zary syndrome: A study of 176 patients at Se Mayo Clinic

Agnieszka W. Kubica, MD,d Mark D. P. Davis, MD,a Amy L. Weaver, MS,b Jill M. Killian, BS,b and Mark R. Pittelkow, MDa,c Rochester, Minnesota
Background: S ezary syndrome (SS), a leukemic variant of cutaneous T-cell lymphoma, is characterized by erythroderma and by atypical lymphocytes (S ezary cells) in peripheral blood. Although numerous studies have examined the range of disease in cutaneous T-cell lymphoma, a relative paucity of data exists to describe the long-term outcome of patients with SS. Objective: We sought to study long-term survival and prognostic factors of patients with SS. Methods: A retrospective chart review was conducted to identify patients with SS seen at Mayo Clinic from 1976 to 2010. Cox proportional hazards regression models, adjusted for age, were fit to evaluate factors associated with overall survival. Results: In total, 176 patients were identified with a clinicopathologic diagnosis of SS. Overall survival was 86.1% and 42.3% at 1 and 5 years, respectively, after diagnosis (median survival, 4.0 years). After adjustment for age, potential predictors of worse survival included lactate dehydrogenase level at presentation (hazard ratio [HR] 1.71; 95% confidence interval [CI] 1.18-2.47 per doubling), prior diagnosis of mycosis fungoides (HR 2.68; 95% CI 1.44-4.98), and the presence of T-cell receptor gene rearrangements in skin (HR 2.59; 95% CI 1.38-4.87) and in blood (HR 2.05; 95% CI 1.00-4.21). Limitations: This study is retrospective and represents a single academic center population. Conclusions: To our knowledge, this research evaluated the largest population of patients with SS studied to date. It shows that overall survival continues to be poor, with a median survival of 4.0 years after diagnosis. ( J Am Acad Dermatol 2012;67:1189-99.) Key words: cutaneous T-cell lymphoma; outcomes assessment; prognosis; S ezary syndrome; survival. 

ezary syndrome (SS) is a leukemic variant of cutaneous T-cell lymphoma (CTCL) that arises from skin-homing lymphocytes. It is characterized by erythroderma, keratoderma, lymphadenopathy, and the presence of atypical lymphocytes with cerebriform nuclei (S ezary cells) in peripheral blood.1-5 Over the past several decades, the diagnosis of SS has undergone progressive revisions, with the most recent diagnostic criteria proposed in 2007 by the International Society for Cutaneous Lymphomas (ISCL)/European Organization for Research and Treatment of Cancer (EORTC) and

S

Abbreviations used: CI: confidence interval CTCL: cutaneous T-cell lymphoma EORTC: European Organization for Research and Treatment of Cancer HR: hazard ratio IQR: interquartile range ISCL: International Society for Cutaneous Lymphomas LDH: lactate dehydrogenase MF: mycosis fungoides SS: S ezary syndrome TCR: T-cell receptor

From the Department of Dermatology,a Division of Biomedical Statistics and Informatics,b Department of Biochemistry and Molecular Biology,c and Mayo Medical School, College of Medicine,d Mayo Clinic. Funding sources: None. Conflicts of interest: None declared. Accepted for publication April 28, 2012.

Reprint requests: Mark D. P. Davis, MD, Department of Dermatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail: davis.mark2@mayo.edu. Published online May 28, 2012. 0190-9622/$36.00 Ó 2012 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2012.04.043

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and increased emphasis was who had not denied access to their records for placed on defining the deresearch purposes.7-9 When these changes over time.5% of all CTCLs. in accorgree of peripheral blood indance with Minnesota Statute CAPSULE SUMMARY volvement in establishing a 144. additional imaging. In essence. with reported median overtime. chest CTCL. in the blood. Therefore. For the diagnostic criteria extracutaneous involvement of the viscera is identiused in this study. classification system that was previously used to Medical records were reviewed for only the patients define MF and SS. The data in the Because the study period spanned more than 3 medical literature suggest a poor prognosis for this decades and the definition of SS evolved during this aggressive CTCL variant. and mansyndrome reported in the medical ratory evaluation for these ual S ezary cell count of peliterature and reaffirms the poor subtypes of CTCL. When lymph node or This investigation analyzes prognostic standing of CTCL and the visceral involvement was factors that are specific to this group of rarity of SS in comparison suspected.335. This collective. These criteria updated the 1979 National Cancer A retrospective chart review was conducted to Institute and MF Cooperative Group TNM(B) staging ensure that the cases fulfilled SS diagnostic criteria. Rochester. Epidemiology. the S ezary syndrome is an aggressive variant clinical challenges in definpatients generally underof cutaneous T-cell lymphoma that is ing SS and separating it from went a complete physical exassociated with a poor prognosis. Given that all patients in unstratified data on the actual survival. as The Mayo Clinic Institutional Review Board defined by the 2007 ISCL/EORTC classification approved this study. 1000 cells/L or molecular evidence of clonality by T-cell receptor (TCR) gene rearrangement (using Southern blot or. the study had SS. A data retrieval specialist d d d . or positron stages of MF with SS. MN. polymerase chain METHODS reaction). MF. diagnosis. other erythrodermic CTCLs. general chemistry is the largest of patients with S ezary established criteria and labopanel. mon CTCL variant.15-17 However. patients typically patients and adds data to the literature with the relatively more comunderwent lymph node bion S ezary syndrome. computed tomography.7 Mayo Clinic. following the proposed criteria of Results. and End 1000 cells/L.10-13 ([80% of total body surface area involved with At our tertiary care academic referral institution.1190 Kubica et al J AM ACAD DERMATOL DECEMBER 2012 including immunophenotyping and molecular criteperformed an electronic search of the medical diagria. more indolent forms of bone-marrow biopsy. in patients who received nostic factors in these patients. SS. progression. erythroderma) and definitive leukemic involvement. leukemic involvement was defined as absoonly about 2. a diagnosis of SS after the mid-1980s (and in which single-institution experience over the past 4 decades molecular studies were available at diagnosis). eg. SS cases included those with T4 fied.5. in an effort to better distinguish SS from mycosis nosis index to identify patients with SS diagnosed at fungoides (MF) and other erythrodermic CTCLs. according to data lute S ezary cell counts greater than or equal to obtained from Surveillance. the diagnostic criteria in the study reflected all survival ranging from 2 to 4 years. or As a result of both the prognosis of this disease. we examined the SS 1980s. few because it is not included in the 2007 ISCL/EORTC published data exist on the long-term outcome and criteria (Table I). studopsy or fine-needle aspiraies have frequently grouped tion and other staging (eg. which constitutes 1980s.14 With the incidence of CTCL increasing Winkelmann. implemented and became incorporated into SS difocusing on long-term survival and identifying progagnostic criteria. disease course of patients with SS. complete blood To our knowledge. more recently. resulting in incomplete or emission tomography). median survival is typically 2. this study population the ISCL in 2002 also further cell count. leuintends to supplement the literature on this more rare kemic involvement consistent with SS included an and aggressive lymphoma-leukemia and to compare absolute S ezary cell count greater than or equal to our survival data with the literature at large.6 Recognizing the At primary evaluation. or both. between 1976 and 2010. the dermatology department evaluates and cares for In patients whose SS was diagnosed before the mida large number of patients with SS.7 ripheral blood smears.6. such as erythrodermic MF or early to later radiograph. clinical molecular diagnostic techniques were population at our institution over the recent decades. flow cytometry of peripheral constantly evolving underblood. data on imaging were not collected and outcomes of documented SS. skin biopsy. amination.5 years or less.4 Therefore. beginning in the mid3 dramatically since the 1970s.

05 was considered statistically significant. sex-. presence of TCR clones in blood. *Necessary criteria for S ezary syndrome. expanded CD41 or CD31 cells with CD4/CD8 ratio $ 10. lactate dehydrogenase (LDH) at presentation. or a combination. using the Hakulinen cohort method. SAS Institute Inc.and sex-specific person-years of follow-up in our cohort. erythrodermic MF.2. a signifies clone negative. Therefore. histopathology Dutch grade 2 or NCI LN0-2 Clinically abnormal peripheral LNs. NCI. For patients who no longer corresponded with or were no longer seen at our institution. A 1-sample log rank test was used to compare the observed and expected curves. Requires positive clonal rearrangement of TCR plus one of the following: absolute S ezary cell count $ 1000/L. each factor was evaluated in a Cox model adjusted for age. including loss of CD7 ( $ 40%) or CD26 ( $ 30%) M. peripheral blood B0y Absence of notable blood involvement: # 5% of peripheral blood lymphocytes are S ezary cells B1y Low blood tumor burden: [5% of peripheral blood lymphocytes are S ezary cells B2* High blood tumor burden. clone positive or negative Clinically abnormal peripheral LNs. Overall survival was estimated with the Kaplan-Meier method. Standard descriptive statistics were used to summarize these data. metastases/ visceral organs M0 No visceral organ involvement M1 Visceral organ involvement with pathologic confirmation From Olsen et al. following the above criteria. S ezary cell counts. y Can be divided into a and b if information on clone with polymerase chain reaction or Southern blot analysis of TCR is available. histopathology Dutch grade 3-4 or NCI LN4. Statistical analyses were performed with a software package (SAS. date of last follow-up at our institution. sex. National Cancer Institute. symptoms at presentation. RESULTS A total of 487 patients with possible SS were identified on a preliminary search over 35 years of patient records. The strength of each association was summarized using the hazard ratio (HR) and corresponding 95% confidence interval (CI). and P less than . race. and/or plaques \10% body surface area Patches and/or plaques $ 10% body surface area $ 1 tumor ( $ 1 cm in diameter) Erythroderma (erythema $ 80% of body surface area) No clinically abnormal peripheral LNs Clinically abnormal peripheral LNs. T-cell receptor. b signifies clone positive. All calculated P values were 2 sided.6 Used with permission. in reference to the end point that is relevant to this study (overall survival). The information extracted from the medical records included date of birth. NC). generalized .18 Demographic and clinical factors present at diagnosis were each evaluated univariately for an association with survival (death by any cause) by fitting separate Cox proportional hazards regression models. no patients were lost to follow-up. skin. Version 9. 311 were excluded because another final diagnosis was identified (eg. Vt). TCR. papules. Among these patients. Cary. tumor T1 T2 T3 T4* N. no histopathology provided N3 NX B. and calendar-yearespecific mortality from the US white population to the age. Duration of follow-up was calculated from the date of SS diagnosis to the date of death by any cause or of last follow-up. NUMBER 6 Kubica et al 1191 Table I. prior diagnosis of MF. guidelines.J AM ACAD DERMATOL VOLUME 67. vital status and death date information were queried through an institutionally approved fee-based Internet research and location service (Accurint.6 Time of SS diagnosis was defined as the time of initial evaluation at Mayo Clinic or an outside institution. LexisNexis Risk Solutions. or bone marrow. Lymph node. TNMB components and definitions for mycosis fungoides and S ezary syndrome based on 2007 International Society for Cutaneous Lymphomas/European Organization for Research and Treatment of Cancer Classification Characteristics T. nodal N0 N1y N2y Patches. LN. In addition. expanded CD41 cells with abnormal immunophenotype. and date of death. lymph node. The primary end point was overall survival (death by any cause) because we were unable to evaluate disease-specific survival given the lack of data on disease course and cause of death for many patients. was T4N0-3M0-1B2 (Table I) in the current study. histopathology Dutch grade 2 or NCI LN3 Clinically abnormal peripheral LNs. The expected survival was derived by applying age-. Burlington.

5) Lymph node 21/27 (77.6-2.5-30. y Data available. S ezary syndrome. in these cases.4) 1778 (1215-3481) 19.4) TCR clone present in bone 119 (90. graftversus-host disease. In particular.9) 1 (0.7 years (IQR 0.2-32.7) Range 26. Cont’d Characteristic Value. reactive erythroderma.8) LDH level at presentation Data available. of patients 81 Mean (SD) 1.0) Range 0.0 years). x Most frequently noted to be atypical epidermal lymphocytic band. resulting in 176 patients who had SS as defined by the established criteria.2-7.8) 20 (17. the patients fulfilled the inclusion criteria for diagnosis of SS on the basis of the other molecular criteria listed in Table I.0) Range 0.3-6.2) Tumors 4 (2.5) Keratoderma 30 (17.1) Lichenification 13 (7. To verify the diagnosis of SS and exclude other hematologic or dermatologic processes.0) 163 (92. *Values are presented as No. lymph node. 25th and 75th percentiles. the average duration of erythroderma before diagnosis was 1.6 Race Caucasian 168 (95.6) years.4) Patches 1 (0. T-cell receptor. (%) unless specified otherwise. interquartile range. MF.4) 13 (18. atopic dermatitis).4) CTCL.5) Age. lactate dehydrogenase.8) marrow.5) Female 66 (37. LDH. Other symptoms are also listed in Table II.6-2. median.8) Plaques 39 (22.3) Continued Lymph node biopsy results Architecture consistent with SSz Molecular data consistent with SS Architecture and molecular data consistent with SSz No lymph node involvement Bone-marrow biopsy performed Bone-marrow biopsy results Architecture consistent with SS Molecular data consistent with SS Architecture and molecular data consistent with SS Nondiagnostic No bone-marrow involvement S ezary cell count. blood.0 years).3) 9 (7. Because erythroderma is an essential component of the diagnosis.3-6. Cutaneous T-cell lymphoma. mycosis fungoides.4) Median (IQR) 3.0 years of dermatologic symptoms before diagnosis (interquartile range [IQR] 1. many patients underwent biopsies of lymph node and bone .* N = 176 Demographic and clinical features Sex.2 (12.0 Erythroderma at presentation 176 (100) Duration of erythroderma before presentation.3) 114 (64.3) Pruritus 176 (100) Alopecia 29 (16.3) Middle Eastern 1 (0. all patients had this finding at presentation. The mean (range) age at SS diagnosis was 66.0 (1. IQR. Demographic and clinical features and diagnostic criteria for 176 patients with S ezary syndrome Characteristic Value. SS.2-89. 23 had S ezary cell counts that were not recorded (n = 7) or were recorded to be less than 1000 cells/L at the time of diagnosis (n = 16).6) 13 (7. z Architectural involvement included lymph node effacement caused by tumor and accumulation of dense S ezary cell infiltrate in lymphoid tissue.6) Prior MF diagnosis 12 (6.9) 78 (68.6) Lymph node biopsy performed 71 (40.7 (0.6) Unknown 3 (1.5) 6 (5.7 (1.2-89. Table II summarizes the patient demographic characteristics and clinical features at presentation for the 176 patients with SS in this study. No.4) African American 4 (2. y Total percentage exceeds 100% because some patients had [1 symptom at presentation.4 (4.3) Diagnostic criteria Molecular data available 131 (74.7) Bone marrow 15/28 (53. or skin Skin 69/89 (77.1192 Kubica et al J AM ACAD DERMATOL DECEMBER 2012 Table II.8) Blood 104/120 (86.1) 3 (4. TCR. No.7) Duration of symptoms before presentation. cells/L (IQR) S ezary cells. % (IQR) Results of skin biopsy Consistent with CTCL/SSx Nondiagnostic 37 (52. Among these patients. contact dermatitis. median. % Male 110 (62.5) Median (IQR) 1. with a median duration of 3.2) 18 (25.* N = 176 Table II.2 (26. of patients 81 Median. Patients presented with various symptoms. y Mean (SD) 66. U/L (IQR) 197 (130-275) # 222 U/L 48 (59.0 Other symptoms at presentationy Adenopathy 100 (56.0 (11. y Mean (SD) 4.

to standardize assessments of symptoms.4 years (IQR 1. and skin.20 The mean age at SS diagnosise66.3-82.0-20.7) (14. In addition. with 110 men (62. A multivariable model was not fit because the data for each of these factors were not available for all patients.5-50. As summarized in Table III and Fig 1.21-23 with a significant increase in incidence associated with increasing age.2-24. and molecular studies of the lymph nodes.6-56.7 years). blood.5 (81. respectively. the median duration of follow-up was 4. only limited data exist regarding the disease course itself.1% and 42.3% at 1 and 5 years. Overall survival after diagnosis of S ezary syndrome Time since diagnosis. lymph node.3 13. diagnosis of MF before SS.3 28. prior diagnosis of MF.8) (35. immunomodulatory agents.4 17.5%) and 66 women (37.J AM ACAD DERMATOL VOLUME 67. marrow.5 63.1 75. Median survival after SS diagnosis was 4. bone marrow. N = 176 Survival. published a consensus recommendation for clinical trials in patients with CTCL.0 24.19 in collaboration with the ISCL. Among the other 26 patients.8. particularly in the subset of patients with SS. presence of skin clone.2-31.14. Longitudinal data are also limited regarding incorporation of the changes that occurred over the past decades.1-91. and accurate future studies. overall survival was 86. and presence of TCR gene rearrangements in skin and blood.0) (41. Olsen et al. Among the 176 patients at follow-up. such as inclusion of new molecular tests and diagnostic criteria. Over the past several decades. the median survival was 5. Of note. where a larger. and calendar year (P \. men are affected twice as often as women.1 19. we present the survival data over the past 35 years on. The observed survival was significantly worse than the expected survival derived from the US Caucasian population for the same sex.5) (21.001).1-26.8-35.13. of patients at risk.1. and more targeted agents as treatment.4) (9. some heterogeneity exists in the literature regarding survival and prognosis for patients with SS because of the discrepancies in diagnostic criteria and the inclusion of patients without SS in many of the analyses.4) (69.1 years).4-71. validated. newer retinoids.4 Nevertheless.2 yearsein our study was similar to other reported data on SS.6-10. DISCUSSION In this study.0 years. our survival data on 176 patients reinforce the trends found in the literature and reaffirm several prognostic markers of worse survival outcomes in patients with SS. the association between each factor and survival was assessed after adjusting for age (Table V).2) (56. generally. with a median time to death after SS diagnosis of 3. The implementation of such uniform criteria will greatly assist in providing international collaboration for research in CTCL. Overall survival from diagnosis of S ezary syndrome to 10 years after diagnosis. extensive research advances in SS and CTCL have generated improved diagnostic techniques in an effort to more effectively diagnose SS and distinguish it from other subsets of CTCL.5%).4 Recently. and visceral organ involvement. and end points for response. y No. Advanced age at SS diagnosis.4 Additional confounding factors in establishing clear epidemiologic data on survival include the frequent exclusion of patients with SS from clinical trials on CTCL treatment and the myriad of definitions used as end points in various studies. multicenter cohort of patients should allow for more standardized.4 Nevertheless. NUMBER 6 Kubica et al 1193 Table III. The group of patients in this study reflected the reported male predilection.7) (12. after diagnosis. Currently. skin.3 48.3) The following factors were individually associated with survival after adjustment for age: LDH level at presentation. Cox proportional hazards models were fit to univariately evaluate potential predictors of survival in patients with SS. and higher LDH levels at presentation were each identified as significantly associated with poorer survival (Table IV). presence of blood clone.7-5.1. % (95% CI) 1 2 3 4 5 6 7 8 9 10 CI. 147 126 104 79 65 43 37 28 23 18 86. to our knowledge. . blood.5 years (IQR 1. age.6 42. 150 were known to be deceased. monoclonal antibodies. and use of extracorporeal photopheresis. Confidence interval.5 years after onset of erythroderma in the 81 patients for whom this clinical finding was recorded.9) (18. Fig 1. the largest group of patients with SS studied to date.

5 (67.6 (48.8 (79.58-1.7) 41.6) e y .3) 61.02 (0.2) 86. SS.4-74. Confidence interval.93 (0.7-54.4) 43.5 (81.6) 80.60) \.8) 65.8-97.41-4.7-79.85 (0.7) 86.39) Referent 1.9) 88.53-4.88-3.0) (61.9 5.6 (25.3 (38.8-93.00 (1.36 (1.3) 4.9-98.26) Referent .9 1.62 (0.1 3.85) Referent 2.44) 1.4) 47.9) e e 87.7-76.5 (79.8-78.02) Referent 1.3 (21.5-63.61) Referent .0 Referent 1.0) (72.1) y 4.9 4.43 10 166 12 164 58 13 35 79 69 20 104 16 21 6 169 170 81 e e 86.0-5.2-93.7 (31.6) 34.5 (81.8-100) y y 7.5) 55.3 1.0 4.7) y 86. y Kaplan-Meier estimates are not reported when there are \10 patients left at risk.5 (58.05 70. NA.4 (31.0 1.4-53.51 (0.14 .4) 38.3 (55. Summary of factors evaluated univariately for association with survival after S ezary syndrome diagnosis Factor No.5) 49.2 (50.8-78.0 (64.6-92.3 (65.3 7.0-93. not applicable.4) (81.9) 86.2 86.7 (53. MF.1) 61.8 (56.6) 69.4-52.9-97.6 (56.3-49. mycosis fungoides.7 (80.0 4.1) 66.5-93.7-96.11) 1.0 Adenopathy at presentation Yes No Alopecia at presentation Yes No Plaques at presentation Yes No Systemic symptoms at presentation Yes No MF before SS Yes No Lymph node biopsy Positive Negative Bone-marrow biopsy Positive Negative Skin clone Present Absent Blood clone Present Absent Lymph node clone Present Absent Log2 (S ezary count)* ezary cells)* Log2 (% S Log2 (LDH level at presentation)* 176 110 66 85.6) 35.6) 44.7-74.41 .9) 62.5) y (40.3-99.3-2.001 e CI.1-96. y \1.3) 3.8) y 79.1-72.6 4.76 (0.79-1.4-89.5 4.29) Referent 2.4 (34.0) 65.6) 60.4 (80.9 54.21 (0.4-78.62 (1.2-75.1 (36.0 (64.1 (35.2-66.6 (34.7 (77.5-71.0 3.8 (79.7-54.2) 61.87-1. LDH.1) 87.39 (0.0 3.11 .58 (0.9) 4.1-100) e 90.5) 47. % (95% CI) At 1 y At 3 y At 5 y Median survival.8) (77.3 3.4) 44.27 43 36 43 52 85.5) 41.3 4.94-2.4-91.0-94. .5 (75.001 1.5-74.1-61.7 (34.0-53.1-79.43 .6) 87.5-62.6 1.9-95.8 3.5) y 100 (NA) 91.2) 62.4 4.64-1.75-1.3) 64.41) Referent .4) 43.5 (78.9 3.2 (25.6-67.9 (50.3 (76.9 74.39 (1.72) Referent 1.6) 41.26-2.1 64.0-95.14) Referent 2.4-75.5-73. lactate dehydrogenase.19 .1 (78.8-49.8-54.7 (36.88-1.7-92.90 .3) 89.7 0.2) 90.6 (52.8) 62.7 (71.0 (57.2) 84.1 1.9 (56.2-93.3-57.20 (0. S ezary syndrome.1194 Kubica et al J AM ACAD DERMATOL DECEMBER 2012 Table IV.25 100 76 85.2) 50.7 83.92) 0.7) (52.0 (45.6-92.92 29 147 3.7) 63.7 (37.69-1.7 6.20-1.4) 40.0 0.0-93.7 (74.27-4.6-76.90-2.99 (0.5-73.5 (82.6 (36.3-99.9 $ 6.4 (30.9-54.80 39 127 79.2 (39.3 90.0-96.0-50.50) Referent 1.002 .5 (82. y HR (95% CI) P value Age at SS diagnosis.68) Referent .8-51.9 (52.3 5.06 (0.5-71.3-100) 85.1 (47.1) 60.2) 39.9) 63.1 (56.0 (82.007 .01 (0.1 (52.9 (31.0 5.5 (33.28-1.3) 43.16) 0.4 4.59) .00-4.7-93.6-99.74-1. *HR is per 10-y increase in age and per doubling in values of factors evaluated after applying log2 transformation.5 (52. HR.2 4.5-73.1) 65. hazard ratio. y* Sex Male Female Symptom duration before presentation. of patients Survival.80 (1.52) .

acting as a marker of the degree of peripheral blood involvement. which have markedly advanced the sensitivity to diagnose malignant lymphoproliferative disorders. Although data on lymph node involvement were not uniformly available for all patients.27 The presence of a peripheral blood TCR clone.93-3.12. are not clearly differentiated from CTCL studies as a whole. lactate dehydrogenase.59 (95% CI 1. therefore. 120 patients had molecular analysis of blood specimens. Kim et al12 evaluated nodal involvement in patients with blood involvement and found that 26 of 28 patients in stage T4B1 (92. a total of 119 (90. with an HR of 2. with an HR of 2. Similar findings were observed in other studies.05 (95% CI 1. hazard ratio. and immunohistochemical findings remains crucial when diagnosing SS.71 (1.18-2. an increased disease-specific death rate was demonstrated by Scarisbrick et al9 with cutoffs for hematologic stage of 1000 cells/L and 10. NUMBER 6 Kubica et al 1195 Table V. Studies have shown that the presence of identical cutaneous and blood TCR clones is an independent prognostic factor for disease progression of SS. 10 of 11 patients (90. overall survival.60. and disease-specific survival of patients with advancing lymph node stage (P \ .8.002 71 114 89 120 81 1. as with other factors and epidemiologic characteristics in patients with SS. A TCR clone found in the skin also portended worse prognosis in our patients.J AM ACAD DERMATOL VOLUME 67. Specifically. pathologic.44-4. LDH.4%).22 2.005 CI. especially when correlated to the skin. Accordingly.9. our study did not find this correlation to be statistically significant.05 (1. The primary purpose of our study was to estimate the overall survival of patients with SS.7%) of these analyses revealed clones.38-4.9. has been shown to be associated with a considerably worse prognosis compared with patients who do not have clonal involvement. sex. *Each factor was assessed in separate Cox proportional hazards regression model that also included age.29 In contrast to MF. We did not find a statistically significant correlation with worse prognosis in patients with lymph node involvement.5%) revealed a clone. indicating that skin biopsies can indeed be helpful when confirming a clone present in the blood.000 cells/L.31 Of the 131 patients with molecular collections performed (74. a small percentage of patients with SS do not show a TCR clone by Southern blot or polymerase chain reaction analysis. HR. Furthermore.31 (0.47) .10.28 Our study confirms these findings. However.8%) had evidence of clonal involvement by a T-cell malignancy.85-2.08 1.25 In addition. the study of patients with MF and SS by Agar et al8 did note decreases in median survival. P \ .87) . and this finding holds true in patients with MF and those with SS.98) . the proportion of S ezary cells present in the blood. this test is nonspecific because only 69 of the 89 patients with molecular data present in the skin (77. y HR is per doubling in LDH level.001).59 (1.26.7%) showed involvement with SS. Available information indicates that the natural disease course of SS is more aggressive than MF. some studies more specifically suggest worse prognosis in cases where lymph nodes had TCR clone present. Factors associated with increased risk of death after S ezary syndrome diagnosis and after adjustment for age at diagnosis No.22. In a study comparing various methods for assessing peripheral involvement by SS. Similarly. Yet. and 104 (86. falsenegative and false-positive results must be considered.24 It is important to note that many data on age. However.00-4.00-4. epidermotropism is frequently absent in cutaneous biopsy specimens of patients with SS. has been correlated with worse prognosis.33 As with all diagnostic techniques. and the prognosis .30 Currently. the presence of a cutaneous TCR clone is not a part of the mandatory diagnostic criteria of SS.9%) had lymph node involvement. More specifically.32 Another study used similar methods and found a TCR clone in 12 of 17 patients (71%). 95% CI 1.003 2.02) . of patients with data available Adjusted HR (95% CI)* P value Factor Prior mycosis fungoides diagnosis (vs none) Positive lymph node biopsy (vs negative) Positive bone-marrow biopsy (vs negative) Present skin clone (vs absent) Present blood clone (vs absent) Log2 (LDH level at presentation)y 176 2. although it has been proposed as part of the laboratory diagnosis for early MF.20-1. our study also confirmed prior findings that worse prognosis is associated with increasing age (HR 1. Confidence interval. 71 patients did undergo lymph node biopsy.68 (1. These data reaffirm the accuracy and utility of molecular tests.85 (0. of which 58 (81.21) after adjustment for age. incorporation of all available clinical.33 These findings further support clinical laboratory recommendations that no single test uniformly establishes the diagnosis of SS.68) .21) .38-4.9%) had a TCR clone.05 1.87) after adjustment for age.001). Nevertheless.39. and race.

disease-specific survival.1 OS NA NA NA NA NA NA NA 42. 22 H4 31 52 28 35 29 4.13 y (37.8 2010 Vidulich et al. 2.10 2008 Willemze et al.4 y (64.4 y for H4 11 y (132 mo) NA 5. % Patients alive at 10 y.22 2003y Kim et al.5 y (42 mo) NA NA NA NA NA NA NA NA CTCL.000 S ezary cells/L) and H4 ( $ 10.000 S ezary cells/L).0 y (48 mo) 3. 15 DSS NA 54. J AM ACAD DERMATOL DECEMBER 2012 . OS.5 y (30 mo) 2. DSS.36 2009* Arulogun et al. 38 at 5 y 40 33. Austria France California Spain 176 1502 124 297 1905 28 525 29 SS MF and SS Erythrodermic CTCL MF and SS CTCL SS MF and SS SS 176 104 101: 79 H3.55 mo) DSS 3. S ezary syndrome.34 1987 J Am Acad Dermatol Ann Oncol Ann Intern Med Blood Texas Italy Maryland Maryland 115 62 152 160 MF and SS SS MF and SS CTCL 12 62 52 60 2.# 10. y Reported only DSS.12 2003 Marti et al.6 y (31 mo) 3. median (overall) Patients alive at 1 y.1196 Kubica et al Table VI. NA.21 1998 Sausville et al.11 1999 Bernengo et al.3 OS 26 OS. MF. % Kubica et al (current study).56 mo) 5. mycosis fungoides. *Study divided patients with SS into 2 groups: H3 ( $ 1000. SS.50 NA 22 NA 12 OS.0 y (36 mo) 4. of patients with SS Survival. not available. 2012 Agar et al. 31 DSS NA 60. Cutaneous T-cell lymphoma.3 y (40 mo) 3.5 2005y Foulc et al. of patients Patients included No.8 OS 24 DSS NA 20 Mean actuarial risk. overall survival.0 y (48 mo) 86.20 2003 Minnesota J Clin Oncol Int J Dermatol Blood Blood Br J Dermatol Arch Dermatol Leuk Lymphoma United Kingdom Texas Australia The Netherlands. Major survival studies on cutaneous T-cell lymphoma with identified subsets of patients who have S ezary syndrome Study Journal Location Total No. % Patients alive at 5 y.25 1988 Schechter et al.4 y for H3.7 OS NA NA NA NA Diamandidou et al.

Of note. In addition. Although CTCL represents a spectrum of disease.13 years after diagnosis.7 Typically. particularly of the 1000 S ezary cell cutoff. less than 10% of patients with MF progress to more advanced disease. it is important to note that the patient population. Further studies are needed to elucidate the clinical course of these patients. Some results were limited because of missing data and inconsistencies in the extent of laboratory evaluation.444.36 These findings could call into question the role of absolute S ezary cell counting. Therefore. increased leukemic burden in the blood. respectively.25. However. these survival data of patients with prior MF could represent an artifact of statistical bias. Frequently. with a median survival of 3. which parallels the findings of many prior studies and thus provides further affirmation of the general uniformity of staging and treatment response that can be more broadly applied for patients with SS cared for at various institutions over several decades. CONCLUSION Because of the aggressive nature of SS compared with other subsets of CTCL. Our study also addressed factors at the time of diagnosis that correlated to increased risk of death (Table V). In the literature.5 years. Although only a select group of these studies were exclusively of SS.8.21.5 years.2.20. and staging.10. in the 2008 study by Arulogun et al. Because this study spanned almost 4 decades.3% of patients in whom LDH levels were available had LDH levels within the reference range at diagnosis. The largest.000 cells/L. the median survival after onset of erythroderma was 5.37.98. in patients with MF who have development of cutaneous tumors or generalized erythroderma. In our study. diagnostic techniques.9. This result has been noted in other publications as zary cells. because of the relative rarity of .8. such as erythrodermic MF or early-stage MF. an indicator of worse prognosis in patients with SS in our investigation was the existence or diagnosis of prior MF (HR 2. The number of circulating S ezary cells did not appear to be a prognostic factor in our study. enlargement of peripheral lymph nodes.0 years. and treatments evolved over this time. Other studies have similarly noted this finding. imaging. the patient population represents a single academic center. Of note.5 to 4. Also. Of note.002).21 although overall. results may not be generalizable to other institutions or populations. it is not understood why this finding was so high.10 the median overall survival was surprisingly high.4 years. CD301 expression or inactivation of the cyclin-dependent kinase inhibitor 2A-2B locus that is associated with inferior outcomes. the prognostic factors associated with worse outcomes include advanced age. given the rarity of this diagnosis and the paucity of data on patients with SS only.J AM ACAD DERMATOL VOLUME 67. 12 patients had prior MF. This finding was also reported in 11. more aggressive variant of CTCL. increased LDH levels. in prognosis of SS.10. LDH level at presentation was a potential predictor of poorer survival after a diagnosis of SS. elevated levels of Se notably those exceeding 10.3. we were not able to assess for certain prognostic factors. 59.35 Because of a lack of data on the disease course of many patients. and well. at 11 years. along with shortcomings inherent in retrospective chart reviews.11. Disease-specific mortality could not be calculated because of the inability to gather data on timing of disease progression and cause of death. perhaps with large-cell. and large-cell transformation. there is little crossover between MF and SS in previous reports. It is possible that patients with SS and prior MF have an atypical. After adjusting for age. but this finding was disease specific.37 Nevertheless.12. NUMBER 6 Kubica et al 1197 for these patients is typically poor. such as large-cell transformation. this phenomenon is not well documented in the literature. we believed that including all major publications that clearly defined the pool of patients with SS would be important. it is imperative to stratify and analyze this distinctive patient population separately.34 Table VI represents major survival studies on CTCL that have identified subsets of patients with SS. our study of 176 patients found a median survival of 4 years.21. Alternatively.22 Yet. Another prognostic factor was the presence of TCR gene rearrangements in skin and blood.8 Similarly.24 Interestingly.68. P = .12 The median overall survival ranges from 2. with various stages based on TNMB classifications. most recent study from the United Kingdom cutaneous lymphoma database evaluated 104 patients with SS and revealed that overall survival at 5 years is 26%.37 These values are more consistent with the prognosis of patients with SS.3% of patients with SS in an Italian SS study.38 Limitations Limitations of this study include its retrospective design. Foulc et al22 studied a group of patients with SS and found a median survival of 5. this development occurs later in the disease course rather than being present at time of diagnosis.2. in studies have identified a subset of patients with a worse prognosis.24. survival decreases from a median of 11 years to a median of 3 years and 4. although the types of MF were not further characterized according to stage or subtype. low percentage of CD81 cells in lymph nodes. 95% CI 1.

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