Evidence-based medicine: facial skin malignancy.

LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Identify common precancerous and malignant cutaneous growths of the head and neck. 2. Recommend surgical treatment, including margins, based on consensus guidelines. 3. Counsel patients as to available evidence for expected recurrence, follow-up, and morbidity. SUMMARY: Skin lesion excision is the most common procedure performed by plastic surgeons. Because of the cumulative risk factors of sun and carcinogen exposure, the head and neck are the most frequently affected regions of the body. Timely diagnosis and treatment are critical for preventing continued spread and metastasis, and it is incumbent on the treating physician to make the appropriate recommendations for surgical margin and the possibility of adjuvant therapy to prevent recurrence and optimize long-term survival. As clinical guidelines are developed from ongoing outcome studies, new generations of treatment recommendations are continuously in development. Therefore, a systematic review of the most relevant guidelines and clinically rigorous studies was performed with a summarization of treatment recommendations for the following: actinic keratosis, Bowen disease (squamous cell in situ), basal cell carcinoma, squamous cell carcinoma, malignant melanoma, and Merkel cell carcinoma of the head and neck.

Cutaneous sarcoidosis and malignancy: An association between sarcoidosis with skin manifestations and systemic neoplasia.

BACKGROUND: Whereas the association between multisystem and pulmonary sarcoidosis and malignancy has been documented, a relationship between cutaneous sarcoidosis and neoplasia has not yet been reported. Because cutaneous manifestations are seen in 20-25 percent of cases of sarcoidosis, this association deserves further investigation. METHODS: We reviewed the relevant literature, in addition to our case series, for a total of 110 cases of cutaneous and non-cutaneous sarcoidosis associated with malignancy with the aim of analyzing possible associations between cutaneous sarcoidosis and malignancy and to enhance the dermatologist's understanding of their critical role in the management of this disease. A search for consecutive cases, which were encountered during the past 20 years, identified 10 cases of confirmed cutaneous sarcoidosis. A review of the relevant literature was also conducted to identify cases of malignancy associated with cutaneous and non-cutaneous sarcoidosis. RESULTS: Cutaneous localization of sarcoidosis was identified in 58 of 100 patients with sarcoidosis and cancer found in the literature (58%) and in 4 of 10 patients in our series (40%). In our series, all cases manifested solid tumors, including breast (n=4 tumors), prostate cancer, colon cancer, kidney cancer, and squamous cell carcinoma of the skin (n=1 of each type). Among the 6 patients in our series with cancers and non-cutaneous sarcoidosis, the types of neoplasias encountered were renal cancer (n=1), mycosis fungoides (n=1), diffuse large B-cell lymphoma (n=1), colon cancer (n=1), and ADK of parotid (n=2). Neoplasias developed after an average of 7.14 years in the literature cases and eight years in our series, following the diagnosis of sarcoidosis. Among the 100 cases of cutaneous (n=58) and non-cutaneous (n=42) sarcoidosis associates with malignancy, which were extracted from the literature, hematologic malignancies accounted for 73 percent of cases and sarcoidosis preceded the detection of neoplasia in a majority (76%) of cases. Among 110 total cases analyzed in this paper, cutaneous sarcoidosis was confirmed in 56.4 percent of overall cases, a figure exceeding expected rates of cutaneous involvement (20-25%) in the general sarcoidosis population. CONCLUSIONS: Sarcoidosis with cutaneous manifestations appears to be associated with malignancy, possibly at a higher rate than other systemic forms of sarcoidosis. The predominant occurrence of sarcoidosis before the development of neoplasia may indicate that an immune dysregulation, such as impairment of cellular immunity mediated by sarcoidosis or the effects of treatment may contribute to an increased risk of malignancy in predisposed individuals. Physician recognition of this link between sarcoidosis and malignancy is critical. Dermatologists, in particular, play an important role, given that many of these associated cases manifest initially, or even solely, with cutaneous findings.

On the missing link between inflammation and cancer.

A various array of cutaneous granulomatous disorders have been found to be associated with internal malignancy. Among them, sarcoidosis, granuloma anulare (GA), psoriasis, pyoderma gangrenosum (PG), or other neutrophilic dermatoses such as the Sweet syndrome and subcorneal pustular dermatosis may precede the development of a neoplastic process by months or years. Pathogenic links of inflammation with cancer are discussed, including inflammation, intrinsic immune dysfunction, cytokines and interleukins, angiogenetic factors, and epigenetic changes.

Melanoma-specific marker expression in skin biopsy tissues as a tool to facilitate melanoma diagnosis.

Diagnosis of cutaneous melanoma requires accurate differentiation of true malignant tumors from highly atypical lesions, which lack the capacity to develop uncontrolled proliferation and to metastasize. We used melanoma markers from previous work to differentiate benign and atypical lesions from melanoma using paraffin-embedded tissue. This critical step in diagnosis generates the most uncertainty and discrepancy between dermatopathologists. A total of 193 biopsy tissues were selected: 47 melanomas, 48 benign nevi, and 98 atypical/suspicious, including 48 atypical nevi and 50 melanomas as later assigned by expert dermatopathologists. Performance for SILV, GDF15, and L1CAM normalized to TYR in unequivocal melanoma versus benign nevi resulted in an area under the curve (AUC) of 0.94, 0.67, and 0.5, respectively. SILV also differentiated atypical cases classified as melanoma from atypical nevi with an AUC=0.74. Furthermore, SILV showed a significant difference between suspicious melanoma and each suspicious atypia group: melanoma versus severe atypia and melanoma versus moderate atypia had P-values of 0.0077 and 0.0009, respectively. SILV showed clear discrimination between melanoma and benign unequivocal cases as well as between different atypia subgroups in the group of suspicious samples. The role and potential utility of this molecular assay as an adjunct to the morphological diagnosis of melanoma are discussed.

Malignant melanoma in African-Americans.

Although relatively uncommon, malignant melanoma in African-Americans and other minority ethnic populations represents an aggressive disease highly associated with invasive lesions and a more advanced stage of disease at diagnosis, and consequently with a decreased survival compared with Caucasians. Data on biology of melanoma in African-Americans is very limited, which complicates the analysis of epidemiological information, as well as identification of accurate prognostic variables. This review article explores critical features of melanoma in African-Americans that distinguish it from disease seen in Caucasians, including the clinical presentation, histological patterns, prognostic indicators, and etiology. Emerging data from biologic and genetic studies will also be discussed, raising the possibility that melanoma in pigmented skin may represent molecular distinct cancers that are inherently more aggressive. Improved understanding of the unique manifestations of melanoma in African-Americans, and its underlying tumor biology, will help improve clinical detection, optimize preventative measures through public health education, and potentially lead to the development of novel targeted therapeutic approaches.

The cutaneous epidermal growth factor network: Can it be translated clinically to stimulate hair growth?

The influences exerted by the epidermal growth factor receptor (EGFR) on the skin act at multiple levels, which involve compartments that normally express EGFR. These include the basal and suprabasal layers of the epidermis, sebaceous glands, and the outer root sheath of the hair follicles. The physiological roles of EGFR ensure epidermal renewal and integrity, along with a gatekeeping and function and hair growth stimulation functions. Important cellular functions that are altered during EGF receptor blocking therapy consist of epidermal differentiation, proliferation, apoptosis, and migration, with an overall dominating effect of inducing growth arrest and terminal differentiation of the keratinocytes in the basal layers. The effects of EGFR blockage on the hair cycle include terminal differentiation of the hair follicle, which in certain cases may be associated with trichomegaly. Trichomegaly of the eyelashes may occur as an isolated occurrence or, frequently, as part of a generalized phenomenon that may be associated with the use of the EGFR inhibitors. Molecular changes associated with EGFR blockage are discussed, relevant to their association with hair growth. Modulation of Akt, AP2alpha, CDK4, Notch-1, p27KIP1, and Hedgehog expression are involved in the initiation of the hair cycle and inducement of the anagen phase, followed by proliferation and differentiation of the hair follicles. Epidermal growth factor receptor inhibitors have been developed as therapeutic molecules directed against cancer; in these regimens the knowledge of EGF receptor signaling functions has been translated into significant clinical results. However, among their various collateral effects on the skin, hair growth is observed to occur in certain patients. A particular "wavy" hair phenotype is observed during the pharmacological EGFR receptor blockade, just as in murine transgenic models that carry loss of function of TGF-alpha or EGFR genes. A better characterization of the individual roles pertaining to the EGF family ligands and receptors, has the potential provide new strategies for the management of hair loss.

Persistent hair growth during treatment with the EGFR inhibitor erlotinib.

Medications belonging to the group of epidermal growth factor (EGFR) inhibitors are currently in widespread use for the treatment of epithelial malignancies. Many cutaneous side effects are known to develop as a result of the use of these agents. Trichomegaly is a newly described side effect, consisting of premature maturation (terminal differentiation) of the hair of the eyelashes and the scalp, which is characterized by a hairy phenotype. Although occurrence of the acneiform skin rash is clearly associated with favorable tumor responses and improvement in patient survival during the use of EGFR inhibitors for the treatment of cancer, the significance of trichomegaly is less clear. A review of all published cases is provided, leading to the observation that trichomegaly also developed in patients whose tumors had a positive response to anti-EGFR therapy. The apparent lack of the development of tolerance to this medication effect and, therefore, the continued clinical sign of trichomegaly is in contrast to the time-limited nature of other cutaneous side effects of EGFR inhibitors, such as the classical papulo-pustular rash. The persistence of trichomegaly in some patients brings into question the precise mechanism of this phenomenon and suggests the possibility of using EGFR inhibition therapeutically to stimulate hair growth.

Keloid pathogenesis and treatment.

BACKGROUND: Keloid management can be difficult and frustrating, and the mechanisms underlying keloid formation are only partially understood. METHODS: Using original and current literature in this field, this comprehensive review presents the major concepts of keloid pathogenesis and the treatment options stemming from them. RESULTS: Mechanisms for keloid formation include alterations in growth factors, collagen turnover, tension alignment, and genetic and immunologic contributions. Treatment strategies for keloids include established (e.g., surgery, steroid, radiation) and experimental (e.g., interferon, 5-fluorouracil, retinoid) regimens. CONCLUSION: The scientific basis and empiric evidence supporting the use of various agents is presented. Combination therapy, using surgical excision followed by intradermal steroid or other adjuvant therapy, currently appears to be the most efficacious and safe current regimen for keloid management.

Important drug interactions and reactions in dermatology.

A constantly expanding pharmacological armamentarium increases the concern for serious drug interactions. This article discusses drug metabolism and how the cytochrome P-450 family facilitates drug biotransformation. Clinically significant drug interactions involving antifungal drugs, antibiotics, retinoids, and immunosuppressive agents, as well as topical anesthetics and various foods, are included.