The prognostic significance of delayed hypersensitivity to dinitrochlorobenzene and mechlorethamine hydrochloride in cutaneous T cell lymphoma.

Recent studies suggest that cells elaborating type 1 cytokines are important mediators of anti-tumor cell-mediated immunity in cutaneous T cell lymphoma. Type 1 cell-mediated immune responsiveness was assessed in 276 patients with cutaneous T cell lymphoma (mycosis fungoides and Sézary syndrome) using 2,4-dinitrochlorobenzene (DNCB) skin testing as part of the initial evaluation. The overall rate of sensitization after one and two DNCB challenges was 32% and 67%, respectively, which is much decreased compared with the expected rate of more than 95% for normal individuals. Moreover, the frequency of DNCB sensitization and allergic contact dermatitis to topically applied mechlorethamine decreased with advancing stage of disease. In addition to the expected strong correlation with stage, we observed that patients who were DNCB test positive were significantly less likely to experience disease progression and had a better overall prognosis compared with DNCB-negative patients. These results support the concept that cell-mediated responses are important in cutaneous T cell lymphoma, and that augmentation of these responses would be therapeutically beneficial.

Increased factor XIIIa transglutaminase expression in dermal dendrocytes after treatment with alpha-hydroxy acids: potential physiologic significance.

BACKGROUND: Topical alpha-hydroxy acids (AHAs) have been shown to improve photoaging in human skin. OBJECTIVE: We studied factor XIIIa transglutaminase expression in dermal dendrocytes (DDs) and mast cell degranulation after treatment of the skin with AHAs. METHODS: Skin biopsy specimens obtained from patients after 4 to 8 months of treatment with lotions containing 25% AHAs were evaluated for factor XIIIa transglutaminase expression with immunoperoxidase and electron microscopy. Immunoperoxidase-stained sections were studied by means of semiquantitative methods and image analysis. Mast cell degranulation was studied by image analysis. RESULTS: Increased factor XIIIa transglutaminase expression was seen after treatment with AHAs. All treated sites had increased scores compared with control sites by semiquantitative methods. Seventy-five percent of treated sites showed an increased mean area over control sites of factor XIIIa transglutaminase positivity with image analysis. These results correlated with an increased level of mast cell degranulation in treated sites and with activation of DDs as seen by electron microscopy. CONCLUSION: Treatment of the skin with AHAs leads to mast cell degranulation and increased expression of factor XIIIa transglutaminase by activated DDs. Mast cell degranulation may lead to activation of DDs and increased factor XIIIa transglutaminase expression, via the action of tumor necrosis factor-alpha. We speculate that clinical and histologic improvement in photoaged skin after treatment with AHAs may be somehow related to this process.

Effects of alpha-hydroxy acids on photoaged skin: a pilot clinical, histologic, and ultrastructural study.

BACKGROUND: alpha-Hydroxy acids (AHAs) have been reported to improve aging skin. The mechanisms of action of AHAs on epidermal and dermal compartments need clarification. OBJECTIVE: Our purpose was to determine the effects of AHAs on photoaged human skin by clinical and microanalytic means. METHODS: Patients applied a lotion containing 25% glycolic, lactic, or citric acid to one forearm and a placebo lotion to the opposite forearm for an average of 6 months. Thickness of forearm skin was measured throughout the study. Biopsy specimens from both forearms were processed for analysis at the end of the study. RESULTS: Treatment with AHAs caused an approximate 25% increase in skin thickness. The epidermis was thicker and papillary dermal changes included increased thickness, increased acid mucopolysaccharides, improved quality of elastic fibers, and increased density of collagen. No inflammation was evident. CONCLUSION: Treatment with AHAs produced significant reversal of epidermal and dermal markers of photoaging.

Use of pyruvic acid in the treatment of actinic keratoses: a clinical and histopathologic study.

Twelve patients with multiple actinic keratoses were treated with either 5-fluorouracil and pyruvic acid or pyruvic acid alone. Three patients were treated with 5 percent 5-fluorouracil cream for one to three weeks for comparison. Exposure time to alpha-hydroxy acids varied between one and ten minutes. Biopsy specimens were taken at times varying from immediately after treatment to eight weeks after treatment. The results show that the combination of 5-fluorouracil and pyruvic acid is an effective treatment for actinic keratoses. In addition, the exposure time to 5-fluorouracil is decreased and therefore this treatment is better tolerated than prolonged treatment with 5-fluorouracil alone.

A controlled clinical trial of a new formulation of betamethasone dipropionate cream in once-daily treatment of psoriasis.

In a multicenter, evaluator-blind, parallel group study of 244 patients with moderate to severe psoriasis, a once-daily application of a new formulation of beta-methasone dipropionate 0.05% cream, augmented formulation (AF), and a twice-daily application of fluocinonide 0.05% cream were compared, with respect to safety and efficacy. Results significantly favored betamethasone dipropionate AF over fluocinonide, as indicated by improvements in signs of erythema, induration, and scaling, as well as the physicians' and patients' global evaluations of response after 14 days of treatment. As a result of adverse experiences, treatment had to be discontinued in three patients on fluocinonide. No patient on betamethasone dipropionate AF had to discontinue treatment.

Risk of second malignancy after cutaneous T-cell lymphoma.

Risk of second primary malignancy was assessed in a population-based follow-up survey of all persons who developed cutaneous T-cell lymphoma (CTCL) in nine geographic areas of the United States covered by the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute during the period 1973 to 1983. Among 544 patients with a first primary tumor reported as CTCL, a second cancer developed in 35 (6%), yielding a significantly elevated relative risk (RR) of 1.7, which reflects excesses for cancers of the lung and colon and non-Hodgkin's lymphoma. Although the excess of lymphoma may be related to the evolution of CTCL to less differentiated T-cell lymphoma, additional studies are needed to clarify the immunologic, genetic, viral, and environmental factors that may contribute to the development of second cancers.

Long-term efficacy, curative potential, and carcinogenicity of topical mechlorethamine chemotherapy in cutaneous T cell lymphoma.

Complete responses lasting from 4 to 14 years were documented in 65 of 331 (20%) patients with cutaneous T cell lymphoma treated with topical mechlorethamine (HN2) between 1968 and 1982. Such long-lasting remissions occurred most often, but not invariably, in patients with patch or plaque phase mycosis fungoides without palpable lymphadenopathy (stage Ia or Ib). The likelihood of a continuous remission was enhanced by initiation of treatment before an unequivocal pathologic diagnosis. Despite the long-lasting responses in these patients, however, relapses have been documented in 11 (17%) of these patients, and all relapses occurred within 8 years of discontinuing maintenance topical chemotherapy. Thus, in our experience, a continuous remission lasting 8 or more years provides evidence that cutaneous T cell lymphoma can be eradicated by aggressive topical chemotherapy. This circumstance was observed in 35 patients, representing a cure rate of at least 11% overall. In addition, when compared with the general population of the United States, patients who received topical HN2 were at an 8.6-fold and a 1.8-fold increased risk for the development of squamous cell carcinoma and enhanced for Hodgkin's disease and colon cancer but not for systemic cancers known to be induced by systemic administration of alkylating drugs. These results compare favorably with experiences with topical HN2 chemotherapy at other centers but raise questions about the risks associated with long-term administration for maintenance of remissions.

Alpha hydroxy acids: procedures for use in clinical practice.

Alpha hydroxy acids and alpha keto acids applied topically in lower concentrations reduce the thickness of hyperkeratotic stratum corneum by reducing corneocyte cohesion at lower levels of the stratum corneum. This property permits efficient clinical control of dry skin, ichthyosis, follicular hyperkeratosis, and other conditions characterized by retention of stratum corneum. Applied topically in higher concentrations, these acids cause epidermolysis. This property provides a new alternative for treating seborrheic keratoses, keratoses commonly known as "age spots," actinic keratoses, and verrucae vulgares; all of which lesions involve distinct epidermal hyperplasia as well as retention of stratum corneum. Facial wrinkles can be modified with topical alpha hydroxy acids, applied in higher concentrations as office procedures, and concomitant daily home application of lower concentrations.

Hyperkeratinization, corneocyte cohesion, and alpha hydroxy acids.

Hyperkeratinization is a primary or fundamental event in a majority of today's skin disorders. Hyperkeratinization is usually the result of decreased desquamation due to increased corneocyte cohesion. Strength of corneocyte cohesion is determined by strength of intercellular bonding. Intercellular bonding is weakened by water and diminished by retinoids and alpha hydroxy acids (AHAs). Conversely, bonding is strengthened or enhanced by dehydration, vitamin A deficiency, and some alpha acetoxy acids (AAAs). Agents that control or modify keratinization can be useful in treatment of many skin disorders.

Home ultraviolet phototherapy of early mycosis fungoides: preliminary observations.

Thirty-one patients with early mycosis fungoides (MF) and three patients with parapsoriasis en plaques were treated with ultraviolet phototherapy (280 to 350 nm) at home using a commercially available light source containing four Westinghouse FS40 lamps. A complete clinical and histologic remission of disease, lasting for a median duration in excess of 18 months, was achieved in nineteen patients (61%) with MF. Although higher complete response rates generally are achieved with other therapeutic modalities, ultraviolet phototherapy with its minimal adverse effects may be indicated for selected patients. Controlled studies are encouraged to evaluate the full potential of conventional phototherapy in the management of MF.

Prolonged remission of tumor-stage mycosis fungoides by topical immunotherpay.

A patient with slowly progressive tumor-stage mycosis fungoides (MF), without apparent extracutaneous involvement, received topical immunotherapy with mechlortethamine hydrochloride as the immunogen. A complete remission was achieved after two months of treatment, and the patient has remained free of detectable disease without further treatment for more than seven years. This case is also unusual in that, before treatment, a temporary exacerbation of MF had occurred during three pregnancies. These observations suggest that the natural resistance against the progression of MF in this patient was enhanced by immunotherapy.

Prognostic significance of cytomorphology in the cutaneous T-cell lymphomas.

In this retrospective study, the degree of differentiation of atypical lymphoid cells was assessed in pretreatment cutaneous biopsy specimens from 248 patients with cutaneous T-cell lymphomas (mycosis fungoides and Sézary syndrome) and the findings were correlated with the subsequent therapeutic results. Overall, patients with a predominance of cells with hyperchromatic nuclei (well-differentiated lymphoid cells) in cutaneous infiltrates responded better to treatment with improved survival rates than patients with infiltrates composed predominantly of cells with pale vascular nuclei (poorly differentiated lymphoid cells). Infiltrates with a predominance of poorly differentiated lymphoid cells were observed primarily in patients with advanced (tumor) stages of disease. However, comparison of the therapeutic results achieved for the two cytomorphologic patterns in patients at comparable stages of advanced disease did not reveal significant differences, indicating that the presence of poorly differentiated cells in large proportions does not have additional prognostic implications beyond those obtained from usual staging procedures. We speculate that the atypical cells with large, pale vesicular nuclei found in lesions of cutaneous T-cell lymphoma are not a more malignant cell population but rather evolve from more hyperchromatic cellular forms, perhaps a byproduct of malignant dedifferentiation.