Periodic Synopsis
Nonmelanoma skin cancer

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Introduction

According to statistics from the American Cancer Society, the annual incidence of nonmelanoma skin cancer (NMSC) in the United States is now estimated at over one million cases and thus approximately equals all other cases of human malignancies combined (www.cancer.org, Cancer Facts and Figures). The overwhelming majority of NMSC cases are basal cell and squamous cell carcinomas (BCCs and SCCs, respectively) in a ratio of approximately 4:1. A wide variety of additional nonmelanoma skin tumors arise from other cell types present in skin, such as lymphocytes, vascular endothelial cells, Merkel cells, mesenchymal stromal cells, and cells forming the adnexal structures. These entities are quite rare relative to BCC and SCC and will not be discussed herein.

Not surprisingly, given the large number of NMSC cases, there is a correspondingly large body of literature addressing various aspects of epidemiology, pathogenesis, and treatment. It is impossible in this format to present a completely comprehensive synopsis that includes all manuscripts relating to this very broad topic. Articles presented herein were chosen in an effort to give a reasonably comprehensive representation of the many lines of active inquiry currently advancing our understanding of NMSC. Selection of specific articles was based on the author's clinical and scientific experience with the published literature, literature review conducted specifically for this synopsis, and consultation with dermatology colleagues. Valuable work from many distinguished authors was unable to be included directly in this article, but is cited within references from papers highlighted herein. This synopsis focuses primarily on those contributions published in English since the turn of the millennium that are believed to be of greatest interest to the majority of currently practicing dermatologists.

Section snippets

General reviews

Alam M, Ratner D. Cutaneous squamous-cell carcinoma. N Engl J Med 2001;344:975-83.

Rubin AI, Chen EH, Ratner D. Basal-cell carcinoma. N Engl J Med 2005;353:2262-9.

This is a pair of well-written, comprehensive general reviews with value for both the dermatologist and general practitioner.

Epidemiology

It is difficult to obtain accurate epidemiological data on NMSC as cases are frequently specifically excluded from state and national cancer registries. Furthermore, incidence rates vary significantly depending on the ethnicity and geographic location of the study population. Despite this variability, most studies show that rates are increasing significantly worldwide, generally thought to be a result of increased cumulative ultraviolet (UV) exposure. This is in large measure an inevitable

Effects of UV radiation, smoking, diet, and tanning bed use on NMSC

Armstrong BK, Kricker A: The epidemiology of UV induced skin cancer. J Photochem Photobiol 2001;63:8-18.

This review summarizes epidemiological evidence supporting a causal role for sun exposure in development of SCC, BCC, and melanoma. Data from many primary articles is synthesized to establish that (1) the incidence rate of each skin cancer type is higher in fairer skinned, sun-sensitive individuals; (2) risk increases with increasing ambient solar radiation; (3) the highest densities are on

Heritable risk factors for NMSC

Box NF, Duffy DL, Irving RE, Russell A, Chen W, Griffyths LR, et al. Melanocortin-1 receptor genotype is a risk factor for basal and squamous cell carcinoma. J Invest Dermatol 2001;116:224-9.

Melanocortin-1 receptor (MC1R) is a 7-pass transmembrane G-protein coupled receptor expressed by melanocytes which regulates eumelanogenesis through activation by the proopiomelanocortin-derived peptides α-melanocyte-stimulating hormone and adrenocorticotropic hormone. Specific MC1R gene variants Arg151Cys,

Special cases: Transplant, PUVA, UVB, and immunosuppressed populations

Over the past two decades there has been a dramatic increase in the number of patients living with chronic immune suppression. This results largely as an unfortunate consequence of the antirejection regimens associated with organ transplantation. The immunosuppressed population is also augmented by an increase in the number and efficacy of immunosuppressive pharmacologic agents used not only in transplant medicine, but also in rheumatologic and autoimmune diseases. These factors coupled with

On the relationship between AK and SCC

Recent debate has been directed at establishing a relationship between SCC and AK. At the center of this discussion is whether the AK is in fact an in situ SCC, or rather, an early, precancerous UV-induced epidermal atypia. Answering the question, of course, depends on how one defines cancer. Employing the use of standard experimental criteria for malignant transformation, including indefinite proliferative capacity in cell culture (immortalization), colony growth in soft agar, and ability to

Risk factors and prognosis for recurrent, invasive, and metastatic SCC

In addition to immunosuppression, several studies have identified other factors that correlate with increasing likelihood of recurrent, invasive, or metastatic disease. It should be recognized, however, that the literature on this topic is not definitively clear, as studies examining the complete complement of known potential risk factors with cohorts large enough to perform statistically meaningful multivariate analysis are lacking. Nonetheless, these findings have implications for patient

Molecular mechanisms driving NMSC

Sunlight is the primary etiologic agent driving both SCC and BCC formation. UV radiation leads directly to characteristic DNA mutations that can be identified within tumor tissue as being caused specifically by UV. While these mutations occur throughout the genome, SCC and BCC tumor cells frequently harbor characteristic mutations in specific pathways. The p53 tumor suppressor protein is mutated in the majority of both SCC and BCC, while mutations in the Patched pathway are frequently

Surgical treatment

Brodland DG, Amonette R, Hanke CW, Robins P. The history and evolution of Mohs micrographic surgery. Dermatol Surg 2000;26:303-7.

This thorough history details the development of Mohs micrographic surgery from its conceptual beginnings in a zoology laboratory where zinc chloride–treated rat tumors were sectioned horizontally, to the early days of chemosurgeons, and the recent establishment of accredited fellowship programs.

McGovern TW, Grossman D, Fitzgerald D, Glusac EJ, Leffell D. Status of

Confocal microscopy

Nori S, Rius-Diaz F, Cuevas J, Goldgeier M, Jaen P, Torres A, et al. Sensitivity and specificity of reflectance-mode confocal microscopy for in vivo diagnosis of basal cell carcinoma: a multicenter study. J Am Acad Dermatol 2004;51:923-30.

While not a treatment for NMSC per se, reflectance-mode confocal microscopy (RCM) is a rapidly developing technology which allows for noninvasive high-resolution imaging of human skin in vivo and may be used as an additional tool to both diagnose NMSC as well

5-Fluorouracil

Kraus S, Miller BH, Swinehart JM, Shavin JS, Georgouras KE, Jenner DA, et al. Intratumoral chemotherapy with fluorouracil/epinephrine injectable gel: a nonsurgical treatment of cutaneous squamous cell carcinoma. J Am Acad Dermatol 1998;38:438-42.

A fluorouracil/epinephrine injectable gel (5-FU/epi gel) was used once weekly for up to 6 weeks to treat 25 patients with biopsy-proven SCC. On follow-up histologic examination, 96% (22 of 23) tumors had complete tumor clearing. There were no clinically

Imiquimod

Imiquimod is an immunomodulating imidazoquinoline amine approved initially in 1997 by the U.S. Food and Drug Administration for treating external genital and perianal warts. The Food and Drug Administration has also now granted approval for treatment of AKs and superficial BCC, although cure rates for superficial BCC are still generally higher with surgery. Limited data suggest that imiquimod may also have some efficacy against nodular and infiltrative BCC, although clearance rates are less

Photodynamic therapy and laser

Marmur ES, Schmults CD, Goldberg DJ. A review of laser and photodynamic therapy for the treatment of nonmelanoma skin cancer. Dermatol Surg 2004;30:264-71.

The authors review the past 40 years of English-language medical literature and identify 20 articles pertaining to the use of laser and light source therapy for the treatment of NMSC with significant patient numbers and follow-up periods to merit inclusion in their study. Clearance rates were reported up to 100% for superficial BCCs, AKs, and

Retinoids

De Graaf YG, Euvrard S, Bouwes Bavinck JN. Systemic and topical retinoids in the management of skin cancer in organ transplant recipients. Dermatol Surg 2004;30:656-61.

This relatively comprehensive review summarizes many of the clinical trials using topical and oral retinoid therapy for prevention of NMSC in both normal immunocompetent individuals as well as in immunosuppressed transplant patients. While there is variation between studies, some general trends can be established. For

Nonsteroidal anti-inflammatory drugs

Rivers JK, Arlette J, Shear N, Guenther L, Carey W, Poulin Y. Topical treatment of actinic keratoses with 3.0% diclofenac in 2.5% hyaluronan gel. Br J Dermatol 2002;146:94-100.

There are no reported studies using topical nonsteroidal anti-inflammatory drugs for SCC or BCC; however, there is evidence showing efficacy against AKs. This double-blind, placebo-controlled study used 195 AK patients to evaluate the efficacy of 3.0% diclofenac in 2.5% hyaluronan topical gel. Treatment efficacy was

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This report reflects the best data available at the time the report was prepared, but caution should be exercised in interpreting the data; the results of future studies may require alteration of the conclusions or recommendations set forth in this report.

Funding sources: None.

Conflict of interest: None declared.

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