Marc D. Brown

Merkel cell carcinoma

Merkel cell carcinoma is a malignant neuroendocrine tumor with features of epithelial differentiation. Biologically aggressive, it may be difficult to diagnose and, particularly in its late stages, even more difficult to treat effectively. This article addresses what is known and what is still controversial about the histogenesis, diagnosis, and management of Merkel cell carcinoma and the structure and function of the Merkel cell from which it is believed to be derived. The incidence, clinical presentation and diagnosis, ultrastructure, immunocytochemistry, treatment, and prognosis of this tumor will be discussed.

Cyclosporine for plaque-type psoriasis: Results of a multidose, double-blind trial

BACKGROUND Severe plaque-type psoriasis has been successfully treated with orally administered cyclosporine, but there has been no comparative, controlled evaluation of various dosages and their efficacy and side effects. METHODS In a 16-week, double-blind trial, we randomly assigned 85 patients with severe psoriasis to receive 3, 5, or 7.5 mg of cyclosporine per kilogram of body weight per day or a placebo consisting of the vehicle for the drug. After eight weeks the dose could be adjusted to improve safety or efficacy while maintaining blinding. RESULTS The psoriasis improved in a dose-dependent fashion. After eight weeks of fixed-dose therapy, 36, 65, and 80 percent of the patients receiving 3, 5, and 7.5 mg of cyclosporine per kilogram per day, respectively, were rated as being clear or almost clear of psoriasis; each group had significant improvement (P less than 0.0001) as compared with the group receiving vehicle, in which none of the patients were rated as clear or almost clear. The patients who received 5 mg per kilogram were the least likely to require dosage adjustments because of side effects or a lack of efficacy. The glomerular filtration rate, measured in a subgroup of 34 patients receiving cyclosporine, decreased by a median of 16 percent. Higher doses of cyclosporine had greater adverse effects on systolic blood pressure, glomerular filtration rate, and serum levels of creatinine, uric acid, bilirubin, and cholesterol. Delayed-type hypersensitivity reactions to skin-test antigens were reduced by cyclosporine administration. Cyclosporine appears to become concentrated in skin. CONCLUSIONS Cyclosporine therapy leads to a rapid and thorough clearing of psoriasis; an initial dose of 5 mg per kilogram per day seems to be appropriate. However, the safety of cyclosporine for the long-term treatment of psoriasis remains to be determined.

Skin cancer in solid organ transplant recipients: Advances in therapy and management: Part II. Management of skin cancer in solid organ transplant recipients

The management of skin cancer in solid organ transplant recipients is a challenge to both the dermatologist and transplant physician. Part II of this continuing medical education review offers an approach to the management of this increasing problem. The importance of specialty dermatology clinics providing access to transplant patients, frequent skin cancer screening, patient education, and multidisciplinary care is discussed. The management of low risk squamous cell carcinoma with topical therapies, photodynamic therapy, systemic retinoids, and capecitabine is reviewed. Revision of immunosuppression in the management of high-risk patients is discussed in association with the potential role of sentinel lymph node biopsy for aggressive disease. Finally, management of in-transit and metastatic squamous cell carcinoma is reviewed, with a discussion of the role of more recent innovative therapies, including epidermal growth factor receptor inhibitors in advanced squamous cell carcinoma in solid organ transplant recipients.

Cyclosporine in dermatology

Cyclosporine is a potent immunosuppressive agent with no appreciable effect on the bone marrow and a selective inhibitory effect on helper T cells. Oral cyclosporine was first used to prevent organ rejection but also has been reported to be effective in other disorders. In cutaneous diseases that respond to oral cyclosporine helper T cells appear to be involved in their pathogenesis. This article reviews the cutaneous diseases that have been treated with cyclosporine and its pharmacology and side effects. Two significant adverse side effects are renal dysfunction and hypertension, both of which are reversible when short-term low-dose (less than 5 mg/kg per day) oral cyclosporine is discontinued. Lymphoma is unlikely in an otherwise healthy patient who has received low-dose oral cyclosporine for limited periods. The use of oral cyclosporine in any patient should be carefully considered in terms of the risk/benefit ratio and needs to be carried out under close medical supervision. In view of the limited experience with cyclosporine in dermatology, whenever possible its use should be confined to formal clinical studies with established protocols and guidelines. Further controlled studies need to be performed to evaluate the efficacy of low-dose cyclosporine in many dermatoses and its side-effect profile, particularly over the long term.

Cyclosporine as maintenance therapy in patients with severe psoriasis

BACKGROUND Low-dose cyclosporine therapy for severe plaque psoriasis is effective. Most side effects can be controlled by patient monitoring, with appropriate dose adjustment or pharmacologic intervention, or both, if indicated. Prevention or reversibility of laboratory and chemical abnormalities may be achieved by discontinuation of therapy after the induction of clearing. However, relapse occurs rapidly on discontinuation. Maintenance therapy with cyclosporine after induction has not been fully evaluated. OBJECTIVE Our purpose was to compare a regimen of 3.0 mg/kg per day of oral cyclosporine with placebo in maintaining remission or improvement in patients with psoriasis. METHODS After a 16-week unblinded induction phase in which 181 patients received cyclosporine, 5.0 mg/kg per day (an increase up to 6.0 mg/kg per day and a decrease to 3.0 mg/kg per day were allowed, if required, to achieve efficacy or tolerability, respectively), those patients showing a 70% decrease or more in involved body surface area (BSA) entered the 24-week maintenance phase and were randomly assigned to either placebo, cyclosporine, 1.5 mg/kg per day, or cyclosporine, 3.0 mg/kg per day. Patients were considered to have had a relapse when BSA returned to 50% or more of the prestudy baseline value. Clinical efficacy, adverse effects, and laboratory values were monitored regularly throughout both study phases. RESULTS During induction, cyclosporine at approximately 5.0 mg/kg per day produced a reduction in BSA of 70% or more in 86% of the patients. During maintenance, the median time to relapse was 6 weeks in both the placebo and cyclosporine 1.5 mg/kg per day groups, but was longer than the 24-week maintenance period in the 3.0 mg/kg per day group (p < 0.001 vs placebo). By the end of the maintenance period, 42% of the patients in the 3.0 mg/kg per day cyclosporine group had a relapse compared with 84% in the placebo group. Changes in laboratory values associated with the higher induction dosage generally exhibited partial or complete return toward mean prestudy baseline values during the maintenance phase, with the greatest degree of normalization in the placebo group. CONCLUSION Cyclosporine, 3.0 mg/kg per day, adequately and safely maintained 58% of patients with psoriasis for a 6-month period after clearing of their psoriasis with doses of approximately 5.0 mg/kg per day.

Treatment of keratoacanthomas with intralesional methotrexate

Multiple modalities exist for the treatment of keratoacanthoma. Excisional surgery is currently the treatment of choice for the majority of keratoacanthomas. This can result in functional and cosmetic defects when large or strategically located lesions are treated. An effective nonsurgical treatment would be desirable in such cases. Intralesional therapy, particularly with 5-fluorouracil, has been shown to be effective in the treatment of keratoacanthomas. Systemic methotrexate has been tried, with variable success. We report an open, noncontrolled study of nine consecutive patients with unusually large or strategically located solitary keratoacanthomas treated successfully with intralesional methotrexate. All lesions responded promptly, with complete resolution after a mean of 3.0 weeks and a mean of 1.7 injections. No side effects occurred, and scarring was minimal. We concluded that intralesional methotrexate is a simple and effective modality for the treatment of select keratoacanthomas and may offer greater efficacy, a more rapid response, decreased pain, and lower cost compared with intralesional 5-fluorouracil.

Genital tumors: Their management by micrographic surgery

Genital tumors represent a special group requiring effective and curative treatment while functional and cosmetic demands require tissue sparing techniques. For these reasons, micrographic surgery is indicated. Over the past 5 years we have treated 24 such patients utilizing standard techniques for micrographic surgery. The patient population included twenty male and four female patients with ages ranging from 27 to 80 years. Histologically confirmed diagnoses included squamous cell carcinoma, Bowens disease, verrucous carcinoma, basal cell carcinoma, Pagets disease, and leiomyosarcoma. These were located on the penis, scrotum, perineum, and buttocks. Seven of these patients were considered to have recurrent tumors. Preexisting conditions existed in 6 patients, including balantis xerotica obliterans, trauma, decubitus ulcer, and hidradenitis suppurativa. All surgery was performed under local anesthesia in the cutaneous surgery unit. Average pretreatment tumor size was 2.0 X 1.9 cm. Average postoperative defect size was 4.5 X 3.7 cm. Tumors were excised with an average of three stages and 18 sections. Most defects (65%) were allowed to heal by secondary intention, five (21%) were closed primarily, and three were referred for closure. After surgery five patients developed metastases in their regional lymphatic system. No patients developed local recurrence. Micrographic surgery is a most useful treatment modality in patients with genital tumors for control of local disease. However, patients with squamous cell carcinoma should be considered for elective regional lymph node biopsy and/or dissection in conjunction with micrographically controlled excision of the primary tumor.

Tanning and cutaneous malignancy.

BACKGROUND Exposure to ultraviolet radiation (UVR) results in a darkening of the skin known as tanning. Recently, it has been shown that tanning is a response to UVR-induced DNA damage and represents the skins efforts to protect itself against further injury. Despite the link between UVR and cutaneous malignancy, people continue to pursue tanning from natural and artificial sources. This trend is reflected in the exponential rise in skin cancer incidence. OBJECTIVE The objective of this study was to review our current understanding of the factors controlling the tanning response and the relationship to cutaneous carcinogenesis, as well as the impact that the multibillion dollar tanning industry has had on the practice of dermatology. MATERIALS AND METHODS Extensive literature review was conducted in subjects related to tanning and the relationship to cutaneous malignancy. RESULTS Our knowledge of tanning and its effects on the skin has increased tremendously. It is clear that tanning contributes to the development of skin cancer. Despite this information, the incidence of skin cancer continues to increase exponentially. CONCLUSIONS Skin cancer poses a major public health concern and tanning remains the most modifiable risk factor in its etiology. Social, economic, and legislative issues have become tightly intertwined with the complex nature of human behavior in the continued pursuit of an activity that clearly has detrimental effects on ones health.

Immediate intraoperative tissue expansion.

We report a modification of the controlled tissue expansion technique, that is, immediate intraoperative tissue expansion. The procedure is performed by placing tissue expanders at the time of surgery. After placement, three to four cycles of inflation/deflation of the expander for 3 to 5 minutes are performed. In a one-stage procedure the stretched skin is then immediately used to close the surgical defect. Three case reports demonstrating the immediate intraoperative tissue expansion technique, in which the Foley catheter balloon was used as the tissue expander, are presented. These cases illustrate that this technique may allow the surgeon to cover defects more easily with less tension and with a better cosmetic result than with other closure techniques.

Constitutive absence and interferon-γ-induced expression of adhesion molecules in basal cell carcinoma

Adhesion of lymphocytes to target cells via certain cell surface molecules is important in cytotoxic T lymphocyte-mediated immune reactions. The binding of lymphocyte function-associated (LFA) antigens 1 and 2, with their respective ligands, intercellular adhesion molecule-1 (ICAM-1) and LFA-3, which are expressed on the surface of nonlymphoid cells, has been shown to be critical for lymphocyte adhesion. To determine whether basal cell carcinomas (BCCs) can escape immunodetection as a result of the inability of cytotoxic T lymphocytes to bind tumor cells, the expression of adhesion molecules on numerous BCCs, before and after exposure to interferon-gamma (IFN-gamma), was examined. Ninety-three percent of 30 freshly excised invasive BCCs did not express ICAM-1 and 73% of 11 BCCs did not express LFA-3. However, the normal-appearing basal keratinocytes in epidermis overlying nests of BCC, did express ICAM-1, particularly when a marked LFA-1+ and LFA-2+ dermal lymphocytic infiltrate was present. After BCC tissue was incubated in vitro with IFN-gamma the expression of ICAM-1 was induced on 85% of tumors studied. Thus tumor cells did not possess an absolute inability to express adhesion molecules; rather the constitutive absence of such molecules may be due to insufficient in vivo cytokine levels necessary to induce expression or a barrier preventing cytokines from reaching and interacting with tumor cells. We conclude that the absence of ICAM-1 and LFA-3 adhesion molecules is a mechanism by which BCCs can avoid immunosurveillance.