In situ photoimmunotherapy: a tumour-directed treatment for melanoma.

We report a new immunological treatment for advanced cutaneous melanoma which combines laser stimulation with topical application of a toll-like receptor agonist. This treatment, in situ photoimmunotherapy (ISPI), provides an alternative to traditional therapies for melanoma patients with cutaneous metastases. A 6-week cycle of ISPI is carried out on cutaneous metastases located in a designated 20 x 20 cm treatment area: 2 weeks of pretreatment with twice-daily topical applications of imiquimod (5% cream under plastic occlusion), with a laser treatment session at week 2 and again at week 4. Topical imiquimod is continued for the entire 6-week cycle. Two patients with late-stage melanoma were treated with ISPI. Patient 1 had the primary tumour and local metastases on the left arm, as well as metastatic tumours in the lungs [American Joint Committee on Cancer (AJCC) stage IV]. Patient 2 had a head and neck melanoma with multiple local metastases (AJCC stage IIIC), which had failed repeated attempts at surgical resection and high-dose radiation therapy. Patient 1 is now free of all clinically detectable tumours (including the lung metastases) >20 months after the first treatment cycle. Patient 2 has been free of any clinical evidence of the tumour for over 6 months. These two cases demonstrate that ISPI can clear local tumour and trigger beneficial systemic responses, with a side-effect profile that compares favourably with other treatments for advanced melanoma.

Treatment of lentigo maligna with topical imiquimod.

A published case report and anecdotal experience suggested that topical imiquimod is an effective treatment for stage 0 melanoma (lentigo maligna). To gauge the efficacy of this therapy, we undertook a trial of topical imiquimod in 30 subjects with histologically confirmed lentigo maligna. Thirty subjects with lentigo maligna were recruited for an open-labelled efficacy trial with daily topical application of imiquimod 5% cream for 3 months. Study subjects were enrolled from the Dermatology service of the University of Oklahoma, the Oklahoma City Veteran's Administration Hospital Dermatology service and from referrals for the study from other practitioners. In order to determine an initial response rate, a four-quadrant biopsy was carried out on all patients 1 month after cessation of treatment, targeting the most clinically and dermatoscopically suspicious areas. Of 28 evaluable subjects who have completed the 3-month treatment phase, 26 (93%) were complete responders and two were treatment failures at the time of the 4-quadrant biopsy. Over 80% of the 28 subjects that completed treatment have been followed for more than 1 year with no relapses. The results of this study demonstrate that topical imiquimod produces a high complete response rate in lentigo maligna when applied daily for 3 months.

Reliability of counting actinic keratoses before and after brief consensus discussion: the VA topical tretinoin chemoprevention (VATTC) trial.

OBJECTIVE: To assess the reliability of counts of actinic keratoses (AKs) and the effect of a brief joint discussion of discrepancies on that reliability. DESIGN AND INTERVENTION: Seven dermatologists independently counted AKs on the face and ears before and after a brief joint discussion of discrepancies. SETTING AND PATIENTS: A volunteer sample of 9 patients from the ongoing VA (Department of Veterans Affairs) Topical Tretinoin Chemoprevention (VATTC) Trial. All participating individuals are veterans and have had 2 or more keratinocyte carcinomas (basal or squamous cell carcinoma) in the 5 years before enrollment in the study. MAIN OUTCOME MEASURE: Standard deviation of estimates of the Poisson regression parameter for the dermatologists. RESULTS: Substantial variation was found among the dermatologists in their AK counts. The SD of the parameter estimates for the dermatologists decreased from 0.45 to 0.24 after the brief joint discussion, a 47% decrease (P =.076). The variation attributable to the dermatologists also decreased substantially (chi(2)(6) decrease, 94 to 12). CONCLUSIONS: Actinic keratoses are common, and there is a continuous spectrum of lesions that ranges from sun-damaged skin to squamous cell carcinoma in situ. Clinical distinguishing features may be difficult to delineate precisely. Counts of AK are commonly performed, but appear to be unreliable, even when performed by experienced dermatologists. Joint discussion of discrepancies may enhance the reliability of these counts, although substantial variation remains. Research that relied on these counts must be reevaluated in light of the marked variation among expert observers. Future studies should consider measures to assess and enhance reliability.

Melanoma vaccines.

Melanoma vaccines are the best near term hope for improving mortality in patients with advanced disease. Although these vaccines are being developed for treatment of patients with advanced disease, their relatively low toxicity make them attractive for adjuvant therapy in stage I patients at high risk for recurrence. Recent developments in melanoma vaccines are reviewed and their importance to dermatologists is emphasized.

Noninvasive methods of diagnosing thoracic splenosis.

Thoracic splenosis is a rare condition resulting from concomitant rupture of the spleen and left hemidiaphragm, with autotransplantation of splenic tissue into the left hemithorax. It is usually an incidental finding on chest plain film or computed tomogram and is rarely diagnosed without biopsy or operation. A history of old splenic trauma and findings of left-sided, pleural-based nodules should indicate the diagnosis, which can be confirmed with nuclear medicine studies.

The role of human papillomavirus in the development of pyogenic granulomas.

BACKGROUND: Pyogenic granulomas (lobular capillary hemangiomas) and condyloma acuminata share similar locations and risk factors. Human papillomavirus (HPV) types 6 and 11 are commonly associated with condyloma acuminata, but their association with pyogenic granulomas has not been evaluated. The purpose of this study was to determine whether pyogenic granulomas contain evidence of infection with condyloma-producing HPVs. METHODS: Polymerase chain reaction assays for the E6 and E7 gene sequences of HPV types 6 and 11 and another assay for the E7 region of HPV types 16, 31, 33, 35, 42, and 58 were used to evaluate deoxyribonucleic acid (DNA) extracted from archival pyogenic granuloma biopsies taken from cutaneous and oral epithelium. RESULTS: Neither cutaneous nor oral pyogenic granulomas contain amplifiable E6 or E7 sequences from any of these viruses. CONCLUSIONS: Pyogenic granulomas are not caused by HPV 6, 11, 16, 31, 33, 35, 42, or 58. This study does not exclude the possibility that other viruses may be responsible for these tumors.

The case for sunscreens. A review of their use in preventing actinic damage and neoplasia.

BACKGROUND: Recent controversy surrounding sunscreens has stimulated a reexamination of their use. The purposes of this article are to weigh the evidence regarding the value of sunscreens in preventing actinic damage and neoplasia and to evaluate the merit of objections that have been raised against their use for this purpose. Scientific aspects of damage from UV light, neoplasia, and sunscreens are reviewed. The value of sunscreen use in preventing actinic damage is discussed and a number of sunscreen controversies are revisited. OBSERVATIONS: The evidence favors the safety and efficacy of sunscreens for the prevention of actinic damage, melanoma, and nonmelanoma skin cancer. CONCLUSION: Sunscreens continue to be a practical and useful tool for the prevention of actinic damage and neoplasia.

Erythema, skin cancer risk, and sunscreens.

Ultraviolet-induced erythema is now recognized as an important clinical marker for skin cancer risk. People with a history of repeated erythematous exposures to sunlight are more likely to develop both melanoma and nonmelanoma skin cancers. Is erythema the most important thing we need to be concerned about in terms of protecting the public from the harmful effects of sunlight? What do we know about UV-induced erythema, and why is it a powerful influence on skin cancer risk?

9p21 deletions in primary melanoma.

Formalin-fixed, paraffin-embedded primary melanoma biopsies were evaluated for evidence of genomic loss on the short arm of chromosome 9 using microsatellite PCR assays for the D9S157, D9S161 and D9S171 loci. Paired normal and tumor DNA was extracted from the same block for comparison of microsatellite marker patterns. Some detectable abnormality was seen in at least one of these loci in 15 of 44 evaluable specimens (34%). Homozygous deletions were detectable at these loci in 8 of 44 informative specimens (18%) and hemizygous deletions were seen in 11 of 44 informative specimens (25%). Deletions at 9p were more likely to be found as primary tumor thickness increased (p < 0.05). This evidence supports the concept that 9p21 deletions are involved in primary sporadic melanomas, and that 9p deletions are not solely an in vitro phenomenon.

Absence of Epstein-Barr virus in lymphoepitheliomalike carcinoma of the skin. Polymerase chain reaction evidence and review of five cases.

Lymphoepithelioma is a lymphocyte-rich, poorly differentiated, nonkeratinizing carcinoma of the nasopharynx with distinctive clinical, epidemiologic, and etiologic features. Histologically and immunophenotypically identical tumors arising outside the nasopharynx are designated lymphoepitheliomalike carcinomas (LELCs), and have been described in the gastrointestinal tract, lung, salivary glands, thymus, and increasingly in the skin. Despite similarities between LELC and nasopharyngeal lymphoepithelioma, there is growing evidence that they are etiologically distinct. Serologic studies and molecular techniques have consistently demonstrated an etiopathologic association between Epstein-Barr virus (EBV) and lymphoepithelioma and LELC of several locations, including stomach, salivary gland, lung, and thymus. Though histologically similar. lymphoepitheliomalike carcinoma of the skin (LELCS) does not contain EBV DNA by RNA in situ hybridization. Recently, techniques for polymerase chain reaction (PCR) using fixed tissue have been described that to our knowledge have not been applied to LELCS. We studied five cases of LELCS, taking advantage of the higher sensitivity of PCR to evaluate the role, if any, of EBV specifically in the pathogenesis of LELCS.

Elastofibroma dorsi: radiologic findings in 12 patients.

OBJECTIVE: We report radiologic findings in 12 patients with elastofibroma dorsi to heighten radiologist awareness of the imaging characteristics of these benign, often asymptomatic lesions. Because these lesions can usually be diagnosed on the basis of their imaging characteristics, increased awareness of these characteristics will decrease misdiagnosis of these lesions as malignancies and avoid unnecessary biopsies and surgeries. MATERIALS AND METHODS: We retrospectively reviewed the radiology and pathology of nine patients with surgically excised elastofibromas and the radiology of three patients with radiologically diagnosed elastofibromas. RESULTS: Twenty-one elastofibromas were imaged in 12 patients. Female-to-male ratio was 5:1; mean age was 65 years old. Of the nine patients in whom both sides of the chest wall were imaged, all (100%) had bilateral elastofibromas. Nineteen elastofibromas (90%) had the typical CT and MR appearances described in the literature: a poorly circumscribed, heterogeneous soft-tissue mass, with tissue of attenuation or signal intensity similar to that of skeletal muscle interlaced with strands of fat. One elastofibroma imaged twice over a 4-year period showed interval growth. All elastofibromas were sub- or infrascapular or in both locations. Of the 21 elastofibromas imaged, only four were perceived by the initial interpreting radiologist, and of these, only one was correctly diagnosed. CONCLUSION: Our study shows that many radiologists may not be aware of the diagnosis of elastofibroma, as few of the cases in our series were perceived or correctly diagnosed by the interpreting radiologist. Our cases show many of the classic findings of elastofibromas described in the literature. In addition, our series shows that elastofibromas are commonly bilateral, a feature that has not been strongly emphasized in the literature but one that is helpful in making the radiologic diagnosis. The finding of a similar contralateral lesion, when present, virtually eliminates malignancy from the differential diagnosis and further supports the presumptive diagnosis of elastofibromas. Increased awareness of the characteristic appearance and location of these benign, often asymptomatic lesions will increase radiologic diagnosis, decrease the need for biopsy, and decrease surgical removal of elastofibromas as presumed malignancies.

Sun exposure, sunscreens, and skin cancer prevention: a year-round concern.

OBJECTIVE: To review the role of sunlight in skin aging and skin cancer formation, and to provide guidelines on the use of sunscreens to minimize the adverse effects of sun damage. DATA SOURCES: A MEDLINE search of applicable articles on ultraviolet (UV) radiation, melanoma, sunscreens, and skin cancer, evaluating both human and animal studies. Published and unpublished original research as well as clinical experience were also used. DATA SYNTHESIS: The interaction of UV radiation and skin type plays a central role in melanoma formation. Mortality from melanoma is highest in geographic locations near the equator, where UV intensity is greatest. The incidence of melanomas in light-complected individuals (skin types I-III) is several times higher than those with darker skin types (types IV-VI), even in similar geographic regions. The UVB portion of the spectrum appears to be primarily responsible for skin cancer formation and photoaging, while short wave UVA rays play a significant contributing role. Regular sunscreen use has been shown to reduce the formation of precancerous actinic keratoses (AK) lesions by 36%. A dose-response relationship has also been found between the amount of sunscreen used and AK formation. CONCLUSIONS: Sunscreens have now been shown to reduce the carcinogenic effects of sunlight in humans. Patients should be advised of the long-term consequences of sun exposure and the benefits of regular sunscreen use.

Involvement of the p16INK4 (CDKN2) gene in familial melanoma.

Recent work on the molecular genetics of familial melanoma has suggested that the p16 kinase inhibitor gene (CDKN2) is one of the genes causing familial melanoma. Evidence for the candidacy of the p16 gene as a familial melanoma gene is summarized and the characteristics of this class of cell cycle control proteins are reviewed.

Rathke cleft cyst: CT, MR, and pathology of 23 cases.

OBJECTIVE: We report the radiologic findings in 23 cases of Rathke cleft cyst (RCC) and correlate them with the histopathology. MATERIALS AND METHODS: We reviewed the radiology and pathology of 23 cases of surgically treated RCC operated upon at our institution or referred in consultation. RESULTS: There appears to be a correlation between the MR and CT appearance of the cyst, the gross appearance of the cyst contents, and the histopathologic characteristics of the cyst lining. Some of the lesions demonstrated peripheral enhancement, which in two cases was clearly due to a peripherally displaced rim of pituitary tissue. CONCLUSION: The appearance of RCC with CT and MRI is variable, and radiologic diagnosis can be difficult. Imaging features such as a sellar epicenter, smooth contour, absence of calcification, absence of internal enhancement, and homogeneous attenuation or signal intensity within the lesion suggest the diagnosis of RCC. Rim enhancement does not correlate with the presence of squamous metaplasia, hemosiderin, or cholesterol within the cyst wall and is not consistently seen in cases with changes of mild, chronic inflammation. In some cases, rim enhancement is due to a peripherally displaced rim of pituitary tissue.

Barium studies in esophageal cicatricial pemphigoid.

BACKGROUND: Cicatricial pemphigoid (CP) (benign mucous membrane pemphigoid) is a rare, blistering disease of skin and mucous membrane. The disease rarely extends to involve the esophagus, and there are only a few cases reported in the radiological literature. The aims of this study were to document the frequency of esophageal involvement and to describe the findings on upper GI barium studies. METHODS: A total of 197 patients with CP were seen at our institution from 1981 to 1991. The clinical and radiological findings of these patients were reviewed and compared with findings reported in the literature. RESULTS: Esophageal involvement was documented in seven patients. Cervical esophageal webs were found in five of the seven patients. Two patients had single esophageal webs while three had multiple webs. Frank strictures of the esophagus were also seen in five patients. These were most common in the cervical esophagus, but strictures were also found in the mid and lower esophagus. Two of the strictures resulted in significant dysphagia and required multiple endoscopic dilatations. One of the dilatations was complicated by mucosal injury, and follow-up barium examination showed dissection of the esophageal mucosa from the cervical esophagus to the esophagogastric junction. One patient demonstrated intramural pseudodiverticulosis in the cervical esophagus. Functional disturbances demonstrated on barium studies included tracheal aspiration in two patients and nasopharyngeal reflux in three. CONCLUSIONS: CP involves the esophagus in approximately 5% of cases. The hypopharynx and cervical esophagus are most commonly involved, but any portion of the esophagus may be involved, and multiple levels of involvement may be seen. Cervical esophageal webs, often multiple or complex, are the most common appearance on barium studies, but frank strictures are also found. Secondary manifestations of esophageal involvement include nasopharyngeal reflux, tracheal aspiration, and intramural pseudodiverticulosis.

High sun protection factor sunscreens in the suppression of actinic neoplasia.

BACKGROUND AND DESIGN: A controlled trial was undertaken from December 1987 to December 1990 to test the hypothesis that a strong sunscreen can reduce the number of cancerous and precancerous skin lesions. Candidates were selected from a high-risk population attending either a university- or Veterans Affairs-based dermatology practice in Lubbock, Tex, for a prospective, double-blind, controlled trial of daily application of sunscreen vs placebo over a 2-year period. Participants were asked to volunteer if they had demonstrated premalignant changes (actinic keratoses) or nonmelanoma skin cancer (basal cell carcinoma or squamous cell carcinoma), had continuing sun exposure, and were not using sunscreen on a regular basis. Fifty-three volunteers were initially enrolled in the study, and 37 came for the final 24-month visit. RESULTS: The rate of appearance of new precancerous skin lesions was less for the treatment group than for control subjects. People with darker skin had fewer actinic keratoses, women had fewer lesions than men, and people with fewer lesions at enrollment had fewer lesions during the study. The numbers of new nonmelanoma skin cancers appearing during the study period were too small for statistical analysis. CONCLUSIONS: The regular use of sunscreens can significantly reduce cutaneous neoplasia, as indicated by its suppression of precancerous lesions. A longer and/or larger study would be necessary to demonstrate an effect on malignant lesions.

Effects of single-dose ultraviolet radiation on skin superoxide dismutase, catalase, and xanthine oxidase in hairless mice.

The effects of a single exposure to UVB radiation on skin antioxidant enzymes and superoxide-generating xanthine oxidase were examined in Skh:HR-1 hairless mice. Significant decreases in superoxide dismutase (SOD) and catalase (CAT) were observed by 12 h after UV irradiation and remained depressed for up to 72 h. No induction of xanthine dehydrogenase (XD) or xanthine oxidase (XO) occurred with UV treatment, although significant hyperplasia was evident. Ornithine decarboxylase was induced after UV irradiation as has been previously reported. These results demonstrate significant biochemical effects of a single dose of UVB on murine epidermis, especially in terms of antioxidant defenses.