Second Lymphomas and Other Malignant Neoplasms in Patients with Mycosis Fungoides and Se´Zary Syndrome Evidence from Population-Based and Clinical Cohorts

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STUDY Second Lymphomas and Other Malignant Neoplasms in Patients With Mycosis Fungoides and Se´zary Syndrome Evidence From Population-Based and Clinical Cohorts

Kathie P. Huang, MD; Martin A. Weinstock, MD, PhD; Christina A. Clarke, PhD; Alex McMillan, PhD; Richard T. Hoppe, MD; Youn H. Kim, MD

Objective: To assess risks for developing second ma- Results: In the SEER-9 cohort (n=1798), there were lignancies in patients with mycosis fungoides or Se´zary 197 second instances of cancer (SIR=1.32; 95% confi- syndrome. dence interval [CI], 1.15-1.52) at all sites. Significantly elevated risk (PϽ.01) was observed for Hodgkin disease Design: Retrospective study of 2 cohorts. (6 cases; SIR=17.14; 95% CI, 6.25-37.26) and non- Hodgkin lymphoma (27 cases; SIR=5.08; 95% CI, 3.34- Setting: Nine population-based US cancer registries that 7.38). Elevated risk (PϽ.05) was also observed for constitute the Surveillance, Epidemiology, and End Re- melanoma (10 cases; SIR=2.60; 95% CI, 1.25-4.79), sults Program (SEER-9), and Stanford University refer- and urinary cancer (21 cases; SIR=1.74; 95% CI, 1.08- ral center cohort of patients with cutaneous lymphoma. 2.66). In the Stanford University cohort (n=429), there were 37 second instances of cancer (SIR=1.04; 95% CI, Patients: Patients with mycosis fungoides or Se´zary syn- Ͻ drome from the SEER-9 registry diagnosed and fol- 0.76-1.44). Elevated risk (P .01) was observed for Hodgkin disease (3 cases; SIR=27.27; 95% CI, 5.35- lowed up from 1984 through 2001 and from the Stan- Ͻ ford University cohort diagnosed and followed up from 77.54). Elevated risk (P .05) was also observed for 1973 through 2001. biliary cancer (2 cases; SIR=11.76; 95% CI, 1.51- 42.02). Main Outcome Measures: Relative risk was estimated using the standardized incidence ratio (SIR). The Conclusion: Updated SEER (population based) and Stan- expected cancer incidence for both cohorts was calcu- ford (clinic based) data confirm the generalizability of lated using age-, sex-, race-, and calendar year–specific earlier findings of increased risk of lymphoma in pa- SEER-9 incidence rates for the general population. Non- tients with mycosis fungoides or Se´zary syndrome. melanoma skin cancers were excluded because these cancers are not routinely reported by the SEER database. Arch Dermatol. 2007;143:45-50

YCOSIS FUNGOIDES entity distinct6 from MF, although the dis- (MF) is an extranodal, eases may have overlapping clinical fea- non-Hodgkin, cutane- tures. Mycosis fungoides tends to be in- ous T-cell lymphoma dolent in early stages, with intermediate first described in the to high risk of death in advanced stages. literature in 1806.1-4 Classically, it is mani- Although mortality rates for MF have been M 7 fested as a flat patch or thin plaque and declining, studies have suggested that pa- can progress to tumor and extracutane- tients with MF are at higher risk for de- ous involvement.4,5 Se´zary syndrome (SS) veloping secondary primary cancers com- is the leukemic form of cutaneous T-cell pared with the general population.8-12 In lymphoma and is manifested with pru- particular, studies have suggested evi- ritic erythroderma, generalized lymph- dence for increased risk of melanoma and adenopathy, and circulating Se´zary cells.3 other cutaneous malignancies.12 Kantor et In the new World Health Organization– al,11 using population-based data from the European Organization for Research and National Cancer Institute Surveillance, Author Affiliations are listed at Treatment of Cancer classification for cu- Epidemiology, and End Results (SEER) the end of this article. taneous lymphomas, SS is described as an Program for 1973 through 1983, did not

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 observe an increased incidence of cutaneous malignant Lymphoma Clinic, Stanford, Calif. This is part of a cohort pre- neoplasm, but relative risk exceeding 1.5 was detected viously described by Kim et al.14 Institutional review board ap- for lung cancer, colon cancer, and non-Hodgkin lym- proval was obtained to use the Stanford University data for this phoma (NHL). Previous studies of second instances of research project. Patients having MF or SS diagnosed earlier cancers in patients with MF or SS have shown conflict- than 6 months before treatment at the Stanford University clinic were excluded from the cohort to minimize treatment hetero- ing results. With increasing prevalence of MF and SS, more geneity within the cohort. Patients having second primary can- detailed and precise studies are needed in larger popu- cers diagnosed within 2 months of diagnosis of MF or SS were 13 lation cohorts. excluded from the analysis. Race was reported by the patients The purposes of this study were to assess increased or the investigator and was used to compare the demographic risk for second malignant neoplasms in patients with MF data for the Stanford cohort with those of the SEER popula- or SS and to describe this second cancer profile in 2 dis- tion. Keratinocyte carcinomas were excluded from consider- tinct cohorts: a large, population-based series of pa- ation. Occurrence of large-cell transformation of MF or lym- tients with MF or SS (n=1798) diagnosed from January phomatoid papulosis was not recorded as a second cancer. SIR 1984 through December 2001 compiled by the SEER-9 was calculated using methods comparable to those described Program, and a clinical cohort of patients with MF or SS for the SEER cohort. Follow-up was reported as person-years starting from MF or SS diagnosis to development of the sec- treated at Stanford University, Stanford, Calif, from Janu- ond neoplasm, death, last follow-up date, or the end of the ob- ary 1973 through December 2001 (n=429). The Stan- servation period, whichever occurred first. ford group is part of a cohort recently used in a study 14 for very long-term outcome in patients with MF or SS. STATISTICAL ANALYSIS

METHODS The 95% CIs were calculated using a binomial distribution. We used SAS statistical software (SAS Institute Inc, Cary, NC) for this analysis. Confidence intervals for quantiles of time to sec- PATIENTS AND DESIGN ond malignant neoplasm were calculated with 5000 bootstrap iterations according to the method of Akritas19 as imple- mented by Harrell20 in the R computing environment.20,21 SEER Cohort

The SEER-9 cohort consists of residents with cancer newly di- RESULTS agnosed from January 1984 through December 2001 from 9 SEER cancer registries: Atlanta, Ga; Connecticut; Detroit, Mich; Ha- SEER COHORT waii; Iowa; New Mexico; San Francisco–Oakland, Calif; Seattle– Puget Sound, Wash; and Utah.15 This period was chosen to avert 11 The mean age at diagnosis in the 1798 patients having overlap with previously published data. Analysis was limited MF and SS diagnosed and followed up from 1984 through to patients with MF or SS (International Classification of Diseases— Oncology, Third Edition [ICD-O-3] morphology codes 9700- 2001 was 59 years (age range, 10-88 years); 1081 pa- 9701) as the first primary malignant neoplasm. Patients having tients were male and 717 were female. In this cohort, there second primary malignant cancers within 2 months of having were 1432 white patients, 266 black patients, and 100 MF or SS diagnosed were excluded (72 patients). Only second patients of other race. Patients were followed up for a mean primary malignant neoplasms were considered for this analy- of 5.6 years, and the cohort was followed up for 10 069 sis. Keratinocyte carcinomas (basal and squamous cell carcino- person-years. Of the 197 patients in whom second can- mas of the skin) are not routinely reported to the SEER pro- cers developed, mean latency time to development of a gram and, thus, are not included in this study. Second primary second cancer was 4.1 years (49 months). One hundred cancer sites were defined using the SEER site recode of ICD-O-3 16 thirty-five were male and 62 were female. There were 159 site and histologic information. Relative risk was estimated with white patients, 31 black patients, and 7 patients of other the standardized incidence ratio (SIR; the ratio of observed number of cancers divided by the expected number of cancers). The race. Based on the expected number of cancers calcu- expected number of second cancers was generated by calculat- lated, 149 second cancers would be expected from SEER ing person-years of follow-up and applying appropriate SEER- incidence data, yielding an overall SIR of 1.32 (95% CI, 9–based sex-, age-, race- (white, black, or other), and calendar 1.15-1.52). Staging information for MF and SS was un- year–specific incidence rates for each. Follow-up was reported available for patients in the SEER cohort. in person-years, starting from 2 months after diagnosis of MF Statistically significant increased incidence of mela- or SS to development of the second malignant neoplasm, death, noma (10 cases; SIR=2.60; 95% CI, 1.25-4.79), urinary loss to follow-up, or the end of the observation period, which- system cancers (21 cases; SIR=1.74; 95% CI, 1.08-2.66), ever occurred first. A SIR of 1.0 indicates no difference from popu- Hodgkin disease (HD; 6 cases; SIR=17.14; 95% CI, 6.25- lation incidence. Statistical significance of the SIR was calcu- 37.26), and NHL (27 cases; SIR=5.08; 95% CI, 3.34- lated using the Poisson distribution to calculate 95% confidence intervals (CIs). The SEER*Stat software program, version 6.4.1 7.38) was observed in the cohort (Table 1). Of these, HD (Surveillance Research Program, National Cancer Institute, and NHL were the only malignancies with significantly el- Bethesda, Md) was used for this analysis.16-18 evated risk using the more conservative PϽ.01 criterion.

Stanford Cohort STANFORD COHORT

Between January 1973 and December 2001, 429 patients with The mean age at diagnosis in the 429 patients having MF MF or SS received a diagnosis and had their conditions man- or SS diagnosed and managed at the Stanford University aged at the Stanford University Multidisciplinary Cutaneous clinic from 1973 through 2001 was 55 years (Table 2).

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Table 1. Standardized Incidence Ratios for Second Cancers After MF or SS Diagnosis in SEER Cohort,* 1984 to 2001

Observed, Expected, 95% Confidence Cancer Site No. No. SIR Interval P Value† All sites‡ 197 148.77 1.32 1.15-1.52 Ͻ.01 Digestive system§ 23 30.93 0.74 0.47-1.12 Colon and rectum 16 18.85 0.85 0.48-1.38 Liver and intrahepatic bile duct 1 1.53 0.65 0.01-3.63 Respiratory system࿣ 36 25.54 1.41 0.99-1.95 Lungs and bronchi 33 23.31 1.42 0.97-1.99 Skin, excluding basal and squamous cells¶ 12 4.53 2.65 1.37-4.63 Ͻ.01 Melanoma 10 3.84 2.60 1.25-4.79 Ͻ.05 Urinary system# 21 12.06 1.74 1.08-2.66 Ͻ.05 Urinary bladder 14 8.21 1.71 0.93-2.86 Kidney and renal pelvis 6 3.50 1.71 0.63-3.73 Lymphoma 33 5.67 5.82 4.00-8.17 Ͻ.01 Hodgkin disease 6 0.35 17.14 6.25-37.26 Ͻ.01 Non-Hodgkin lymphoma 27 5.32 5.08 3.34-7.38 Ͻ.01

Abbreviations: MF, mycosis fungoides; SEER, Surveillance, Epidemiology, and End Results Program; SIR, standardized incidence ratio (ie, the ratio of observed number of cancers divided by the expected number of cancers); SS, Se´zary syndrome. *n = 1798; person-years = 10 069. †P values are adjusted for multiple comparisons. ‡Also includes the following (number of cases): oral cavity and pharynx (5), bones and joints (0), soft tissue including heart (1), breast (14), female genital system (7), male genital system (32), eye and orbit (0), brain and other nervous system (2), endocrine (1), myeloma (0), leukemia (4), and miscellaneous (6). §Also includes the following (number of cases): esophagus (0); stomach (2); small intestine (2); anus, anal canal, and anorectum (1); gallbladder (0); pancreas (1); and retroperitoneum (0). ࿣Also includes the following (number of cases): nose, nasal cavity, and middle ear (1); larynx (2); pleura (0); trachea, mediastinum, and other respiratory organs (0). ¶Also includes the following (number of cases): nonepithelial skin cancers (2). #Also includes the following (number of cases): ureter (1).

Patients were followed up for a mean of 7.8 years, with a total of 3341 person-years. Table 2. Patient Demographic Data for Stanford Cohort Thirty-seven second cancers were observed, with an SIR With MF or SS, 1973 Through 2001 of 1.04 (95% CI, 0.76-1.44). Significant increases in incidence were observed for HD (3 cases; SIR=27.27; 95% CI, Patients With Second Malignant 5.35-77.54) and biliary cancer (2 cases; SIR=11.76; 95% Patients, No. Neoplasms, No. CI, 1.51-42.02) (Table 3). Of these, HD was the only ma- Variable (n = 429) (n = 37) lignant neoplasm with significantly elevated risk using the Ͻ Sex more conservative P .01 criterion. Incidence of HD and Male 265 23 NHL considered as a single entity (all lymphomas) was Female 164 14 also statistically elevated (7 cases; SIR=5.11; 95% CI, 2.06- Race/ethnicity 10.40). Of the 4 patients having NHL, 2 had B-cell sub- White 366 35 types, 1 had natural killer T-cell lymphoma, and 1 had his- Black 17 2 tiocytic gastric lymphoma. Of the 37 patients in whom Other 46 0 Stage of MF at initial manifestation second cancers developed, mean time to development of IA 144 14 a second cancer was 4 years for all types, 6 years for HD, IB 112 10 1 year for NHL, and 9 years for biliary cancer. In this pa- IIA 44 7 tient group, MF stage at diagnosis was IA in 14 patients, IIB 66 4 IB in 10 patients, IIA in 7 patients, IIB in 4 patients, and IIIA 11 0 IIIB in 2 patients (Table 2). The life table estimate for sec- IIIB 27 2 IVA 24 0 ond malignant neoplasm was observed in 1% of the popu- IVB 1 0 lation at 1 year (95% CI, 0.7-2.1), in 5% at 4.9 years (95% CI, 4.0-6.5), and in 10% at 8.6 years (95% CI, 5.8-12) Abbreviations: MF, mycosis fungoides; NA, not available; SS, Se´zary (Figure). Cox regression analysis showed that there was syndrome. no difference between stage at diagnosis of MF and time to onset of second malignant neoplasm. of at least 2 previous studies.8,11 Our analysis of data for patients in the SEER Program diagnosed between 1984 COMMENT and 2001 demonstrated a different pattern of second can- Our study demonstrates that patients with MF and SS are cer development when compared with the Stanford co- at significantly increased risk of developing a second pri- hort. The Stanford cohort, but not the SEER cohort, had mary lymphoma, especially HD. This increased risk was an increased risk of biliary cancer. Increased risk of mela- consistent in both cohorts studied and confirms reports noma and urinary cancer were seen in the SEER cohort

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Table 3. Standardized Incidence Ratio for Second Malignant Neoplasms After MF or SS Diagnosis in Stanford Cohort,* 1973 Through 2001

Observed, Expected, 95% Confidence Cancer Site No. No. SIR Interval P Value† All sites‡ 37 35.61 1.04 0.76-1.44 Biliary system 2 0.17 11.76 1.51-42.02 Ͻ.05 Colon 5 4.84 1.03 0.34-2.39 Lung 5 6.09 0.82 0.27-1.90 Skin: Melanoma 1 0.92 1.09 0.05-5.99 Bladder 0 2.07 0.00 0.00-1.78 Lymphoma 7 1.37 5.11 2.06-10.40 Ͻ.05 Hodgkin disease 3 0.11 27.27 5.35-77.54 Ͻ.01 Non-Hodgkin lymphoma 4 1.26 3.17 0.85-8.06

Abbreviations: MF, mycosis fungoides; SIR, standardized incidence ratio (ie, the ratio of observed number of cancers divided by the expected number of cancers); SS, Se´zary syndrome. *n = 429; person-years = 3341. †P values are adjusted for multiple comparisons. ‡Also includes the following (number of cases): breast (7), prostate gland (4), sinuses (1), hepatic system (1), uterus (1), central nervous system (1), endocrine glands (1), and leukemia (1).

not found in the Stanford cohort, and the increase in 15 biliary cancer was not found in the aggregated 1973- 2001 SEER cohort. The consistently increased incidence of second lymphomas in 2 different cohorts during the same period supports the generalizability of this finding to other populations. 10 A major strength of this study is inclusion of data from both a population-based cohort and a clinical cohort. To our knowledge, this study constitutes the largest cohort of patients with MF or SS followed up for second can- 5

Cumulative Incidence, % cers reported to date. While the SEER cohort has the great- est number of patients with MF or SS, our assessments were limited somewhat by the lack of detailed staging and treatment data for these patients. This deficit was ame- 0 liorated by examining the Stanford clinical cohort, for 0 5 10 15 20 25 which treatment protocols were consistent, inasmuch as (429) (215) (126) (68) (30) (7) all patients were evaluated and treated by the same mul- Time to Second Malignancy, y tidisciplinary cutaneous oncology group. The liability of studying a clinical cohort from a tertiary referral center Figure. Cumulative incidence of second malignant neoplasm in the Stanford such as Stanford University Medical Center may be re- cohort. The number of subjects at risk at each time point are given in parentheses. The life table estimate for second malignant neoplasm was ferral bias or other nongeneralizability properties of the observed in 1% of the population at 1 year (95% confidence interval [CI], patient population. Stanford cohort patients were gen- 0.7-2.1), 5% at 4.9 years (95% CI, 4.0-6.5), and 10% at 8.6 years (95% CI, erally northern California residents, with a small pro- 5.8-12). portion of patients traveling from other states or coun- but not in the Stanford cohort. Increased risk of biliary tries. To minimize treatment heterogeneity and referral or urinary cancer has not been reported in previous stud- bias in the Stanford cohort, we excluded any patients hav- ies and the clinical basis of these findings is unknown. ing MF or SS diagnosed more than 6 months before treat- Kantor et al11 reported an overall increase of second can- ment at Stanford University Medical Center. cers in patients in the SEER cohort having MF or SS diag- Our study of the SEER cohort has confirmed previ- nosed from 1973 through 1983, specifically with in- ous reports of an increased risk overall for development creased risk of NHL, lung cancer, and colon cancer. of second cancers; however, previous smaller studies re- Increased incidence of colon and lung cancers was not found ported different second cancer profiles from ours. Vakeva in either the Stanford cohort or the updated SEER cohort et al8 observed an increased incidence of lymphoma and for the more contemporary periods investigated in our study. lung cancers. Olsen et al22 found an overall increase in When we aggregated data from the SEER cohort for second cancers but without predominance of specific can- the 2 periods under study from 1973 through 2001 cer type; however, this study differed from ours by in- (N=2232), equivalent to the study period in the Stan- cluding cancers diagnosed before MF diagnosis. Differ- ford cohort, we found significant increases in inci- ences among the various studies can also be attributed dence of second cancers overall, as well as lung can- to the various types of populations and treatments used cer, HD, and NHL. The increase in lung cancer was at different institutions.

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 In the Stanford cohort, most of the second cancers oc- (Dr Clarke), and Radiation Oncology (Dr Hoppe), curred in patients with stage IA and IB disease. Kim et al14 Multidisciplinary Cutaneous Lymphoma Clinic have described better prognosis and long-term outcomes (Drs Huang, Hoppe, and Kim), and Division of Biosta- in patients having cancers diagnosed at earlier stages. It is tistics (Dr McMillan), Stanford University, Stanford, Calif; possible that more second cancers were observed in this Dermatoepidemiology Unit, VA Medical Center subset of patients because they had better survival, lead- Providence, Department of Dermatology, Rhode Island ing to longer follow-up in the study. The mean time to de- Hospital, and Departments of Dermatology and Com- velopment of second cancers in the Stanford cohort was munity Health, Brown University, Providence, RI 4 years. Follow-up in patients with stage IA to IIA disease (Dr Weinstock); and Northern California Cancer Cen- ranged from 7.2 to 11.7 years compared with 2.3 to 5.8 ter, Fremont (Dr Clarke). years in patients with stage IIB to IVB disease. Correspondence: Youn H. Kim, MD, Department of Der- While an increased risk of developing melanoma sub- matology, 900 Blake Wilbur Dr, Room W0069, Stan- sequent to diagnosis of MF or SS was observed in our SEER ford University School of Medicine, Stanford, CA 94305 cohort, this has not been reported in previous cohort stud- ([email protected]). ies.11,22 Smaller case reports, however, have reported this Author Contributions: Drs Huang and Kim had full ac- relationship.23-25 These studies included cases in which cess to all the data in the study and take responsibility melanoma was diagnosed either before or after MF, for the integrity of the data and the accuracy of the data whereas other studies only considered second cancers di- analysis. Study concept and design: Huang, Weinstock, agnosed after MF diagnosis. Patients with MF are pos- Hoppe, and Kim. Acquisition of data: Huang, Hoppe, and sibly at increased risk for melanoma as a result of the vari- Kim. Analysis and interpretation of data: Huang, Wein- ous topical treatments for MF; for example, an increased stock, Clarke, McMillan, and Kim. Drafting of the manu- incidence of melanoma has been found in patients who script: Huang and Kim. Critical revision of the manu- receive oral methoxsalen (psoralen) and UV-A radia- script for important intellectual content: Huang, Weinstock, tion therapy or other skin-damaging agents used to treat Clarke, McMillan, Hoppe, and Kim. Statistical analysis: MF and SS.23,25,26 Because various institutions have dif- Weinstock, Clarke, and McMillan. Obtained funding: Kim. ferent protocols for treating MF, it is likely that differ- Administrative, technical, and material support: Huang and ent treatment centers would note variable risk for devel- Kim. Study supervision: Weinstock and Kim. opment of melanoma in patients with MF. Previous studies Financial Disclosure: None reported. have also found that there is a genetic mutation in both Funding/Support: This study was supported in part by melanoma and MF in the p16 gene.24,27-29 Thus, further the Stanford Cutaneous Lymphoma Research Fund. larger studies should continue to investigate the association between MF and SS, and melanoma. REFERENCES It is uncertain why patients with MF and SS are at increased risk of developing second malignant neoplasms, 1. Hoppe R, Kim YH. Clinical features, diagnosis, and staging of mycosis fungoi- especially lymphomas. It is possible that these second can- des and Sezary syndrome. In: Rose BD, ed. UpToDate. 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