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 t to evaluate factors associated with overall survival. Results: In total, 176 patients were identied 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% condence 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

Abbreviations used: CI: condence 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 2012 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2012.04.043

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including immunophenotyping and molecular criteperformed an electronic search of the medical diagria, in an effort to better distinguish SS from mycosis nosis index to identify patients with SS diagnosed at fungoides (MF) and other erythrodermic CTCLs.6,7 Mayo Clinic, Rochester, MN, between 1976 and 2010. 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 fullled SS diagnostic criteria. classification system that was previously used to Medical records were reviewed for only the patients define MF and SS, and increased emphasis was who had not denied access to their records for placed on defining the deresearch purposes, in accorgree of peripheral blood indance with Minnesota Statute CAPSULE SUMMARY volvement in establishing a 144.335. diagnosis.6 Recognizing the At primary evaluation, 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. other erythrodermic CTCLs, amination, complete blood To our knowledge, this study population the ISCL in 2002 also further cell count, general chemistry is the largest of patients with S ezary established criteria and labopanel, skin biopsy, and mansyndrome reported in the medical ratory evaluation for these ual S ezary cell count of peliterature and reaffirms the poor subtypes of CTCL.7 ripheral blood smears, or As a result of both the prognosis of this disease. ow cytometry of peripheral constantly evolving underblood. 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, patients typically patients and adds data to the literature with the relatively more comunderwent lymph node bion S ezary syndrome. mon CTCL variant, MF, studopsy or ne-needle aspiraies have frequently grouped tion and other staging (eg, more indolent forms of bone-marrow biopsy; additional imaging, eg, chest CTCL, such as erythrodermic MF or early to later radiograph, computed tomography, or positron stages of MF with SS, resulting in incomplete or emission tomography). Given that all patients in unstratied data on the actual survival, progression, the study had SS, data on imaging were not collected and outcomes of documented SS.4 Therefore, few because it is not included in the 2007 ISCL/EORTC published data exist on the long-term outcome and criteria (Table I). disease course of patients with SS. The data in the Because the study period spanned more than 3 medical literature suggest a poor prognosis for this decades and the denition of SS evolved during this aggressive CTCL variant, with reported median overtime, the diagnostic criteria in the study reected all survival ranging from 2 to 4 years.5,7-9 When these changes over time. For the diagnostic criteria extracutaneous involvement of the viscera is identiused in this study, SS cases included those with T4 fied, median survival is typically 2.5 years or less.10-13 ([80% of total body surface area involved with At our tertiary care academic referral institution, erythroderma) and denitive leukemic involvement. the dermatology department evaluates and cares for In patients whose SS was diagnosed before the mida large number of patients with SS, which constitutes 1980s, leukemic involvement was dened as absoonly about 2.5% of all CTCLs, according to data lute S ezary cell counts greater than or equal to obtained from Surveillance, Epidemiology, and End 1000 cells/L, following the proposed criteria of Results.14 With the incidence of CTCL increasing Winkelmann.15-17 However, beginning in the mid3 dramatically since the 1970s, we examined the SS 1980s, clinical molecular diagnostic techniques were population at our institution over the recent decades, implemented and became incorporated into SS difocusing on long-term survival and identifying progagnostic criteria. Therefore, in patients who received nostic factors in these patients. This collective, 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), 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. 1000 cells/L or molecular evidence of clonality by T-cell receptor (TCR) gene rearrangement (using Southern blot or, more recently, polymerase chain METHODS reaction), or both, in the blood. In essence, SS, as The Mayo Clinic Institutional Review Board defined by the 2007 ISCL/EORTC classification approved this study. A data retrieval specialist
d d d

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Table I. 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, tumor T1 T2 T3 T4* N, nodal N0 N1y N2y

Patches, papules, 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, histopathology Dutch grade 2 or NCI LN0-2 Clinically abnormal peripheral LNs, histopathology Dutch grade 2 or NCI LN3 Clinically abnormal peripheral LNs, histopathology Dutch grade 3-4 or NCI LN4; clone positive or negative Clinically abnormal peripheral LNs; no histopathology provided

N3

NX

B, 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. Requires positive clonal rearrangement of TCR plus one of the following: absolute S ezary cell count $ 1000/L; expanded CD41 or CD31 cells with CD4/CD8 ratio $ 10; expanded CD41 cells with abnormal immunophenotype, including loss of CD7 ( $ 40%) or CD26 ( $ 30%) M, metastases/ visceral organs M0 No visceral organ involvement M1 Visceral organ involvement with pathologic confirmation
From Olsen et al.6 Used with permission. LN, Lymph node; NCI, National Cancer Institute; TCR, T-cell receptor. *Necessary criteria for S ezary syndrome. y Can be divided into a and b if information on clone with polymerase chain reaction or Southern blot analysis of TCR is available. a signifies clone negative; b signifies clone positive.

guidelines, was T4N0-3M0-1B2 (Table I) in the current study.6 Time of SS diagnosis was defined as the time of initial evaluation at Mayo Clinic or an outside institution, following the above criteria. The information extracted from the medical records included date of birth; sex; race; symptoms at presentation; prior diagnosis of MF; lactate dehydrogenase (LDH) at presentation; S ezary cell counts; presence of TCR clones in blood, skin, lymph node, or bone marrow, or a combination; date of last follow-up at our institution; and date of death. For patients who no longer corresponded with or were no longer seen at our institution, vital status and death date information were queried through an institutionally approved fee-based Internet research and location service (Accurint, LexisNexis Risk Solutions, Burlington, Vt). Therefore, in reference to the end point that is relevant to this study (overall survival), no patients were lost to follow-up. Standard descriptive statistics were used to summarize these data. The primary end point was overall survival (death by any cause) because we were unable to evaluate disease-specic survival given the lack of data on disease course and cause of death for many patients. 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. Overall survival was estimated with the Kaplan-Meier method. The expected survival was derived by applying age-, sex-, and calendar-yearespecic mortality from the US white population to the age- and sex-specic person-years of follow-up in our cohort, using the Hakulinen cohort method. A 1-sample log rank test was used to compare the observed and expected curves.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. In addition, each factor was evaluated in a Cox model adjusted for age. The strength of each association was summarized using the hazard ratio (HR) and corresponding 95% confidence interval (CI). All calculated P values were 2 sided, and P less than .05 was considered statistically significant. Statistical analyses were performed with a software package (SAS, Version 9.2, SAS Institute Inc, Cary, NC).

RESULTS
A total of 487 patients with possible SS were identied on a preliminary search over 35 years of patient records. Among these patients, 311 were excluded because another nal diagnosis was identied (eg, erythrodermic MF, generalized

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Table II. Demographic and clinical features and diagnostic criteria for 176 patients with S ezary syndrome
Characteristic Value,* N = 176

Table II. Contd

Characteristic Value,* N = 176

Demographic and clinical features Sex, % Male 110 (62.5) Female 66 (37.5) Age, y Mean (SD) 66.2 (12.7) Range 26.2-89.6 Race Caucasian 168 (95.4) African American 4 (2.3) Middle Eastern 1 (0.6) Unknown 3 (1.7) Duration of symptoms before presentation, y Mean (SD) 4.4 (4.4) Median (IQR) 3.0 (1.3-6.0) Range 0.2-32.0 Erythroderma at presentation 176 (100) Duration of erythroderma before presentation, y Data available, No. of patients 81 Mean (SD) 1.7 (1.5) Median (IQR) 1.7 (0.6-2.0) Range 0.2-7.0 Other symptoms at presentationy Adenopathy 100 (56.8) Plaques 39 (22.2) Tumors 4 (2.3) Pruritus 176 (100) Alopecia 29 (16.5) Keratoderma 30 (17.1) Lichenification 13 (7.4) Patches 1 (0.6) Prior MF diagnosis 12 (6.8) LDH level at presentation Data available, No. of patients 81 Median, U/L (IQR) 197 (130-275) # 222 U/L 48 (59.3) Diagnostic criteria Molecular data available 131 (74.4) TCR clone present in bone 119 (90.8) marrow, lymph node, blood, or skin Skin 69/89 (77.5) Lymph node 21/27 (77.8) Blood 104/120 (86.7) Bone marrow 15/28 (53.6) Lymph node biopsy performed 71 (40.3) 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, median, cells/L (IQR) S ezary cells, median, % (IQR) Results of skin biopsy Consistent with CTCL/SSx Nondiagnostic

37 (52.1) 3 (4.2) 18 (25.4) 13 (18.3) 114 (64.8) 20 (17.5) 6 (5.3) 9 (7.9) 1 (0.9) 78 (68.4) 1778 (1215-3481) 19.0 (11.5-30.0) 163 (92.6) 13 (7.4)

CTCL, Cutaneous T-cell lymphoma; IQR, interquartile range, 25th and 75th percentiles; LDH, lactate dehydrogenase; MF, mycosis fungoides; SS, S ezary syndrome; TCR, T-cell receptor. *Values are presented as No. (%) unless specified otherwise. y Total percentage exceeds 100% because some patients had [1 symptom at presentation. z Architectural involvement included lymph node effacement caused by tumor and accumulation of dense S ezary cell infiltrate in lymphoid tissue. x Most frequently noted to be atypical epidermal lymphocytic band.

contact dermatitis, reactive erythroderma, graftversus-host disease, atopic dermatitis), resulting in 176 patients who had SS as dened by the established criteria. Among these patients, 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); in these cases, the patients fullled the inclusion criteria for diagnosis of SS on the basis of the other molecular criteria listed in Table I. Table II summarizes the patient demographic characteristics and clinical features at presentation for the 176 patients with SS in this study. The mean (range) age at SS diagnosis was 66.2 (26.2-89.6) years. Patients presented with various symptoms, with a median duration of 3.0 years of dermatologic symptoms before diagnosis (interquartile range [IQR] 1.3-6.0 years). Because erythroderma is an essential component of the diagnosis, all patients had this finding at presentation. In particular, the average duration of erythroderma before diagnosis was 1.7 years (IQR 0.6-2.0 years). Other symptoms are also listed in Table II. To verify the diagnosis of SS and exclude other hematologic or dermatologic processes, many patients underwent biopsies of lymph node and bone

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Table III. Overall survival after diagnosis of S ezary syndrome

Time since diagnosis, y No. of patients at risk, N = 176 Survival, % (95% CI)

1 2 3 4 5 6 7 8 9 10
CI, Confidence interval.

147 126 104 79 65 43 37 28 23 18

86.1 75.5 63.3 48.6 42.3 28.0 24.1 19.4 17.3 13.5

(81.1-91.4) (69.3-82.2) (56.4-71.0) (41.6-56.8) (35.5-50.5) (21.8-35.9) (18.2-31.7) (14.1-26.7) (12.2-24.4) (9.0-20.3)

The following factors were individually associated with survival after adjustment for age: LDH level at presentation, prior diagnosis of MF, and presence of TCR gene rearrangements in skin and blood. A multivariable model was not fit because the data for each of these factors were not available for all patients.

DISCUSSION
In this study, we present the survival data over the past 35 years on, to our knowledge, the largest group of patients with SS studied to date. Currently, 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 Nevertheless, 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. Over the past several decades, 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.1,4 Nevertheless, only limited data exist regarding the disease course itself. Longitudinal data are also limited regarding incorporation of the changes that occurred over the past decades, such as inclusion of new molecular tests and diagnostic criteria, and use of extracorporeal photopheresis, newer retinoids, immunomodulatory agents, monoclonal antibodies, and more targeted agents as treatment.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.4 Recently, Olsen et al,19 in collaboration with the ISCL, published a consensus recommendation for clinical trials in patients with CTCL, to standardize assessments of symptoms; skin, lymph node, blood, and visceral organ involvement; and end points for response. The implementation of such uniform criteria will greatly assist in providing international collaboration for research in CTCL, particularly in the subset of patients with SS, where a larger, multicenter cohort of patients should allow for more standardized, validated, and accurate future studies. The group of patients in this study reected the reported male predilection, with 110 men (62.5%) and 66 women (37.5%); generally, men are affected twice as often as women.1,8,13,14,20 The mean age at SS diagnosise66.2 yearsein our study was similar to other reported data on SS,21-23 with a significant increase in incidence associated with increasing age.

Fig 1. Overall survival from diagnosis of S ezary syndrome to 10 years after diagnosis.

marrow, and molecular studies of the lymph nodes, bone marrow, blood, and skin. Among the 176 patients at follow-up, 150 were known to be deceased, with a median time to death after SS diagnosis of 3.5 years (IQR 1.7-5.7 years). Among the other 26 patients, the median duration of follow-up was 4.4 years (IQR 1.6-10.1 years). Median survival after SS diagnosis was 4.0 years. As summarized in Table III and Fig 1, overall survival was 86.1% and 42.3% at 1 and 5 years, respectively, after diagnosis. The observed survival was significantly worse than the expected survival derived from the US Caucasian population for the same sex, age, and calendar year (P \.001). Of note, the median survival was 5.5 years after onset of erythroderma in the 81 patients for whom this clinical finding was recorded. Cox proportional hazards models were t to univariately evaluate potential predictors of survival in patients with SS. Advanced age at SS diagnosis, diagnosis of MF before SS, presence of skin clone, presence of blood clone, and higher LDH levels at presentation were each identied as signicantly associated with poorer survival (Table IV). In addition, the association between each factor and survival was assessed after adjusting for age (Table V).

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Table IV. Summary of factors evaluated univariately for association with survival after S ezary syndrome diagnosis
Factor No. of patients Survival, % (95% CI) At 1 y At 3 y At 5 y Median survival, y HR (95% CI) P value

Age at SS diagnosis, y* Sex Male Female Symptom duration before presentation, y \1.3 1.3-2.9 3.0-5.9 $ 6.0 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 85.1 (78.7-92.1) 61.1 (52.5-71.2) 39.4 (31.0-50.1) 87.7 (80.1-96.1) 66.8 (56.1-79.5) 47.1 (36.1-61.3) 3.6 4.6

1.39 (1.20-1.60) \.001 1.21 (0.87-1.68) Referent .27

43 36 43 52

85.7 83.3 90.2 86.5

(75.8-97.0) (72.0-96.4) (81.6-99.8) (77.7-96.3)

61.9 54.9 74.1 64.6

(48.8-78.5) 49.7 (36.6-67.5) y (40.7-74.0) (61.4-89.4) 38.2 (25.3-57.7) (52.7-79.2) 50.3 (38.2-66.3)

4.0 3.3 3.9 5.0

Referent 1.51 (0.94-2.44) 1.20 (0.75-1.92) 0.99 (0.64-1.52)

.25

100 76

85.8 (79.2-93.0) 65.1 (56.2-75.3) 43.6 (34.7-54.9) 86.5 (79.0-94.6) 60.9 (50.5-73.4) 40.4 (30.4-53.8)
y 79.3 (65.9-95.5) 55.2 (39.7-76.6) 87.5 (82.2-93.1) 65.0 (57.5-73.4) 44.7 (37.0-53.9)

4.0 3.9

1.02 (0.74-1.41) Referent

.92

29 147

3.9 4.1

1.06 (0.69-1.61) Referent

.80

39 127

79.5 (67.8-93.2) 61.1 (47.4-78.6) 44.9 (31.5-63.9) 88.0 (82.7-93.7) 63.9 (56.1-72.7) 41.5 (33.8-51.1)
y

4.0 4.0

0.85 (0.58-1.26) Referent

.43

10 166 12 164 58 13 35 79 69 20 104 16 21 6 169 170 81

e e 86.5 (81.4-91.9) 63.6 (56.5-71.5) 41.4 (34.3-49.9) e e 87.5 (82.6-92.8) 65.5 (58.5-73.4) 43.6 (36.4-52.3) 89.5 (81.9-97.8) 62.2 (50.6-76.4) 47.1 (35.5-62.5) y 100 (NA) 91.7 (77.3-100) 85.7 (74.9-98.1) 60.0 (45.8-78.6) 34.3 (21.7-54.2) 84.3 (76.6-92.9) 62.5 (52.4-74.6) 41.7 (31.8-54.7) 86.8 (79.0-95.2) 62.9 (52.4-75.6) 35.6 (25.8-49.2) 90.0 (64.3-99.6) 80.0 (64.3-99.6) 69.6 (52.0-93.2) 86.4 (80.0-93.3) 64.3 (55.5-74.4) 43.7 (34.9-54.7) y 86.7 (71.1-100) e 90.5 (78.8-100)
y y

7.4 4.0 1.5 4.0 4.3 5.8 3.3 4.1 3.7 6.4 4.0 5.2 4.3 7.7

0.62 (0.28-1.29) Referent 2.36 (1.27-4.39) Referent 1.76 (0.88-3.50) Referent 1.39 (0.90-2.14) Referent 2.62 (1.41-4.85) Referent 2.00 (1.00-4.02) Referent 1.58 (0.53-4.72) Referent 1.01 (0.88-1.16) 0.93 (0.79-1.11) 1.80 (1.26-2.59)

.19

.007

.11

.14

.002

.05

70.7 (53.5-93.6) e

.41 .90 .43 .001

CI, Confidence interval; HR, hazard ratio; LDH, lactate dehydrogenase; MF, mycosis fungoides; NA, not applicable; SS, S ezary syndrome. *HR is per 10-y increase in age and per doubling in values of factors evaluated after applying log2 transformation. y Kaplan-Meier estimates are not reported when there are \10 patients left at risk.

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Table V. Factors associated with increased risk of death after S ezary syndrome diagnosis and after adjustment for age at diagnosis
No. 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

2.68 (1.44-4.98) .002

71 114 89 120 81

1.85 (0.93-3.68) .08 1.31 (0.85-2.02) .22 2.59 (1.38-4.87) .003 2.05 (1.00-4.21) .05 1.71 (1.18-2.47) .005

CI, Confidence interval; HR, hazard ratio; LDH, lactate dehydrogenase. *Each factor was assessed in separate Cox proportional hazards regression model that also included age. y HR is per doubling in LDH level.

Accordingly, our study also confirmed prior findings that worse prognosis is associated with increasing age (HR 1.39; 95% CI 1.20-1.60; P \ .001).10,12,24 It is important to note that many data on age, sex, and race, as with other factors and epidemiologic characteristics in patients with SS, are not clearly differentiated from CTCL studies as a whole. Although data on lymph node involvement were not uniformly available for all patients, 71 patients did undergo lymph node biopsy, of which 58 (81.7%) showed involvement with SS. Similarly, Kim et al12 evaluated nodal involvement in patients with blood involvement and found that 26 of 28 patients in stage T4B1 (92.9%) had lymph node involvement. We did not find a statistically significant correlation with worse prognosis in patients with lymph node involvement. However, the study of patients with MF and SS by Agar et al8 did note decreases in median survival, overall survival, and disease-specific survival of patients with advancing lymph node stage (P \ .001). Similar findings were observed in other studies.9,25 In addition, some studies more specifically suggest worse prognosis in cases where lymph nodes had TCR clone present.26,27 The presence of a peripheral blood TCR clone, especially when correlated to the skin, has been shown to be associated with a considerably worse prognosis compared with patients who do not have clonal involvement, and this nding holds true in

patients with MF and those with SS.8,9,28 Our study confirms these findings, with an HR of 2.05 (95% CI 1.00-4.21) after adjustment for age. Furthermore, the proportion of S ezary cells present in the blood, acting as a marker of the degree of peripheral blood involvement, has been correlated with worse prognosis. Specifically, an increased disease-specific death rate was demonstrated by Scarisbrick et al9 with cutoffs for hematologic stage of 1000 cells/L and 10,000 cells/L. Yet, our study did not find this correlation to be statistically significant. A TCR clone found in the skin also portended worse prognosis in our patients, with an HR of 2.59 (95% CI 1.38-4.87) after adjustment for age. However, this test is nonspecic because only 69 of the 89 patients with molecular data present in the skin (77.5%) revealed a clone. Studies have shown that the presence of identical cutaneous and blood TCR clones is an independent prognostic factor for disease progression of SS, indicating that skin biopsies can indeed be helpful when conrming a clone present in the blood.22,29 In contrast to MF, epidermotropism is frequently absent in cutaneous biopsy specimens of patients with SS.30 Currently, the presence of a cutaneous TCR clone is not a part of the mandatory diagnostic criteria of SS, although it has been proposed as part of the laboratory diagnosis for early MF.31 Of the 131 patients with molecular collections performed (74.4%), a total of 119 (90.8%) had evidence of clonal involvement by a T-cell malignancy. More specically, 120 patients had molecular analysis of blood specimens, and 104 (86.7%) of these analyses revealed clones. These data reafrm the accuracy and utility of molecular tests, which have markedly advanced the sensitivity to diagnose malignant lymphoproliferative disorders. Nevertheless, a small percentage of patients with SS do not show a TCR clone by Southern blot or polymerase chain reaction analysis. In a study comparing various methods for assessing peripheral involvement by SS, 10 of 11 patients (90.9%) had a TCR clone.32 Another study used similar methods and found a TCR clone in 12 of 17 patients (71%).33 These findings further support clinical laboratory recommendations that no single test uniformly establishes the diagnosis of SS.33 As with all diagnostic techniques, falsenegative and false-positive results must be considered; therefore, incorporation of all available clinical, pathologic, and immunohistochemical findings remains crucial when diagnosing SS. The primary purpose of our study was to estimate the overall survival of patients with SS. Available information indicates that the natural disease course of SS is more aggressive than MF, and the prognosis

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Table VI. Major survival studies on cutaneous T-cell lymphoma with identified subsets of patients who have S ezary syndrome
Study Journal Location Total No. of patients Patients included No. of patients with SS Survival, median (overall) Patients alive at 1 y, % Patients alive at 5 y, % Patients alive at 10 y, %

Kubica et al (current study), 2012 Agar et al,8 2010 Vidulich et al,36 2009* Arulogun et al,10 2008 Willemze et al,5 2005y Foulc et al,22 2003y Kim et al,12 2003 Marti et al,20 2003

Minnesota J Clin Oncol Int J Dermatol Blood Blood Br J Dermatol Arch Dermatol Leuk Lymphoma United Kingdom Texas Australia The Netherlands, 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, 22 H4 31 52 28 35 29

4.0 y (48 mo) 3.13 y (37.56 mo) 5.4 y for H3; 2.4 y for H4 11 y (132 mo) NA 5.4 y (64.55 mo) DSS 3.0 y (36 mo) 4.0 y (48 mo)

86.1 OS NA NA NA NA NA NA NA

42.3 OS 26 OS; 31 DSS NA 60.8 OS 24 DSS NA 20 Mean actuarial risk, 38 at 5 y 40 33.50 NA 22

NA 12 OS; 15 DSS NA 54.7 OS NA NA NA NA

Diamandidou et al,11 1999 Bernengo et al,21 1998 Sausville et al,25 1988 Schechter et al,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

2.5 y (30 mo) 2.6 y (31 mo) 3.3 y (40 mo) 3.5 y (42 mo)

NA NA NA NA

NA NA NA NA

CTCL, Cutaneous T-cell lymphoma; DSS, disease-specific survival; MF, mycosis fungoides; NA, not available; OS, overall survival; SS, S ezary syndrome. *Study divided patients with SS into 2 groups: H3 ( $ 1000- # 10,000 S ezary cells/L) and H4 ( $ 10,000 S ezary cells/L). y Reported only DSS.

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for these patients is typically poor.12 The median overall survival ranges from 2.5 to 4.0 years.8,11,12,20,21,25,34 Table VI represents major survival studies on CTCL that have identified subsets of patients with SS. Although only a select group of these studies were exclusively of SS, we believed that including all major publications that clearly defined the pool of patients with SS would be important, given the rarity of this diagnosis and the paucity of data on patients with SS only. Of note, in the 2008 study by Arulogun et al,10 the median overall survival was surprisingly high, at 11 years; it is not understood why this finding was so high. Also, Foulc et al22 studied a group of patients with SS and found a median survival of 5.4 years, but this finding was disease specific. The largest, 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%, with a median survival of 3.13 years after diagnosis.8 Similarly, our study of 176 patients found a median survival of 4 years, 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. Of note, the median survival after onset of erythroderma was 5.5 years. Disease-specific mortality could not be calculated because of the inability to gather data on timing of disease progression and cause of death. Our study also addressed factors at the time of diagnosis that correlated to increased risk of death (Table V). After adjusting for age, LDH level at presentation was a potential predictor of poorer survival after a diagnosis of SS. Other studies have similarly noted this finding.2,10,24 Interestingly, 59.3% of patients in whom LDH levels were available had LDH levels within the reference range at diagnosis. Another prognostic factor was the presence of TCR gene rearrangements in skin and blood. In the literature, the prognostic factors associated with worse outcomes include advanced age, enlargement of peripheral lymph nodes, increased leukemic burden in the blood, increased LDH levels, low percentage of CD81 cells in lymph nodes, and large-cell transformation.2,3,8,10,24,35 Because of a lack of data on the disease course of many patients, we were not able to assess for certain prognostic factors, such as large-cell transformation. Frequently, this development occurs later in the disease course rather than being present at time of diagnosis. The number of circulating S ezary cells did not appear to be a prognostic factor in our study. This result has been noted in other publications as

zary cells, and well.21,22 Yet, elevated levels of Se notably those exceeding 10,000 cells/L, in studies have identified a subset of patients with a worse prognosis.9,36 These findings could call into question the role of absolute S ezary cell counting, particularly of the 1000 S ezary cell cutoff, in prognosis of SS. Of note, an indicator of worse prognosis in patients with SS in our investigation was the existence or diagnosis of prior MF (HR 2.68; 95% CI 1.444.98; P = .002). In our study, 12 patients had prior MF, although the types of MF were not further characterized according to stage or subtype. This finding was also reported in 11.3% of patients with SS in an Italian SS study,21 although overall, this phenomenon is not well documented in the literature.7 Typically, less than 10% of patients with MF progress to more advanced disease.37 Nevertheless, in patients with MF who have development of cutaneous tumors or generalized erythroderma, survival decreases from a median of 11 years to a median of 3 years and 4.5 years, respectively.37 These values are more consistent with the prognosis of patients with SS. Although CTCL represents a spectrum of disease, with various stages based on TNMB classifications, there is little crossover between MF and SS in previous reports. It is possible that patients with SS and prior MF have an atypical, more aggressive variant of CTCL, perhaps with large-cell, CD301 expression or inactivation of the cyclin-dependent kinase inhibitor 2A-2B locus that is associated with inferior outcomes. Alternatively, these survival data of patients with prior MF could represent an artifact of statistical bias. Further studies are needed to elucidate the clinical course of these patients.37,38 Limitations Limitations of this study include its retrospective design. In addition, the patient population represents a single academic center. Therefore, results may not be generalizable to other institutions or populations. Because this study spanned almost 4 decades, it is important to note that the patient population, diagnostic techniques, and treatments evolved over this time. Some results were limited because of missing data and inconsistencies in the extent of laboratory evaluation, imaging, and staging, along with shortcomings inherent in retrospective chart reviews.

CONCLUSION
Because of the aggressive nature of SS compared with other subsets of CTCL, such as erythrodermic MF or early-stage MF, it is imperative to stratify and analyze this distinctive patient population separately. However, because of the relative rarity of

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this disease, the continual evolution of diagnostic criteria to document skin and blood involvement by SS, and the occasional overlap in the spectrum of CTCL, it is difcult not only to identify, but also robustly analyze, the group of patients with SS. With the long-standing experience and large volume of patients with SS seen at our institution, we were able to assemble a well-dened SS cohort on the basis of characteristic clinical features and blood involvement by CTCL. We found that this group of patients has a poor prognosis, with a median survival of 4.0 years after SS diagnosis. Further studies need to identify improved diagnostic techniques and molecular prognostic markers, and assess the impact of novel therapeutics to improve the outcomes of patients with SS.
REFERENCES 1. Hwang ST, Janik JE, Jaffe ES, Wilson WH. Mycosis fungoides and S ezary syndrome. Lancet 2008;371:945-57. 2. Kim EJ, Lin J, Junkins-Hopkins JM, Vittorio CC, Rook AH. Mycosis fungoides and S ezary syndrome: an update. Curr Oncol Rep 2006;8:376-86. 3. Lansigan F, Choi J, Foss FM. Cutaneous T-cell lymphoma. Hematol Oncol Clin North Am 2008;22:979-96. 4. Olsen EA, Rook AH, Zic J, Kim Y, Porcu P, Querfeld C, et al. S ezary syndrome: immunopathogenesis, literature review of therapeutic options, and recommendations for therapy by the United States Cutaneous Lymphoma Consortium (USCLC). J Am Acad Dermatol 2011;64:352-404. 5. Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH, et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005;105:3768-85. 6. Olsen E, Vonderheid E, Pimpinelli N, Willemze R, Kim Y, Knobler R, et al. Revisions to the staging and classification of mycosis fungoides and S ezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood 2007;110:1713-22. 7. Vonderheid EC, Bernengo MG, Burg G, Duvic M, Heald P, Laroche L, et al. Update on erythrodermic cutaneous T-cell lymphoma: report of the International Society for Cutaneous Lymphomas. J Am Acad Dermatol 2002;46:95-106. 8. Agar NS, Wedgeworth E, Crichton S, Mitchell TJ, Cox M, Ferreira S, et al. Survival outcomes and prognostic factors in mycosis fungoides/S ezary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organization for Research and Treatment of Cancer staging proposal. J Clin Oncol 2010;28:4730-9. 9. Scarisbrick JJ, Whittaker S, Evans AV, Fraser-Andrews EA, Child FJ, Dean A, et al. Prognostic significance of tumor burden in the blood of patients with erythrodermic primary cutaneous T-cell lymphoma. Blood 2001;97:624-30. 10. Arulogun SO, Prince HM, Ng J, Lade S, Ryan GF, Blewitt O, et al. Long-term outcomes of patients with advanced-stage cutaneous T-cell lymphoma and large cell transformation. Blood 2008;112:3082-7. 11. Diamandidou E, Colome M, Fayad L, Duvic M, Kurzrock R. Prognostic factor analysis in mycosis fungoides/S ezary syndrome. J Am Acad Dermatol 1999;40:914-24.

12. Kim YH, Liu HL, Mraz-Gernhard S, Varghese A, Hoppe RT. Long-term outcome of 525 patients with mycosis fungoides and S ezary syndrome: clinical prognostic factors and risk for disease progression. Arch Dermatol 2003;139:857-66. 13. Zackheim HS, Amin S, Kashani-Sabet M, McMillan A. Prognosis in cutaneous T-cell lymphoma by skin stage: long-term survival in 489 patients. J Am Acad Dermatol 1999;40:418-25. 14. Criscione VD, Weinstock MA. Incidence of cutaneous T-cell lymphoma in the United States, 1973-2002. Arch Dermatol 2007;143:854-9. 15. Winkelmann RK. Clinical studies of T-cell erythroderma in the S ezary syndrome. Mayo Clin Proc 1974;49:519-25. 16. Duncan SC, Winkelmann RK. Circulating S ezary cells in hospitalized dermatology patients. Br J Dermatol 1978;99:171-8. 17. Buechner SA, Winkelmann RK. S ezary syndrome: a clinicopathologic study of 39 cases. Arch Dermatol 1983;119:979-86. 18. Therneau T, Offord J. Expected survival based on hazard rates (update). Rochester (MN): Mayo Clinic, Division of Biostatistics and Informatics; 1999 Feb. 26 p. Technical Report No. 63. 19. Olsen EA, Whittaker S, Kim YH, Duvic M, Prince HM, Lessin SR, et al. Clinical end points and response criteria in mycosis fungoides and S ezary syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organization for Research and Treatment of Cancer. J Clin Oncol 2011;29:2598-607. 20. Marti RM, Pujol RM, Servitje O, Palou J, Romagosa V, Bordes R, et al. S ezary syndrome and related variants of classic cutaneous T-cell lymphoma: a descriptive and prognostic clinicopathologic study of 29 cases. Leuk Lymphoma 2003;44:59-69. 21. Bernengo MG, Quaglino P, Novelli M, Cappello N, Doveil GC, Lisa F, et al. Prognostic factors in S ezary syndrome: a multivariate analysis of clinical, hematological and immunological features. Ann Oncol 1998;9:857-63. 22. Foulc P, NGuyen JM, Dreno B. Prognostic factors in S ezary syndrome: a study of 28 patients. Br J Dermatol 2003;149: 1152-8. 23. Scarisbrick JJ, Child FJ, Evans AV, Fraser-Andrews EA, Spittle M, Russell-Jones R. Secondary malignant neoplasms in 71 patients with S ezary syndrome. Arch Dermatol 1999;135:1381-5. 24. Vonderheid EC, Pena J, Nowell P. S ezary cell counts in erythrodermic cutaneous T-cell lymphoma: implications for prognosis and staging. Leuk Lymphoma 2006;47:1841-56. 25. Sausville EA, Eddy JL, Makuch RW, Fischmann AB, Schechter GP, Matthews M, et al. Histopathologic staging at initial diagnosis of mycosis fungoides and the S ezary syndrome: definition of three distinctive prognostic groups. Ann Intern Med 1988;109:372-82. 26. Assaf C, Hummel M, Steinhoff M, Geilen CC, Orawa H, Stein H, et al. Early TCR-beta and TCR-gamma PCR detection of T-cell clonality indicates minimal tumor disease in lymph nodes of cutaneous T-cell lymphoma: diagnostic and prognostic implications. Blood 2005;105:503-10. 27. Fraser-Andrews EA, Mitchell T, Ferreira S, Seed PT, Russell-Jones R, Calonje E, et al. Molecular staging of lymph nodes from 60 patients with mycosis fungoides and S ezary syndrome: correlation with histopathology and outcome suggests prognostic relevance in mycosis fungoides. Br J Dermatol 2006;155: 756-62. 28. Fraser-Andrews EA, Woolford AJ, Russell-Jones R, Seed PT, Whittaker SJ. Detection of a peripheral blood T cell clone is an independent prognostic marker in mycosis fungoides. J Invest Dermatol 2000;114:117-21. 29. Beylot-Barry M, Sibaud V, Thiebaut R, Vergier B, Beylot C, Delaunay M, et al. Evidence that an identical T cell clone in

J AM ACAD DERMATOL
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Kubica et al 1199

30.

31.

32.

33.

skin and peripheral blood lymphocytes is an independent prognostic factor in primary cutaneous T cell lymphomas. J Invest Dermatol 2001;117:920-6. Diwan AH, Prieto VG, Herling M, Duvic M, Jone D. Primary S ezary syndrome commonly shows low-grade cytologic atypia and an absence of epidermotropism. Am J Clin Pathol 2005; 123:510-5. Pimpinelli N, Olsen EA, Santucci M, Vonderheid E, Haeffner AC, Stevens S, et al. International Society for Cutaneous Lymphoma. Defining early mycosis fungoides. J Am Acad Dermatol 2005;53:1053-63. Morice WG, Katzmann JA, Pittelkow MR, el-Azhary RA, Gibson LE, Hanson CA. A comparison of morphologic features, flow cytometry, TCR-Vbeta analysis, and TCR-PCR in qualitative and quantitative assessment of peripheral blood involvement by S ezary syndrome. Am J Clin Pathol 2006;125:364-74. Klemke CD, Brade J, Weckesser S, Sachse MM, Booken N, Neumaier M, et al. The diagnosis of S ezary syndrome on

34.

35. 36.

37. 38.

peripheral blood by flow cytometry requires the use of multiple markers. Br J Dermatol 2008;159:871-80. Schechter GP, Sausville EA, Fischmann AB, Soehnlen F, Eddy J, Matthews M, et al. Evaluation of circulating malignant cells provides prognostic information in cutaneous T cell lymphoma. Blood 1987;69:841-9. Prince HM, Whittaker S, Hoppe RT. How I treat mycosis fungoides and S ezary syndrome. Blood 2009;114:4337-53. Vidulich KA, Talpur R, Bassett RL, Duvic M. Overall survival in erythrodermic cutaneous T-cell lymphoma: an analysis of prognostic factors in a cohort of patients with erythrodermic cutaneous T-cell lymphoma. Int J Dermatol 2009;48:243-52. Zinzani PL, Ferreri AJ, Cerroni L. Mycosis fungoides. Crit Rev Oncol Hematol 2008;65:172-82. Laharanne E, Chevret E, Idrissi Y, Gentil C, Longy M, Ferrer J, et al. CDKN2A-CDKN2B deletion defines an aggressive subset of cutaneous T-cell lymphoma. Mod Pathol 2010;23: 547-58.