Evidence- and consensus-based (S3) Guidelines for the Treatment of Actinic Keratosis - International League of Dermatological Societies in cooperation with the European Dermatology Forum - Short version.

BACKGROUND: Actinic keratosis (AK) is a frequent health condition attributable to chronic exposure to ultraviolet radiation. Several treatment options are available and evidence based guidelines are missing. OBJECTIVES: The goal of these evidence- and consensus-based guidelines was the development of treatment recommendations appropriate for different subgroups of patients presenting with AK. A secondary aim of these guidelines was the implementation of knowledge relating to the clinical background of AK, including consensus-based recommendations for the histopathological definition, diagnosis and the assessment of patients. METHODS: The guidelines development followed a pre-defined and structured process. For the underlying systematic literature review of interventions for AK, the methodology suggested by the Cochrane Handbook for Systematic Reviews of Interventions, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was adapted. All recommendations were consented during a consensus conference using a formal consensus methodology. Strength of recommendations was expressed based on the GRADE approach. If expert opinion without external evidence was incorporated into the reasoning for making a certain recommendation, the rationale was provided. The Guidelines underwent open public review and approval by the commissioning societies. RESULTS: Various interventions for the treatment of AK have been assessed for their efficacy. The consenting procedure led to a treatment algorithm as shown in the guidelines document. Based on expert consensus, the present guidelines present recommendations on the classification of patients, diagnosis and histopathological definition of AK. Details on the methods and results of the systematic literature review and guideline development process have been published separately. CONCLUSIONS: International guidelines are intended to be adapted to national or regional circumstances (regulatory approval, availability and reimbursement of treatments).

Decreased urinary polyamines in patients with psoriasis treated with etretinate.

Oral administration of the aromatic retinoid etretinate is effective therapy for psoriasis and other epidermal hyperproliferative disorders. Since polyamine metabolism is known to be important in cell growth and differentiation, we measured urinary levels of the polyamines putrescine, spermidine, and spermine as a reflection of cutaneous polyamine metabolism in 19 psoriatic patients treated with etretinate for 16 weeks. Using thin-layer chromatography, polyamine determinations were performed on urine collected pretherapy, during therapy, and 8 weeks after therapy was concluded. Good to excellent clearing of psoriasis occurred in 18 of 19 patients. All urinary polyamines showed a downward trend in the first week of therapy, prior to significant clinical improvement. At week 16 of therapy, the greatest reduction in mean urinary polyamine content occurred. Mean putrescine levels decreased from pretherapy to week 16 by 27% (p less than 0.001), mean spermidine values fell by 34% (p less than 0.001), and mean spermine levels declined by 37% (p = 0.005). These data are consistent with the hypothesis that etretinate inhibits polyamine biosynthesis.

Complete microscopic controlled surgery for head and neck cancer.

Mohs surgery, as it has evolved since its inception by Mohs, is a technique for removing certain cancers using careful, precise microscopic marginal control. The contemporary technique using fresh tissue has enabled the application of Mohs surgery to the treatment of malignancies of the upper aerodigestive tract. Mohs surgery, once limited to large recurrent basal cell carcinomas, has expanded to include several cutaneous and noncutaneous neoplasms. With better understanding of the Mohs technique, its indications, applications, and advantages, an interdisciplinary approach to manage certain head and neck neoplasms is proposed.

Mohs surgery: techniques, indications, and applications in head and neck surgery.

Mohs surgery, as it has evolved since its inception by Dr. Mohs, is a technique for removal of certain cancers using careful, precise microscopic marginal control. The contemporary technique using fresh tissue is detailed, illustrating advantages that include maximal conservation of normal surrounding tissue and structures, an extremely high cure rate, and a tumor-free defect which can be reconstructed immediately. The indications and applications for Mohs surgery, once limited to large recurrent basal cell carcinomas, have expanded to include several cutaneous and paracutaneous neoplasms. These, with an emphasis on certain basal cell carcinomas, are discussed in detail. With better understanding of the Mohs technique, its indications, applications, and advantages, an interdisciplinary approach to certain cutaneous and paracutaneous neoplasms is proposed.

Mohs surgery. Technique, indications, applications, and the future.

Each year, it is estimated, more than 500,000 new cases of nonmelanoma skin cancer develop. The majority of these cutaneous neoplasms are treated by various modalities that include excision, electrodesiccation and curettage, cryosurgery, and irradiation, with greater than 90% success. Certain of the remaining primary tumors, as well as recurrent carcinomas, present a demanding therapeutic challenge. For these lesions, Mohs surgery has evolved as the most reliable and cost-effective treatment modality, offering maximal preservation of normal tissue and therefore the lowest functional and cosmetic morbidity. In this review, the history and evolution of Mohs surgery and the technique itself will be briefly outlined. The indications for Mohs surgery, together with methods of handling the postoperative wound and future applications of the technique, will be discussed in detail.

Plantar verrucous carcinoma. Literature review and treatment by the Mohs' chemosurgery technique.

Verrucous carcinoma, a variant of squamous cell carcinoma, is recognized as a distinct clinicopathologic entity. It occurs principally in three anatomic sites: panoral, genitogluteal, and plantar. Two cases of plantar verrucous carcinoma treated by the Mohs' chemosurgery technique are reported, and the literature is reviewed. The clinical and pathologic appearance of these lesions make them recognizable in a patient with a persistent plantar lesion usually diagnosed as a wart but unresponsive to conventional therapy. The role of irradiation, a possible viral etiology of the tumor, and the necessity for a deep biopsy are discussed. Because these tumors are characterized by extensive local growth, Mohs' chemosurgery is proposed as the treatment of choice. In this way, total tumor ablation is obtained with maximum preservation of normal tissue structure and function.

Phenol alcohol technique for permanent matricectomy.

A simple technique for partial or complete destruction of the nail matrix with the use of phenol alcohol is outlined. A retrospective analysis of 30 random patients suggests that it has a low morbidity, is easy to perform, and has a high success rate. Therefore, it offers an excellent option to cold steel surgery, especially for the nonsurgically oriented dermatologist.

Intradermal implantation of bovine collagen. Humoral immune responses associated with clinical reactions.

A special collagen implant (Zyderm) (ZCI) is a biomaterial used for the correction of dermal contour deformities. Although infrequent, reactions believed to be of an immunologic nature have followed treatment. To investigate whether humoral immunity is associated with these reactions, we studied 40 patients for the presence of anti-ZCI antibodies using an enzyme-linked immunosorbent assay. Ten patients who had had adverse treatment reactions uniformly exhibited circulating anti-ZCI antibodies. Twenty-nine of 30 control patients, including nine who had received ZCI without adverse reaction, failed to produce the high levels of antibodies found in all clinical reactors. This difference was statistically significant. Additional investigations confirmed that the antibodies studied were directed primarily against the bovine collagen component of the ZCI. These data suggest that the humoral immune system is capable of recognizing ZCI and that the presence of antibodies to the ZCI correlates with the occurrence of adverse reactions.

Arachidonic acid metabolites in cutaneous carcinomas. Evidence suggesting that elevated levels of prostaglandins in basal cell carcinomas are associated with an aggressive growth pattern.

There is evidence suggesting a role of eicosanoids in the growth of certain tumors. In this study, tissue samples were collected from basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) of the skin. Both BCCs and SCCs contained more prostaglandin E2 and F2 alpha (PGE2 and PGF2 alpha) than normal epidermis. In vitro incubation of tumor samples with arachidonic acid also resulted in PGE2 and PGF2 alpha formation. Basal cell carcinomas exhibiting a histologically aggressive growth pattern contained higher levels of prostaglandins than those with a nonaggressive growth pattern, both in vivo and after in vitro incubation. Lipoxygenase products (12- and 15-hydroxyeicosatetraenoic acid) were present in smaller amounts than cyclo-oxygenase products (PGE2 and PGF2 alpha) in vivo. Compared with normal epidermis, SCCs and, particularly, BCCs produced smaller amounts of 12-hydroxyeicosatetraenoic acid during in vitro incubation with arachidonic acid. The levels of lipoxygenase products were not related to the tumor growth pattern. These results indicate that excessive prostaglandin levels in BCCs may be associated with an aggressive growth pattern.

Aggressive-growth basal cell carcinoma in young adults.

Aggressive-growth basal cell carcinoma (AG-BCC) defines a group of basal cell cancers that are histologically and clinically aggressive. This group includes morpheaform, infiltrating, and recurrent BCCs. Because of the clinical observation that the incidence of AG-BCC may be increased in patients under 35 years of age, compared with those older, we performed a retrospective study. We reviewed the pathologic findings of 3381 patients diagnosed with BCC, including 102 patients with BCC referred for Mohs surgery to determine whether AG-BCC occurs with increased frequency in patients younger than than 35 years of age. Among patients under 35 years of age, 38% of women had AG-BCC compared with 9% of women in the older age group. Similarly, 25% of men under 35 years of age had AG-BCC compared with 11% among men in the older age group. Aggressive-growth BCC is more frequently noted in patients under 35 years of age than in those older. Failure to diagnose this type of BCC, which may be clinically subtle, may lead to incomplete or inadequate treatment. Because of the tendency of these tumors to recur, greater long-term morbidity may result.

Topical treatment of alopecia areata.

It has been shown previously that alopecia areata can be treated with dinitrochlorobenzene (DNCB) and other contact allergens. Whether these agents work by inducing immunologic stimulation or simply a nonspecific inflammatory reaction has not been definitively demonstrated. To test the relative importance of these two mechanisms, we have randomly studied 22 patients with alopecia areata to whom either DNCB or croton oil was applied topically. Sixty-three percent of patients without spontaneous regrowth of hair regrew hair after DNCB application. None of those treated with croton oil regrew hair when treated later with DNCB. Therefore, a proved contact allergen was shown to be required for therapeutic success. Patient acceptance of the induced contact dermatitis was excellent. In light of recent data on the mutagenicity of DNCB to bacteria, other contact allergens for topical immunotherapy are being sought.

Etretinate therapy causes increases in lipid levels in patients with psoriasis.

We investigated changes in serum triglyceride, cholesterol, and high-density lipoprotein cholesterol (HDLC) levels during etretinate administration in 21 patients with psoriasis. Mean serum triglyceride and cholesterol values showed a statistically significant increase during etretinate therapy compared with placebo treatment; mean HDLC levels did not change. During etretinate therapy, elevations out of the normal range occurred in 77% of the patients for serum triglycerides and 25% for serum cholesterol. Eight weeks after discontinuation of the drug regimen, patients' mean serum triglyceride and cholesterol levels were not statistically different from those found prior to therapy. Nevertheless, eight weeks after therapy had been stopped, six (32%) of 19 patients had cholesterol values that were still 20% or more above their baseline levels; the prolonged etretinate excretion time could have been responsible. The mechanisms for the etretinate-induced lipid elevations are unknown.

Characterization of the humoral immune response to bovine collagen implants.

The use of bovine collagen implants (BCIs) for the correction of dermal contour deformities is becoming widespread. A small percentage of patients receiving treatment with BCIs suffer adverse reactions that appear to be of an immune nature. Circulating antibodies to BCIs are found in all patients suffering adverse treatment reactions and in small numbers of normal individuals and BCI-treated patients not suffering adverse reactions. These antibodies are always IgG, although quite often IgA is also present. The anti-BCI antibodies are quite stable, suffering virtually no loss of activity after storage at room temperature for 54 days. Immunoblotting studies indicate that no singular component of the BCI collagen is the prime antigenic component; multiple regions of the collagen molecule are recognized by patients' antibodies.

The association of HLA and immune responses to bovine collagen implants.

The HLA type of patients with various kinds of immune reactions to bovine collagen implants were evaluated to determine a possible genetic basis for such responses. All patients suffering adverse clinical reactions to bovine collagen implants were lacking the HLA-DR4 antigen. All patients who received multiple bovine collagen injections without having adverse clinical reactions were lacking HLA-B5 and HLA-DR5 and had a significantly increased incidence of HLA-DR4. Combinations of histocompatibility antigens may influence immune response to bovine collagen implants.

Tissue expansion.

Controlled tissue expansion began as a concept based on primitive ideas and observations. Its application to breast reconstruction has played a major role in the tissue and psychologic rejuvenation following surgery for breast carcinoma. During the last several years, controlled expansion of tissue has been applied to many other anatomic sites treating many difficult reconstructive and excisional surgeries which heretofore were either impossible or required several stages to accomplish. As experience has grown, the use of tissue expansion has become safer and has been applied to many excisional and reconstructive efforts. The future use of tissue expansion is extremely bright and limited only by the creativity of the surgeon familiar with the technique. In the future, under study is controlled expansion of bone, of nerves, and of other body parts that may prove to be valuable in the surgeon's armamentarium. The dermatologic surgeon should become familiar with the concept and practice of tissue expansion, whether or not it is used in his or her practice. By being familiar with what the reconstructive surgeon can do with tissue expansion, the dermatologist can treat entities perhaps not otherwise treated in the past. For the dermatologist experienced in cutaneous surgery, tissue expansion can be added to his armamentarium in the treatment of male pattern baldness, some local flaps, congenital nevi and larger excisions requiring serial excision in the past as well as tattoos.

Clinical applications of tissue expansion in head and neck surgery.

Tissue expansion offers a new frontier in head and neck reconstruction in that it provides the capability of creating additional new skin for restoration of defects with skin of identical color, thickness, and appendages. The applicability of tissue expansion is only beginning to be appreciated as it is used in various aspects of head and neck surgery. Currently, the technique is most frequently used in scalp surgery for correction of male pattern baldness. Other uses of tissue expansion are in cranial facial surgery and expansion of distant, regional, or microsurgical flaps. Perhaps its greatest value from a reconstructive perspective, however, is in providing new skin for reconstruction of various facial defects through the use of primary wound closure or a multitude of local flaps.

Local control of auricular, periauricular, and external canal cutaneous malignancies with Mohs surgery.

Three hundred ninety-seven patients with 407 cutaneous malignancies of the auricle, periauricular region, and cartilaginous external ear canal were reviewed. Tumors were most commonly located in the preauricular and postauricular regions, followed by the helix, concha, antihelix, and ear canal. All lesions were excised with Mohs microscopic control of margins. For lesions requiring lateral temporal bone resection, an adaptation of fresh-tissue microscopic control was used to analyze deep and anterior margins suspected of harboring residual tumor. Two-year minimum follow-up of 229 patients with periauricular and auricular tumors (N = 231 tumors) and 14 patients with cartilaginous ear canal tumors (N = 14 tumors) revealed recurrence rates of 6.9% and 14.3%, respectively. Recurrences were most common in cases of large tumors (greater than 2.5 cm), basal cell carcinomas with morphea elements, and multiply recurrent lesions. We conclude that Mohs surgery is comparatively effective, though not uniformly curative, and can be adapted to supplement excision of large tumors in these regions.

Rapid intraoperative tissue expansion in reconstruction of the head and neck.

A prolonged tissue expansion has the advantage of creating large amounts of additional skin for reconstructing cutaneous defects that might not be possible without the use of multiple, regional, distant, or microsurgical flaps. In spite of this, there are disadvantages, many of which can be circumvented by the use of rapid intraoperative tissue expansion instead. Although rapid expansion does not increase skin surface area as much as prolonged expansion, it may be helpful in assisting with closure of defects that might otherwise be problematic.

Tissue expansion of the head and neck. Indications, technique, and complications.

Tissue expansion is indicated in the reconstruction of various defects of the head and neck in instances where there is inadequate adjacent tissue to allow either primary closure of the defect or repair with a local flap. It may also be indicated in instances where repair of a defect by an alternative method such as a local, regional, or distant flap will result in an unacceptable donor or recipient site deformity. Although tissue expansion is simplistic in concept, it does require judgment and indepth preoperative planning to ensure optimal results. The complication rate is high for tissue expansion in the head and neck, particularly in the cheek and neck area. Despite the frequency of complications, in the vast majority of cases the intended reconstruction is successful.