New developments in Sézary syndrome

Sézary syndrome (SS) represents 3% of cutaneous T-cell lymphomas (CTCL). It is an aggressive epidermotropic CTCL with a 5-year survival rate of 24%. According to EORTC (European organization for research and treatment of cancer), SS is defined by erythroderma, diffuse lymphadenopathy, atypical T lymphocytes (>1000/mm(3)), and the presence of a major blood, cutaneous and nodal T cell clone. A specific marker for atypical tumoral T lymphocytes known as Sézary cells was identified in 2001, namely KIR3DL2 (CD158k) receptor, which allows more specific diagnosis of SS; levels of this marker are highly correlated with the clinical course of the disease. In therapeutic terms, clinical trials are being conducted on new molecules that point towards an improved prognosis for this disease. We propose a review of Sézary syndrome, which is currently the subject of scientific papers concerning both physiopathology and therapeutics, with new prospects of targeted therapy.     

Sézary syndrome: a summary

Sézary syndrome is the leukemic form of primary cutaneous T-cell lymphoma. It is an aggressive disease, with the lowest reported median survival of all cutaneous lymphomas. Patients with Sézary syndrome live with the awareness that they are suffering from an incurable disease. Having to cope daily with extensive skin care regimens, these patients can benefit tremendously from the expertise of dermatology nurses, who can teach them skin selfcare and who are aware of the psychologic impact of this disease. The symptoms, treatments, and emotional distress related to Sézary syndrome are summarized.     

Oral bexarotene in a therapy-resistant Sézary syndrome patient: observations on Sézary cell compartmentalization

BACKGROUND: A 63-year-old man with therapy-resistant Sézary syndrome was enrolled in a multicenter trial of oral bexarotene for advanced-stage cutaneous T-cell lymphoma (CTCL). METHODS: Monthly evaluations for efficacy and side-effects were conducted and documented. RESULTS: Gradual improvement in erythema, pruritus, and scale was noted during the initial 16-week trial period and treatment was extended to 40 weeks. From week 20 to week 40, the erythroderma continued to improve and the lymph node burden decreased, but the absolute Sézary cell count inversely increased. By week 40, intractable pruritus and erythroderma abruptly recurred, and bexarotene was discontinued. CONCLUSIONS: Bexarotene is well tolerated and can be efficacious in patients with Sézary syndrome. Shifting of Sézary cells between different compartments was noted. Further studies on the interaction between the skin, lymph nodes, and peripheral blood compartments during bexarotene treatment in this subset of patients with CTCL are needed.     

The man behind the eponym dermatology in historical perspective: Albert Sézary and the Sézary syndrome

In a series of papers from 1938 to 1949, Albert Sézary, a French dermatologist and syphilologist, described erythroderma with cellules monstrueuses (monster cells) in the skin and blood, which is now known as Sézary syndrome or Sézary disease. This historical note reprises the life and work of Sézary. It outlines his original reports and his thoughts about the pathogenesis of the disease as a reticulosis, and lists a composite classification of the reticuloses, which includes that of Sézary. We touch briefly on the articles that first used the terms Sézary reticulosis and Sézary syndrome and the changing concepts of the reticuloses and the reticuloendothelial system. We conclude that Sézary syndrome (Sézary disease, Sézary reticulosis) cannot be separated from mycosis fungoides clinically, histopathologically, hematologically, or viscerally and, therefore, is not a disease sui generis. Despite our conclusions, present day consensus defines Sézary disease clinically as a generalized pruritic erythroderma: histopathologically with an epidermal and dermal infiltrate, lymphadenopathy and visceral involvement all containing monster cells (Lutzner/Sézary cells) in the skin, peripheral blood, lymph nodes, and viscera, a disease different and separate from mycosis fungoides.     

Sustained remission of Sézary syndrome

Sézary syndrome, an aggressive form of cutaneous T-cell lymphoma, is a devastating, highly symptomatic form of non-Hodgkin lymphoma. Malignant clones of mature helper CD4 T cells containing large, convoluted nuclei known as Sézary cells circulate in the blood and infiltrate the skin. Clinical features include exfoliative erythroderma, generalized lymphadenopathy, alopecia, onychodystrophy, palmoplantar hyperkeratosis, and ectropion. Patients often have severe pruritus, burning sensations, pain, bleeding from excoriations, and disfigurement. Extracorporeal photopheresis, an immunomodulatory therapy, has become a primary therapy for these patients. This pheresis-based therapy uses psoralen and ultraviolet A radiation-mediated photochemotherapy to induce immune responses. The effects of extracorporeal photopheresis vary considerably. We report sustained remission (2 years) in a patient with Sézary syndrome. Previously he had received extracorporeal photopheresis and interferon alfa-2b injections. He is the only one of 55 patients with Sézary syndrome treated at Mayo Clinic (Rochester, Minnesota, USA) to achieve sustained remission on extracorporeal photopheresis alone.     

Prognostic factors in Sézary syndrome: a study of 28 patients

BACKGROUND: The new European Organization for Research and Treatment of Cancer classification considers Sézary syndrome (SS) among the aggressive epidermotropic cutaneous T-cell lymphomas (ECTLs). Recent technological advances have facilitated the diagnosis of this disease, but it remains practically incurable, with a median survival of about 2.5-5 years. Deaths are due in part to the iatrogenic effects of treatments, which suggests that the management of SS could be improved. OBJECTIVES: Retrospectively to study the prognostic criteria related to disease progression. METHODS: Thirty patients with SS were followed up in the Dermatology Department of the University Hospital in Nantes, France, between January 1989 and May 2000. The diagnosis of SS was based on at least three of the following criteria: erythroderma, histological evidence of ECTL, a level of 20% or more circulating Sézary cells, and loss of My7 antigen expression by basal cells of the epidermis. Two patients not seen again after the initial diagnosis were excluded from the statistical study. RESULTS: The median disease-specific survival of the 28 patients was 64.55 +/- 10.11 months. The prognostic factors found in univariate analysis were age at diagnosis (P = 0.0109), interval before diagnosis (P = 0.0566), lactate dehydrogenase (LDH) level (P = 0.042) and presence of the Epstein-Barr virus (EBV) genome (BHLF in in situ hybridization) in skin (P = 0.0079). The prognostic factors found in multivariate analysis were age, interval before diagnosis and presence of the EBV genome in keratinocytes. A decreased number of Langerhans cells in the epidermis did not appear to be a prognostic factor. CONCLUSIONS: Our study confirms the prognostic value of age and LDH level, and for the first time demonstrates the prognostic value of the identification of the EBV genome in the skin. This seems consistent with a marked immune deficit during severe forms of SS.     

Sézary syndrome: diagnostic criteria and therapeutic options

Sézary syndrome (SS) is a rare form of erythrodermic cutaneous T-cell lymphoma with hematological involvement and a poor prognosis. Therapies include photopheresis, with or without interferon, chemotherapy, and total skin electron beam therapy. The lack of any randomized studies makes it difficult to assess the effect of current therapy on survival. In addition, the different response rates reported for individual treatments may depend as much on the criteria used to define SS as the therapy itself. This article reviews the diagnostic tests that are needed to reliably diagnose SS and offers a critical analysis of current treatment options.     

Secondary malignant neoplasms in 71 patients with Sézary syndrome

BACKGROUND: Sézary syndrome (SS) is characterized by a malignant proliferation of CD4+ve T cells, which may result in a degree of immunoparesis. Immunosuppression is associated with an increased incidence of internal malignant neoplasms and a high rate of nonmelanoma skin cancer, particularly squamous cell carcinoma. Therefore, we reviewed the incidence of secondary malignant neoplasms in patients with SS. OBSERVATIONS: Of 71 patients with SS, 16 (23%) developed 19 secondary and tertiary malignant neoplasms. These malignant neoplasms included 8 cutaneous squamous cell carcinomas, 2 squamous cell carcinomas of the oral mucosa, and 9 other internal malignant neoplasms. The incidence of internal malignant neoplasms was twice that reported in patients of similar age treated for Hodgkin disease (P = .02). Furthermore, the incidence of cutaneous squamous cell carcinoma in the cohort was 42 times that observed in a study conducted in England of an age-matched population (1657 per 1 x 10(5) vs 39 per 1 x 10(5) person-years [95% confidence interval, 626-2856]). CONCLUSIONS: A number of therapeutic modalities for SS are known to be carcinogenic. We compared the different therapeutic modalities received by our patients and found no significant difference between the total cohort of patients with SS and the patients who developed secondary malignant neoplasms. These data indicate that the high incidence of secondary malignant neoplasms in patients with SS is due, at least in part, to the disease itself. The clonal proliferation of CD4+ve T cells and the relative lymphopenia (compared with a healthy population) of nonneoplastic T cells may result in compromised immunosurveillance, so that early neoplasia, whether arising spontaneously or as a result of therapy, are not dealt with appropriately.     

A case of bullous Sézary syndrome

Sézary syndrome is an aggressive variant of cutaneous T cell lymphoma with poor prognosis and clinically characterized by erythroderma and Sézary cells in the blood. Here we report a case of bullous Sézary syndrome. A seventy-year-old male presented with erythroderma and inguinal lymph node swelling. Histopathological examination showed dermal and epidermal infiltration of atypical lymphocytes and Sézary cells could be detected in peripheral blood samples. He was therefore diagnosed as Sézary syndrome. Four months after the onset, he developed bullae on axillary and inguinal areas, featuring subepidermal blistering with basal cell degeneration and dense infiltration of atypical lymphocytes. Autoimmune bullous diseases were excluded by negative immunofluorescence. Bullous forms of Sézary syndrome are extremely rare although several cases of a bullous variant of mycosis fungoides have been reported.     

Systemic Hodgkin's lymphoma in a patient with Sézary syndrome

We report a case of a 71-year-old male with Sézary syndrome diagnosed in 1996 who subsequently developed systemic Hodgkin's lymphoma. His only past treatment was bath psoralen plus ultraviolet A. He has since been treated with multiagent chemotherapy (ChlVPP/PABLOE) which induced a remission in his Hodgkin's disease. Eighteen months later he remains in remission from Hodgkin's disease but the Sézary syndrome remains active. He has also developed a squamous cell carcinoma on the upper lip. Sézary syndrome is a primary cutaneous T-cell lymphoma characterized by a malignant proliferation of CD4-positive cells in the skin and peripheral circulation. The CD4 count may be markedly elevated but this results from expansion of a neoplastic T-cell clone and there is a relative lymphopenia of normal T cells leading to a degree of immunoparesis. Immunosuppression is known to be associated with an increased rate of malignancies and this may account for the occurrence of Hodgkin's disease and squamous cell carcinoma in this patient with Sézary syndrome.     

Pathogenetic mechanisms of vitiligo in a patient with Sézary syndrome

Patients exhibiting association between vitiligo and cutaneous T-cell lymphoma (CTCL) remain rare and it is not known whether some T-cell subpopulations of CTCL in the skin are able to recognize specific melanocytic epitopes and thus induce vitiligo. The aim of our study was to determine whether T cells specific to melanocyte differentiation antigens were detectable among tumour-infiltrating lymphocytes (TIL) in the hypopigmented skin of a patient with Sézary syndrome (SS). A 71-year-old patient presented with SS and developed vitiligo during the course of her disease. Immunohistochemical studies showed staining with HMB45 and MelanA antibodies in the pigmented skin biopsy, whereas no staining was observed in the hypopigmented skin biopsy. To analyse responses to melanocyte differentiation antigens, we used a transient COS transfection assay that permits an estimation of CD8 T-cell responses against a large number of HLA/antigen combinations. This technique allowed the detection of melanocyte differentiation antigen-specific T lymphocytes, directed mainly against Melan-A/MART1 antigen in the HLA-A*23 context. Our study supports the concept that vitiligo that has developed during the evolution of a CTCL is related to the presence of a T-lymphocyte subpopulation reactive against melanocyte differentiation antigens (mainly Melan-A/MART1) present in skin lesions. The role of interferon in the induction of this T-lymphocyte subpopulation is discussed.     

Sézary syndrome in a young man with severe atopic dermatitis

Sézary syndrome (SS) is a rare cutaneous T-cell lymphoma. SS usually develops de novo. We describe a 23-year-old man with a proven history of severe atopic dermatitis since childhood, who developed SS. This case contributes to the discussion about the possibility of a relationship between inflammatory dermatitis, atopy and subsequent SS. We provide criteria that should be fulfilled to define such an association.     

Sézary syndrome in a patient receiving infliximab for ankylosing spondylitis

Infliximab, a tumour necrosis factor (TNF)-alpha antagonist, has shown striking efficacy in the treatment of chronic inflammatory rheumatological diseases such as rheumatoid arthritis and ankylosing spondylitis. However, long-term follow-up studies support that treatment with infliximab is associated with an increased risk of non-Hodgkin lymphoma. So far, few cases of cutaneous lymphoma have been reported in patients receiving TNF-alpha-blocking agents. We report a patient who developed Sézary syndrome 17 months after the onset of infliximab therapy for ankylosing spondylitis. Cutaneous lesions partially remitted following infliximab withdrawal and methotrexate treatment. Although the causal link between infliximab and the emergence of Sézary syndrome is uncertain, the present case raises the need for exhaustive long-term registries of malignancies, including primary cutaneous lymphomas, in patients receiving TNF-alpha-blocking agents.