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Survival in Mycosis Fungoides and Sezary Syndrome: How Can We Predict Outcome?

  • Julia J. Scarisbrick
    Correspondence
    Correspondence: Julia J. Scarisbrick, Department of Dermatology, University Hospital Birmingham, Birmingham, B15 2TH, United Kingdom.
    Affiliations
    Department of Dermatology, University Hospital Birmingham, Birmingham, United Kingdom
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      Early-stage mycosis fungoides (MF) has been associated with long survival. A recent meta-analysis including 6,279 patients with MF and Sezary syndrome found that about 10–20% of stage IB patients don’t survive 5 years, whereas patients with advanced-stage MF and Sezary syndrome have a 5-year survival chance of about 20–60%. Identifying prognostic markers to better identify those at risk of limited survival may allow improved management choices and this, coupled with newer treatments, could improve survival.
      • Survival in stage IB mycosis fungoides is significantly reduced in up to one in five patients, with death within 5 years of diagnosis.
      • Survival is poor in advanced mycosis fungoides and Sezary syndrome, and 5-year survival rates range from 20–60%.
      • Identifying risk factors for poorer survival may allow individualized treatment choices.
      Cancer staging systems are used to estimate the survival of patients with specific cancers and help to determine best management. However, there are ranges of survival within individual cancer stages.
      • Mourad A.
      • Gniadecki R.
      Overall survival in mycosis fungoides: A systematic review and meta-analysis [e-pub ahead of print].
      performed a systematic review and metanalysis of overall survival (OS) in patients with stage IB–IVB mycosis fungoides (MF) and Sezary syndrome (SS). They identified 10 studies including 6,279 patients. All were retrospective cohort studies that were mostly limited to single centers, and thus there is no uniformity in definitions. The median age at diagnosis ranged from 52–62 years and all studies had a male predominance of 1.6 (male:female ratio 6:4) in accordance with previous reports (
      • Willemze R.
      • Jaffe E.S.
      • Burg G.
      • Cerroni L.
      • Berti E.
      • Swerdlow S.H.
      • et al.
      WHO/EORTC classification for cutaneous lymphomas.
      ). The authors concentrated on OS because detailed information on cause of death was not available. This is a logical approach in retrospective cohort studies when data may be inconsistently defined between centers or incomplete.
      • Mourad A.
      • Gniadecki R.
      Overall survival in mycosis fungoides: A systematic review and meta-analysis [e-pub ahead of print].
      reported a median survival and included best- and worst-case scenarios. The authors achieved this by calculating median 5-year OS rates and then defining best case as the upper 10th percentile for each stage and worst case as the lower 10th percentile. They showed OS to be 85.8% in stage IB, reflecting significant mortality in these patients with early-stage MF, with a best case of 88.8% and a worst case of 82.1%. The authors showed that development of tumors (progression from stage I to IIB), Sézary syndrome (stage IVA1), nodal effacement (stage IVA2), and metastatic spread (stage IVB) had powerful, negative impacts on survival. However, these features are reflected in the staging algorithm and don’t give additional information on the patients’ clinical or pathological phenotypes, which may provide further prognostic information.
      The Prospective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study is a global prospective effort collecting clinical, pathological, genotypic, treatment, and health-related quality of life (HRQoL) data on all stages of MF and SS with the aim to develop a prognostic index to stratify patients for better management decisions and to improve survival. PROCLIPI recently reported the median age of diagnosis of stage IB MF as 57 years (interquartile range = 45–67yrs) (
      • Scarisbrick J.J.
      • Quaglino P.
      • Prince H.M.
      • Papadavid E.
      • Hodak E.
      • Bagot M.
      • et al.
      The PROCLIPI international registry of early stage mycosis fungoides identifies substantial diagnostic delay in most patients.
      ). As the reported 5-year OS by
      • Mourad A.
      • Gniadecki R.
      Overall survival in mycosis fungoides: A systematic review and meta-analysis [e-pub ahead of print].
      is 85.8% in stage IB MF, this shows that some patients with stage IB MF have considerable reductions in life expectancy. Longer survival data (10- to 20-year OS) was not reported, but it is known that many patients with stage I MF have a long survival (
      • Willemze R.
      • Jaffe E.S.
      • Burg G.
      • Cerroni L.
      • Berti E.
      • Swerdlow S.H.
      • et al.
      WHO/EORTC classification for cutaneous lymphomas.
      ). It would be useful to identify prognostic markers in stage IB that could predict those with a more aggressive phenotype but also provide reassurance for those with a less aggressive phenotype. In PROCLIPI, factors being tracked as possible poor prognostic markers in stage IB include folliculotropic MF (FMF; recorded in 24.8% of patients with stage IB MF), large cell transformation (LCT) in skin (which is defined as >25% overall or microscopic nodules of atypical lymphocytes being greater than normal size [recorded in 1.7% of patients with stage IB MF]), low level blood involvement with circulating aberrant lymphocytes (typically CD4+, CD7-, or CD26-) between 250 and 1000 IU as defined by B1 (recorded in 26.1% of patients with stage IB MF), and raised serum lactate dehydrogenase (LDH; recorded in 8.9% of patients with stage IB MF). Factors that are possibly associated with improved survival include the clinical variants manifesting poikiloderma (recorded in 15.2% of patients with early-stage MF) and hypopigmentation (recorded in 8.0% of patients with early-stage MF), malignant lymphocytes which are CD4-CD8+ by immunohistochemical staining (recorded in 4.6% of patients with early-stage MF), and the association with lesions of lymphomatoid papulosis (
      • Scarisbrick J.J.
      • Quaglino P.
      • Prince H.M.
      • Papadavid E.
      • Hodak E.
      • Bagot M.
      • et al.
      The PROCLIPI international registry of early stage mycosis fungoides identifies substantial diagnostic delay in most patients.
      ).
      Advanced stages of MF and SS present more often at older ages than early stages, with a median age at diagnosis of ∼63 years (range = 8–98 years) (
      • Scarisbrick J.J.
      • Prince H.M.
      • Vermeer M.H.
      • Quaglino P.
      • Horwitz S.
      • Porcu P.
      • et al.
      Cutaneous Lymphoma International Consortium (CLIC) study of outcome in advanced stages of mycosis fungoides & Sézary syndrome: effect of specific prognostic markers on survival and development of a prognostic model.
      ,
      • Talpur R.
      • Singh L.
      • Daulat S.
      • Liu P.
      • Seyfer S.
      • Trynosky T.
      • et al.
      Long-term outcomes of 1,263 patients with mycosis fungoides and Sézary syndrome from 1982 to 2009.
      ). Advanced stages of MF and SS are comprised of stages IIB–IVB and are associated with a worse prognosis than early-stage disease. Median survival historically has been quoted at about 3 years (
      • Willemze R.
      • Jaffe E.S.
      • Burg G.
      • Cerroni L.
      • Berti E.
      • Swerdlow S.H.
      • et al.
      WHO/EORTC classification for cutaneous lymphomas.
      ). Individual studies reporting 5-year survival in the advanced cohort reported by
      • Mourad A.
      • Gniadecki R.
      Overall survival in mycosis fungoides: A systematic review and meta-analysis [e-pub ahead of print].
      found a 5-year OS ranging from 41–68.5% and a 10-year OS of 25–58.8%, indicating that not all advanced patients have a poor outcome and that some patients may survive more than a decade. The meta-analysis reported a median 5 year-OS in stage IIB as 62.2% (best 67.9%, worst 56%), 59.7% in stage IIIA (best 67.6%, worst 50.7%), 54% in stage IIIB (best 63.4%, worst 43.3%), 52.5% in stage IVA1 (best 52.5%, worst 43.2%), 34% in stage IVA2 (best 46.3%, worst 22.1%), and 23.3% in stage IVB (best 39.7%, worst 10%) (
      • Mourad A.
      • Gniadecki R.
      Overall survival in mycosis fungoides: A systematic review and meta-analysis [e-pub ahead of print].
      ). These results will allow more detailed information on OS to be available for patients but also show a 10–20% difference in the best- and worst-case scenarios. This may be confusing for patients until we can identify those factors that may better differentiate survival risks. It is likely patients will want to know if they are more likely to survive >10 years for future life and family planning.
      Deciding how best to inform patients regarding 5-year OS may also be challenging for physicians, especially in metastatic disease (stage IVB) where the best-case scenario gives a 40% 5-year OS compared with just 10% in the worst case. Factors previously reported to be associated with worsened survival in advanced stages of MF include age greater than 60 years at diagnosis, partially or completely effaced nodal involvement (N3), B2 blood involvement (as defined by ≥1000 IU aberrantly circulating lymphocytes), visceral involvement, LCT in skin, and raised serum LDH (
      • Benton E.C.
      • Crichton S.
      • Talpur R.
      • Agar N.S.
      • Fields P.A.
      • Wedgeworth E.
      • et al.
      A cutaneous lymphoma international prognostic index (CLIPi) for mycosis fungoides & Sezary syndrome.
      ,
      • Scarisbrick J.J.
      • Prince H.M.
      • Vermeer M.H.
      • Quaglino P.
      • Horwitz S.
      • Porcu P.
      • et al.
      Cutaneous Lymphoma International Consortium (CLIC) study of outcome in advanced stages of mycosis fungoides & Sézary syndrome: effect of specific prognostic markers on survival and development of a prognostic model.
      ). PROCLIPI is recording these factors as well as histological markers such as CD30% and Ki-67 (
      • Gru A.
      • Battistella M.
      • Kim J.
      • Pulitzer M.
      • Guitart J.
      • Hong E.
      • et al.
      The use of digital slide scanning as a tool for central pathology review in patients with advanced stage mycosis fungoides and Sezary syndrome: a multi-institutional and international pathology study.
      ).
      Variation in survival within the stages of MF and SS is acknowledged and the importance of poor prognostic indices outside the staging system has been recognized. The International Society for Cutaneous Lymphoma and European Organisation for Research and Treatment of Cancer Cutaneous Lymphoma Task Force recommend the tracking of patients with FMF or LCT to determine if either warrants a different staging system from classical MF and SS. A staging system that relates to prognosis is vital, as this dictates treatment choices for patients with MF or SS. Patients with early-stage MF (stages IA–IIA) are treated with skin-directed therapy. Patients with advanced-stage MF or SS (stages IIB–IVB) typically require immunotherapy or chemotherapy, and sequential treatments are given as the disease progresses (https://www.nccn.org/professionals/physician_gls/pdf/primary_cutaneous.pdf). Treatment is frequently palliative and decided on an individual patient basis. Allogeneic stem cell transplant may be considered for eligible patients with poor survival risk. It produces some good responses, but careful consideration is required as transplant-related mortality at year 1 is significant (∼34%) (
      • Duarte R.F.
      • Canals C.
      • Onida F.
      • Gabriel I.H.
      • Arranz R.
      • Arcese W.
      • et al.
      Allogeneic haematopoietic cell transplantation for patients with mycosis fungoides and Sezary syndrome: a retrospective analysis of the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation.
      ).
      Treatment of MF and SS rarely results in complete responses, and partial responses or stable disease is common (https://www.nccn.org/professionals/physician_gls/pdf/primary_cutaneous.pdf). Patients therefore live for long periods with significant morbidity from skin tumor burden, which impacts quality of life.
      • Molloy K.
      • Jonak C.
      • Woei-A-Jin F.J.S.H.
      • Guenova E.
      • Busschots A.M.
      • Bervoets A.
      • Hauben E.
      • et al.
      Characteristics associated with significantly worse quality of life in mycosis fungoides/Sézary syndrome from the Prospective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study [e-pub ahead of print].
      recently reported on HRQoL, as measured by Skindex-29, in patients with MF and SS. HRQoL was found to be worse in women, patients with SS, patients with alopecia, those with high skin tumor burden, and those in advanced-stage disease. Female sex and alopecia were the only independent predictors of worsened global HRQoL. Item-level analysis showed that the HRQoL impairment in women occurred because of a higher impact of the symptoms of burning/stinging, pruritus, and irritation and worse emotional scores of depression, shame, embarrassment, and annoyance with their diagnosis of MF or SS (
      • Molloy K.
      • Jonak C.
      • Woei-A-Jin F.J.S.H.
      • Guenova E.
      • Busschots A.M.
      • Bervoets A.
      • Hauben E.
      • et al.
      Characteristics associated with significantly worse quality of life in mycosis fungoides/Sézary syndrome from the Prospective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study [e-pub ahead of print].
      ).
      The likely survival outcomes of individual patients is often their greatest concern. Identifying prognostic markers will provide more relevant personalized information for patients than stage alone and allow better management decisions. More specifically, if prognostic markers can be modeled into a prognostic index, this may provide individualized survival outcomes and allow personalized management choices. A prognostic index for aggressive non-Hodgkin lymphoma was developed in 1993, and it has been widely used to stratify patients for treatment (
      • Shipp M.A.
      Prognostic factors in aggressive non-Hodgkin’s lymphoma: who has ‘high-risk’ disease?.
      ). Development of a useful prognostic index requires international collaboration, and it must be done prospectively with well-defined criteria to ensure comparable measures. Retrospective data may be flawed because of poor recording, differing definitions, and inaccurate recall. The PROCLIPI study provides an established registry with centrally reviewed clinicopathological data (
      • Gru A.
      • Battistella M.
      • Kim J.
      • Pulitzer M.
      • Guitart J.
      • Hong E.
      • et al.
      The use of digital slide scanning as a tool for central pathology review in patients with advanced stage mycosis fungoides and Sezary syndrome: a multi-institutional and international pathology study.
      ) with the aim of producing a prognostic index in MF and SS to stratify patients according to survival. It is hoped that such an international prognostic index will provide an improved basis for selecting patients for appropriate therapies and for stratification into clinical trials, and that it will improve survival in this group of patients with poor outcome.
      • Mourad A.
      • Gniadecki R.
      Overall survival in mycosis fungoides: A systematic review and meta-analysis [e-pub ahead of print].
      have provided a useful data source that can be used to give guidance to patients and treating physicians in the likely survival outcomes of patients with MF and SS according to stage.

      ORCID

      Conflict of Interest

      The author states no conflict of interest.

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      Linked Article

      • Overall Survival in Mycosis Fungoides: A Systematic Review and Meta-Analysis
        Journal of Investigative DermatologyVol. 140Issue 2
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          Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma that confers significant mortality in advanced-stage disease (Suzuki et al., 2010; Vollmer, 2014). Although stage-specific survival data are available from different cohorts, there have been no attempts to combine existing overall survival (OS) data in this disease (Suzuki et al., 2010). Moreover, the hitherto published OS data are presented as Kaplan-Meier curves and mortality risks, which are of limited utility for the patients who prefer to have an estimate of their chances of survival (Kiely et al., 2011).
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