Cutaneous T‐cell lymphoma and atopy: is there an association?

BACKGROUND: Case reports have suggested a relationship between atopic diatheses and Sézary syndrome, pre-Sézary syndrome or mycosis fungoides. However, Sézary and pre-Sézary syndromes are rare entities, and this association has never been analysed in greater detail for specific subtypes of cutaneous T-cell lymphoma (CTCL). OBJECTIVES: To evaluate the prevalence of atopy in subjects with Sézary syndrome, pre-Sézary syndrome or mycosis fungoides, and to compare the rates with the reported prevalence of atopy in the general population. METHODS: We retrospectively reviewed the records of 157 patients with the diagnosis of Sézary or pre-Sézary syndrome seen between 1965 and 2000, and 102 patients with the diagnosis of mycosis fungoides evaluated from 1994 to 2000 at Mayo Clinic. RESULTS: Of 157 subjects with Sézary or pre-Sézary syndrome and 102 subjects with mycosis fungoides, 18 and 12, respectively, were identified as having a history of atopic dermatitis, asthma or allergic rhinitis. The prevalence rates of atopy in Sézary or pre-Sézary syndrome and mycosis fungoides were 11.5% (95% confidence interval 6.9-17.5%) and 11.8% (6.2-19.7%), respectively. CONCLUSIONS: No significant difference exists in the prevalence of atopy in Sézary or pre-Sézary syndrome compared with that in mycosis fungoides (chi2-test, P = 1.00). Furthermore, the rates of atopy in Sézary or pre-Sézary syndrome and mycosis fungoides are not significantly different from the prevalence of atopy in the general population (17-40%). On the basis of these observations, no evidence currently implicates a causal association of CTCL with atopy.     

Cutaneous T cell lymphoma in children.

Cutaneous T cell lymphoma (CTCL) is a term used to describe a heterogeneous group of lymphoproliferative disorders that involve the skin. Mycosis fungoides and Sézary syndrome are two forms of CTCL that arise in adults and are uncommon in children. Dermatologists frequently employ the term CTCL as a synonym for mycosis fungoides and Sézary syndrome. There has been increased recognition that the mycosis fungoides and Sézary syndrome forms of CTCL may arise in children and adolescents. Moreover, younger adults with these types of CTCL report onset of symptoms during adolescence. The literature regarding CTCL in childhood is limited. The purpose of this article is the review the literature regarding CTCL arising in children. The clinical presentation including morphologic variants, diagnosis, prognosis, and management are summarized.     

A modified staging classification for cutaneous T-cell lymphoma

BACKGROUND: Despite refinements in the diagnosis of cutaneous T-cell lymphoma (CTCL), since 1979 there have been no changes to the staging of CTCL used to classify mycosis fungoides and Sézary syndrome. OBJECTIVE: We reviewed the current staging of CTCL and examined the usefulness of a new staging scheme for mycosis fungoides and Sézary syndrome. METHODS: We determined overall survival of 450 patients with mycosis fungoides and Sézary syndrome using the current and modified staging classifications. RESULTS: There were no significant differences between survival of patients with stage IB (patches/plaques involving greater than 10% body surface area) and IIA (peripheral adenopathy) disease and of patients with stage IIB (tumor) and III (erythroderma) disease. There was a significant difference in survival between patients with extensive patch versus extensive plaque stage disease. Modification of the current classification by splitting T2 into patch versus plaque stage disease and incorporating tumors and erythroderma into stage III proved superior to the current scheme in predicting overall survival. CONCLUSION: Modification of the current staging classification for CTCL yields subgroups useful in the prognostic assessment of CTCL.     

CD25+ folliculotropic Sézary syndrome with CD30+ large cell transformation

Folliculotropic Sézary syndrome is a rare and unique variant of cutaneous T‐cell lymphoma (CTCL) characterised by both follicular and leukaemic involvement of mycosis fungoides (MF). It is associated with a more aggressive clinical course and fatal outcomes. Large cell transformation (LCT) of mycosis fungoides/Sézary syndrome is also associated with an aggressive disease course and shortened survival, requiring an intensive therapeutic approach. This report describes a case of folliculotropic Sézary syndrome with CD30+ LCT. Most of the larger lymphocytes in the lesions were positive for CD25, the expression of which is associated with advanced CTCL. In addition, we review the literature on this unusual CTCL and provide evidence that this entity represents a distinct clinicopathological entity occasionally associated with extracutaneous involvement and LCT.     

Infrequent Expression of Protein p53 in Epidermotropic Variants of Cutaneous T-Cell Lymphoma

Although diverse types of lymphomas have been examined for immunohistochemical detection of p53 protein, little information is available with regard to p53 protein expression in CTCL. We analyzed cutaneous biopsy specimens of 22 patients with the diagnoses of mycosis fungoides or Sézary syndrome with polyclonal rabbit anti-p53 antiserum CM-1. Staining of neoplastic cells was observed only in two patients with advanced disease. Overexpression of p53 protein does not seem to be a major feature of either mycosis fungoides or Sézary syndrome.     

Interleukin-15 expression in cutaneous T-cell lymphoma (mycosis fungoides and Sézary syndrome)

BACKGROUND: Cytokines are of potential importance in the pathogenesis of cutaneous T-cell mediated disorders, including cutaneous T-cell lymphoma (CTCL). OBJECTIVES: To compare interleukin (IL)-15 expression in certain inflammatory cutaneous diseases, with that in CTCL (mycosis fungoides and Sézary syndrome). METHODS: IL-15 mRNA and protein expression were examined by in situ hybridization and immunohistochemistry, respectively, on formalin-fixed, paraffin-embedded biopsies of normal human skin, atopic dermatitis, psoriasis, parapsoriasis and CTCL. RESULTS: Despite similar expression of IL-15 mRNA, we found differences in IL-15 protein expression between normal human skin, atopic dermatitis and psoriasis on the one hand, and parapsoriasis and CTCL on the other. IL-15 protein expression was not detected in normal human skin, atopic dermatitis or psoriasis, but was detected, mainly at low levels but in a few patients at higher levels, in epidermal keratinocytes in parapsoriasis, mycosis fungoides and Sézary syndrome. CONCLUSIONS: Induction of keratinocyte IL-15 expression appears to be a feature of CTCL. The factors stimulating such an expression remain unknown.     

Sézary Cell Count in Exfoliative Dermatitis

Sézary cells were present in a number of less than 1000/mm3 in 52 of 78 cases of various benign diffuse dermatoses and mycosis fungoides. The count was higher than 1000/mm3 in two cases of Sézary syndrome in which the histopathology was that of mycosis fungoides and in six cases of exfoliative erythroderma of undetermined etiology with the histopathology of nonspecific chronic dermatitis. One of these six cases developed palmoplantar keratoderma, but abnormal cells were not present in the tissue. The diagnosis of Sézary syndrome in these cases of exfoliative erythroderma could not be established, even though the Sézary cell count was more than 1000/mm3, because the abnormal cells were absent in the skin biopsy specimen. It is concluded that the number of Sézary cells present is not significant for the diagnosis of Sézary syndrome. Our cases with the diagnosis of Sézary syndrome are an erythrodermic variant of mycosis fungoides rather than a progressive conversion from exfoliative erythroderma.     

Macrophage inhibitor factor (MIF) in cutaneous lymphoproliferative diseases

Macrophage migration inhibitor factor (MIF) activity in the sera of patients with mycosis fungoides, Sézary syndrome, and cutaneous lymphoma was observed in the sera of eight of the ten patients with stage II (infiltrative) mycosis fungoides, but in only one of the eight patients with stage I and in neither of the two patients with stage III mycosis fungoides. Two of the three patients with Sézary syndrome had MIF in the serum. No MIF was observed in cutaneous lymphoma. These data support the concept that Sézary syndrome and mycosis fungoides are T-cell diseases, and transitional, prelymphomatous diseases.     

Patch tests in Sézary syndrome and mycosis fungoides

A retrospective series of 34 patients with the diagnoses of Sézary syndrome, pre-Sézary syndrome, or mycosis fungoides had had patch testing. Of these, 27 had at least 1 positive reaction (11 of 12 with pre-Sézary syndrome, 6 of 10 with Sézary syndrome, and 10 of 12 with mycosis fungoides). The highest average number of positive reactions was observed in patients with pre-Sézary syndrome (4.7 per patient). There was no predominance of positive reactions to any one allergen, but 13 of the 27 patients reacted to a metal allergen. Only 1 of 5 patients who had photopatch testing had a positive result. This retrospective study revealed delayed contact hypersensitivity responses in this group of patients and should serve as a basis for prospective consideration of contact dermatitis factors in patients with mycosis fungoides and Sézary states.     

Leu-8/CD7 antigen expression by CD3+ T cells: comparative analysis of skin and blood in mycosis fungoides/Sézary syndrome relative to normal blood values.

Deficiencies of Leu-8 and CD7 antigens are exhibited by CD3+ T cells in the skin lesions of most patients with mycosis fungoides/Sézary syndrome. To determine whether these antigenic abnormalities are limited to involved skin, we studied Leu-8/CD7 expression in 21 skin lesions of mycosis fungoides/Sézary syndrome obtained from 16 patients and compared them with their peripheral blood leukocytes obtained concurrently. There was no correlation between Leu-8/CD7 values in skin lesions versus blood. Blood values were relatively uniform; most patients had 50% or greater of CD3+, Leu-8+ T cells and CD3+, CD7+ T cells. In contrast, skin values were highly heterogeneous; most patients lacked expression of Leu-8 or CD7 by the majority of lesional CD3+ T cells. Furthermore, Leu-8/CD7 antigen deficiency was present in lesional skin in one patient with mycosis fungoides but not in her concurrently sampled pityriasis lichenoides chronica or blood. These findings suggest that Leu-8/CD7 antigen deficiencies in skin lesions of mycosis fungoides/Sézary syndrome do not represent generalized antigenic abnormalities of CD3+ T cells in other body compartments and that within the skin, these deficiencies are disease specific within individual patients with more than one dermatosis. Comparative peripheral blood immunophenotyping of the patients with mycosis fungoides/Sézary syndrome and of the control subjects indicated that the control ranges of CD3+/Leu-8+ and CD3+/CD7+ T cells (33% or greater) extend lower than reported previously (60% or greater) and suggested that leukemic involvement in patients with mycosis fungoides/Sézary syndrome may correlate with percentages of CD3+, Leu8+ and/or CD3+, CD7+ T cells that fall below the revised control range.     

Aneuploidy in cutaneous T-cell lymphoma

A new method is described which makes it possible using skin specimens to perform flow cytometric analysis of DNA content. DNA content analysis was performed on 28 skin specimens and 9 blood samples from 18 patients with mycosis fungoides and Sézary syndrome. The reproducibility was fair, with almost identical results in 6 cases (mycosis fungoides and Sézary syndrome) where two samples (skin specimens or blood samples) were taken 6 hours to 10 days apart. Hyperdiploidy was found in 7 of 11 skin specimens from patients with mycosis fungoides stage I with negative histology. In 13 skin specimens and 3 blood samples from patients with mycosis fungoides stages II and IV, abnormalities including hyperdiploidy, near-tetraploidy and near-hexaploidy were found in 8 of 13 skin specimens and in 2 of 3 blood samples. Four patients with Sézary syndrome were studied: 2 patients in remission showed normal DNA histograms (2 skin specimens, 3 blood samples) and 2 patients with active disease showed aneuploidy in the 2 skin specimens examined and in 1 of 3 blood samples. These studies demonstrate: 1) the importance of flow cytometry as a diagnostic tool for use on skin specimens in the early stages of mycosis fungoides where routine histology is non-diagnostic; 2) the diagnostic and prognostic aid of flow cytometry during the course of mycosis fungoides and Sézary syndrome in addition to the probability of measuring the effect of treatment.     

Alemtuzumab in Sézary syndrome: efficient but not innocent

Mycosis fungoides is the most common form of cutaneous T-cell lymphomas. The related Sézary syndrome is a more aggressive form in which the skin is diffusely affected and the peripheral blood is involved. Although easily managed during its early phases, late-stage mycosis fungoides/Sézary syndrome is usually difficult to treat and becomes refractory to chemotherapy. Recently, promising case-based results have been obtained with alemtuzumab, a humanized immunoglobulin G1 monoclonal antibody that binds to CD52 cell surface antigens, in the treatment of advanced stage mycosis fungoides/Sézary syndrome. We report a case of Sézary syndrome treated successfully with alemtuzumab but who died of treatment-related infection.     

Fulminant Cutaneous T-cell Lymphoma and Sézary Syndrome

The term cutaneous T-cell lymphoma (CTCL) has recently been coined to describe a group of rare lymphoproliferative T-cell disorders classically beginning in the skin and pursuing a chronic, progressive, and indolent course eventually followed by visceral involvement. This term encompasses the spectrum of the traditional mycosis fungoides and Sézary syndrome. A unique case of CTCL that developed a fulminant course leading to death within a few months following the initial symptoms is presented. The clinical course bears a striking similarity to a group of acute T-cell malignancies, while the cytologic-pathologic findings favor the diagnosis of Sézary syndrome. Regardless of the exact classifications, this entity appears to be a highly malignant T-cell disorder, resistant to chemotherapy.     

Mycosis fungoides und Sézary-Syndrom – Überblick und Ausblick

Mycosis fungoides and Sézary syndrome are the most important representatives of the heterogeneous group of cutaneous T-cell lymphomas. The diseases are rare and the diagnosis, which always requires a clinical-pathological correlation, is often delayed, especially in early forms of mycosis fungoides. The prognosis of mycosis fungoides depends on its stage and is usually favorable in the early stages. Clinically relevant prognostic parameters are missing and their development is the subject of current clinical research. Sézary syndrome, characterized by initial erythroderma and blood involvement, is a disease with a high mortality rate, in which good responses can now be achieved in many cases with new treatment options. The pathogenesis and immunology of the diseases is heterogeneous, with recent results pointing primarily to changes in specific signal transduction pathways that may be suitable as future treatment targets. Current therapy for mycosis fungoides and Sézary syndrome is primarily palliative with topical and systemic options either used alone or in combination. Only with allogeneic stem cell transplantation durable remissions can be achieved in selected patients. Similar to other areas of oncology, the development of new therapies for cutaneous lymphomas is currently changing from relatively untargeted empiricism to disease-specific, targeted pharmacotherapy based on knowledge from experimental research.     

Allelotyping in mycosis fungoides and Sézary syndrome: common regions of allelic loss identified on 9p, 10q, and 17p

Allelotyping studies have been extensively used in a wide variety of malignancies to define chromosomal regions of allelic loss and sites of putative tumor suppressor genes; however, until now this technique has not been used in cutaneous lymphoma. We have analyzed 51 samples from patients with mycosis fungoides and 15 with Sézary syndrome using methods to detect loss of heterozygosity. Micro satellite markers were selected on 15 chromosomal arms because of their proximity to either known tumor suppressor genes or chromosomal abnormalities identified in previous cytogenetic studies in cutaneous lymphoma. Allelic loss was present in 45% of patients with mycosis fungoides and 67% with Sézary syndrome. Loss of heterozygosity was found in over 10% of patients with mycosis fungoides on 9p, 10q, 1p, and 17p and was present in 37% with early stage (T1 and T2) and 57% with advanced disease (T3 and T4). Allelic loss on 1p and 9p were found in all stages of mycosis fungoides, whereas losses on 17p and 10q were limited to advanced disease. In Sézary syndrome high rates of loss of heterozygosity were detected on 9p (46%) and 17p (42%) with lower rates on 2p (12%), 6q (7%), and 10q (12%). There was no significant difference in the age at diagnosis or number of treatments received by those with loss of heterozygosity and those without, suggesting that increasing age and multiple treatments do not predispose to allelic loss. These results provide the basis for further studies defining more accurately chromosomal regions of deletions and candidate tumor suppressor genes involved in mycosis fungoides and Sézary syndrome.     

New aspects of the clinicopathological features and treatment of mycosis fungoides and Sézary syndrome

Mycosis fungoides and Sézary syndrome are T‐helper (Th)2‐skewed cutaneous lymphomas. The clinical course of mycosis fungoides is classically indolent, manifesting as patches, plaques and tumors. Along with their progression, Th2 dominance tends to be accelerated. In this review, we discuss the epidemiology, clinicopathogenetic features and therapeutic approaches in mycosis fungoides and Sézary syndrome.     

Increased anti–Epstein—Barr virus antibodies in epidermotropic cutaneous T–cell lymphoma: a study of 64 patients

Epstein—Barr virus (EBV) is often associated with non–Hodgkin's T–cell lymphomas and has recently been found in the lesions of mycosis fungoides and Sézary syndrome. We sought to determine whether the anti–EBV antibody profile was disturbed in mycosis fungoides and Sézary syndrome and whether there are particular profiles characteristic of disease stage. Anti–EBV antibodies (anti–VCA,–EA and –EBNA) were studied in the sera of 64 patients. An immunoenzymatic technique was used, and the results were compared with the same number of age– and sex–matched healthy controls. Patients with mycosis fungoides and Sézary syndrome developed higher anti–VCA antibody titres (median 1200) than controls (median 320). Thirty–seven patients had anti–VCA ≥ 1200 vs. 19 controls (P<0.01). These elevated anti–VCA antibody titres were associated with positive EA in 19 patients versus three controls. No differences were found between the illness stages. Anti–EBV antibodies were most often found in mycosis fungoides and Sézary syndrome when the serological profile was similar to that of cellular immune deficiencies and EBV–related non–Hodgkin's lymphoma. EBV could be involved, either directly on lymphocytes or, more likely, indirectly by chronic antigenic stimulation.     

Histopathologic studies in Sézary syndrome and erythrodermic mycosis fungoides: a comparison with benign forms of erythroderma

Histologic sections from eleven patients with Sézary syndrome were reviewed and compared with those of four patients with erythrodermic mycosis fungoides and twenty-four patients with a benign form of erythroderma, including fifteen patients with chronic dermatitis, four with a generalized drug eruption, and five with an erythrodermic psoriasis. The most important discriminating histologic feature in patients with Sézary syndrome was the presence of a monotonous bandlike or perivascular infiltrate in the papillary dermis, mainly composed of large cerebriform-mononuclear cells, as seen in seven of eleven Sézary syndrome patients. Pautrier's microabscesses were observed in seven of eleven Sézary syndrome patients, two of four patients with erythrodermic mycosis fungoides, but not in any of the patients with a benign form of erythroderma; their presence was therefore considered a reliable criterion in differentiating erythrodermic cutaneous T cell lymphoma from benign forms of erythroderma. However, features of chronic dermatitis were often found superimposed on those of Sézary syndrome and were even predominating in four of eleven Sézary syndrome patients. Moreover, four patients with a benign form of erythroderma showed a histologic picture suggestive of cutaneous T cell lymphoma. Therefore, in dubious cases repeated skin biopsies, additional investigations of lymph nodes and peripheral blood, and careful follow-up are mandatory for the achievement of a correct diagnosis.     

Oral retinoids in mycosis fungoides and Sézary syndrome: a comparison of isotretinoin and etretinate. A study from the Scandinavian Mycosis Fungoides Group

Thirty-nine patients with mycosis fungoides in various stages or Sézary syndrome were treated with isotretinoin and 29 with etretinate as single drug therapy. Complete remission within 2 months was obtained with isotretinoin in 8 cases (21%) and partial remission in another 15 cases (38%). Etretinate induced complete remission in 5 cases (21%) and partial remission in 11 (46%). Only 1 case with Sézary syndrome went into partial remission. The first sign of remission occurred in 2 to 4 weeks. During continued treatment remissions could not always be maintained. Isotretinoin and etretinate were considered to be of equal potency in the treatment of mycosis fungoides.