Prognosis of 100 Japanese patients with mycosis fungoides and Sézary syndrome

BackgroundSurvival analysis of a large series of patients with mycosis fungoides (MF) and Sézary syndrome (SS) has not been performed in Japan. Revision to the staging system for MF and SS was recently published.ObjectiveTo determine the long-term prognosis of Japanese patients with MF and SS, to identify factors predictive of survival, and to evaluate the prognostic significance of the revised staging system.MethodsWe performed a retrospective cohort study of 100 Japanese patients with MF and SS managed at the dermatology division of Niigata University Hospital between April 1, 1982 and March 31, 2006. We estimated survival according to the patient's clinical characteristics including the stages, and assessed their prognostic significance.ResultsSurvival rates of Japanese patients with MF and SS were similar to those shown in previous studies conducted in the United States and Europe. Prognosis of patients with skin tumor (stage IIB) and extracutaneous involvement (stage IV) was significantly worse than that of those with early-stage disease (stages IA–IIA), but erythrodermic MF patients without blood involvement (stage IIIA) showed excellent survival. Independent prognostic factors in multivariate analyses were higher age and the presence of skin tumor and extracutaneous disease.ConclusionPatient age and stage are the most important clinical prognostic factors in Japanese patients with MF and SS. The revised staging system is useful for predicting survival of the patients, but at least a subpopulation of stage IIIA patients may have a favorable prognosis.     

Prevalence and treatment of Staphylococcus aureus colonization in patients with mycosis fungoides and Sézary syndrome

Background  Mycosis fungoides (MF) and Sézary syndrome (SS), variants of cutaneous T-cell lymphoma, may arise from antigen-driven clonal expansion and accumulation of helper-memory T cells. Superantigens from Staphylococcus aureus can stimulate T cells.
Objectives  (i) To determine the prevalence of S. aureus carriage in nares and skin in patients with MF/SS compared with historical rates in other conditions. (ii) To determine whether eradication of S. aureus carriage is associated with clinical improvement.
Methods  Skin and nares cultures were performed prospectively. Patients with positive nares and skin cultures were treated with oral antibiotics and intranasal mupirocin 2% and samples were taken for reculturing at 3 days, 4 weeks and 8 weeks. An exact binomial test was used to compare the carriage rates among different groups.
Results  Among 106 patients with MF/SS, 67 (63%) had skin colonization and 57 (54%) had nasal colonization. Staphylococcus aureus was isolated from 44 patients, 33 (31%) each from skin and nares. Colonization was highest in erythrodermic SS (48%), similar to atopic dermatitis (64%), and lowest in MF without erythroderma (26%), psoriasis (21%), and the general population (10%). Oral and topical antibiotics eradicated S. aureus colonization in nares in 28 of 33 (85%) patients and in MF skin lesions in 30 of 33 (91%) patients at 4–8 weeks, with rapid clinical improvement seen in 58% of S. aureus -colonized patients.
Conclusions  Staphylococcal carriage in nares and skin lesions of patients with MF is similar to that in atopic dermatitis. Eradication of staphylococci from the skin is possible with treatment and was associated with clinical improvement.     

Long-term follow-up in 51 patients with mycosis fungoides and Sézary syndrome treated by interferon-alfa

Although interferon-alfa (IFN-alpha) has proved effective in treating epidermotropic cutaneous T-cell lymphoma (ECTL), few studies have considered the follow-up of treated patients and whether complete remission was maintained. We studied 51 patients (one stage Ia, seven stage Ib, one stage IIa, 30 stage IIb, 11 stage III (Sézary syndrome) and one stage IV) who received low-dose IFN-alpha as monotherapy for ECTL (mean daily dose of IFN-alpha 2.7 x 106 units for 14.9 months), giving special consideration to the significance of My7 (CD13) antigen expression by epidermal basal cells in predicting the maintenance of complete remission. For a mean follow-up period of 43.4 months, the results showed 21 complete remissions, 13 partial remissions and 17 patients with stable or progressive disease. Twelve patients died during the follow-up (3-52 months). IFN-alpha led to an improved response in the early stages, with a greater number of complete remissions (P = 0.03) and partial remissions (P = 0.01). The mean time to complete remission was 4 months, regardless of clinical stage (P = 0.1). Of 21 patients in complete remission, 57% had a relapse within a mean period of 7.5 months. For patients maintained in complete remission, the mean period of response was 31 months. The length of complete remission was independent of clinical stage, and My7 antigen expression was not predictive of complete remission.     

Molecular staging of lymph nodes from 60 patients with mycosis fungoides and Sézary syndrome: correlation with histopathology and outcome suggests prognostic relevance in mycosis fungoides

BACKGROUND: Histological evidence of lymph node involvement is associated with a poor prognosis in patients with cutaneous T-cell lymphoma (CTCL). OBJECTIVES: To determine whether T-cell receptor (TCR) gene analysis is of prognostic relevance in CTCL. METHODS: TCR gene analysis was performed on lymph node specimens from 60 patients with mycosis fungoides (MF) and Sézary syndrome (SS) using a highly sensitive polymerase chain reaction (PCR)/single-strand conformational polymorphism analysis and results were correlated with skin, overall clinical and histological lymph node stages. RESULTS: The frequency with which a T-cell clone was detected in lymph node samples from patients with MF increased with skin stage, overall clinical stage and with the degree of histological involvement: six of 19 patients with uninvolved lymph nodes or limited histological involvement (LN0-2) and 13 of 14 patients with advanced histological involvement (LN3-4) had a detectable T-cell clone. In SS, 22 of 27 patients had a detectable lymph node T-cell clone. The clonal patients had a poorer prognosis than nonclonal patients (median survival from biopsy of > 72 months vs. 16 months for MF and 41.5 vs. 16.5 months for SS). Regression analysis confirmed that TCR gene analysis identifies a group of MF patients with a worse prognosis (P = 0.013). However, the molecular lymph node stage did not provide independent prognostic information in this cohort of patients in multivariate analysis. CONCLUSIONS: Molecular staging in MF and SS using a PCR-based method for TCR gene analysis provides additional information to histological examination. Specifically, this study identified a group of MF patients with early lymph node involvement with a poorer prognosis. However, a larger prospective study of patients with MF and early histological lymph node involvement is required to confirm whether molecular staging of lymph nodes provides independent prognostic information in a multivariate model.     

Bexarotene treatment of late-stage mycosis fungoides and Sézary syndrome: development of extracutaneous lymphoma in 6 patients

Bexarotene is a retinoid drug that is approved for the treatment of cutaneous T-cell lymphoma. We report 6 cases in which the initiation of bexarotene therapy for cutaneous T-cell lymphoma was temporally associated with the progression of internal disease despite improvement in cutaneous signs and symptoms. It is possible that bexarotene contributed to this progression. Although bexarotene therapy may alleviate symptoms and signs of cutaneous T-cell lymphoma, careful surveillance of lymph nodes and solid organs during treatment is advised.     

Systemic chemotherapy for the treatment of mycosis fungoides and Sézary syndrome

The treatment of mycosis fungoides and Sézary syndrome is unique. The treatments of choice are highly stage-and practitioner-dependent. For early stage patients, treatment with palliative topical therapies is often adequate to yield excellent, high-quality and durable responses. For the more advanced stages, systemic approaches are more appropriate, either alone or in combination, to palliate patients. There is still little convincing evidence from randomized trials that any single approach is favorable for improving survival. Many practitioners believe the disease can be controlled with the host immune system, but there again is little scientific support for this conclusion. It has been hypothesized that some of our therapies work through this mechanism, such as photopheresis and perhaps even psoralen and ultraviolet A. Unfortunately, even the use of biologic response modifiers, such as interferon and the interleukins, is not absolutely supportive of an active role for immune surveillance since these agents have been shown to have cytotoxic and differentiating effects. Because of the above, many practitioners have actively discouraged the use of chemotherapy because it may impair the host immune system; certainly, the purine analogs would fall into this category. However, there is little evidence supporting significant immune effects for other chemotherapeutics, and clearly, the responses seen would support their use in appropriate patients. As the present authors will detail in this paper, the advances in understanding cancer biology and mechanisms of resistance should, in the future, lead to optimal selection of agents that are predicted to be optimally active, limiting the toxicity and waste associated with ineffective drug usage.     

Increased serum immunoglobulin levels are common in mycosis fungoides and Sézary syndrome

BACKGROUND: Patients with cutaneous T-cell lymphoma (CTCL; mycosis fungoides [MF] and Sézary syndrome [SS]) acquire immunodeficiency and opportunistic infections. OBJECTIVE: We attempted to determine whether abnormalities of humoral immunoglobulin levels are present. METHODS: A retrospective analysis of serum immunoglobulin levels in patients with CTCL at baseline evaluation at a cancer center was compared to levels in patients with leukemias and levels in healthy control subjects. RESULTS: A total of 254 of 650 patients with CTCL evaluated between 1987 and 2001 had baseline quantitative immunoglobulin levels. Mean IgG, IgA, and IgM levels were similar among all MF/SS patients versus controls. The percentages of MF/SS patients with elevated levels of each immunoglobulin class were higher than percentages in healthy controls, and elevated IgA levels occurred among late versus early patients (P =.043). CONCLUSION: High immunoglobulin levels are more frequent in patients with MF and SS than in healthy controls, patients with chronic lymphocytic leukemia, and patients with hairy cell leukemia. High IgA levels are more frequent in late stage MF/SS.     

Abnormal expression of interleukin-23 in mycosis fungoides/Sézary syndrome lesions

Progression of mycosis fungoides (MF) to Sézary syndrome (SS) is accompanied by a shift from a T(H)1 to a T(H)2 cytokine profile. Interleukin (IL)-23 is a novel cytokine that shares a common p40 subunit with the T(H)1 inducer, IL-12. IL-23 induces a third profile, T(H)IL-17, that is dominant in inflammation and autoimmunity. Although IL-23 induces an eczematous-like skin reaction in mice, and is expressed in T(H)1-mediated skin disorders such as psoriasis, it has not been evaluated in MF/SS. To study the role of IL-23 in MF/SS development, 40 MF/SS lesions of all stages were immunohistochemically analyzed with a novel anti-human IL-23 antibody raised against full-length human IL-23. IL-23 was detected with the catalyzed signal amplification system. The intensity and frequency of IL-23 staining were semi-quantitatively graded in both the dermal infiltrate and the epidermis. Increased expression of IL-23 was observed throughout the epidermal keratinocytes and in dermal lymphocytes compared to normal skin. IL-23 intensity did not differ significantly among the stages of MF/SS; however, in stage IVB patients, we observed lower frequency of IL-23 expression in dermal lymphocytes than in other stage patients [P = 0.13, analysis of variance (ANOVA)]. Interestingly, clusters of atypical lymphocytes, especially the epidermotropic tumor cells, demonstrated weak or absent IL-23 staining in 18 of 40 (45%) lesions. This finding was present in 4 of 5 (80%) of the stage IVB lesions and 7 of 11 (64%) of the lesions from Sézary patients. These findings indicate that abnormal IL-23 expression may play a role in the pathogenesis and progression of MF/SS.     

Follicular mucinosis: a critical reappraisal of clinicopathologic features and association with mycosis fungoides and Sézary syndrome

CONTEXT: Beginning in 1957, patients have been described with localized alopecia characterized histopathologically by mucin deposition within hair follicles (follicular mucinosis [FM]). At least 2 distinct diagnostic entities have been proposed: one occurring in children and young adults without association with other diseases ("idiopathic" FM), the other occurring in elderly patients and associated with mycosis fungoides or Sézary syndrome ("lymphoma-associated" FM). OBJECTIVE: To determine whether idiopathic and lymphoma-associated FM are distinct or related entities. DESIGN: Case series. SETTING: Department of Dermatology, University of Graz, Graz, Austria. PATIENTS: Forty-four patients with FM were divided into 2 groups. Group 1 comprised 16 patients (mean age, 37.5 years) with no associated mycosis fungoides or Sézary syndrome; group 2 was made up of the other 28 (mean age, 52.2 years), who had clinicopathologic evidence of cutaneous T-cell lymphoma. RESULTS: Mean age was lower in patients with idiopathic FM, but a considerable overlapping among the 2 groups was present. Location on the head and neck region was common in both groups, but most patients with lymphoma-associated FM had lesions also on other body sites. In fact, solitary lesions at presentation were common in patients with idiopathic FM (11 [68.8%] of 16 patients), but uncommon in those with lymphoma-associated FM (2 [7.1%] of 28 patients). Histopathologic findings did not allow clear-cut differentiation of the 2 groups. Finally, a monoclonal rearrangement of the T-cell receptor gamma gene was demonstrated by polymerase chain reaction analysis in about 50% of tested cases from each group. CONCLUSIONS: Criteria previously reported to differentiate idiopathic from lymphoma-associated FM proved ineffective. In analogy to localized pagetoid reticulosis (Woringer-Kolopp disease), small-plaque parapsoriasis, and so-called solitary mycosis fungoides, idiopathic FM may represent a form of localized cutaneous T-cell lymphoma.     

The relevance of peripheral blood T-helper 1 and 2 cytokine pattern in the evaluation of patients with mycosis fungoides and Sézary syndrome

BACKGROUND: There is evidence that a T-helper (Th) 2 cytokine pattern dominates in the peripheral blood as well as in tissue of patients with Sézary syndrome (SS), and that the malignant clone is of Th2 phenotype. However, there are conflicting studies on the cytokine pattern in the peripheral blood in different stages of cutaneous T-cell lymphoma (CTCL). OBJECTIVES: To examine, by means of flow cytometry (FC), the Th1/Th2 cytokine profile [cytoplasmic interferon (IFN)-gamma/interleukin (IL)-4] in peripheral blood T cells from patients with mycosis fungoides (MF) and SS, the most common forms of CTCL, and to correlate their expression with clinical stage, clonality and T-cell immunophenotype changes in order to evaluate their relevance in CTCL progression. METHODS: We investigated by FC the percentage of CD3+ T cells expressing cytoplasmic IFN-gamma and IL-4 after stimulation in blood specimens of 43 CTCL patients (32 stage I-II and 11 stage III-IV), eight of whom were erythrodermic. Next, we compared cytoplasmic IFN-gamma and IL-4 expression between patients of different stages and controls, and correlated our findings to T-cell receptor (TCR)-gamma gene rearrangement, used as a marker of clonality, and changes in T-cell immunophenotype (CD4+, CD8+, CD4+/CD7-, CD4+/CD25+) and natural killer cells. Polymerase chain reaction amplification of the TCR-gamma gene was performed in 41 blood and 26 skin specimens. We also examined the cytokine expression pattern in patients with erythrodermic MF and SS. RESULTS: A significantly higher frequency of CD3+/IL-4+ T cells was found in late (III-IV) compared with early (I-II) CTCL patients (P = 0.002) or controls (P < 0.001). There were significant positive correlations between the percentages of CD3+/IL-4+ and the percentages of CD3+/CD4+ T cells (r = 0.385, P = 0.05), CD4+/CD7- T cells (r = 0.335, P < 0.05) and CD4+/CD25+ T cells (r = 0.433, P = 0.01); there was a negative correlation between the percentages of CD3+/IL-4+ and CD3+/CD8+ T cells (r = -0.463, P = 0.005) and a positive correlation between the percentages of CD3+/IFN-gamma+ and CD3+/CD8+ T cells (r = 0.368, P = 0.02). Increased percentages of CD3+/IL-4+, CD3+/CD4+ and CD4+/CD7- T lymphocytes were associated with the presence of clonality (P = 0.025, P < 0.001 and P = 0.0031, respectively). All independent variables showed a statistically significant difference between SS and erythrodermic MF patients, or controls, apart from cytoplasmic IL-4, which was high both in erythrodermic MF and SS patients compared with controls (P = 0.003 and P = 0.008, respectively). In multiple regression logistic analysis, the probability of belonging to advanced CTCL stages was associated only with increased cytoplasmic IL-4 (P = 0.007, odds ratio 1.13, 95% confidence interval 1.033-1.229). CONCLUSIONS: Increased T-cell cytoplasmic IL-4 is more frequent in late CTCL stages, correlates with T-cell immunophenotype changes found in advanced disease and is associated with clonality. Increased cytoplasmic IL-4 is frequent both in erythrodermic MF and SS patients, in contrast to other variables found increased only in SS, suggesting that IL-4 may be an early indicator of disease progression. Moreover, our results show that increased cytoplasmic IL-4 is the sole predictor of advanced CTCL disease and confirm the relevance of FC determination of IL-4 in the routine evaluation of CTCL cases.     

Prognostic factors and prediction of prognosis by the CTCL Severity Index in mycosis fungoides and Sézary syndrome

BACKGROUND: Cutaneous T-cell lymphoma (CTCL) is a slowly progressive malignancy for which there is no cure. Therefore, accurate prediction of prognosis is important for the conduct of clinical trials and for counselling of individuals. OBJECTIVES: To improve prediction of survival in patients with CTCL. METHODS: Prognostic factors including tumour-node-metastasis (TNM) criteria and the CTCL Severity Index (CTCL-SI) were analysed using a Weibull model for multivariate analysis in a sample of 62 patients with classical CTCL (mycosis fungoides and Sézary syndrome). The Brier score was used to quantify the quality of individual prediction. RESULTS: Estimated 5-year survival rate (SR5) differed according to TNM stage: stage IA, 100% (95% confidence interval 70-100%); IB-III, 86% (73-100%); IVA, 54% (32-91%); IVB, 0% (0-52%). In a multivariate analysis, two independent prognostic factors were identified: lymph node (P = 0.036) and blood involvement (P = 0.015). A probability of survival model showed correlation of CTCL-SI with survival in patients with CTCL-SI > 20 according to the following formula: SR5 = 124-2 x (CTCL-SI)%. Calibration of SR5 against CTCL-SI-independent CTCL subsets revealed underestimation of Sézary syndrome. When CTCL-SI parameters were adjusted accordingly, the probability of survival model did not change significantly, while SR5 values became adequate. In addition, CTCL-SI was shown to be superior to TNM by 30% regarding individual predictive power. CONCLUSIONS: Probability of survival in CTCL can be accurately predicted by a CTCL-SI-based survival rate formula. Careful monitoring of lymph node and blood compartments and quantification by CTCL-SI are reliable tools for follow-up of patients with CTCL and allow progression-adjusted prediction of prognosis.