Nonmelanoma Skin Cancer: Today's Epidemic

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Journal Article -- February 2001

Symposium on Cancer: What Primary Care Physicians Need To Know

By Byron L. Limmer, MD

The practicing physician encounters many benign and malignant skin neoplasms daily. Basal cell carcinoma and squamous cell carcinoma represent the vast majority of the malignant tumors. Identification of predisposing factors, intrinsic and extrinsic, can decrease future tumor development. Early recognition, biopsy confirmation, and treatment selection can reduce patient morbidity.

The following scenario is played out in hundreds of offices across the United States each year:

Patient: I have skin cancer?

Physician: Yes, sir. The spot on your nose is a basal cell carcinoma-type skin cancer.

Patient: But that's been there for some time.

Physician: I understand, but I believe we need to biopsy this bleeding spot.

Patient: Well, I just cut it this morning while shaving. I really think it's okay. It usually heals in a couple of days.

Physician: This type of growth often acts that way. Let's first take a simple biopsy and then we can decide how to proceed from there.

Nonmelanoma skin cancer is the most common cancer of US citizens. More than 1 million cases will be diagnosed this year alone. Basal cell carcinoma and squamous cell carcinoma account for most of these tumors. This article will outline the tenets for early diagnosis and treatment.

Basal cell carcinoma

Basal cell carcinoma (BCC) constitutes approximately 75% of nonmelanoma skin cancer (1). These tumors have a male predominance and mean onset in the seventh decade of life. More than 85% occur over the head and neck region (2).

Intrinsic and extrinsic factors predispose persons to develop BCC. Genetic predisposition to BCC development is seen to have an increased incidence in patients with basal cell nevus syndrome, Bazex syndrome, Rombo syndrome, xeroderma pigmentosum, linear unilateral basal cell nevus, albinism, and nevus sebaceus (3,4). Basal cell nevus syndrome, the most common of these syndromes, is an autosomal dominantly inherited disease demonstrating BCC development in childhood, palmoplantar pits, jaw cysts, skeletal abnormalities, and medulloblastomas.

Environmental insults including ultraviolet light, PUVA therapy, radiation therapy, arsenic exposure, scars, and immunosuppression are factors in tumor development (5). While examining cellular changes induced specifically by ultraviolet light, some scientists have focused on the alterations precipitated in p53 protein. P53 protein is a nuclear phosphoprotein that suppresses uncontrolled cell division. Mutations of this protein have been found in malignancies including colon, breast, liver, lung, esophagus, brain, and blood. Increased native p53 expression has been noted in skin around BCC and sun-exposed skin, suggesting a protective up-regulation of this gene by the host in response to ultraviolet light (6). Assays have shown an increase in mutant p53 clones in BCC and surrounding skin, suggesting a field effect of tissue damage (6). These data would seem to support the epidemiologic findings showing BCC distributed primarily over sun-exposed skin. Sunscreens have proven to reduce p53 mutations and, consequently, we would suspect a reduction of subsequent tumor development (7).

Early diagnosis is important to reduce the morbidity associated with BCC. Most often, BCC presents as a nodule-ulcerative, telangiectatic ivory papule or plaque. Subtypes include nodular, pigmented, and superficial forms of BCC. These subtypes are often lumped together because they show a higher cure rate with varying therapies. Recurrence rates for field therapies (cryosurgery, electrosurgery, and radiotherapy) range from 3% to 8% (8).

Too often, physicians fail to diagnose and adequately treat the more aggressive subtypes of BCC: infiltrative and morpheic. These tumors grow inconspicuously as indiscreet scars or indurated areas of skin. A high degree of suspicion is paramount for early diagnosis. Clinically, these tumors are indiscreet and show significantly greater risk of recurrence. Histologically, they demonstrate increased evidence of perineural infiltration. Biologically, they exhibit enhanced motility via increased contractile proteins (myofibroblasts), loss of membrane components (laminin, type IV collagen), and increased stromal fibronecin (possibly masking immunosurveillance), suggesting biologic means to achieve greater tissue invasion (9).

Choosing the modality of therapy is important when treating these narrow strands of invasive tumor. The success of field therapies (including radiotherapy, cryosurgery, and electrosurgery) depends on the physician's ability to clinically identify margins so as to treat the tumor and a surrounding margin of normal tissue. Because of difficulty estimating these criteria in the infiltrative subtype, a higher cure rate can be achieved with forms of treatment that use conservative margin control, excisional surgery with peripheral margin evaluation or Mohs' surgery (10). Mohs' surgery has proven repeatedly to be the gold standard for treatment of these invasive tumors as well as of recurrent tumors. The meticulous peripheral margin examination, tissue mapping, and narrow margins make Mohs' surgery well adapted to treatment of these tumors (11).

Squamous cell carcinoma

Squamous cell carcinoma (SCC) is the second most common nonmelanoma skin cancer (1). Representing approximately 20% of skin cancers, SCC shows a male predominance with mean onset in the seventh decade. Ninety-five percent are found over the head and neck (12).

Multifactorial etiologies are implicated in development of SCC. Genetic and environmental factors predispose individuals to SCC. Genetic predisposition is noted in patients with xeroderma pigmentosum, epidermodysplasia verruciformis, and dyskeratosis congenita. Environmental factors include radiation (ultraviolet and x-ray), immunosuppression, human papilloma virus, and chemical carcinogens (13).

Ultraviolet radiation is the most common environmental factor. Epidemiologic studies have demonstrated an increased incidence rate for SCC in climates near the equator, at higher altitudes, and with greater numbers of sunny days per year (14). Also, tumor density (number of tumors per unit area) are shown to be greater on the nose than on the trunk and in Caucasians rather than in blacks (15). These epidemiologic data imply that greater ultraviolet light exposure will lead to greater SCC development.

The predisposition of immunocompromised people has been clearly seen in renal transplant patients (16). These people are at significantly higher risk for development of SCC. Onset usually appears from 2 to 7 years after transplant surgery. Multiple lesions are common. As transplant surgery of other organs becomes more successful with longer survivals, these patients are expected to have similar risks for SCC development.

Human papilloma virus has been investigated in conjunction with tumor development. Clearly, impaired host defenses such as seen in epidermodysplasia verruciformis allow for both increased human papilloma virus and increased carcinoma development (17). The exact nature of these findings remains to be better delineated.

Chemical carcinogens have long been associated with SCC development. Arsenicals found in insecticides and older asthma medications once exposed a large population to carcinogenesis. Similarly, hydrocarbons found in soot predisposed chimney sweeps to SCC development.

Clinically, SCC of the skin appears as a friable or ulcerated nodule. Usually an indurated, elevated, erythematous border is present. A background of chronic sun exposure -- including erythema, scale, pigment irregularities, and telangiectasias -- is found. Histologic examination of a biopsy specimen confirms the diagnosis.

Treatment of SCC is tailored to the clinical features and histologic findings. Surgical options are similar to those discussed previously for treatment of BCC.

Field therapies, including cryosurgery, electrosurgery, and radiation therapy, target treatment of a defined area including both tumor and a surrounding margin of normal tissue. In contrast to excisional surgery, we have no post-treatment histologic confirmation of cure. Selection criteria for tumors responding with high cure rates to field therapies include well-defined clinical margins, small size (5-15 mm), location over firm surfaces (ie, forehead, temple, and back), and less aggressive histology (well- or moderately differentiated tumor) (18). Local tissue characteristics are important because areas with free margins (ie, ears and alae) or minimal dermal thickness (ie, eyelids) do not allow for manuevers such as curettage to estimate tumor depth and, therefore, increase the risk of incomplete tumor removal.

Tumor variables identified with more aggressive subtypes are best addressed with excisional surgery using peripheral margin control or Mohs surgery (19). These variables include tumors with ill-defined margins and tumors larger than 2 cm. Also, nasal, periocular, auricular, mucosal, and scalp locations have a high risk of recurrence. Histologic features exhibiting poorly differentiated morphology, perineural invasion, or depth of invasion greater than 4 mm appear to identify tumors at higher risk for subsequent metastases and local recurrence.

Summary

As the elderly population in the United States continues to grow, we will see increasing numbers of skin cancers. Early recognition and diagnosis are the mainstays to improving cure rates. Subsequent tailoring of treatments to specific tumor characteristics will allow for higher cure rates, economy of health care dollars, and better cosmesis.

References

  1. Cancer statistics, 1989. CA . 1989;39:3-20.
  2. Miller SJ. Biology of basal cell carcinoma, part 1. J Am Acad Dermatol . 1991;24:1-13.
  3. Carter DM, Lin AN. Basal cell carcinoma. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF, eds. Dermatology in General Medicine . 4th ed. New York, NY: McGraw-Hill; 1993:840-847.
  4. Lever WF, Schaumburg-Lever G. Tumors of the epidermal appendages. In: Histopathology of the Skin . 7th ed. Philadelphia, Pa: JB Lippincott; 1990:578.
  5. Nguyen AV, Whitaker DC, Frodel J. Differentiation of basal cell carcinoma. Otolaryngol Clin North Am . 1993;26(1):37-56.
  6. Urano Y, Asano T, Yoshimoto K, et al. Frequent p53 accumulation in the chronically sun-exposed epidermis and clonal expansion of p53 mutant cells in the epidermis adjacent to basal cell carcinoma. J Invest Dermatol . 1995;104:928-932.
  7. Ponten F, Berne B, Ren ZP, Nister M, Ponten J. Ultraviolet light induces expression of p53 and p21 in human skin: effect of sunscreen and constitutive p21 expression in skin appendages. J Invest Dermatol . 1995;105:402-406.
  8. Limmer BL, Clark D. Nonsurgical management of primary skin malignancies. Otolarngol Clin North Am . 1993;26(2):167-183.
  9. DeRosa G, Barra E, Guarino M, Staibano S, Donofrio V, Boscaino A. Fibronectin, laminin, type IV collagen distribution, and myofibroblastic stromal reaction in aggressive and nonaggressive basal cell carcinoma. Am J Dermatopathol . 1994;16(3):258-267.
  10. Hendrix JD, Parlette HL. Duplicitous growth of infiltrative basal cell carcinoma. Dermatol Surg . 1996;22:535-539.
  11. Zitelli JA. Mohs surgery: concepts and misconceptions. Int J Dermatol . 1985;24:541-548.
  12. Haydon RC. Cutaneous squamous carcinoma and related lesions. Otolaryngol Clin North Am . 1993;26(1):57-71.
  13. Kwa RE, Campana K, Moy RL. Biology of cutaneous squamous cell carcinoma. J Am Acad Dermatol . 1992;26:1-26.
  14. Scotto J, Fears TR, Fraumeni JF Jr. Incidence of nonmelanoma skin cancer in the US. Bethesda, Md: US Dept of Health and Human Services, National Institutes of Health; 1983. NIH Publication No. 83-2433.
  15. Pearl DK, Scott EL. The anatomical distribution of skin cancers. Int J Epidemiol. 1986;15:502-506.
  16. Gupta AK, Cardella CJ, Haberman HF. Cutaneous malignant neoplasms in patients with renal transplants. Arch Dermatol. 1986;122:1288-1293.
  17. Lutzner MA, Blanchet-Bardon C, Orth G. Clinical observations, virologic studies and treatment trials in patients with epidermodysplasia verruciformis, a disease induced by specific human papillomaviruses. J Invest Dermatol . 1984;83(suppl):18-25.
  18. Albright S. Treatment of skin cancer using multiple modalities. J Am Acad Dermatol . 1982;7:143-171.
  19. Rowe DE, Carroll RJ, Day CL. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. J Am Acad Dermatol . 1992;26:976-990.

Dr Limmer is a dermatologist in San Antonio.

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