Mycosis fungoides in relation to environmental exposures and immune response: a case-control study.

Mycosis fungoides is a cutaneous T-cell lymphoma of unknown etiology, thought to be a rare sequela of chronic antigenic stimulation that may occur, for example, with exposure to contact allergens. To explore this possibility, we interviewed 174 patients with mycosis fungoides and 294 randomly selected control subjects in the San Francisco, Los Angeles, and Seattle areas concerning their lifetime histories of employment, chemical exposures, allergy, atopy, and certain medical conditions. Patients reported higher prevalence of cancers other than the non-Hodgkin's lymphomas and skin cancers (relative risk = 3.3, P less than .001) and were more likely than controls to burn when exposed to the sun (for nonblacks, relative risk = 1.7, P = .01). The latter difference may reflect a manifestation rather than a precursor of the disease. We found no consistent or biologically plausible differences between patients and controls with respect to types of jobs held, or to occupational or vocational exposures to chemicals. These findings do not support the hypothesis that persistent antigenic stimulation by contact allergens is etiologically important in the pathogenesis of mycosis fungoides.

Mycosis fungoides: management with topical nitrogen mustard.

The technique of treatment, response rate, freedom from relapse, survival, and complications of therapy in 123 patients treated with topical nitrogen mustard (HN2) for cutaneous mycosis fungoides (MF) at Stanford University Medical Center are reviewed. Patients were treated with HN2 in an aqueous or ointment base with equal efficacy. Response rates depended on the extent of skin involvement. In limited plaque (T1) disease, complete and overall response rates were 51% and 88%, respectively, while in generalized plaque (T2) disease they were 26% and 69%. No patients with tumorous involvement (T3) achieved complete skin clearance and all 13 of these patients developed progression of disease. Only two of nine patients with erythrodema (T4) achieved a complete response (CR), and both later relapsed. After achieving a CR, 40% of patients with T1 disease and 60% with T2 disease later relapsed; however, subsequent therapies, including repeat courses of topical HN2, often were successful in achieving later skin clearance. Overall, 42% of T1 patients and 31% of T2 patients were without evidence of MF at last follow-up. When death occurred, it was usually unrelated to MF in the T1 group. However, half of the deaths of patients with T2 disease were attributable to MF. Among the 22 patients with T3 or T4 disease, 80% of deaths were attributable to MF. The most common complication observed was a cutaneous hypersensitivity reaction, which occurred much more commonly with the aqueous than the ointment preparation. Fourteen patients (11%) developed subsequent cutaneous malignancies.

Reproducibility of the immunofluorescent test for antimelanoma antibodies.

The reproducibility of the indirect immunofluorescent test for antibodies to human malignant melanoma cytoplasmic antigens was investigated by testing panels of melanoma and normal sera against cells of each of several different melanomas. Tests were performed in replicate, read blindly by two observers, and repeated on different days. Different observers agreed in the interpretation of replicate assays in approximately 80 to 90% of cases. Variability increased considerably when assays were repeated on different days or when different in as few as 21% of tests. Thus, the results of the indirect immunofluorescent test for melanoma cytoplasmic antibodies must, at the present time, be interpreted with great caution.

Epidermal cytoplasmic antibodies: incidence and type in normal persons and patients with melanoma.

Antibodies to epidermal cytoplasmic antigens were present in 25 to 34% of 32 normal persons and in 34 to 50% of 53 patients with melanoma. There were at least two different types of cytoplasmic antibodies. The most common reacted to cytoplasmic antigens present only in the upper layers of the epidermis. This type of antibody occurred with equal frequency in patients with melanoma and in normal persons. The increased incidence of cytoplasmic antibodies in melanoma was due to antibodies to cytoplasmic antigens present throughout the epidermis. These antibodies were 2 1/2 times more common in patients with melanoma than in normal persons. The presence of different cytoplasmic antigens in distinct strata of the epidermis suggests they result from epidermal cell differentiation. The epidermal cytoplasmic antigens present throughout the epidermis appear to partially cross-react with cytoplasmic antigens in melanoma cells.

Expression of HLA-DR antigen in skin from patients with psoriasis.

Using murine monoclonal antibodies against human HLA-DR antigen and against human T cells, we investigated the indirect immunofluorescence staining pattern of involved and uninvolved skin from patients with psoriasis. The staining pattern of involved psoriatic epidermis is different from the pattern seen in uninvolved skin from the same patient and consists of scattered, single HLA-DR positive cells alternating with groups of HLA-DR positive cells. These HLA-DR positive cell clusters can be seen at any level of the epidermis. In some patients, the dermis of involved skin shows prominent accumulations of T cells which are HLA-DR positive and thus represent activated T cells.

Expression of T-cell receptor antigens in mycosis fungoides and inflammatory skin lesions.

Using immunohistologic methods, we studied the expression of the T-cell receptor (TCR)-associated antigens CD3, TCR-beta, and TCR-delta by cutaneous T cells in mycosis fungoides (MF) (36 patients) and a variety of inflammatory diseases (16 patients). Most T cells in the inflammatory diseases and patch/plaque mycosis fungoides expressed the immunophenotype characteristic of the vast majority of mature peripheral T cells: CD3+ TCR-beta+ TCR-delta-. In contrast, abnormal CD3/TCR-beta antigen expression was seen in 3 of 6 cases (50%) of tumor stage mycosis fungoides. Furthermore, we were able to document its evolution from the normal pattern present in earlier patch/plaque lesions of the two cases in which serial biopsies were available for study. Divergence of epidermal versus dermal CD3/TCR-beta antigen expression was seen in 2 of 34 (6%) of biopsies of patch/plaque mycosis fungoides but not in inflammatory controls. The TCR-delta+ cells were generally rare regardless of diagnosis. We conclude that inflammatory skin diseases and most patch/plaque mycosis fungoides are typically composed of T lymphocytes that resemble mature peripheral T cells in regard to their expression of TCR-associated antigens. In contrast, aberrant patterns of TCR-associated antigen expression can be seen in tumor stage MF, and, more rarely in patch/plaque MF.

Allergic contact dermatitis: novel immunohistologic features.

Leu-8 is a novel antigen expressed by the majority of mature T cells and certain other cells. Recent studies of the allogeneic mixed leukocyte reaction indicate that both Leu-8+ and Leu-8- subsets of Leu-3+ T cells have important functions in cell-mediated immunity in vitro. In order to determine whether Leu-3+8+ and/or Leu-3+8- T cells are present in cell-mediated immune reactions in vivo, we studied the immunohistology of allergic contact dermatitis in 8 biopsies from 8 patients with positive patch tests and 3 biopsies from 2 patients with Rhus dermatitis. Both Leu-3+8+ and Leu-3+8- T cells were present in each biopsy. Only 1 case had a definite minority of the Leu-3+8+ subset. These results suggest that, analogous to in vitro systems, both Leu-8+ and Leu-8- subsets of Leu-3+ T cells are involved in cell-mediated immunity in vivo. HLA-DR+ keratinocytes were present in only 3 of 11 biopsies at days 3-7. No HLA-DQ+ keratinocytes were identified. We also confirmed prior findings that Leu-3+ cells are the predominant T-cell population, Langerhans cells are increased, and B cells and NK cells are rare. Furthermore, Tac and Ki-67 expression by T cells and Leu-3 expression by Langerhans cells tended to increase over time.

Detection of clonal T-cell receptor gene rearrangements in the peripheral blood of patients with mycosis fungoides/Sezary syndrome.

Involvement of the peripheral blood in mycosis fungoides/Sezary syndrome (MF/SS) has a significant impact upon prognosis, but it is often difficult to distinguish circulating cells of MF/SS from atypical reactive lymphocytes. We compared the standard morphologic method of identifying leukemic cells, the Sezary preparation, to a genotypic method using Southern blot analysis of T-cell receptor gene rearrangements in concurrent blood samples. We studied 26 MF/SS patients, five of them in remission, together with five controls from cases of various non-MF/SS skin diseases. Six of 26 MF/SS patients had morphologically atypical circulating leukocytes (3%, 4%, 5%, 14%, 16%, 19%). Seven of 26 MF/SS patients had clonal T-cell receptor gene rearrangements, including the four patients with the greatest percentages of atypical cells and three patients lacking atypical cells. Six of seven patients had skin disease at the time of sampling, including three with erythroderma, two with generalized thick plaques, and one with generalized patches, while one patient was in clinical remission. All five controls lacked morphologic and genotypic evidence of atypical or clonal T-cells. Relative to genotyping, in our series the Sezary preparation was less sensitive and less specific. There were three apparent false negative results in the Sezary preparations, and two potential false positive (patients with 3% and 4% atypical leukocytes); however, there was agreement between the two techniques in most cases. We conclude that gene rearrangement studies may provide an effective test with which to assess the peripheral blood of MF/SS patients.

Expression of Leu-8 antigen, a majority T-cell marker, is uncommon in mycosis fungoides.

Predominance of mature helper T cells with the Leu-1+, 2-, 3+, 4+, 5+ phenotype was confirmed in 22 biopsy specimens of mycosis fungoides from 15 patients. Dissection of the T helper/inducer cells into phenotypically distinct subsets was performed with the use of a new monoclonal antibody, anti-Leu-8. One might predict a predominance of Leu-8+ in mycosis fungoides, as the known ratio of Leu-8+/Leu-8- cells is approximately 70/30 in the peripheral blood. Unexpectedly, a deficiency of Leu-8 was demonstrated in 18 of the 22 specimens from 13 of 15 patients. This finding could not be attributed to an artifact of the staining method or to therapy, and was present in early- as well as late-stage disease. Whether neoplastic cells in mycosis fungoides derive from Leu-8-subset of T cells at risk for malignant transformation, or whether there is antigen loss with malignant transformation remains to be determined. Implications of our finding with regard to etiopathogenesis of mycosis fungoides are discussed.

Bullous pemphigoid. Occurrence in psoriasis treated with psoralens plus long-wave ultraviolet radiation.

The occurrence of bullous pemphigoid during treatment for psoriasis has been described in the literature. We saw a case of psoriasis that was complicated by bullous pemphigoid in a patient receiving orally administered psoralen followed by long-wave ultraviolet radiation (PUVA) therapy. In our patient the localization of bullous lesions to psoriatic plaques demonstrates that the PUVA-treated psoriatic skin may have a decreased threshold for the development of clinical bullous pemphigoid. This suggests factors other than simple coexistence of the two diseases. Therapy with PUVA might induce bullous pemphigoid in psoriasis, either primarily or by facilitating the expression of a previously existing subclinical form of the bullous disorder.

Epidermal dystrophy. Occurrence after psoriasis therapy with psoralen and long-wave ultraviolet light.

Focal dystrophy of epidermal cells has been recognized in about half of 37 patients treated with psoralen and long-wave ultraviolet radiation (PUVA) for psoriasis. This lesion appeared in many patients by the end of the clearing phase of therapy and was present to a similar degree one year after the beginning of the treatment. It is probable that most such changes are transient, but the appearance suggests the possibility that cells have undergone somatic mutation that potentially could be dangerous.

PUVA treatment of erythrodermic and plaque-type mycosis fungoides. Ten-year follow-up study.

Since our preliminary report of psoralen plus long-wave ultraviolet A (PUVA) therapy in ten patients with erythroderma-type or plaque-type mycosis fungoides (MF), we have treated 38 patients with biopsy-proved MF. Approximately one third, mostly patients with erythroderma, received PUVA as primary therapy; the remainder had recurrent disease following electron beam irradiation or topical mechlorethamine (Mustargen) hydrochloride. Follow-up data are presented in 29 patients who completed an initial course of PUVA given two to three times weekly. A complete clinical response was observed in ten patients with plaque-type MF and seven with erythroderma without Sézary syndrome. The PUVA therapy was palliative for patients with advanced disease, in combination with other therapies. The mean observation period was approximately five years. Despite maintenance PUVA, most patients relapsed between ten and twenty months and were treated with another intensive course. Long-term maintenance therapy with PUVA was necessary to control the disease.

Long-term risks of psoralen and UV-A therapy for psoriasis.

It has been more than eight years since photochemotherapy with methoxsalen and UV-A (psoralen and UV-A [PUVA]) was introduced for the treatment of psoriasis. This treatment remained under investigation until May 1982 because of concerns about possible chronic toxic effects. With recent Food and Drug Administration approval of PUVA therapy for severe psoriasis, strict drug labeling for administration and patient use and continued monitoring of side effects have become essential. The full effects of PUVA in regard to carcinogenicity, prematurely induced aging of the skin, pigmentary changes, immunologic alterations, and ocular side effects are still unknown. A review of the risks of PUVA therapy is presented, with the aim of maintaining a proper perspective for its limited use in treating selected patients.

Treatment of palmoplantar psoriasis with topical methoxsalen plus long-wave ultraviolet light.

Fourteen patients with chronic plaque-type psoriasis involving the palms and soles and 14 patients with palmoplantar vesiculopustular dermatosis, including three cases of localized pustular psoriasis, were treated with topical application of methoxsalen, followed by exposure to long-wave ultraviolet energy (topical PUVA). Approximately two thirds of the patients with palmoplantar plaque-type psoriasis and half of those with vesiculopustular dermatosis responded with considerable improvement, as evidenced by flattening of plaques, decreased scaling and erythema, and decreased vesicle and pustule formation after 15 to 40 treatments. Complete clearing of the treated areas was achieved in five patients with palmoplantar psoriasis, three of whom had the pustular variety. Most patients required continued maintenance therapy with topical PUVA. The condition of the patients with palmoplantar vesiculopustular dermatosis, especially those with severe involvement, was more labile and more difficult to control with PUVA therapy than in those with chronic scaling plaques.

Perforating pseudoxanthoma elasticum associated with chronic renal failure and hemodialysis.

A patient with hypertension and chronic renal failure of an undetermined cause who was undergoing hemodialysis developed bilateral crusted, focally eroded plaques on her breasts. A biopsy specimen of the lesional skin revealed typical histologic changes of pseudoxanthoma elasticum, with epidermal perforation. A biopsy specimen of lesion-free skin revealed characteristics typical of pseudoxanthoma elasticum. Perforating pseudoxanthoma elasticum should be added to the growing list of cutaneous disorders that occur in patients with chronic renal failure who are undergoing hemodialysis.

Poikilodermatous mycosis fungoides and atrophic large-plaque parapsoriasis exhibit similar abnormalities of T-cell antigen expression.

We studied the immunohistologic findings of skin biopsy specimens from 21 patients with poikiloderma (14 with mycosis fungoides [MF] and seven with atrophic large-plaque parapsoriasis [ALPP]). Both types of poikiloderma were similar with regard to T-cell antigen expression. In each case, most T cells expressed the CD4+ (helper/inducer) phenotype and lacked Leu-8 antigen. T cells were also deficient in Leu-9 antigen in most cases (MF, 11/14 [79%]; ALPP, 4/7 [57%]). These T-cell antigen deficiencies are similar to those described previously in various types of MF and indicate that such deficiencies are common in minimally infiltrated, patch-stage MF lesions. Because combined Leu-8/Leu-9 antigen deficiencies are uncommon in inflammatory skin diseases, our findings are consistent with the view that ALPP is an early form of MF, as had been suggested previously by results of clinicopathologic studies.

DNA repair elicited by UVB during PUVA therapy for psoriasis.

The skin of patients receiving psoralen and UVA (PUVA) therapy for psoriasis is exposed to trace amounts of UVB radiation emitted by PUVA irradiators in addition to UVA. DNA repair activity was measured using autoradiography in the uninvolved skin of PUVA-treated patients in order to determine whether 8-methoxypsoralen (8-MOP) plus UVA elicits repair, inhibits the skin repair response to UVB, or protects epidermal-cell DNA from UVB damage by promoting a tan. Epidermal-DNA repair activity was observed in 27 out of 37 patients following the first PUVA treatment. Phototesting with multiples of the initial UV dose elicited a linear increase in repair activity. Glass-filtered radiation failed to stimulate repair, indicating that the reaction was due to UVB, not to 8-MOP plus UVA. The same amount of repair activity was observed in the skin of patients irradiated either before or after 8-MOP ingestion, demonstrating that the drug did not interfere with the response of the skin to UVB. At clearing, however, the repair activity was never greater than that elicited at the initial treatment and was often undetectable despite a tenfold increase in UV exposure. It is proposed that DNA damage should be measured to determine whether epidermal cells are entirely protected from UVB radiation at the completion of therapy.

Topical treatment of psoriasis with the topoisomerase inhibitors novobiocin and nalidixic acid: a pilot study.

Our studies in human epidermal keratinocytes as a model system have suggested that the antibiotic topoisomerase II inhibitors, novobiocin and nalidixic acid, may be of value for the treatment of hyperproliferative skin disorders. We have therefore conducted a pilot study of the clinical efficacy of these compounds for the treatment of psoriasis. The compounds were administered topically to psoriatic plaques in seven healthy patients over a period of 6 weeks. Nalidixic acid (2%) or novobiocin (2% or 5%) in methylcellulose were applied twice daily under occlusion, and methylcellulose alone was used as a control. In six of the seven patients, one or both compounds effected somewhat greater improvement than in the control within 3 weeks of treatment.

Mycosis fungoides and the Sézary syndrome: pathology, staging, and treatment.

Mycosis fungoides and the Sézary syndrome are forms of cutaneous T-cell lymphoma. Mycosis fungoides is an uncommon disease: only about 500 new cases are diagnosed in the United States annually. The median age of onset is 55 years and there is a 2:1 male predominance. The etiology of mycosis fungoides is unknown. Although occupational exposures have been implicated, case control studies fail to support this hypothesis. Mycosis fungoides is typified by cutaneous plaques which may evolve into tumors over the course of time. It is often preceded by a lengthy pre-mycotic phase prior to the time of definitive diagnosis. In its earliest diagnostic phase, there may only be slightly scaling patches with a limited distribution. Indurated lesions evolve into plaques, which may become more generalized in their distribution. As the severity of skin involvement increases, there is an increasing likelihood of spread to extracutaneous sites. The pathology of this disease is marked by involvement of the epidermis (Pautrier microabscesses). Immunologic studies characterize these cells as belonging to the helper T-cell subset. Genotypic analysis demonstrates monoclonal rearrangements of the T-cell receptors of the infiltrating cells. The staging system for mycosis fungoides considers the extent of skin involvement, presence of lymph node or visceral disease, and detection of abnormal cells in the peripheral blood. Patients with disease limited to the skin (90% of newly diagnosed cases) are treated best with topical or cutaneous therapies. Common modalities include psoralen photochemotherapy (PUVA), topical chemotherapy (nitrogen mustard) and total skin electron beam therapy. Both topical nitrogen mustard and electron beam therapy have good initial response rates (73% and 100%) and may achieve long-term disease-free survival, especially in patients with initially limited disease. Even if the response is incomplete or relapse occurs, substantial and very important palliation is generally achieved with topical therapy. Recurrent or resistant cutaneous disease will require the use of sequential topical treatment. The median survival time of patients who present with disease limited to the skin is greater than 10 years, and many deaths in this group are from intercurrent causes, especially in patients with limited or generalized plaque disease. If cutaneous tumors are present, the majority of these patients will eventually die from disease-related causes. The prognosis of patients who develop extracutaneous disease is exceedingly poor (median survival time, approximately 1 year).(ABSTRACT TRUNCATED AT 400 WORDS)

Phototherapy.

This review illustrates that UVB phototherapy is not only a time-honored treatment, but also highly effective for widespread psoriasis. Treatment parameters include the frequency of irradiation, initial dose based on skin type or MED, increments of UV exposure, and maintenance schedule, according to defined protocols. UVB can be combined with adjunctive topical or systemic therapies either concomitantly or sequentially for additive effect. The use of various therapeutic modalities, including UVB phototherapy on a rotational basis, has been advocated for long-term control with reduced toxicity. UVB with emollients in an erythemogenic dosage schedule is as effective as PUVA for clearing of psoriasis in selected fair-skinned patients. Unlike PUVA, it does not involve a systemic photosensitizing drug and is relatively convenient and simple to use. UVB is the most commonly used therapy by dermatologists for widespread psoriasis that does not respond to topical therapies; it has been shown to be one of the most cost-effective therapies for widespread psoriasis.