Thomas B. Fitzpatrick

Photochemotherapy of psoriasis with oral methoxsalen and longwave ultraviolet light.

Abstract Oral administration of a photoactive drug, 8-methoxypsoralen (methoxsalen), followed by exposure to a high-intensity, longwave ultraviolet-light system resulted in complete clearing of generalized psoriasis in 21 patients. In 16 of these cases, a paired comparison showed methoxsalen followed by longwave ultraviolet light to be more effective than conventional ultraviolet light. 8-Methoxypsoralen followed by exposure to longwave ultraviolet light has previously been shown to inhibit epidermal DNA synthesis; this may be its mechanism of action in psoriasis, a disorder characterized by an accelerated cell cycle and rate of DNA synthesis. The term photochemotherapy is used to emphasize the point that the effect on epidermal proliferation and the therapeutic response require the interaction of light and drug. (N Engl J Med 291:1207–1211, 1974)

Risk of Cutaneous Carcinoma in Patients Treated with Oral Methoxsalen Photochemotherapy for Psoriasis

A 2.1-year prospective study of 1373 patients given oral 8-methoxypsoralen photochemotherapy for psoriasis revealed 30 patients with a total of 48 basal-cell and squamous-cell carcinomas. The observed incidence of cutaneous carcinoma was 2.63 (95 per cent confidence limits = 1.91 to 3.90) times that expected for an age, sex and geographically matched population. Relative risk to patients with history of ionizing radiation was 3.68 (99 per cent confidence limits, 2.42 to 8.69). Patients with a previous cutaneous carcinoma had a relative risk of 10.22 (99 per cent confidence limits, 4.78 to 37.08). A higher than expected proportion of squamous-cell carcinomas and an excess of squamous-cell carcinomas in areas not exposed to sun were seen. New patients with known histories of ionizing-radiation exposure or of skin tumors should be given 8-methyoxypsoralen photochemotherapy only if they understand the risks and have disabling psoriasis untreatable by other means.

Cutaneous Squamous-Cell Carcinoma in Patients Treated with PUVA

A 5.7-year prospective study of 1380 patients treated for psoriasis with oral methoxsalen (8-methoxypsoralen) and ultraviolet A photochemotherapy (PUVA) revealed that after adjustment for exposures to ionizing radiation and topical tar preparations, the risk that cutaneous squamous-cell carcinoma would develop at least 22 months after the first exposure to PUVA was 12.8 times higher in patients exposed to a high dose than in those exposed to a low dose (95 per cent confidence interval, 5.8 to 28.5). No substantial dose-related increase was noted for basal-cell carcinoma. The dose-dependent risk of cutaneous squamous-cell carcinoma suggests that PUVA can act as an independent carcinogen. In our study, morbidity associated with these tumors has been limited, but further follow-up is needed. Meanwhile, patients treated with PUVA should be followed closely for the possible development of cutaneous squamous-cell carcinoma.

Melasma: A clinical, light microscopic, ultrastructural, and immunofluorescence study

Melasma is an acquired brown hypermelanosis of the face. Although it is thought that melasma is associated with multiple etiologic factors (pregnancy, gastric, racial, and endocrine), one of the primary causes of its exacerbation appears to be exposure to sunlight. Three patterns of melasma are recognized clinically: (1) a centrofacial pattern, (2) a malar pattern, and (3) a mandibular pattern. Examination of patients with Woods light (320--400 nm) is useful in classifying the specific type of melasma in correlation with the localization of pigment granules (melanosomes) in the epidermis and dermis. Four types of melasma are described on the basis of Woods light examination: (1) an epidermal type, (2) a dermal type, (3) a mixed type, and (4) a fourth type, described in patients of dark complexion, in which the lesions, for lack of contrast, are not discernible on Woods light examination, perhaps due to the increased number of melanosomes in the normal skin of black individuals. Light, histochemical, and electron microscopic studies revealed an increase in number and activity of type-specific melanocytes which appeared to be engaged in increased formation, melanization, and transfer of pigment granules (melanosomes) to the epidermis as well as to the dermis. The melanocyte seems to undergo a functional alteration brought about by a combination of multiple factors, including persistent sun exposure, hormonal factors, and genetic predisposition.

Oral methoxsalen photochemotherapy of mycosis fungoides

The cutaneous manifestations of mycosis fungoides have been successfully treated in nine patients for 16 to 28 months with oral methoxsalen and subsequent irradiation with longwave ultraviolet light. The efficacy of this therapy was confirmed in one patient, who showed complete clearing of generalized plaques after 1 month (12 treatments) except for a shielded control area which worsened during this period. Methoxsalen photochemotherapy may prove a valuable addition to therapies currently available for mycosis fungoides and may obviate some of the problems associated with conventional management of this disorder.

The malignant potential of small congenital nevocellular nevi: An estimate of association based on a histologic study of 234 primary cutaneous melanomas

In order to assess a relationship between small congenital nevocellular nevi and cutaneous melanoma, histologic features commonly associated with congenital nevi were sought in 234 melanomas. The detection of one or more histologic features of congenital nevi in 8.1% (19/234) of melanoma specimens was directly related to the number of slides and tissue sections with melanoma available for review, the predominance of superficial spreading melanoma (SSM) and the historic relationship to a preexisting pigmented nevus at the tumor site. The histologic association was inversely related to melanoma thickness and tumor location on the lower extremities. The observed frequency of histologic association was estimated to be approximately 4,000 to 13,000 times greater than expected on the basis of surface area by chance alone. These findings suggest that small congenital nevi may be precursors for at least some cases of cutaneous melanoma. The strength of histologic association is highly dependent on the specificity of methods used for detecting congenital nevi in melanoma specimens.

Oral psoralen photochemotherapy of atopic eczema.

Oral administration of 8‐methoxypsoralen followed by exposure to a high‐intensity longwave ultraviolet treatment system resulted in clearing of atopic eczema in 15 patients. Paired‐comparison studies demonstrated that this treatment was superior both to conventional ultraviolet light therapy and to no treatment. Short‐term observation suggests that regular therapy is necessary to maintain remission of the disease.

Dysplastic melanocytic nevi in histologic association with 234 primary cutaneous melanomas

Dysplastic melanocytic nevi (DMN) are irregularly pigmented lesions characterized by (1) atypical melanocytic hyperplasia in a lentiginous epidermal pattern (AMHL), (2) one or more dermal mesenchymal changes, and (3) frequently a dermal nevocellular nevus. In order to determine an association between DMN and cutaneous melanoma, the dominant histologic feature of DMN (namely, AMHL) was sought in histologic contiguity with 234 primary melanomas. Of these 234 cases, 9 were lentigo maligna melanomas. Of the remaining 225 cases, 49 (21.8%) were associated with AMHL in the same histologic section as (but beyond the most lateral margin of) intraepidermal and invasive melanoma. AMHL was directly associated with the presence of dermal nevocellular nevi in histologic contiguity with melanoma, and a greater number of histologic slides with melanoma available for review. AMHL was inversely associated with nodular melanoma. Most of the AMHL cases were not associated with familial melanoma, but the total number of familial cases was low. The histologic association between AMHL and melanoma in one fifth of cases in this series supports the hypothesis that at least some cutaneous melanomas may have an origin in DMN.

Prognostic Factors for Patients with Clinical Stage I Melanoma of Intermediate Thickness (1.51–3.99 mm)* A Conceptual Model for Tumor Growth and Metastasis

Fourteen variables were tested for their ability to predict visceral or bony metastases in 177 patients with clinical Stage I melanoma of intermediate thickness (1.51–3.99 mm). A Cox multivariate analysis yielded a combination of four variables that best predicted bony or visceral metastases for these patients: 1) mitoses > 6/mm2 (p = 0.0007), 2) location other than the forearm or leg) p = 0.009), 3) ulceration width > 3 mm (p = 0.04), and 4) microscopic satellites (p = 0.05). The overall prognostic model chi square was 32.40 with 4° of freedom (p < 10-5). Combinations of the above variables were used to separate these patients into at least two risk groups. The high risk patients had at least a 35% or greater chance of developing visceral metastases within five years, while the low risk group had greater than an 85% chance of being disease free at five years. Criteria for the high risk group were as follows: 1) mitoses > 6/mm2 in at least one area of the tumor, irrespective of primary tumor location, or 2) a melanoma located at some site other than the forearm or leg and histologic evidence in the primary tumor of either ulceration > 3 mm wide or microscopic satellites. The low risk group was defined as follows: 1) mitoses ≤ 6/mm2 and a location on the leg or forearm, or 2) mitoses ≤ 6/mm2 and the absence in histologic sections of the primary tumor of both microscopic satellites and ulceration ≥ 3 mm wide. The number of patients in this series who did not undergo elective regional node dissection (N = 47) was probably too small to detect any benefit from this procedure. Based on survival rates from this and other studies, it is estimated that approximately 1500 patients with clinical Stage I melanoma of intermediate thickness in each arm of a randomized clinical trial would be needed to detect an increase in survival rates from elective regional node dissection.

Prognostic factors for melanoma patients with lesions 0.76 - 1.69 mm in thickness. An appraisal of "thin" level IV lesions.

Fourteen variables were tested for their prognostic usefulness in 203 patients with clinical Stage I melanoma and primary tumors 0.76–1.69 mm thick. Only two variables, primary tumor location and level of invasion, were useful in predicting death from melanoma for these patients. Of the 12 deaths from melanoma, 11 occurred in patients with primary tumors located on the upper back, posterior arm, posterior neck, and posterior scalp (= BANS). There has been only one death from melanoma in 136 patients with melanoma located at other sites (11/67 vs 1/136, p < 0.0001 Fishers Exact Test). Of the 67 BANS patients, 51 had level II or level III lesions and five (10%) died of melanoma. This compares with six deaths from melanoma in 16 patients (37.5%) with level IV BANS lesions (5/51 vs 6/16, p = 0.01 Fishers Exact Test). The relatively high incidence of both melanoma deaths and regional node metastases for the BANS group merits consideration for testing the efficacy of elective regional node dissection for these patients.