Robert Knobler

WHO/EORTC classification of cutaneous lymphomas 2005: histological and molecular aspects.

Abstract:  The new WHO/EORTC classification for cutaneous lymphomas comprises mature T‐cell and natural killer (NK)‐cell neoplasms, mature B‐cell neoplasms, and immature hematopoietic malignancies. It reflects the unique features of lymphoproliferative diseases of the skin, and at the same time it is as compatible as possible with the concepts underlying the WHO classification for nodal lymphomas and the EORTC classification of cutaneous lymphomas. This article reviews the histological, phenotypical, and molecular genetic features of the various nosological entities included in this new classification. These findings always have to be interpreted in the context of the clinical features and biologic behavior.

A multicenter prospective phase 2 randomized study of extracorporeal photopheresis for treatment of chronic graft-versus-host disease

Chronic graft-versus-host disease (cGVHD) is a major limitation of successful hematopoietic cell transplantation. The safety and efficacy of extracorporeal photopheresis (ECP) for 12 to 24 weeks together with standard therapy was compared with standard therapy alone in patients with cutaneous manifestations of cGVHD that could not be adequately controlled by corticosteroid treatment. The primary efficacy end point was a blinded quantitative comparison of percent change from baseline in Total Skin Score (TSS) of 10 body regions at week 12. Ninety-five patients were randomized to either ECP and standard therapy (n = 48) or standard therapy alone (n = 47). The median percentage improvement in TSS at week 12 was 14.5% for the ECP arm and 8.5% for the control arm (P = .48). The proportion of patients who had at least a 50% reduction in steroid dose and at least a 25% decrease from baseline in TSS was 8.3% in the ECP arm at week 12 and 0% in the control arm (P = .04). The nonblinded investigator assessment of skin complete or partial responses revealed a significant improvement in favor of ECP (P < .001). ECP was generally well tolerated. These results suggest that ECP may have a steroid-sparing effect in the treatment of cGVHD. Clinical trials registered at www.ClinicalTrials.gov as NCT00054613.

EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma

Primary cutaneous CD30(+) lymphoproliferative disorders (CD30(+) LPDs) are the second most common form of cutaneous T-cell lymphomas and include lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma. Despite the anaplastic cytomorphology of tumor cells that suggest an aggressive course, CD30(+) LPDs are characterized by an excellent prognosis. Although a broad spectrum of therapeutic strategies has been reported, these have been limited mostly to small retrospective cohort series or case reports, and only very few prospective controlled or multicenter studies have been performed, which results in a low level of evidence for most therapies. The response rates to treatment, recurrence rates, and outcome have not been analyzed in a systematic review. Moreover, international guidelines for staging and treatment of CD30(+) LPDs have not yet been presented. Based on a literature analysis and discussions, recommendations were elaborated by a multidisciplinary expert panel of the Cutaneous Lymphoma Task Force of the European Organization for Research and Treatment of Cancer, the International Society for Cutaneous Lymphomas, and the United States Cutaneous Lymphoma Consortium. The recommendations represent the state-of-the-art management of CD30(+) LPDs and include definitions for clinical endpoints as well as response criteria for future clinical trials in CD30(+) LPDs.

Treatment of erythrodermic cutaneous T-cell lymphoma with extracorporeal photochemotherapy

BACKGROUND This original cohort of patients with erythrodermic cutaneous T-cell lymphoma (CTCL) was reported to have clinical improvement with photopheresis during the 12 months of the original study. No long-term follow-up data have been available to examine the impact of this therapy on the disease. OBJECTIVE Our purpose was to provide long-term follow-up on the original 29 erythrodermic CTCL patients treated with photopheresis and to compare these results with historical controls. METHODS Files of patients from the original photopheresis study centers were reviewed and their current status was documented. RESULTS The median survival of the treated patients was 60.33 months from the date of diagnosis and 47.9 months from the date of the start of photopheresis therapy. A complete remission has been maintained in four of the six patients who achieved complete responses in the original study. The best responses were seen in patients with a lower CD4/CD8 ratio in the peripheral blood at the start of therapy. CONCLUSION Photopheresis can influence the natural history of erythrodermic CTCL by inducing remissions and prolonging survival with minimal toxicity.

Enzyme histochemical analysis of cell viability after argon laser-induced coagulation necrosis of the skin.

Reduction of nitroblue tetrazolium chloride, a redox indicator, by nicotinamide adenine dinucleotide diaphorase produces in frozen tissue sections an intense blue cytoplasmic pigment. The activity of this enzyme has been shown to subside immediately upon cell death. Twelve patients with port-wine stains were treated with an argon laser. Frozen tissue sections from biopsy specimens obtained before and 10 minutes, 24 hours, and 48 hours after laser application were processed for nitroblue tetrazolium chloride staining. In normal skin all epidermal and dermal cells displayed dense cytoplasmic blue granular pigment that spared the nuclei. In port-wine stains the laser-induced coagulation necrosis was first seen as an arc-shaped, sharply demarcated, unstained, nitroblue tetrazolium chloride-negative area. Initiation of epidermal repair could be observed in all 48-hour sections. The nitroblue tetrazolium chloride method, when compared with hematoxylin and eosin staining, allowed an easier and more accurate definition of laser injury because of the color difference between damaged and normal tissue.

Granulomatous mycosis fungoides and granulomatous slack skin: a multicenter study of the Cutaneous Lymphoma Histopathology Task Force Group of the European Organization For Research and Treatment of Cancer (EORTC)

BACKGROUND Granulomatous cutaneous T-cell lymphomas (CTCLs) are rare and represent a diagnostic challenge. Only limited data on the clinicopathological and prognostic features of granulomatous CTCLs are available. We studied 19 patients with granulomatous CTCLs to further characterize the clinicopathological, therapeutic, and prognostic features. OBSERVATIONS The group included 15 patients with granulomatous mycosis fungoides (GMF) and 4 with granulomatous slack skin (GSS) defined according to the World Health Organization-European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas. Patients with GMF and GSS displayed overlapping histologic features and differed only clinically by the development of bulky skin folds in GSS. Histologically, epidermotropism of lymphocytes was not a prominent feature and was absent in 9 of 19 cases (47%). Stable or progressive disease was observed in most patients despite various treatment modalities. Extracutaneous spread occurred in 5 of 19 patients (26%), second lymphoid neoplasms developed in 4 of 19 patients (21%), and 6 of 19 patients (32%) died of their disease. Disease-specific 5-year survival rate in GMF was 66%. CONCLUSIONS There are clinical differences between GMF and GSS, but they show overlapping histologic findings and therefore cannot be discriminated by histologic examination alone. Development of hanging skin folds is restricted to the intertriginous body regions. Granulomatous CTCLs show a therapy-resistant, slowly progressive course. The prognosis of GMF appears worse than that of classic nongranulomatous mycosis fungoides.

Treatment of cutaneous T cell lymphoma with a combination of low-dose interferon alfa-2b and retinoids

In a pilot study the therapeutic effect and side effect profile of low-dose interferon alfa-2b in combination with a retinoid for the treatment of cutaneous T cell lymphoma were evaluated. Seven patients (four women, three men) with histologically confirmed cutaneous T cell lymphoma were included. Four patients had received therapy previously. The treatment schedule consisted of 2 million U of interferon alfa-2b administered subcutaneously three times per week and oral 13-cis-retinoic acid, 1 mg/kg/day, with subsequent dose reduction in case of response. The combination therapy produced two complete and two partial remissions. Responses were maintained by continuous therapy for up to 15 months even after dose reduction of both agents by 50%. Side effects were negligible and did not result in discontinuation of treatment in any patient.

The optimal use of bexarotene in cutaneous T‐cell lymphoma

The management goal in cutaneous T‐cell lymphomas (CTCLs) is to improve symptoms and induce remission. Early‐stage disease is generally treated with skin‐directed therapies. However, if these do not control the disease, systemic therapy becomes necessary. Bexarotene, a novel rexinoid, is an oral, noncytotoxic drug that has been approved in Europe for the treatment of refractory advanced‐stage CTCL and in the U.S.A. for refractory CTCL. We provide guidance on the use of bexarotene in the management of CTCL, based on data from phase II/III clinical trials and the authors’ clinical experience, and suggest how the potential of the drug can be maximized. The clinical trial results with bexarotene are reviewed, especially in comparison with interferon‐α, which is the other commonly used noncytotoxic systemic therapy for CTCL. A treatment algorithm for bexarotene in refractory CTCL is suggested. As bexarotene may take time to achieve a maximum response, this algorithm recommends that therapy should be continued for a sufficient period to allow for a delayed onset of action. In addition, possible combination therapies with bexarotene are discussed. We conclude that bexarotene is effective in the management of CTCL, and has the advantage of oral administration. An on‐going randomized clinical trial comparing psoralen plus ultraviolet A (PUVA) with PUVA plus bexarotene will provide valuable information about this combination regimen in early‐stage disease, but further data are needed on the relative efficacies of other combination therapies with bexarotene in CTCL.

Variable pulsed light is less painful than light-emitting diodes for topical photodynamic therapy of actinic keratosis : a prospective randomized controlled trial

Background  Photodynamic therapy (PDT) of actinic keratosis (AK) using methylaminolaevulinate (MAL) is an effective and safe treatment option, but the procedure is painful.

Minimizing adverse side-effects of oral bexarotene in cutaneous T-cell lymphoma: an expert opinion

Bexarotene is an oral retinoid therapy that is effective for the treatment of early and advanced‐stage cutaneous T‐cell lymphoma (CTCL) in patients who have failed on other therapies. However, bexarotene treatment is associated with unavoidable side‐effects, in particular hypertriglyceridaemia and hypothyroidism, which are manageable with adequate concomitant medications and are reversible on cessation of treatment. A pragmatic strategy for minimizing bexarotene‐associated hypertriglyceridaemia and hypothyroidism is suggested, based on data from the studies with bexarotene in CTCL and on day‐to‐day experience with this agent in the clinical setting. The strategy anticipates that these common adverse events are likely to occur and recommends the early use of preventive therapy to lower triglycerides and elevate thyroid hormone levels in the blood, followed by subsequent monitoring, dose adjustment during bexarotene treatment, and titration of the daily bexarotene dose from 150 to 300 mg m−2, which is optimal for most patients. When further information becomes available on how bexarotene interacts with lipid metabolism and thyroid function, the management approach suggested here may need to be changed.