above, radiation therapy has been compared with excision in a randomized trial that showed better response and cosmesis associated with surgery.[14,15][Level of evidence: 1iiDii]
2. In a single-center trial, 93 patients with BCC were randomly assigned to receive either EBRT (130 kV x-rays, dosimetry depending on lesion size) or cryotherapy (two freeze-thaw cycles with liquid nitrogen by spray gun). Patients with lesions on the nose or ear were excluded because the investigators felt that EBRT is the treatment of choice for tumors in these locations.[24][Level of evidence 1iiDiv]
   • Radiation was superior to cryotherapy in local control at 2 years.
   • By 1 year, the recurrence rate was 4% in the radiation arm and 39% in the cryotherapy arm in a per-protocol analysis. The investigators did not perform a statistical analysis, but the authors of a systematic literature review calculated a relative risk of 0.11 in favor of radiation (95% CI, 0.03–0.43).[10][Level of evidence 1iiDiv]

Curettage and electrodesiccation

Curettage and electrodesiccation is a widely employed method for removing primary BCCs, especially superficial lesions of the neck, trunk, and extremities that are considered to be at low risk of recurrence. A sharp curette is used to scrape the tumor down to its base, followed by electrodesiccation of the lesion base. Although curettage and electrodesiccation is a quick method for destroying the tumor, the adequacy of treatment cannot be assessed immediately because the surgeon cannot visually detect the depth of microscopic tumor invasion. This procedure is also sometimes called electrosurgery.

Evidence (curettage and electrodesiccation):

1. A Cochrane Collaboration systematic review found no randomized trials comparing this treatment method with other approaches.[10]
2. In a large, single-center case series of 2,314 previously untreated BCCs managed at a major skin cancer unit, the 5-year recurrence rate of BCCs of the neck, trunk, and extremities after curettage and electrodesiccation was 3.3%. However, rates increased substantially for tumors larger than 6 mm in diameter at other anatomic sites.[25][Level of evidence 3iiiDii]

Cryosurgery

Cryosurgery may be considered for patients with small, clinically well-defined primary tumors.[26,27,28] It is infrequently used for the management of BCC, but cryosurgery may be useful for patients with medical conditions that preclude other types of surgery.[8,29,30,31,32,33,34,35] Contraindications for cryosurgery include the following:

• Abnormal cold tolerance.
• Cryoglobulinemia or cryofibrinogenemia.
• Raynaud disease (in the case of lesions on the hands and feet).
• Platelet deficiency disorders.
• Tumors of the scalp, ala nasi, nasolabial fold, tragus, postauricular sulcus, free eyelid margin, upper lip vermillion border, and lower legs.
• Tumors near nerves.

Caution should also be used before treating nodular ulcerative neoplasia more than 3 cm in diameter, carcinomas fixed to the underlying bone or cartilage, tumors situated on the lateral margins of the fingers and at the ulnar fossa of the elbow, or recurrent carcinomas following surgical excision. Permanent pigment loss at the treatment site is unavoidable, so the treatment is not well suited to dark-skinned patients.

Edema is common after treatment, especially around the periorbital region, temple, and forehead. Treated tumors usually exude necrotic material, after which an eschar forms and persists for about 4 weeks. Atrophy and hypertrophic scarring have been reported, as have instances of motor and sensory neuropathy.

Evidence (cryosurgery):

1. As noted in the section on radiation therapy, a small 93-patient trial comparing cryosurgery with radiation therapy, with only 1 year of follow-up, showed a statistically significant higher recurrence rate with cryosurgery than with radiation therapy (39% vs. 4%).[24][Level of evidence 1iiDiv]
2. In a small, single-center, randomized study, 88 patients were assigned to undergo either cryosurgery in two freeze-thaw cycles; or PDT using delta-aminolevulinic acid as the photosensitizing agent and 635 nm wavelength light with 60 J/cm² energy delivered by neodymium-doped yttrium aluminum garnet (Nd:YAG) laser.[36][Level of evidence 1iiD]
   • Overall clinical efficacy was similar in evaluable lesions at 1 year (5 of 39 recurrences for cryosurgery vs. 2 of 44 recurrences for PDT), but more re-treatments were needed with PDT to achieve complete responses.[36][Level of evidence 1iiD]
   • Cosmetic outcomes favored PDT (93% good or excellent after PDT vs. 54% after cryosurgery, P < .001).
3. In another randomized study of 118 patients, reported in abstract form only, cryosurgery was compared with PDT with methyl aminolevulinic acid.[37,38][Level of evidence 1iiDiv]
   • Tumor control rates at 3 years were similar (74%), but cosmetic outcomes were better in the PDT group. These cryosurgery-PDT comparisons were reported on a per-protocol basis rather than an intent-to-treat basis.[37,38][Level of evidence 1iiDiv]

Photodynamic therapy

PDT with photosensitizers is used in the management of a wide spectrum of superficial epithelial tumors.[39] A topical photosensitizing agent such as 5-aminolevulinic acid or methyl aminolevulinate is applied to the tumor, followed by exposure to a specific wavelength of light (laser or broad band), depending on the absorption characteristics of the photosensitizer. In the case of multiple BCCs, the use of short-acting systemic (intravenous) photosensitizers such as verteporfin has been investigated.[40] Upon light activation, the photosensitizer reacts with oxygen in the tissue to form singlet oxygen species, resulting in local cell destruction.

Evidence (PDT):

1. In case series, PDT has been associated with high initial CR rates. However, substantial regrowth rates of up to 50% have been reported with long-term follow-up.[39]
2. A randomized trial of PDT versus excision is described in the Surgical excision with margin evaluation section.[16]
3. Two small trials, one reported in abstract form only, comparing PDT with cryosurgery are summarized in the Cryosurgery section, showing similar antitumor efficacy but better cosmesis with PDT.[36,37,38]

Topical fluorouracil (5-FU)

Topical 5-FU, as a 5% cream, may be useful in specific limited circumstances. It is a U.S. Food and Drug Administration (FDA)–approved treatment for superficial BCCs in patients for whom conventional methods are impractical, such as individuals with multiple lesions or difficult treatment sites. Safety and efficacy in other indications have not been established.[41,42][Level of evidence: 3iiiDiv] Given the superficial nature of the effects of topical 5-FU, nonvisible dermal involvement may persist, giving a false impression of treatment success. In addition, the brisk accompanying inflammatory reaction may cause substantial skin toxicity and discomfort in a large proportion of patients.

Imiquimod topical therapy

Imiquimod is an agonist for the toll-like receptor 7 and/or 8, inducing a helper T-cell cytokine cascade and interferon production. It purportedly acts as an immunomodulator.

Although imiquimod is an FDA-approved treatment for superficial BCCs, some investigators in the field do not recommend it for initial monotherapy for BCC; some reserve its use for patients with small lesions in low-risk sites who cannot undergo treatment with more established therapies.[42] Imiquimod is available as a 5% cream and is used in schedules ranging from twice weekly to twice daily over 5 to 15 weeks. Most of the experience is limited to case series of BCCs that are smaller than 2 cm² in area and that are not in high-risk locations (e.g., within 1 cm of the hairline, eyes, nose, mouth, or ear; or in the anogenital, hand, or foot regions).[42] Follow-up times have also been generally short. Reported CR rates vary widely, from about 40% to 100%.[42][Level of evidence 3iiiDiv]

There have been a number of randomized trials of imiquimod.[43,44,45,46,47,48] However, the designs of all of them make interpretation of long-term efficacy impossible. Most were industry-sponsored dose-finding studies, with small numbers of patients on any given regimen; and patients were only monitored for 6 to 12 weeks, with excision at that time to determine histologic response.[42][Level of evidence 1iDiv]

Carbon dioxide laser

The carbon dioxide laser is used very infrequently in the management of BCC because of the difficulty in controlling tumor margins.[49] Few clinicians have extensive experience with the technique for BCC treatment. There are no randomized trials comparing it with other modalities.

Treatment for Metastatic Basal Cell Carcinoma (or Locally Advanced Disease Untreatable by Local Modalities)

Treatment options for metastatic BCC of the skin (or locally advanced disease untreatable by local modalities) include the following:

1. Hedgehog pathway inhibitors.
   • Vismodegib.
   • Sonidegib.
2. Chemotherapy.

Hedgehog pathway inhibitors

BCCs frequently exhibit constitutive activation of the Hedgehog/PTCH1 signaling pathway. Vismodegib and sonidegib, two inhibitors of Smoothened, a transmembrane protein involved in the Hedgehog pathway, are approved for the treatment of adults with metastatic BCC, patients with locally advanced BCC that has recurred after surgery, and patients who are not candidates for surgery or radiation therapy.

Evidence (vismodegib):

1. FDA approval was supported by an international, multicenter, open-label, two-cohort trial enrolling 104 patients: 33 with metastatic BCC and 71 with locally advanced BCC with inoperable disease or for whom surgery was inappropriate. Patients received vismodegib 150 mg daily.[50][Level of evidence: 3iiiDiv] Objective response rate (RR) assessed by an independent review committee was the primary endpoint. The study was sized to test whether the RR was higher than 10% in patients with metastatic BCC and higher than 20% in patients with locally advanced BCC by exact binomial 1-sided tests. Of the 104 patients, 96 were evaluable for RR, with 8 patients who had locally advanced BCC excluded from analysis after the independent pathologist did not identify BCC in the biopsy specimens. In both cohorts, the median duration of treatment was 10.2 months (range, 0.7–18.7 months).
   • In 33 patients with metastatic BCC, the RR was 30% (95% CI, 16%–48%; P = .001). In 63 patients with locally advanced BCC, the RR was 43% (95% CI, 31%–56%; P < .001), with complete responses in 13 patients (21%). In both cohorts, the median duration of response was 7.6 months.[50][Level of evidence: 3iiiDiv]
   • The most common adverse events were muscle spasms, alopecia, dysgeusia, weight loss, and fatigue. Adverse events led to the discontinuation of vismodegib in 12% of patients.
   • There were fatal adverse events in seven patients: three deaths from unknown causes; and one death each from hypovolemic shock, myocardial infarction, meningeal disease, and ischemic stroke. The relationship between the study drug and the deaths is unknown.

Evidence (sonidegib):

1. Sonidegib was evaluated at two doses in a multinational, double-blind, multiple-cohort trial conducted in patients with metastatic BCC (n = 36) or locally advanced BCC (n = 194).[51][Level of evidence: 1iDiv] Patients were randomly assigned (in a 2:1 fashion) to receive 200 mg or 800 mg orally, once a day. The primary endpoint was RR, with data collected up to 6 months after randomization of the last patient and determined by blinded central review. A sample size of 210 patients was targeted to ensure 150 patients for the primary efficacy analysis, which required locally advanced disease to be assessable by modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Success was prespecified as a 30% RR.
   • In the 200-mg cohort, a central review identified 18 of 42 patients with locally advanced BCC (43%; 95% CI, 28%–59%) and 2 of 13 patients with metastatic BCC (15%; 95% CI, 2%–45%) who had an objective response and qualified for the primary efficacy analysis. The median duration of response was not reached. RR was similar in the two-dose cohorts, with fewer adverse events at the lower dose, leading to FDA approval of the 200-mg once-daily dose.[51][Level of evidence: 1iDiv]
   • Frequent adverse events included muscle spasms, alopecia, dysgeusia, fatigue, nausea, vomiting, decreased appetite, decreased weight, myalgia, and pain.
   • Four patients in the 800-mg cohort died during the study: two from cardiac death and two from metastatic disease progression.

Chemotherapy

No standard chemotherapy regimens exist, and there are only anecdotal reports in the literature.[52]

Because there is no curative therapy for metastatic BCC of the skin, clinical trials are appropriate. Information about ongoing clinical trials is available from the NCI website.

Treatment for Recurrent Nonmetastatic Basal Cell Carcinoma of the Skin

After treatment for BCC, patients are followed up clinically and examined regularly. Most recurrences occur within 5 years, but about 18% of recurrences are diagnosed beyond that point.[11]

Patients who develop a primary BCCs are also at increased risk of subsequent primary skin cancers because the susceptibility of their sun-damaged skin to additional cancers persists.[53,54,55] This effect is sometimes termed field carcinogenesis. Age at diagnosis of the first BCC (<65 years), red hair, and initial BCC on the upper extremities appear to be associated with a higher risk of subsequent new BCCs.[56]

Treatment options for recurrent nonmetastatic BCC of the skin include the following:

1. Surgical excision.
2. Mohs micrographic surgery.

Mohs micrographic surgery is commonly used for local recurrences of BCC.

Evidence (surgical excision vs. Mohs micrographic surgery):

1. In a separate group within a randomized trial comparing excision to Mohs micrographic surgery for primary BCCs, 204 patients with recurrent BCCs were randomly assigned to undergo either excision or Mohs micrographic surgery.[12][Level of evidence 1iiDii]
   • The recurrence rates were 8 of 102 patients assigned to excision and 2 of 102 patients assigned to Mohs micrographic surgery, after a mean follow-up of 2.08 years (P = NS).[12][Level of evidence 1iiDii]
   • There were more postoperative complications—including wound infections, graft necrosis, or bleeding—in the excision group than in the Mohs surgery group (19% vs. 8%, P = .021).
   • As with primary tumors, the operative costs associated with Mohs surgery were higher than those associated with excision (489.06 Euros vs. 323.49 Euros [P = .001]).

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

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4. Roozeboom MH, Arits AH, Nelemans PJ, et al.: Overall treatment success after treatment of primary superficial basal cell carcinoma: a systematic review and meta-analysis of randomized and nonrandomized trials. Br J Dermatol 167 (4): 733-56, 2012.
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8. Peikert JM: Prospective trial of curettage and cryosurgery in the management of non-facial, superficial, and minimally invasive basal and squamous cell carcinoma. Int J Dermatol 50 (9): 1135-8, 2011.
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12. Smeets NW, Krekels GA, Ostertag JU, et al.: Surgical excision vs Mohs’ micrographic surgery for basal-cell carcinoma of the face: randomised controlled trial. Lancet 364 (9447): 1766-72, 2004 Nov 13-19.
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22. Caccialanza M, Piccinno R, Moretti D, et al.: Radiotherapy of carcinomas of the skin overlying the cartilage of the nose: results in 405 lesions. Eur J Dermatol 13 (5): 462-5, 2003 Sep-Oct.
23. Lovett RD, Perez CA, Shapiro SJ, et al.: External irradiation of epithelial skin cancer. Int J Radiat Oncol Biol Phys 19 (2): 235-42, 1990.
24. Hall VL, Leppard BJ, McGill J, et al.: Treatment of basal-cell carcinoma: comparison of radiotherapy and cryotherapy. Clin Radiol 37 (1): 33-4, 1986.
25. Silverman MK, Kopf AW, Grin CM, et al.: Recurrence rates of treated basal cell carcinomas. Part 2: Curettage-electrodesiccation. J Dermatol Surg Oncol 17 (9): 720-6, 1991.
26. Divine J, Stefaniwksy L, Reddy R, et al.: A comprehensive guide to the surgical management of nonmelanoma skin cancer. Curr Probl Cancer 39 (4): 216-25, 2015 Jul-Aug.
27. Weshahy AH, Abdel Hay RM, Metwally D, et al.: The efficacy of intralesional cryosurgery in the treatment of small- and medium-sized basal cell carcinoma: A pilot study. J Dermatolog Treat 26 (2): 147-50, 2015.
28. Gaitanis G, Bassukas ID: Immunocryosurgery for non-superficial basal cell carcinoma: a pro-spective, open-label phase III study for tumours ≤ 2 cm in diameter. Acta Derm Venereol 94 (1): 38-44, 2014.
29. Har-Shai Y, Sommer A, Gil T, et al.: Intralesional cryosurgery for the treatment of basal cell carcinoma of the lower extremities in elderly subjects: a feasibility study. Int J Dermatol 55 (3): 342-50, 2016.
30. Gaitanis G, Kalogeropoulos CD, Bassukas ID: Cryosurgery during Imiquimod (Immunocryosurgery) for Periocular Basal Cell Carcinomas: An Efficacious Minimally Invasive Treatment Alternative. Dermatology 232 (1): 17-21, 2016.
31. Samain A, Boullié MC, Duval-Modeste AB, et al.: Cryosurgery and curettage-cryosurgery for basal cell carcinomas of the mid-face. J Eur Acad Dermatol Venereol 29 (7): 1291-6, 2015.
32. Lindgren G, Larkö O: Cryosurgery of eyelid basal cell carcinomas including 781 cases treated over 30 years. Acta Ophthalmol 92 (8): 787-92, 2014.
33. Nakuçi M, Bassukas ID: Office-based treatment of basal cell carcinoma with immunocryosurgery: feasibility and efficacy. Acta Dermatovenerol Alp Pannonica Adriat 22 (2): 35-8, 2013.
34. Lindemalm-Lundstam B, Dalenbäck J: Prospective follow-up after curettage-cryosurgery for scalp and face skin cancers. Br J Dermatol 161 (3): 568-76, 2009.
35. Gaitanis G, Alexopoulos EC, Bassukas ID: Cryosurgery is more effective in the treatment of primary, non-superficial basal cell carcinomas when applied during and not prior to a five week imiquimod course: a randomized, prospective, open-label study. Eur J Dermatol 21 (6): 952-8, 2011 Nov-Dec.
36. Wang I, Bendsoe N, Klinteberg CA, et al.: Photodynamic therapy vs. cryosurgery of basal cell carcinomas: results of a phase III clinical trial. Br J Dermatol 144 (4): 832-40, 2001.
37. Basset-Séguin N, Ibbotson S, Emtestam L, et al.: Photodynamic therapy using methyl aminolaevulinate is as efficacious as cryotherapy in basal cell carcinoma, with better cosmetic results. [Abstract] Br J Dermatol 149 (Suppl 64): A-P-66, 46, 2003.
38. Basset-Séguin N, Ibbotson S, Emtestam L, et al.: Methyl aminolaevulinate photodynamic therapy vs. cryotherapy in primary superficial basal cell carcinoma: results of a 36-month follow-up. [Abstract] Br J Dermatol 153 (Suppl 1): A-P-30, 29. 2005.
39. Hsi RA, Rosenthal DI, Glatstein E: Photodynamic therapy in the treatment of cancer: current state of the art. Drugs 57 (5): 725-34, 1999.
40. Lui H, Hobbs L, Tope WD, et al.: Photodynamic therapy of multiple nonmelanoma skin cancers with verteporfin and red light-emitting diodes: two-year results evaluating tumor response and cosmetic outcomes. Arch Dermatol 140 (1): 26-32, 2004.
41. Efudex® (fluorouracil) cream, 5% [package insert]. Aliso Viejo, Ca: Valeant Pharmaceuticals International, 2005. Available online. Last accessed December 8, 2016.
42. Love WE, Bernhard JD, Bordeaux JS: Topical imiquimod or fluorouracil therapy for basal and squamous cell carcinoma: a systematic review. Arch Dermatol 145 (12): 1431-8, 2009.
43. Beutner KR, Geisse JK, Helman D, et al.: Therapeutic response of basal cell carcinoma to the immune response modifier imiquimod 5% cream. J Am Acad Dermatol 41 (6): 1002-7, 1999.
44. Geisse JK, Rich P, Pandya A, et al.: Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: a double-blind, randomized, vehicle-controlled study. J Am Acad Dermatol 47 (3): 390-8, 2002.
45. Geisse J, Caro I, Lindholm J, et al.: Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from two phase III, randomized, vehicle-controlled studies. J Am Acad Dermatol 50 (5): 722-33, 2004.
46. Shumack S, Robinson J, Kossard S, et al.: Efficacy of topical 5% imiquimod cream for the treatment of nodular basal cell carcinoma: comparison of dosing regimens. Arch Dermatol 138 (9): 1165-71, 2002.
47. Marks R, Gebauer K, Shumack S, et al.: Imiquimod 5% cream in the treatment of superficial basal cell carcinoma: results of a multicenter 6-week dose-response trial. J Am Acad Dermatol 44 (5): 807-13, 2001.
48. Schulze HJ, Cribier B, Requena L, et al.: Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from a randomized vehicle-controlled phase III study in Europe. Br J Dermatol 152 (5): 939-47, 2005.
49. Reszko A, Aasi SZ, Wilson LD, et al.: Cancer of the skin. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1610-33.
50. Sekulic A, Migden MR, Oro AE, et al.: Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 366 (23): 2171-9, 2012.
51. Migden MR, Guminski A, Gutzmer R, et al.: Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial. Lancet Oncol 16 (6): 716-28, 2015.
52. Khandekar JD: Complete response of metastatic basal cell carcinoma to cisplatin chemotherapy: a report on two patients. Arch Dermatol 126 (12): 1660, 1990.
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54. Karagas MR, Stukel TA, Greenberg ER, et al.: Risk of subsequent basal cell carcinoma and squamous cell carcinoma of the skin among patients with prior skin cancer. Skin Cancer Prevention Study Group. JAMA 267 (24): 3305-10, 1992.
55. Schinstine M, Goldman GD: Risk of synchronous and metachronous second nonmelanoma skin cancer when referred for Mohs micrographic surgery. J Am Acad Dermatol 44 (3): 497-9, 2001.
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Squamous Cell Carcinoma of the Skin Treatment

Localized squamous cell carcinoma (SCC) of the skin is a highly curable disease.[1] There are a variety of treatment approaches to localized SCC, including excision, radiation therapy, cryosurgery, and electrodesiccation and curettage.

There is little to no good-quality evidence that allows direct comparison of outcomes for patients with sporadic, clinically localized SCCs treated with local therapies. A systematic literature review found only one randomized controlled trial in the management of such patients, and that trial compared adjuvant therapy with observation after initial local therapy rather than different local therapies.[2] In that small single-center trial, 66 patients with high-risk, clinically localized SCC were randomly assigned, after surgical excision of the primary tumor (with or without radiation, depending on clinical judgment), to either receive combined isotretinoin (1 mg/kg orally per day) plus interferon alpha (3 × 10⁶ U subcutaneously 3 times/week) for 6 months or undergo observation.[3] In the 65 evaluable patients after a median follow-up of 21.5 months, there was no difference in the combined (primary) endpoint of SCC recurrence or second primary tumor (45% vs. 38%; hazard ratio = 1.13; 95% confidence interval [CI], 0.53–2.41), or in either of the individual components of the primary endpoint.[3][Level of evidence 1iiDii]

The management of clinically localized cutaneous SCC is based on case series and consensus statements from experts because of the absence of high-quality evidence from controlled clinical trials.[4] The commonly used treatments are listed below.

Treatment for Squamous Cell Carcinoma of the Skin (Localized Disease)

Treatment options for SCC of the skin (localized disease) include the following:

1. Surgical excision with margin evaluation.
2. Mohs micrographic surgery.
3. Radiation therapy.
4. Curettage and electrodesiccation.
5. Cryosurgery.

Surgical excision with margin evaluation

Excision is probably the most common therapy for SCC.[4] This traditional surgical treatment usually relies on surgical margins ranging from 4 mm to 10 mm, depending on the diameter of the tumor and degree of differentiation. In a prospective case series of 141 SCCs, a 4-mm margin was adequate to encompass all subclinical microscopic tumor extension in more than 95% of well-differentiated tumors up to 19 mm in diameter. Wider margins of 6 mm to 10 mm were needed for larger or less-differentiated tumors or tumors in high-risk locations (e.g., scalp, ears, eyelids, nose, and lips).[5] Re-excision may be required if the surgical margin is found to be inadequate on permanent sectioning.

Mohs micrographic surgery

Mohs micrographic surgery is a form of tumor excision that involves progressive radial sectioning and real-time examination of the resection margins until adequate uninvolved margins have been achieved, avoiding wider margins than needed. It is a specialized technique used to achieve the narrowest margins necessary to avoid tumor recurrence while maximally preserving cosmesis. The tumor is microscopically delineated, with serial radial resection, until it is completely removed as assessed with real-time frozen sections. However, because the technique removes tumor growing in contiguity and may miss noncontiguous in-transit cutaneous micrometastases, some practitioners remove an additional margin of skin in high-risk lesions even after the Mohs surgical procedure confirms uninvolved margins.[4][Level of evidence: 3iiiDiv] In case series, Mohs surgery has been associated with a lower local recurrence rate than the other local modalities,[6] but there are no randomized trials allowing direct comparison.[2]
Mohs surgery. A surgical procedure to remove skin cancer in several steps. First, a thin layer of cancerous tissue is removed. Then, a second thin layer of tissue is removed and viewed under a microscope to check for cancer cells. More layers are removed one at a time until the tissue viewed under a microscope shows no remaining cancer. This type of surgery is used to remove as little normal tissue as possible and is often used to remove skin cancer on the face.

This surgery is best suited to the management of tumors in cosmetically sensitive areas (e.g., eyelid periorbital area, nasolabial fold, nose-cheek angle, posterior cheek sulcus, pinna, ear canal, forehead, scalp, fingers, and genitalia) or for tumors that have recurred after initial excision.[7,8] Mohs micrographic surgery is also used to treat high-risk tumors with poorly defined clinical borders or with perineural invasion.

Radiation therapy

Radiation therapy is a logical treatment choice, particularly for patients with primary lesions requiring difficult or extensive surgery (e.g., lesions on the nose, lips, or ears).[4,9] Radiation therapy eliminates the need for skin grafting in cases where surgery would result in an extensive defect. Cosmetic results are generally good, with a small amount of hypopigmentation or telangiectasia in the treatment port. Radiation therapy can also be used for lesions that recur after a primary surgical approach.[10]

Radiation therapy is avoided in patients with conditions that predispose them to radiation-induced cancers, such as xeroderma pigmentosum or basal cell nevus syndrome.

Although radiation therapy, with or without excision of the primary tumor, is used for histologically proven clinical lymph node metastases and has been associated with favorable disease-free survival rates, the retrospective nature of these case series makes it difficult to know the impact of nodal radiation on survival.[11,12][Level of evidence 3iiiDii]

Curettage and electrodesiccation

Curettage and electrodesiccation is used to treat squamous cell carcinoma of the skin. A sharp curette is used to scrape the tumor down to its base, followed by electrodesiccation of the lesion base. Although curettage and electrodesiccation is a quick method for destroying the tumor, the adequacy of treatment cannot be assessed immediately because the surgeon cannot visually detect the depth of microscopic tumor invasion. Its use is limited to small (<1 cm), well-defined, and well-differentiated tumors.[4][Level of evidence: 3iiiDii] This procedure is also sometimes called electrosurgery.

Cryosurgery

Cryosurgery may be considered for patients with small, clinically well-defined primary tumors. It may be useful for patients with medical conditions that preclude other types of surgery.[13,14] Contraindications for cryosurgery include the following:

• Abnormal cold tolerance.
• Cryoglobulinemia or cryofibrinogenemia.
• Raynaud disease (in the case of lesions on the hands and feet).
• Platelet deficiency disorders.
• Tumors of the scalp, ala nasi, nasolabial fold, tragus, postauricular sulcus, free eyelid margin, upper lip vermillion border, and lower legs.
• Tumors near nerves.

Caution should also be used before treating nodular ulcerative neoplasia more than 3 cm in diameter, carcinomas fixed to the underlying bone or cartilage, tumors situated on the lateral margins of the fingers and at the ulnar fossa of the elbow, or recurrent carcinomas following surgical excision. Permanent pigment loss at the treatment site is unavoidable, so the treatment is not well suited to dark-skinned patients.

Edema is common after treatment, especially around the periorbital region, temple, and forehead. Treated tumors usually exude necrotic material, after which an eschar forms and persists for about 4 weeks. Atrophy and hypertrophic scarring have been reported, as have instances of motor and sensory neuropathy.

Treatment of SCC in situ (Bowen disease)

The management of SCC in situ (Bowen disease) is similar to that for good-risk SCC. However, because Bowen disease is noninvasive, surgical excision, including Mohs micrographic surgery, is usually not necessary. In addition, high complete response (CR) rates are achievable with photodynamic therapy (PDT).

Evidence (PDT):

1. In a multicenter trial, 229 patients (209 evaluated in a per-protocol/per-lesion analysis) were randomly assigned to receive PDT (methyl aminolevulinate + 570–670 nm red light; n = 91); placebo cream with red light (n = 15); or treatment by physician choice (cryotherapy, n = 77; topical fluorouracil, n = 26).[15][Level of evidence 1iiDii]
   • The sustained complete clinical response rates at 12 months were 80% for PDT, 67% for placebo cream with red light, and 69% for treatment of physician choice (P = .04 for the comparison between PDT and the two combined physician-choice groups).[15][Level of evidence 1iiDii]
   • The cosmetic results were best in the PDT group. (For comparison, the CR rates at 3 months were 93% for PDT and 21% for placebo/PDT.)

Treatment for Metastatic Squamous Cell Carcinoma (or Advanced Disease Untreatable by Local Modalities)

As is the case with BCC, metastatic and far-advanced SCC is unusual, and reports of systemic therapy are limited to case reports and very small case series with tumor response as the endpoint.[Level of evidence 3iiiDiv] The metastatic rate for primary tumors of sun-exposed skin is 5%; for tumors of the external ear, 9%; and for tumors of the lip, 14%. Metastases occur at an even higher rate (about 38%) for primary SCCs in scar carcinomas or in nonexposed areas of skin.[6] About 69% of metastases are diagnosed within 1 year, 91% within 3 years, and 96% within 5 years.

Treatment options for metastatic SCC (or advanced disease untreatable by local modalities) include the following:

1. Chemotherapy. Cisplatin-based regimens appear to be associated with high initial tumor response rates.[16,17]
2. Isotretinoin plus interferon alpha-2a. High response rates have also been reported with the use of isotretinoin plus interferon alpha-2a.[18]

Because there is no standard therapy for metastatic SCC of the skin, clinical trials are appropriate. Information about ongoing clinical trials is available from the NCI website.

Treatment for Recurrent Nonmetastatic Squamous Cell Carcinoma of the Skin

SCCs have definite metastatic potential, and patients are followed up regularly after initial treatment. Overall, local recurrence rates after treatment of primary SCCs have ranged from about 3% to 23%, depending on anatomic site.[6] About 58% of local recurrences manifest within 1 year, 83% within 3 years, and 95% within 5 years. Tumors that are 2 cm or larger in diameter, 4 mm or greater in depth, or poorly differentiated have a relatively poor prognosis [19] and even higher local recurrence and metastasis rates than those listed.[6] Reported local recurrence rates also vary by treatment modality, with the lowest rates associated with Mohs micrographic surgery; however, at least some of the variation may be the result of patient selection factors. No randomized trials directly compare the various local treatment modalities.

Treatment options for recurrent nonmetastatic SCCs include the following:

1. Surgical excision.
2. Mohs micrographic surgery.
3. Radiation therapy.

Recurrent nonmetastatic SCCs are considered high risk and are generally treated with excision, often using Mohs micrographic surgery. Radiation therapy is used for lesions that cannot be completely resected.

As is the case with BCC, patients who develop a primary SCC are also at increased risk of subsequent primary skin cancers.[20,21]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Preston DS, Stern RS: Nonmelanoma cancers of the skin. N Engl J Med 327 (23): 1649-62, 1992.
2. Lansbury L, Leonardi-Bee J, Perkins W, et al.: Interventions for non-metastatic squamous cell carcinoma of the skin. Cochrane Database Syst Rev (4): CD007869, 2010.
3. Brewster AM, Lee JJ, Clayman GL, et al.: Randomized trial of adjuvant 13-cis-retinoic acid and interferon alfa for patients with aggressive skin squamous cell carcinoma. J Clin Oncol 25 (15): 1974-8, 2007.
4. Motley R, Kersey P, Lawrence C, et al.: Multiprofessional guidelines for the management of the patient with primary cutaneous squamous cell carcinoma. Br J Dermatol 146 (1): 18-25, 2002.
5. Brodland DG, Zitelli JA: Surgical margins for excision of primary cutaneous squamous cell carcinoma. J Am Acad Dermatol 27 (2 Pt 1): 241-8, 1992.
6. Rowe DE, Carroll RJ, Day CL Jr: Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection. J Am Acad Dermatol 26 (6): 976-90, 1992.
7. Thomas RM, Amonette RA: Mohs micrographic surgery. Am Fam Physician 37 (3): 135-42, 1988.
8. Rowe DE, Carroll RJ, Day CL Jr: Mohs surgery is the treatment of choice for recurrent (previously treated) basal cell carcinoma. J Dermatol Surg Oncol 15 (4): 424-31, 1989.
9. Caccialanza M, Piccinno R, Moretti D, et al.: Radiotherapy of carcinomas of the skin overlying the cartilage of the nose: results in 405 lesions. Eur J Dermatol 13 (5): 462-5, 2003 Sep-Oct.
10. Lovett RD, Perez CA, Shapiro SJ, et al.: External irradiation of epithelial skin cancer. Int J Radiat Oncol Biol Phys 19 (2): 235-42, 1990.
11. Shimm DS, Wilder RB: Radiation therapy for squamous cell carcinoma of the skin. Am J Clin Oncol 14 (5): 383-6, 1991.
12. Veness MJ, Palme CE, Smith M, et al.: Cutaneous head and neck squamous cell carcinoma metastatic to cervical lymph nodes (nonparotid): a better outcome with surgery and adjuvant radiotherapy. Laryngoscope 113 (10): 1827-33, 2003.
13. Gaitanis G, Bassukas ID: Immunocryosurgery – an effective combinational modality for Bowen’s disease. Dermatol Ther 29 (5): 334-337, 2016.
14. Almeida Gonçalves JC: Advanced cancer of the extremities treated by cryosurgery. G Ital Dermatol Venereol 146 (4): 249-55, 2011.
15. Morton C, Horn M, Leman J, et al.: Comparison of topical methyl aminolevulinate photodynamic therapy with cryotherapy or Fluorouracil for treatment of squamous cell carcinoma in situ: Results of a multicenter randomized trial. Arch Dermatol 142 (6): 729-35, 2006.
16. Luxenberg MN, Guthrie TH Jr: Chemotherapy of basal cell and squamous cell carcinoma of the eyelids and periorbital tissues. Ophthalmology 93 (4): 504-10, 1986.
17. Sadek H, Azli N, Wendling JL, et al.: Treatment of advanced squamous cell carcinoma of the skin with cisplatin, 5-fluorouracil, and bleomycin. Cancer 66 (8): 1692-6, 1990.
18. Lippman SM, Parkinson DR, Itri LM, et al.: 13-cis-retinoic acid and interferon alpha-2a: effective combination therapy for advanced squamous cell carcinoma of the skin. J Natl Cancer Inst 84 (4): 235-41, 1992.
19. Cherpelis BS, Marcusen C, Lang PG: Prognostic factors for metastasis in squamous cell carcinoma of the skin. Dermatol Surg 28 (3): 268-73, 2002.
20. Karagas MR, Stukel TA, Greenberg ER, et al.: Risk of subsequent basal cell carcinoma and squamous cell carcinoma of the skin among patients with prior skin cancer. Skin Cancer Prevention Study Group. JAMA 267 (24): 3305-10, 1992.
21. Schinstine M, Goldman GD: Risk of synchronous and metachronous second nonmelanoma skin cancer when referred for Mohs micrographic surgery. J Am Acad Dermatol 44 (3): 497-9, 2001.

Treatment of Actinic Keratosis

Actinic keratoses commonly appear in areas of chronic sun exposure, such as the face and dorsa of the hands. Actinic cheilitis is a related condition that usually appears on the lower lips.[1] These conditions represent early epithelial transformation that may eventually evolve into invasive squamous cell carcinoma (SCC).

Actinic keratoses are noninvasive lesions. The progression rate is extremely low. In a prospective study, the progression rate to SCC was less than 1 in 1,000 per year, calling into question the cost-effectiveness of treating all actinic keratoses to prevent SCC.[2] Moreover, in a population-based longitudinal study, there was a spontaneous regression rate of approximately 26% for solar keratoses within 1 year of a screening examination.[3] Therefore, studies designed to test the efficacy of any treatment for progression of actinic keratoses to SCC are impractical (or impossible). Nevertheless, a variety of treatment approaches have been reviewed.[4]

Treatment options for actinic keratosis depend on whether the lesions are isolated or whether there are multiple lesions in the same field.

Treatment options for actinic keratosis (not listed hierarchically) include the following:

1. Topical agents.
   • Fluorouracil (5-FU).
   • Imiquimod cream.
   • Diclofenac sodium 3% gel.
   • Ingenol mebutate.
2. Chemical peels.
   • Trichloroacetic acid.
3. Surgery.
   • Surgical excision.
   • Shave excision.
   • Curettage with or without electrodessication.
   • Dermabrasion.
4. Photodynamic therapy.
5. Laser therapy (carbon dioxide or erbium-doped yttrium aluminum garnet [Er:YAG] laser).

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Picascia DD, Robinson JK: Actinic cheilitis: a review of the etiology, differential diagnosis, and treatment. J Am Acad Dermatol 17 (2 Pt 1): 255-64, 1987.
2. Marks R, Rennie G, Selwood TS: Malignant transformation of solar keratoses to squamous cell carcinoma. Lancet 1 (8589): 795-7, 1988.
3. Marks R, Foley P, Goodman G, et al.: Spontaneous remission of solar keratoses: the case for conservative management. Br J Dermatol 115 (6): 649-55, 1986.
4. Jorizzo J, ed.: Actinic keratosis. Waltham, Ma: UpToDate Inc, 2011. Available online with free registration. Last accessed February 19, 2018.

Changes to This Summary (04 / 26 / 2018)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

This summary was comprehensively reviewed, extensively revised, and reformatted.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® – NCI’s Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of skin cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewer for Skin Cancer Treatment is:

• Russell S. Berman, MD (New York University School of Medicine)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Skin Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/skin/hp/skin-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389366]

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Last Revised: 2018-04-26