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Photo- und Photochemotherapie des kutanen T-Zell-Lymphoms
Abstract
Unter den kutanen T-Zell-Lymphomen (CTCL) versteht man eine Gruppe verschiedener Non-Hodgkin-Lymphome, die sich primär an der Haut manifestieren und deren Infiltrate zum Großteil aus malignen T-Lymphozyten bestehen. Die häufigste klinische CTCL-Variante ist die sogenannte Mycosis fungoides (MF). Die MF gehört zu den niedrigmalignen Non-Hodgkin-Lymphomen, deren klinischer Verlauf durch eine langsame Progression von einem frühen Plaquestadium über ein Tumorstadium bis hin zur Lymphknoten- und Organbeteiligung gekennzeichnet ist. Häufig überlappen sich jedoch die klinischen Stadien, oder es kommt zum Überspringen einzelner Stadien. Das Sézary-Syndrom (SS) ist eine Sonderform der MF mit generalisiertem Hautbefall im Sinne einer Ery-throdermie und einer Leukozytose mit malignen Lymphozyten. Weitere typische klinische Zeichen sind Befall der Handflächen und Fußsohlen mit palmoplantarer Hyperkeratose und tumoröse Infiltrate des Gesichtes (Facies leonina). MF und SS sind histopathologisch durch infiltrierende und/oder zirkulierende kleine T-Lymphozyten mit zerebriformen Zellkernen gekennzeichnet, die typischerweise den T-Helferphänotyp aufweisen (CD3+, CD4+, CD8+)
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An international multi-institutional clinicopathologic study of 1175 cases of non-Hodgkin's lymphoma sponsored by the National Cancer Institute has been completed. Histologic slides and clinical records were examined from previously untreated patients seen during the period between July 1971 and December 1975 at four institutions, three in the United States and one in Italy. The reproducibility and clinical relevance of the six major classifications of the non-Hodgkin's lymphomas was tested by six “expert” pathologists, each a proponent of a major classification, and six very experienced pathologists not identified with one of the major classifications. Immunologic methods were not employed in the study design. A summary of the methods employed and the conclusions of the study is described. The major conclusion was that all six classifications were valuable and comparable in reproducibility and clinical correlations. The clinical significance of a follicular architecture, independent of cell type was confirmed. A working formulation of non-Hodgkin's lymphomas is described which separates the disease into ten major types utilizing morphologic criteria only. Subtypes are also described which allow translation of all of the major classifications into comparable groups. Histologic criteria are presented for each major type and equivalent terms are given for each type in the six major classifications. The formulation is not proposed as a new classification but a means of translation among the various systems and to facilitate clinical comparisons of case reports and therapeutic trials. The report contains commentaries by five of the “expert” pathologists on the value and conclusions of this unique study.
• Background and Design.—
Cutaneous T-cell lymphoma (CTCL) is a slowly advancing disease that initially presents in the skin and may later progress to involve the lymph nodes and viscera. Since CTCL most often presents on non-sunlight-exposed regions of the body, a possible protective role for UVB irradiation has been suggested. Recent observations have also found that UVB irradiation serves an immunoregulatory role. Given that limited data are available regarding the use of UVB phototherapy in treating CTCL, a retrospective nonrandomized study of 37 nonconsecutive patients with early CTCL was performed to assess the efficacy of UVB phototherapy in the treatment of CTCL.
Results.—
Twenty-five (71%) of the 35 patients treated with UVB phototherapy (two were unavailable for follow-up) achieved a total clinical remission. Median time to remission was 5 months, and median duration of the remission was 22 months. Twenty-five (83%) of 30 patients with disease limited to patches achieved remission, whereas none of the patients with plaque-level disease achieved a remission. Of the 25 patients who achieved complete remission, five (20%) had a recurrence of CTCL.
Conclusions.—
Phototherapy with UVB appears to be effective in patients with early patch-stage CTCL.(Arch Dermatol. 1992;128:931-933)
Primary cutaneous CD30 (Ki-1)-positive, large cell lymphomas (LCLs) represent a recently recognized group of cutaneous T-cell lymphomas with a favorable prognosis. The characteristic features of this cutaneous lymphoma are reviewed, differences with primary noncutaneous CD30+ LCLs emphasized, and its relation with other CD30+ cutaneous lymphoproliferative disorders, in particular lymphomatoid papulosis, is discussed. These primary cutaneous CD30+ LCLs, lymphomatoid papulosis, and related conditions represent a clinical and histologic continuum. A classification with practical guidelines for the management and treatment of patients within this spectrum of lymphoproliferative disorders is presented.
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.
Authors of most textbooks of dermatology and dermatopathology consider guttate parapsoriasis and digitate dermatosis to be variants of small plaque parapsoriasis which, they aver, is not related to mycosis fungoides. On the basis of a study of clinical and histopathologic findings in guttate parapsoriasis and digitate dermatosis, we conclude that those conditions actually represent two of the many clinical faces of mycosis fungoides.
T-cell receptor gene rearrangement analysis is a useful technique to detect clonality and determine lineage of lymphoid neoplasms. We examined 103 patients with mycosis fungoides, Sézary syndrome, peripheral T cell lymphoma, potentially malignant lymphoproliferative disorders including pre-Sézary syndrome, large plaque parapsoriasis, lymphomatoid papulosis and follicular mucinosis, and various benign inflammatory infiltrates. A clonal rearrangement was detected in skin samples in 20 of 24 patients with mycosis fungoides and in peripheral blood samples in 19 of 21 patients with Sézary syndrome. A clonal population was also detected in seven of eight cases classified as peripheral T cell lymphoma. The potentially malignant dermatoses tended to have clonal rearrangement, with the exception of large plaque parapsoriasis, and further follow-up is needed to correlate clonality with the disease course. These studies demonstrate the value of molecular genetics as an adjunct to morphology in the examination of patients with cutaneous lymphoproliferative disease.
Sixty-nine patients with mycosis fungoides, plaque stage, were treated in an open study with photochemotherapy (PUVA) or the combination of oral retinoids and PUVA (RePUVA). The response rate of Re-PUVA was equal to that of PUVA, with complete remission in 73% and 72%, respectively. Remissions were obtained with fewer PUVA sessions, and with a lower UVA dosage, if PUVA was combined with retinoids. A lower UVA dosage was needed if treatment was given four times weekly in stead of twice weekly. The duration of the remissions tended to be prolonged if retinoids were given as maintenance therapy.
Mycosis fungoides is a T-cell lymphoma that arises in the skin and progresses at highly variable rates. Nonradomized studies have suggested that early aggressive therapy may improve the prognosis in this usually fatal disease. We studied 103 patients with mycosis fungoides, who, after complete staging, were randomly assigned to receive either combination therapy, consisting of 3000 cGy of electron-beam radiation to the skin combined with parenteral chemotherapy with cyclophosphamide, doxorubicin, etoposide, and vincristine (n = 52) or sequential topical treatment (n = 51). The prognostic factors were well balanced in the two groups. Combined therapy produced considerable toxicity: 12 patients required hospitalization for fever and transient neutropenia, 5 had congestive heart failure, and 2 were later found to have acute nonlymphocytic leukemia. Patients receiving combined therapy had a significantly higher rate of complete response, documented by biopsy, than patients receiving conservative therapy (38 percent vs. 18 percent; P = 0.032). After a median follow-up of 75 months, however, there was no significant difference between the treatment groups in disease-free or overall survival. We conclude that early aggressive therapy with radiation and chemotherapy does not improve the prognosis for patients with mycosis fungoides as compared with conservative treatment beginning with sequential topical therapies.
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.
Specific treatments for mycosis fungoides, including electron beam irradiation, topical mechlorethamine, and psoralen plus ultraviolet A (PUVA) may be associated with the development of skin cancers after a variable latency period. Because these treatments are often not curative, topical therapies for mycosis fungoides, administered sequentially or concomitantly, are being used increasingly in order to control recurrent disease. This report documents the development of multiple cutaneous tumors, including squamous cell carcinoma, basal cell carcinoma, actinic keratoses, keratoacanthomas, and one case of lentigo maligna, in seven patients who received topical therapies for mycosis fungoides. In contrast to the usual latency period between ionizing radiation therapy and the development of skin cancer, two of our patients who had received prior PUVA therapy developed multiple skin tumors upon completion of electron beam irradiation. The development of metastatic squamous cell carcinoma in two of the other seven patients with multiple cutaneous neoplasms suggests that this potential hazard must be considered in the evaluation and treatment of patients with mycosis fungoides.
Forty-three patients with clinical plaque- and tumor-stage mycosis fungoides, the erythrodermic/Sézary syndrome variant of mycosis fungoides, and parapsoriasis en plaques were treated with oral psoralens and ultraviolet A (PUVA). Pretreatment skin biopsies, evaluated by light microscopy, revealed seventeen diagnostic, seventeen suggestive, and nine nonspecific specimens. Clinical and histologic parameters were followed for an average of 38.4 months (range, 4-67 months). Twenty-five patients had complete clearing, and fourteen did not respond. Most patients in the complete-response group had either plaque lesions of mycosis fungoides or parapsoriasis en plaques prior to PUVA. Most patients in the no-response group had either tumor lesions or the erythrodermic/Sézary mycosis fungoides at the start of PUVA. In the no-response group the treatment modalities used prior to PUVA were twice the number used in the complete-response group. Patients in the complete-response group had clearing of their lesions after an average PUVA dose of 117 joules/cm2. Relapse occurred in seventeen patients after an average remission time of 6.3 months and responded to additional PUVA. Patients whose skin remained clear after the first course of PUVA continued to have clear skin for up to 58 months, with an average complete remission of 29.5 months by the end of the study period. Histologic evaluation before PUVA and at clearing revealed a definite trend toward a normal microscopic picture, but at least a mild inflammatory infiltrate usually persisted. At the end of the study period, the lesions of ten patients had entirely cleared for an average of 44 months, the lesions of five had cleared during a second course of PUVA, five had stable limited-plaque disease while receiving maintenance PUVA, eleven were undergoing electron beam radiation therapy or chemotherapy for progressive disease, ten had died, and two patients were lost to follow-up. Therefore, in the early stage of mycosis fungoides, PUVA may induce significant disease-free intervals. Prior treatment with a variety of modalities, the patient's age, and/or the duration of disease may affect response to PUVA.
In a multicentre study in eighteen European cities 3175 patients were treated with photochemotherapy (PUVA) for severe psoriasis and data obtained during a period of 39 months were analysed. A response better than marked improvement was obtained in 88.8% of patients; twenty exposures and a total cumulative UVA dose of 96 J/cm2 were required for clearing, the duration of the clearing phase being 5.3 weeks. A comparison of the results of this study with those of a similar multicentre study in the United States on 1300 patients and using a different treatment protocol, revealed that while treatment results and the number of individual treatment sessions were similar the European protocol requires only half the time and less than half the total cumulative UVA dose for clearing of psoriasis. When patients in the European study who received continuous maintenance treatment were compared with patients who received no maintenance treatment the probability that a patient would remain in remission for a period of 80 weeks was the same, irrespective of whether patients received maintenance treatment or not. This study confirms the dramatic efficacy of PUVA in clearing psoriasis and contains two important messages for the reduction of possible long-term hazards of this treatment. Firstly, the total UVA energy requirements for clearing psoriasis strongly depend on the treatment schedule and can be kept low if an individual approach aimed at rapid clearing of psoriasis is used. Secondly, maintenance therapy may not significantly prevent recurrences for prolonged periods of time and may thus not be necessary in most patients.
In 1975 we started a prospective study on oral methoxsalen photochemotherapy (PUVA) in cutaneous T cell lymphoma (CTCL). The first short-term follow-up of nineteen patients (1978) showed that PUVA may induce long-lasting remission in early stages, and that eventual relapses respond comparably well when PUVA is resumed. We now present the follow-up data of the original nineteen patients, covering a period of up to 7 years, and of an additional twenty-five patients who have entered the trial since April, 1977. Similar to earlier reports, all patients with eczematoid and plaque lesions (stages IA and IB) cleared. Likewise, eczematoid and plaque lesions in patients with early tumors (stage IIB) were cleared. During a mean follow-up of 44 months, 55% of stage IA patients and 39% of stage IB patients remained free of disease. In patients who experienced relapses, the mean disease-free interval was 20 months for stage IA and 17 months for stage IB. All patients with stage IIB experienced multiple relapses and only three of seven were alive after 6 years, despite additional x-ray or cytotoxic therapy. The observation in this study that five of nine stage IA patients and ten of twenty-six stage IB patients have remained in continuous remission after a single PUVA course for up to 79 months indicates that PUVA may induce long-lasting disease-free intervals if used in the early stage of disease. However, the observation period still does not prove whether permanent cure can be achieved in some cases or not.
Cutaneous T cell lymphoma (CTCL) is a clinically and immunologically defined neoplasm which encompasses epidermotropic (mycosis fungoides, Sézary syndrome) and nonepidermotropic variants. A natural evolution apparently occurs from the epidermotropic to the nonepidermotropic form. In this review, cellular properties of the neoplastic cells are correlated with specific clinical observations, and recent therapeutic advances are discussed. Advances in our understanding of the pathogenesis of CTCL, including preliminary evidence suggesting that keratinocytes may elaborate a hormonal substance capable of inducing T lymphocyte differentiation, are discussed.
Mycosis fungoides (MF) is a non-Hodgkin's T-cell lymphoma of the skin that often begins as limited patches and plaques with slow progression to systemic involvement. No studies have been published comparing photochemotherapy (PUVA) with other topical therapies in the treatment of early-stage disease.
The purpose of the study was to examine our long-term experience using PUVA to treat early-stage MF and to compare its effectiveness and side-effect profile with other previously reported topical therapies.
Eighty-two patients with MF (83% stage IA or IB) were treated with PUVA. Clinical and histologic features were observed for a period from 2 months to 15 years (median, 43 months).
A response was noted in 78 patients (95%) with complete clinical and histologic clearing in 53 patients (65%) for all stages. The mean duration of total complete response to PUVA for all stages was 43 months (3.6 years). The mean survival of our study group for all stages was 8.5 years. Signs of chronic actinic skin damage were found in 10% of patients, including three patients with basal cell carcinomas and three patients with squamous cell carcinomas. In a nonrandomized comparison with previously reported data for other topical therapies, the efficacy and side-effect profile of PUVA compared favorably.
PUVA is an effective and safe therapy for MF with prolonged disease-free remissions being achieved. Patients with stage I and II MF respond best to PUVA. Palliative therapy with PUVA is useful in more advanced cases of MF.
This formulation includes a number of disease entities which may alarm those who believe that a lymphoma classification must be simple. The fact remains that these are the tumors that pathologists are seeing and diagnosing, and oncologists must be prepared to deal with them. If several morphologically, immunologically and genetically distinct neoplasms prove to respond identically to currently available treatment, the can be "lumped" for the purposes of clinical treatment selection (see Table 11-3). However, if new forms of treatment become available, particularly if these are directed against antigenic or genetic features, it will be important to recognize and study each disease separately. This study should be regarded as a preliminary effort to develop a consensus on lymphoma categorization, and constitutes merely a framework for further study. The ILSG has not attempted to determine the reproducibility of diagnosis of the various categories, either among different pathologists or by the same pathologist over time. No prior tumor classification has been based on reproducibility and when such studies have been done with existing classifications of lymphoma, they have shown disappointing results. 1,35,119 It is likely that recognition of clearly defined entities, which have characteristic immunophenotypes and in some cases genetic features, as well a characteristics morphology, will facilitate reproducibility among pathologists.189 Formal reproducibility studies should be undertaken, and should in general be a more frequent activity in the pathologic diagnosis of tumors. The ILSG does not have the resources to make a systematic attempt to determine the utility of these histologically and immunologically defined categories in predicting clinical outcome. The task of the pathologist is to attempt to define diseases by morphologic and other criteria applied to tissue specimens, and this has been the goal of the current endeavor. The clinical information about the different entities is taken from studies already published, which clearly show that each of the entities has distinctive clinical behavior, even if distinctive treatments are not currently available. The joint task of clinical oncologist and hematopathologists now is to undertake systematic application of the criteria presented here to defined groups of patients, to determine whether the newly-recognized categories will help to further stratify treatment response and outcome in clinical trials. Several members of the ILSG have already begun to review cases in cooperative group trials, and have found the recognition of these entities within broad Working Formulation categories can have prognostic implications (Grogan, T and Banks, PM, unpublished data from the Southwest Oncology Group [SWOG]).(ABSTRACT TRUNCATED AT 400 WORDS)
PUVA therapy has its roots in ancient India and Egypt and began to come into general use in the highly developed countries in the middle of the 1970's (1). The first reports of PUVA treatment of mycosis fungoides were published in 1976 (2); these were followed by several other studies in the two following years (3-7). Some of the early work on PUVA therapy was carried out in Sweden (8,9), and the modality was in general use in most major clinics by 1977. The dramatic effect on mycosis fungoides of PUVA therapy is well known, but whether the death rate is influenced is not known. For ethical reasons no controlled clinical studies have been performed. Sweden is a highly organized country with reliable death statistics at least for diseases as conspicuous as mycosis fungoides. The purpose of the present study was to provide data on the death rate in mycosis fungoides in Sweden from 1961 to 1990, which we think is relevant to the question whether PUVA treatment decreases the death rate in mycosis fungoides.
To investigate the efficacy of combined topical therapy and systemic interferon alfa-2a in patients with mycosis fungoides (MF) and the Sézary syndrome (SS).
Between December 1987 and April 1993, 39 patients with all stages of MF and SS were treated with combined phototherapy and systemic interferon alfa-2a as part of two institutional studies. The initial phase I study of 15 patients established the maximum-tolerated dose of interferon and has been previously reported. Subsequently, 24 patients have been entered onto a phase II trial. Long-term follow-up data are provided for both studies.
The median follow-up duration for the entire cohort is 28 months. Patients with all stages of disease were enrolled (stage IB, n = 14; IIA, n = 5; IIB, n = 6; III, n = 8; IVA, n = 5; IVB, n = 1). Thirty-four patients had received previous therapy. Overall, 36 of 39 patients achieved a complete response (CR; 62%) or partial response (28%) to therapy. The median response duration is 28 months (range, 1 to 64). Twenty-nine of 39 patients are alive, with a median survival duration of 62 months (range, 1 to 66).
Interferon alfa-2a combined with phototherapy is an effective, safe, durable therapy for MF and SS.
Standard therapy of the CTCL MF and SS consists of topical glucocorticosteroids, PUVA, topical chemotherapy, and total skin electron beam irradiation in stages Ia and IIa; local radiation or total skin electron beam irradiation in stage IIb; and systemic chemotherapy in stages III and IV. The experimental treatment modalities, interferon-alpha and retinoids, especially arotinoid, are most effective in early stages of CTCL; in advanced stages, the effectiveness can be increased by combination regimens. Up to now, the most promising results are obtained by combination therapy of interferon and PUVA. When serotherapy is considered as a therapeutic alternative for patients in stage IIb to IVb, the benefit/risk ratio must be carefully analyzed. Anti-thymocyte-globulin and monoclonal antibodies, either alone or conjugated to radioisotopes or toxin, have shown some therapeutic effect but are still under investigation. Extracorporal photopheresis is well established in erythrodermic patients. Initial reports also have shown encouraging results with this treatment for stage Ib and in combination with methotrexate or interferon. Hexadecylphosphocholine, a new, well-tolerated topical agent, induced a remission rate of 50%, with 25% complete remission in CTCL patients of stage Ia to IIb.
Patients with mycosis fungoides (MF) are frequently treated with UV light and psoralen (PUVA), nitrogen mustard, and electron beam irradiation, modalities known to predispose persons to development of cutaneous malignancies.
We assessed the relation between these therapeutic modalities and the development of secondary cutaneous malignancies.
We reviewed the charts of all patients observed during the past year.
We found that 7 of 71 patients had cutaneous neoplasms in an average follow-up time of 8.3 years. Orthovoltage radiation was used in five of seven cases and PUVA in four of seven. Five of seven patients had multiple neoplasms.
The risk of the development of second malignancies from the treatment of MF is relatively small and appears to be related to the type of therapy.
To review recent studies of systemic therapy for mycosis fungoides and the Sézary syndrome (cutaneous T-cell lymphomas).
English-language articles indexed in MEDLINE from 1988 through 1994.
All therapeutic studies were selected.
The data were abstracted without judgments on response criteria or patient numbers. Data quality and validity were assessed by independent author reviews.
No systemic therapy cures patients with cutaneous T-cell lymphomas. Single and combined chemotherapeutic agents produce high response rates. Whether any of these is preferred is not established. A randomized trial comparing combination chemotherapy plus radiation therapy with topical therapy showed no survival benefit for the combination. Several adenosine analogs and retinoids were active, but their optimal use is uncertain. Interferons are as active as chemotherapeutic agents and may be less toxic. Interferon combined with psoralen plus ultraviolet A light therapy produces high complete response rates and long-lasting remissions. Combinations with other systemic therapies do not increase response rates. Photopheresis therapy should be regarded as experimental. Promising preliminary results were seen with interleukin-2 fusion toxins and several antibody conjugates.
Systemic therapy should be considered effective and palliative. The principles of treating all low-grade lymphomas can be applied. Randomized trials are needed to evaluate new agents (such as a comparison of psoralen plus ultraviolet light with or without interferon), and large phase II trials are needed for new agents such as photopheresis, interleukin-2 fusion toxin, temozolomide, and others.
The term cutaneous T-cell lymphoma designates a group of neoplasms of skin homing T-cells that show considerable variation in clinical presentation, histological appearances, immunophenotype and prognosis. The disadvantages of currently available histological classification schemes are discussed and a new classification is presented. This is based on a combination of clinical, histological and immunophenotypic criteria and it recognizes distinct clinico-pathological entities within this group of diseases.
In 1982 we reported our preliminary observations on the use of home UV phototherapy for patch and early plaque phase mycosis fungoides (MF).
Our purpose was to present follow-up data of the original 31 patients, covering an interval of up to 15 years.
All patients used a commercially available UV phototherapy unit that contained four Westinghouse FS40 fluorescent lamps for daily exposures of their non-sun-exposed skin regions.
A complete clinical and histologic response to home phototherapy occurred in 23 patients (74%) with a maximum duration of the response from 5 months to more than 15 years (median 51 months). After maintenance phototherapy was discontinued, seven patients (23%) had a sustained disease-free interval lasting more than 58 months (median > 90 months). This indicates that cure may have been achieved in a minority of patients. Phototherapy was well tolerated without evidence of significant photodamage or photocarcinogenicity.
These observations indicate that home phototherapy may be a therapeutic option for treatment of selected patients with early MF.
Primary cutaneous CD30 (Ki-1)-positive, large cell lymphomas (LCLs) represent a recently recognized group of cutaneous T-cell lymphomas with a favorable prognosis. The characteristic features of this cutaneous lymphoma are reviewed, differences with primary noncutaneous CD30+ LCLs emphasized, and its relation with other CD30+ cutaneous lymphoproliferative disorders, in particular lymphomatoid papulosis, is discussed. These primary cutaneous CD30+ LCLs, lymphomatoid papulosis, and related conditions represent a clinical and histologic continuum. A classification with practical guidelines for the management and treatment of patients within this spectrum of lymphoproliferative disorders is presented.
Unlabelled:
BACKGROUND AND DESIGN--The optimal therapy for the mycosis fungoides type of cutaneous T-cell lymphoma has yet to be determined. Based on recent reports on the efficacy of high-dose interferon alfa in cutaneous T-cell lymphoma, we chose to test the hypothesis that systemic adjunctive therapy with low-dose interferon alfa along with psoralen and long-wave UV-A radiation (PUVA) could decrease the amount of PUVA necessary to achieve the best response, as well as improve the therapeutic effect of PUVA. Five patients with cutaneous T-cell lymphoma (mycosis fungoides type) were initially treated unsuccessfully with PUVA alone (three times a week for at least 3 months); PUVA was stopped, patients' diseases were re-staged, then interferon alfa (3 x 10(6) U/d for 1 week, then 6 x 10(6) U/d for 1 week) was initiated 2 weeks prior to restarting PUVA. Responses to treatment were graded as complete remission (skin clear, or negative biopsy specimens of remaining dermatitic lesions), partial remission (> 50% improvement), progression (> 25% worsening), or no change (failure to qualify for other categories) at 4, 8, 12, and 16 weeks. OBSERVATIONS--After 3 to 5 months of treatment with PUVA thrice weekly, none of the patients treated with PUVA alone had achieved complete remission. By contrast, systemic adjunctive therapy with low-dose interferon alfa along with PUVA resulted in complete remissions in all five (100%) patients in an average of 3.2 months (in three patients, lesions were cleared by 3 months). Average of 107 additional joules (68% more) and 1.6 additional months of PUVA administered thrice weekly was required to achieve the best response attainable with PUVA alone compared with complete remissions achieved with combined interferon alfa and PUVA therapy.
Conclusion:
--These data indicate that patients with disease refractory to PUVA alone can achieve a complete remission if they restart treatment with PUVA in combination with well-tolerated low doses of interferon alfa. In addition, the duration of PUVA exposure can be reduced with the addition of low-dose interferon alfa to the conventional PUVA treatment of cutaneous T-cell lymphoma of the mycosis fungoides type in such patients.
Cutaneous T-cell lymphoma (CTCL) often begins as limited patches and plaques on the skin that can be effectively treated with ultraviolet radiation. Many long-term remissions and cures have been well documented with the use of ultraviolet radiation alone for stage I CTCL. The side effects of this treatment are minimal.
The significance of oral psoralen photochemotherapy (PUVA) for the development of nonmelanoma skin cancers (NMSC) is still controversial.
We evaluated 496 psoriatics, who received PUVA treatment according to the European PUVA protocol in order to reassess the influence of the cumulative UVA dose on the development of NMSC and to answer the question if there is a UVA threshold dose above which the carcinogenic risk is increased.
The study was conducted as a retrospective investigation. All patients were seen personally. Age, sex, skin type, cumulative UVA dose and carcinogenic risk factors (arsenic, X-rays, tar, UVB, methotrexate) were recorded and investigated by marginal (MA) and partial effects analyses (PA) according to the Cox regression model.
In 14 patients (2.8%), one or multiple histologically confirmed NMSC were diagnosed. Nine patients (1.8%) had squamous cell carcinoma (SCC), 5 patients (1.0%) had basal cell carcinoma (BCC). No patient had both types of NMSC. None of the SCC had metastasized. By taking the appearance of BCC and SCC as the endpoint, arsenic [MA: relative risk (RR) = 7.62; PA:RR = 5.36], tar (MA:RR = 4.51; PA:RR = 3.83) and methotrexate (MTX; MA:RR = 4.97; PA:RR = 4.07) appear to produce strong and significant effects (p < 0.05), both in MA and PA. Using the endpoint SCC only, the effect of the natural logarithm of UVA (ln UVA; RR = 2.47), arsenic (RR = 11.2), tar (RR = 9.92) and MTX (RR = 7.1) is significant (p < 0.05) in MA. In PA, only the effect of arsenic (RR = 5.19) is strong and significant (p < 0.05) while the effects of tar (RR = 7.85), MTX (RR = 3.22) and ln UVA (RR = 2.77) are strong but of borderline significance (p = 0.05-0.11). Nonlinear effects of ln UVA on the risk of SCC were far from significant (p > 0.2).
PUVA with the European treatment protocol appears to be only a weak carcinogen by itself for SCC with a linear increase in tumor risk but not for BCC development.
Updated Kiel classification for lymphomas. Lancet I
- Ag Stansfield
- J Diebold
- Y Kapanacy
Photochemotherapy of mycosis fungoides
- H Konrad K Gschnait F Hönigsmann
- K Wolff
- H Hönigsmann
A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group
- N L Harris
- E S Jaffe
- H Stein
- NL Harris