risk of malignancy in scleroderma: a population-based cohort study

ARTHRITIS & RHEUMATISMVol. 52, No. 8, August 2005, pp 2415–2424DOI 10.1002/art.21225© 2005, American College of Rheumatology

Risk of Malignancy in Scleroderma

A Population-Based Cohort Study

Soumya Chatterjee,1 George W. Dombi,2 Richard K. Severson,2 and Maureen D. Mayes3

Objective. To determine the incidence of cancer inpatients with scleroderma (systemic sclerosis) and tocompare those rates with cancer rates in the localpopulation.

Methods. Cancer risk in scleroderma patients inthe Detroit metropolitan area was assessed by linkingpatient identification codes of the Michigan Sclero-derma Registry to the Metropolitan Detroit CancerSurveillance System database. Patients were screenedbetween the years 1973 and 2002, with additional fol-lowup to 2004. Standardized incidence ratios (SIRs)were calculated for selected malignancies (lung, liver,colon, breast, cervical, and prostate cancers, and non-Hodgkin’s lymphomas), with stratification by sex andrace.

Results. Of 934 patients in the Scleroderma Reg-istry, 538 were included in the study based on tri-countyresidency (436 females and 102 males). Of these, 45 firstmalignancies were noted (37 females and 8 males). Lungcancer (10 cases) was found to be the most commoncancer in scleroderma patients. However, its incidencewas not significantly different from that in the generalpopulation of metropolitan Detroit (SIR 1.23). Othertypes of cancer were examined, and no significantdifferences were found as compared with the rates in thelocal population, with 1 exception: black females with

scleroderma had significantly higher rates of liver can-cer (SIR 45.8).

Conclusion. Contrary to previous studies, thisstudy did not find statistical evidence of an increasedincidence of cancer in scleroderma patients, except forliver cancer. One possible reason is the high back-ground rates of certain cancers in the metropolitanDetroit area. It may be necessary to consider localcancer rates when comparing different sclerodermacohorts.

Scleroderma (systemic sclerosis) is a chronic,multisystem, autoimmune disease that causes significantmorbidity and mortality. Previous studies indicate ahigher incidence of cancer in scleroderma patients (1–7).The strongest association has been with lung cancer(1–14). Isolated case reports suggest a higher incidenceof bronchoalveolar type of lung carcinoma (15–17);however, none of the epidemiologic studies have con-firmed that (1–14). Other types of cancers reportedlymore common in scleroderma patients include breastcancer (1,5,6,10,18–21), nonmelanoma skin cancer (3),non-Hodgkin’s lymphoma (1,22,23), esophageal cancer(24–26), and liver cancer (3).

It is difficult to precisely examine the possibleincreased risk of malignancy in scleroderma patientsbecause of the rarity of this disease and therefore thesmall number of patients available for study. Althoughstudies have suggested an overall higher risk of cancer inscleroderma patients, the standardized incidence ratios(SIRs) for individual cancers were inconsistent. Somestudies showed a significant SIR for a particular type ofcancer, whereas others did not (1–7). The absolute SIRvalues for the overall incidence of cancer and of individ-ual cancers were also quite variable in the differentstudies.

In 2000, we reported the results of a population-based study of cancer in scleroderma patients, using data

Supported in part by the National Cancer Institute (NCI-CN-75064A-29) and the National Institute of Arthritis and Musculoskele-tal and Skin Diseases (N01-AR-5-2217).

1Soumya Chatterjee, MD, MS: The Cleveland Clinic Foun-dation, Cleveland, Ohio; 2George W. Dombi, PhD, Richard K. Sever-son, PhD: Wayne State University School of Medicine, Detroit,Michigan; 3Maureen D. Mayes, MD, MPH: University of Texas HealthSciences Center, Houston.

Address correspondence and reprint requests to SoumyaChatterjee, MD, MS, Department of Rheumatic and ImmunologicDiseases, The Cleveland Clinic Foundation, 9500 Euclid Avenue, DeskA50, Cleveland, OH 44195. E-mail: [email protected].

Submitted for publication December 31, 2004; accepted inrevised form May 11, 2005.

2415

from the Michigan Scleroderma Registry and the Met-ropolitan Detroit Cancer Surveillance System (MDCSS)database (27). That study, which was conducted from1973 to 1998 with followup to 2000, showed no overallincrease in the incidence of cancer among the 490scleroderma patients who were eligible for study. Inaddition, no increased risk of any of the specific types ofcancer was noted.

Our present study is an extension of the originalobservations (27) and includes a larger sclerodermapatient population and a longer followup with theMDCSS database. The objective of the present studywas to determine the relationship (if any) betweenscleroderma and the occurrence of malignancy. If such arelationship exists, it can lead to better insight into thepathogenesis of these diseases and may modify surveil-lance methods in clinical practice. The lack of a relation-ship would provide reassurance to the patients and totheir physicians.

PATIENTS AND METHODS

In this study, scleroderma data were collected fromJanuary 1, 1973, to May 31, 2002, and followup for theoccurrence of cancer was continued to May 20, 2004. The riskof cancer in scleroderma patients living in the Detroit metro-politan area was assessed by linking the following 2 localdisease registries: the Michigan Scleroderma Registry and theMDCSS.

The Michigan Scleroderma Registry. The MichiganScleroderma Registry is a population-based listing of sclero-derma patients diagnosed and treated at local hospitals andclinics in the Detroit metropolitan area between the years 1954and 2003 (28–30). The majority of patients (64%) live in thetri-county area of metropolitan Detroit, which consists ofWayne, Oakland, and Macomb counties. According to the2000 US census data (31), metropolitan Detroit has an overallpopulation of 3.9 million, of whom 68.0% are white, 25.8% areblack, and 6.2% are of other races.

All scleroderma diagnoses were confirmed by review ofrelevant demographic, clinical, and laboratory data from thepatients’ medical records (31). If the diagnosis, eligibility, orother relevant clinical data were unclear, additional chartsources were sought and/or the patient’s physician was con-tacted by telephone.

The diagnosis was recorded as definite if the patientsatisfied the American College of Rheumatology (ACR; for-merly, the American Rheumatism Association) 1980 criteriafor the classification of scleroderma (32). The diagnosis wasrecorded as probable if the physician had diagnosed sclero-derma and the patient had 3 or more features of limitedcutaneous scleroderma (formerly called CREST syndrome,representing calcinosis, Raynaud’s phenomenon, esophagealdysmotility, sclerodactyly, and telangiectasias) and did notfulfill criteria for another defined connective tissue disease,such as systemic lupus erythematosus (33). Scleroderma pa-

tients were identified by the International Classification ofDiseases, Ninth Revision (ICD-9) code 710.1 (34).

The disease was designated as limited or diffuse basedon skin involvement (as documented in the medical records),according to the method described by LeRoy et al (35).Limited disease was defined as skin thickening confined to theextremities and distal to the elbows and/or knees. Diffusedisease was defined as skin thickening involving the proximalextremities (proximal to the elbows and/or knees) or the trunkbelow the clavicles. If the medical record did not include adescription of the extent of skin involvement but the abovecriteria were met, the case was designated as systemic sclero-derma of unknown type. Cases of localized scleroderma (mor-phea and linear scleroderma) were excluded.

The date of diagnosis was defined as the date whenscleroderma was first mentioned or the date when the firstnon–Raynaud’s phenomenon symptom related to sclerodermawas documented in the medical record (31). Patients weremailed an annual questionnaire to check vital status anddisease status, with phone followup if the questionnaire wasnot returned (30). If the patient was not shown to be deceasedaccording to the hospital discharge database or medical chartreview, an annual search of the National Death Index wasperformed to determine whether the patient was deceased and,if so, the date of death (30,31). The address listing wasobtained from the medical record and/or from the commercialguide of household residences with dates of occupancy (Bress-er’s Guide, Detroit, MI) (31). Computerized phone directoriesand “reverse” directories were used to aid in maintainingcorrect address information (30).

In order to obtain as complete a census as possible,multiple sources were used for identification of cases: (a) casesrecruited from the patient population of hospitals and outpa-tient clinics of Wayne State University/Detroit Medical Cen-ter, (b) the practices of local rheumatologists, 70% of whomparticipated in the study, (c) a computerized database ofpatients with the diagnosis of scleroderma (ICD-9 code 710.1[34]) who were discharged from all of the 55 area hospitals,including records from the hospitals and outpatient clinics ofthe University of Michigan Medical Center, (d) the SoutheastMichigan Chapter of the Scleroderma Foundation (a patientsupport group), and (e) other physician referrals and selfreferrals.

Although cases were collected from multiple sources,the census was probably not 100% complete. A countingcorrection technique, based on a capture–recapture method,(36) was used to estimate the total number of persons withscleroderma in the population. The analyses found the Sclero-derma Registry to contain �85% of the possible predictednumber of scleroderma cases (31).

The MDCSS. The MDCSS (37,38) is a population-based listing of cancer patients in the Detroit metropolitanarea who were diagnosed between the years 1973 and 2004. Itis a contributor to the Surveillance, Epidemiology, and End-Results (SEER) program of the National Cancer Institute,from which the cancer rates for the general US population arederived. The MDCSS is responsible for the registration of allpatients who are newly diagnosed as having cancer among theresidents of the Detroit metropolitan area. Followup on eachpatient is conducted annually to assess current vital status.Cancer registrars collect data from the medical records of area

2416 CHATTERJEE ET AL

hospitals, selected neighboring hospitals, physicians’ offices,clinics, radiation oncology facilities, private pathology labora-tories, hospice facilities, nursing homes, death certificates, andthe Michigan Office of Vital Statistics, resulting in an esti-mated capture rate of more than 99% of all cancer cases in thetri-county area (38).

Malignancies occurring in scleroderma patients duringthe study period (from 1973 to 2004) were identified from theMDCSS registry by linking patient identification codes. Pa-tients from the scleroderma registry with a home address in thetri-county area at the time of scleroderma diagnosis wereincluded in the calculation of SIRs. SIR calculations comparethe observed number of cancers in the cohort with an expectednumber, which is obtained by applying the age-specific inci-dence rates from the general local population. Race-specific(black versus white) SIRs were calculated for all cancers andfor each sex separately. Age groups consisted of 18 age clustersgenerally falling 5 years apart from age 0–4 years, 5–9 years,10–14 years. . .75–79 years, 80–84 years, and 85� years.

Age-, race-, and sex-specific cancer rates were deter-mined from the metropolitan Detroit SEER registry data withcensus values from 1973 to 2001. Incidence rates for 2001 wereused as surrogate incidence rates for 2002, 2003, and 2004since at this time, the SEER registry is complete only throughthe year 2001. The point of inclusion in the study was the dateof scleroderma diagnosis that occurred on or after January 1,1973. The end point was the first of 3 possible dates: the dateof cancer diagnosis, the date of death, or May 20, 2004.

SIR values were calculated using the program PAM-COMP, version 1.41 (39). PAMCOMP (person-years andmortality computation program) is an application for calculat-ing person-years and SIRs using external files of cancer ratesand patient information provided by the user. Also reportedwere person-years of followup, observed and expected num-bers of cancers, and 95% confidence intervals (95% CIs) forthe SIR values, calculated using Fisher’s exact test (40) as givenin the PAMCOMP software. The overall SIR calculation wasmade after grouping all invasive cancers together. For calcu-lation of SIRs for individual sites of cancer, all cancers forwhich there were 3 or more cases were determined. Selectedmalignancies for which there were fewer than 3 cases were alsomeasured, such as non-Hodgkin’s lymphoma and colon cancer,which have a high prevalence in the general population.

Further analyses were also conducted on all datastratified by sex, race, and type of scleroderma. These analysesincluded age at scleroderma onset, clinical subgroups of sclero-derma (i.e., limited and diffuse disease, and scleroderma sinesclerosis), serologic subgroups (i.e., presence or absence ofantinuclear antibodies [ANAs], anti–Scl-70 antibodies, anti-centromere antibodies [ACAs], and anti–U1-RNP antibodies),and specific histologic types of lung cancer.

Because this was a retrospective study and the recordswere collected from various physicians, a complete antibodyprofile was not available for all patients (31). Only 50.9% ofthe patients (274 of 538) had a complete antibody profile. Weexamined the distribution of antibodies in scleroderma pa-tients as a function of scleroderma disease type. A previousstudy had suggested that based on demographic, clinical,laboratory, and serologic features and natural history, patientswith scleroderma sine sclerosis should be included in thespectrum of limited scleroderma and should not be considered

a separate disorder (41). Hence, for this analysis, the diffusedisease group was compared with the combined group oflimited disease and scleroderma sine sclerosis. A predictedvalue for the number of people with cancer in each subgroupof patients was calculated using the general cancer rate in thisstudy (number of cancers/total number of patients).

To test the assertion that a specific histologic type oflung cancer is more common in scleroderma patients, thehistology codes for individual lung cancer cell types weretallied according to the nomenclature of the InternationalClassification of Diseases for Oncology, Third Edition (ICD-O-3), 2000.

Approval for study of human subjects. The Institu-tional Review Board of Wayne State University approved thisstudy. Compliance with HIPAA (Health Insurance Portabilityand Accountability Act) regulations was ensured.

Statistical analysis. Comparisons were examined byFisher’s exact test. Age at scleroderma onset was examined byt-test. P values less than or equal to 0.05 were consideredsignificant.

RESULTS

At the time of this study, there were 934 uniquepatients in the Michigan Scleroderma Registry (Figure1). A working subset of 538 patients with 45 primarycancers (8.4%) qualified for inclusion in the SIR calcu-lations. To create the working subset, 396 of the 934patients were excluded: 336 of them were not tri-county

Table 1. Working cohort of scleroderma patients evaluated in thisstudy

Race, sexNo. (%) of

scleroderma patientsNo. (%)

with cancers

White female 288 (53.5) 25 (55.6)Black female 148 (27.5) 12 (26.7)White male 67 (12.5) 7 (15.6)Black male 35 (6.5) 1 (2.2)Total 538 (100) 45 (100)

Figure 1. Flow diagram showing the distribution of the 934 patients inthe Michigan Scleroderma Registry.

RISK OF MALIGNANCY IN SCLERODERMA 2417

residents at the time of scleroderma diagnosis, 27 werediagnosed as having scleroderma before the 1973 start ofthe SEER rate calculations, and 33 developed cancerbefore the onset of scleroderma. Tri-county residencystatus was necessary to ensure capture by the MDCSSregistry.

Demographic data are shown in Table 1. Theoverall SIR for all invasive cancers in the total cohortwas 0.91 (95% CI 0.66–1.22). There were 436 femaleswith 37 cancers and 102 males with 8 cancers. Thedistribution of tumors between male and female patientswas similar (P � 0.794). There were 355 white patients(66.0%) and 183 black patients (34.0%). The overall ageat which patients were diagnosed as having sclerodermawas 45.5 � 15.5 years (mean � SD). On average, blacks

were diagnosed as having scleroderma 5.15 years earlierthan whites (P � 0.001).

The frequencies and types of cancer found in thescleroderma patients are shown in Table 2. SIR calcu-lations were performed on the following malignancies:lung, breast, prostate, cervix uteri, liver, non-Hodgkin’slymphoma, and colon. This group comprised 66.7% ofall the cancers that occurred following a diagnosis ofscleroderma. All cancers were invasive except for 2 insitu cervical cancers.

Lung cancer was the single most common type ofcancer in this study. Of the 10 lung cancer cases (22.2%)reported here, 4 were adenocarcinomas, 2 were squa-mous cell cancers, 1 was a large cell cancer, 1 was a smallcell cancer, 1 was an oat cell cancer, and 1 was anon–small cell cancer. While the MDCSS registry in-cludes a unique code for bronchoalveolar carcinoma,this code was not assigned to any of these lung cancers.

The demographic breakdown of scleroderma dis-ease states by sex, race, and disease type is shown inTable 3. Of the 538 scleroderma patients evaluated inthis study, 187 (34.8%) had diffuse disease, 317 (58.9%)had limited disease, 9 (1.7%) had scleroderma sinesclerosis, and the nature of disease in 25 (4.6%) wasunknown. Even though limited disease was the mostcommon type of scleroderma in the total cohort, therewas a significant difference in the distribution of diseasetypes between black females and white females (P �0.001). White females had significantly fewer cases ofdiffuse disease (n � 78) than was expected (n � 100)and more limited disease (n � 194) than was expected(n � 170). In contrast, black females had significantlymore diffuse disease (n � 71) than was expected (n �51) and less limited disease (n � 64) than was expected(n � 87). Of the 45 scleroderma patients with cancer, 10(22.2%) had diffuse disease, 32 (71.1%) had limiteddisease, none had scleroderma sine sclerosis, and thenature of disease in 3 (6.7%) was unknown.

The demographic breakdown by race and sex of

Table 2. Frequency and type of cancers in 45 scleroderma patients

Site of malignancy No. of cancers

Lung* 10Breast* 9Prostate* 3Cervix uteri* 3†Liver* 3Non-Hodgkin’s lymphoma* 2Colon* 0Multiple myeloma 2Ill-defined sites 2Thyroid 2Esophagus 1Stomach 1Other female genital area 1Penis 1Urinary bladder 1Kidney 1Eye 1Brain 1Leukemia 1Total 45

* Calculations of standardized incidence ratios were performed on thedata for these malignancies.† Consists of 1 invasive and 2 in situ cancers.

Table 3. Distribution of scleroderma disease states in all study patients, by sex and race*

Sclerodermadisease type

White Black

TotalFemale Male Female Male

Diffuse 78† (4) 23 (1) 71† (5) 15 (0) 187 (10)Limited 194† (19) 42 (6) 64† (6) 17 (1) 317 (32)Sine sclerosis 6 (0) 0 (0) 2 (0) 1 (0) 9 (0)Unknown 10 (2) 2 (0) 11 (1) 2 (0) 25 (3)Total 288 (25) 67 (7) 148 (12) 35 (1) 538 (45)

* Values are the number of scleroderma patients (number with cancer).† Value outside of the chi-square predicted value at P � 0.001.


the scleroderma patients who had cancer is also shownin Table 3. The cancer incidence in patients with limiteddisease (32 malignancies) showed an odds ratio of 1.98as compared with patients with diffuse disease (10malignancies), which was significantly different (P �0.042 by Fisher’s exact test). We found no difference inthe distribution of cancers in comparisons of male versusfemale patients (P � 0.581) and black versus whitepatients (P � 0.319) by Fisher’s exact test.

The distribution of antibody types is presented inTable 4. The medical records showed incomplete report-ing of antibody types. Reports of testing for Scl-70antibodies were found in 323 of the 538 study patients(60.0%). In increasing order, U1-RNP antibody wastested in 338 patients (62.8%), ACA was tested in 440patients (81.8%), and ANA was tested in 459 patients(85.3%). None of the stratified antibody groups werefound to have cancer incidences that were statisticallysignificantly different from those predicted by the gen-eral cancer rate found in this study (45 of 538 patients).

SIR values for cancers are shown in Table 5. Thecancers examined included lung, colon, liver, breast,cervical, and prostate cancers, and non-Hodgkin’s lym-phoma. There were a total of 45 cancers, 43 wereinvasive and 2 were in situ cervical cancers. SIR valuesthat were significantly different from 1 are indicated inTable 5. Patients with scleroderma developed cancers(including all invasive cancers combined as well asindividual cancer types) at a rate that was not statisticallysignificantly different from that in the general popula-tion of metropolitan Detroit. This included lung cancer,which was the most common cancer seen in thesepatients. Only liver cancer showed a higher rate, about 7times higher than expected in the general population.

All of these liver cancers where found exclusively infemales, making the odds more than 16 times greaterthan expected in the general female population.

Race-stratified and age-adjusted SIR values werethen calculated for all cancers in all patients as well asseparately in male and female patients (Table 5). Therewere 32 cases of cancer in the white patients, 31 wereinvasive and 1 was an in situ cervical cancer. Whitepatients developed invasive cancers at about the samerate as the general white population (31 observed versus35 expected). None of the individual cancers occurred inthe white scleroderma patients at a rate that was statis-tically significantly different from that in the generalwhite population of metropolitan Detroit. This includedbreast and lung cancer, which were the most commoncancers reported. Fifteen lung cancers and 19 breastcancers would have been necessary to achieve statisticalsignificance in the white population. Even though whitemales had an SIR value of 3 for lung cancer, this was notstatistically significant; the calculated significant numberwould have been 4 lung cancers in the white malepatients.

Table 5 also shows the SIR values for cancers inthe black patients (n � 12). All cancers were invasiveexcept for 1 in situ cervical cancer. Black patients withscleroderma developed invasive cancers (all cancers andindividual cancers) at about the same rate as expected inthe general black population of metropolitan Detroit.All cases of liver cancer (n � 3) occurred in the blackfemale group, at a rate nearly 46 times greater thanexpected in the general black female population. Only 1of the 35 black males with scleroderma developedcancer, which was not statistically significantly differentfrom the expected value of 1.77.

Table 4. Distribution of antibody types by scleroderma disease state, comparing the number ofpredicted and observed cancers*

Serologic status

No cancer Cancer

PLimited Diffuse Limited Diffuse

ANA� 240 152 28 (22.4) 8 (13.4) 0.034ANA� 18 11 1 (1.6) 1 (1.0) 0.632ACA� 75 10 10 (7.1) 1 (0.9) 0.632ACA� 174 143 19 (16.1) 8 (12.6) 0.086Anti–Scl-70� 39 40 3 (3.5) 4 (3.7) 0.526Anti–Scl-70� 131 91 11 (11.9) 4 (7.9) 0.207Anti–U1 RNP� 16 10 0 (1.3) 0 (0.8) 1.000Anti–U1 RNP� 169 124 12 (15.1) 7 (11.0) 0.414

* Values are the number of patients with scleroderma (predicted number of patients with cancer).Predicted numbers of patients with cancer were calculated from the global cancer rate; for example, forthe number of antinuclear antibody (ANA)–positive scleroderma patients with cancer, the predictednumber of patients with cancer was calculated as follows: 45/538 � (240 � 28) � 22.4. P values weredetermined by Fisher’s exact test. ACA � anticentromere antibody.


Tab

le5.

Stan

dard

ized

inci

denc

era

tios,

stra

tifie

dby

sex

and

adju

sted

for

age*

Can

cer

site

All

case

sW

hite

sB

lack

s

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on-

year

sN

o.ob

serv

edN

o.ex

pect

edSI

R(9

5%C

I)Pe

rson

-ye

ars

No.

obse

rved

No.

expe

cted

SIR

(95%

CI)

Pers

on-

year

sN

o.ob

serv

edN

o.ex

pect

edSI

R(9

5%C

I)

Mal

esan

dfe

mal

esA

llin

vasi

ve5,

766.

1443

47.3

50.

91(0

.66–

1.22

)3,

857.

0631

34.7

70.

89(0

.61–

1.27

)1,

902.

2512

12.8

40.

93(0

.48–

1.63

)L

ung

5,89

5.29

108.

161.

23(0

.59–

2.25

)3,

971.

707

6.10

1.15

(0.4

6–2.

37)

1,92

4.11

32.

191.

37(0

.28–

4.00

)C

olon

5,90

1.11

05.

18–

3,97

5.52

03.

74–

1,92

5.59

01.

48–

Liv

er5,

900.

603

0.41

7.35

(1.5

2–21

.49)

†3,

975.

520

0.24

–1,

925.

083

0.18

16.3

2(3

.37–

47.7

0)†

NH

L5,

887.

922

1.69

1.18

(0.1

4–4.

28)

3,96

2.33

21.

331.

50(0

.18–

5.43

)1,

925.

590

0.36

–F

emal

esA

llin

vasi

ve4,

838.

1035

34.6

11.

01(0

.70–

1.41

)3,

264.

7724

25.7

30.

93(0

.60–

1.39

)1,

573.

4211

8.81

1.25

(0.6

2–2.

23)

Bre

ast

4,90

8.66

911

.17

0.81

(0.3

7–1.

53)

3,32

7.15

88.

440.

95(0

.41–

1.87

)1,

581.

511

2.73

0.37

(0.0

1–2.

04)

Lun

g4,

951.

417

5.45

1.29

(0.5

2–2.

65)

3,36

4.01

44.

210.

95(0

.26–

2.43

)1,

587.

403

1.28

2.34

(0.4

8–6.

83)

Col

on4,

954.

770

3.86

–3,

366.

400

2.69

–1,

588.

880

1.20

–L

iver

4,95

4.77

30.

1916

.19

(3.2

4–47

.32)

†3,

366.

400

0.12

–1,

588.

373

0.07

45.8

2(9

.44–

133.

91)†

NH

L4,

942.

002

1.24

1.61

(0.2

0–5.

83)

3,35

3.21

20.

992.

02(0

.24–

7.30

)1,

588.

880

0.25

–C

ervi

xut

eri

4,92

9.80

32.

191.

37(0

.28–

4.01

)3,

347.

752

1.28

1.57

(0.1

9–5.

66)

1,58

2.05

10.

811.

24(0

.03–

6.92

)M

ales

All

inva

sive

928.

048

7.07

1.13

(0.4

9–2.

23)

592.

387

5.40

1.30

(0.5

2–2.

67)

335.

661

1.77

0.56

(0.0

1–3.

14)

Pros

tate

935.

773

2.44

1.23

(0.2

5–3.

59)

600.

112

1.86

1.08

(0.1

3–3.

89)

335.

661

0.56

1.79

(0.0

5–9.

95)

Col

on94

5.83

00.

74–

609.

120

0.59

–33

6.71

00.

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g94

4.39

31.

292.

33(0

.48–

6.80

)60

7.68

31.

003.

00(0

.62–

8.75

)33

6.71

00.

33–

*C

ance

rof

the

cerv

ixut

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repr

esen

tsin

vasi

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canc

ers.

SIR

�st

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nce

ratio

;95

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I�

95%

conf

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cein

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al;

NH

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1.


Table 6 shows the SIR results for all cancersstratified by scleroderma disease types (diffuse andlimited). From the original data set of 538 patients, 187were diagnosed as having diffuse disease and 326 werediagnosed as having limited (n � 317) and sine disease(n � 9) combined. The disease type in 25 patients wasunknown, including 3 patients who had cancer; all thesedata were excluded from the analysis. There was nofurther stratification by race, since the numbers ofcancers were decreasing at each added level of stratifi-cation.

In the limited scleroderma group, there were 30invasive cancers and 2 in situ cancers. Patients withlimited scleroderma developed invasive cancers at ratessimilar to those in the general population. Male patientswith lung cancer were found exclusively in the limitedscleroderma group. No cancer incidence was found to behigher than that expected in the general population.Even the incidence of liver cancers in female patients,which had an SIR of 7.38, also had wide confidencelimits and was not statistically significant; only 1 cancerwas observed, whereas 3 cancers would have beenstatistically significant. This was also true for lung cancerin male patients, which had an SIR of 4 and was notstatistically significant; 3 cancers were observed, whereas4 cancers would have been statistically significant.

In the diffuse scleroderma group, there were 10

invasive cancers. The occurrences of cancers were alsosimilar to those expected in the general population. Onlyliver cancer was significantly higher (20-fold) than thatin the general population of metropolitan Detroit. In thesubgroup of females with diffuse disease, the liver cancerincidence was 50 times higher.

DISCUSSION

In the present study, a working subset of 538patients with 45 primary cancers (8.4%) qualified foranalysis. Women developed scleroderma at a rate �4times higher than that in men, and the overall incidenceof cancer was equivalent on a percentage basis by sex.Limited scleroderma was nearly twice as common asdiffuse scleroderma. Black patients were diagnosed ashaving scleroderma �5 years earlier than whites. Theseresults are consistent with the recently published data onthe demographics of the Michigan Scleroderma Registry(31). Lung cancer and breast cancer were the 2 mostcommon cancers seen in scleroderma patients, as well asin the general population. None of the SIR values forcancer were significant, except for the SIR for livercancer, which occurred only in black females. However,there were only 3 cases of hepatoma, and the calculatedSIR had a wide confidence interval, which calls intoquestion the clinical significance of this finding. There

Table 6. Standardized incidence ratios, stratified by sex and adjusted for age*

Sex, cancer site

Limited scleroderma and scleroderma sine sclerosis Diffuse scleroderma

Person-years

No.observed

No.expected SIR (95% CI)

Person-years

No.observed

No.expected SIR (95% CI)

Males and femalesAll invasive 3,661.79 30 33.45 0.90 (0.81–1.28) 1,790.26 10 11.55 0.87 (0.42–1.59)Lung 3,764.63 7 5.87 1.19 (0.48–2.46) 1,811.96 2 1.89 1.06 (0.13–3.83)Colon 3,768.68 0 3.71 – 1,812.80 0 1.20 –Liver 3,768.57 1 0.29 3.45 (0.09–19.23) 1,812.40 2 0.10 20.23 (2.45–73.07)†NHL 3,760.02 1 1.19 0.84 (0.02–4.68) 1,808.27 1 0.42 2.41 (0.06–13.42)

FemalesAll invasive 3,060.43 23 24.79 0.93 (0.59–1.39) 1,495.77 9 7.82 1.15 (0.53–2.18)Breast 3,117.14 6 8.01 0.75 (0.27–1.63) 1,506.35 2 2.54 0.79 (0.10–2.85)Lung 3,149.63 4 4.03 0.99 (0.27–2.54) 1,515.26 2 1.13 1.77 (0.21–6.41)Colon 3,151.73 0 2.83 – 1,516.10 0 0.80 –Liver 3,151.62 1 0.14 7.38 (0.19–41.09) 1,515.70 2 0.04 50.08 (6.06–180.80)†NHL 3,172.56 1 0.90 1.12 (0.03–6.22) 1,511.57 1 0.27 3.64 (0.09–20.27)Cervix uteri 3,130.42 2 1.27 1.58 (0.19–5.69) 1,551.93 1 0.77 1.30 (0.03–7.24)

MalesAll invasive 601.36 7 4.06 1.72 (0.69–3.55) 294.49 1 3.00 0.34 (0.01–1.87)Prostate 609.09 2 1.38 1.44 (0.17–5.22) 294.49 1 1.05 0.95 (0.02–5.29)Colon 616.95 0 0.36 – 296.70 0 0.30 –Lung 615.51 3 0.75 4.01 (0.83–11.72) 296.70 0 0.54 –

* Cancer of the cervix uteri represents invasive and in situ cervical cancers. SIR � standardized incidence ratio; 95% CI � 95% confidence interval;NHL � non-Hodgkin’s lymphoma.† SIR significantly higher than 1.


was no special distribution of scleroderma disease typesby either sex or race among patients who subsequentlydeveloped cancer.

One of the earliest studies to assess cancer risk inscleroderma was conducted by Duncan and Winkel-mann (42). Of 2,141 scleroderma patients screened, 78patients developed 87 cancers. The relative frequency ofthe types of cancers was similar to that in the generalpopulation. However, there was no mention of a controlpopulation, and no statistical analysis was described.

Since then, other investigators have done moreanalytical work. Abu-Shakra et al (2) reported a studybased on 248 scleroderma patients. The SIR for allcancers was 2.1 times the overall rate in the localpopulation (P � 0.0001). However, this was a chartreview of office visits and, hence, not a population-basedstudy.

A French study of 123 patients with systemicsclerosis who were observed over a mean period of 4years showed 14 cancers (11.4%) (5). Lung cancer wasthe most common. All 3 patients with lung cancer hadlimited scleroderma and ACAs. In our study, there were10 lung cancers: 7 occurred in patients with limitedscleroderma, 2 in patients with diffuse scleroderma, andthe disease type in 1 patient was unknown. Lung canceralso was the most frequent cancer in our cohort but wasnot significantly above background rates. Interestingly,none of our 7 patients with limited disease and lungcancer had ACAs. Only 1 patient with diffuse sclero-derma and lung cancer had ACAs.

Rosenthal et al (3) reported their findings of astudy based on 917 scleroderma patients who werehospitalized between the years 1965 and 1983. The datawere obtained from the Swedish inpatient dischargeregistry, which covered 60% of the Swedish populationin 1969 (the time when data collection for the studystarted), but the capture rate increased to �85% by1983. There was a 1.5-fold increase in the overall risk ofcancer. The SIR values were significant for lung cancer(SIR 4.9), nonmelanoma skin cancer (SIR 4.2), andprimary liver cancer (SIR 3.3). However, the case ascer-tainment rate for scleroderma was incomplete and vari-able over the study period, whereas that for cancer wasnearly complete. This could potentially bias the results,suggesting an apparent increase in the risk of cancer inscleroderma patients. In addition, data were obtainedfrom hospital discharge records, and hence, this was nota population-based study. Similar to the findings of ourstudy, there was a higher incidence of hepatoma.

Roumm and Medsger (4) reported the results ofa retrospective review of 262 scleroderma patients over

a 12-year period (1971–1982). There was a significantrelative difference in malignancies between sclerodermacases and controls (1.81), which was predominantly dueto an increase in cases of lung cancer. Although theircontrol group was obtained from the same population,the time period was different (1969–1971).

Rothfield et al (8) have suggested that the prev-alence of antibody to topoisomerase I (Scl-70) may be arisk factor for malignancy in scleroderma patients.Those investigators reported that cancer developed in 7of 36 patients who had this antibody (19%), as comparedwith only 2 of 112 patients without the antibody (1.8%).Our findings do not confirm those results. We analyzed323 scleroderma patients for an association betweenScl-70 antibody and malignancy. Cancer developed in 7of 86 patients with this antibody (8.1%), as comparedwith 15 of 237 patients without the antibody (6.3%)(data calculated from Table 4). This difference is notsignificant and supports the findings of a recently pub-lished study conducted by Derk et al (43).

More recently, Hill et al (7) reported the resultsof a population-based cohort study in South Australia.The SIR for all cancers was significantly increased(1.99). There was a significant increase in lung cancer(overall SIR 5.9) in both limited and diffuse sclero-derma. Those authors reported that the South Austra-lian Scleroderma Registry corresponds most closely toour Michigan Scleroderma Registry in its comprehen-sive means of ascertaining cases of scleroderma (27).Even though the capture rate was nearly 100% forcancer cases, possibly the rates of ascertainment ofscleroderma cases were much lower, which could falselyincrease the SIR values.

The growing consensus of studies reviewed in2003 by Pearson and Silman (12) indicates that there isan increase in cancer risk related to scleroderma, espe-cially lung cancer. It would provide a greater consistencyof findings if our current findings supported the lungcancer risk, but they do not. The observed differencesfound in the other studies could be real or they could beaccounted for by various combinations of the followingfactors. There could be differences in (a) the methodol-ogy of case ascertainment, (b) the degree of scrutinyapplied to the case definition of scleroderma, (c) thedegree of scrutiny applied to ensure completeness ofcase ascertainment, (d) the nature of the study(population-based versus practice-based or hospital-based, which introduces biases inherent in conveniencesampling), (e) the genetic, racial, ethnic, behavioral,occupational, and environmental risk factors, and (f) the


background incidence of cancer in different geographicareas.

To reiterate the last point, we need to rememberthat there are differences in the background incidence ofcancer in different populations. For example, since 1975,Detroit has had the highest lung cancer rates of the 9regional US collection centers that supply data to theSEER database. The mean � SD age-adjusted rate ofinvasive lung cancer in the population of metropolitanDetroit from 1973 to 2000 was 76.4 � 9.5 cases per100,000 population. In contrast, the overall SEER ratefor invasive lung cancer was 63.1 � 5.7 cases per 100,000(calculated from public access SEER rate tables) (44).The point to be made here is that when sclerodermadatabases are matched to cancer cohorts in definedgeographic areas, it is necessary to consider the localcancer rates.

Our study has several strengths. It is a very largepopulation-based study with a high degree of caseascertainment. It is the largest population of blackpatients with scleroderma ever studied for cancer riskassessment. Also, for the first time, we had an opportu-nity to perform a comparative study of cancer riskassessment between whites and blacks.

Some of the limitations of our study were asfollows: we could not adjust for some known and un-known confounders (risk factors for cancer; e.g., dietaryfactors, cigarette smoking, and alcohol use). A healthierlifestyle among scleroderma patients (e.g., fewer smok-ers) may reduce the risk of cancer. Also, the geneticpredisposition (if any) may be different between whitesand blacks. The SIR for liver cancer was high. Althoughnone of the 3 patients with hepatoma were known tohave primary biliary cirrhosis (a risk factor for livercancer), no data on alcohol use or hepatitis B orhepatitis C status were available for these patients. Wealso did not have data on noncervical in situ cancers andnonmelanoma skin cancers. Data on serology and typeof disease were incomplete. Moreover, we had no infor-mation on tumor behavior (aggressiveness of cancer),response rate to standard therapy, and natural history ofcancer in scleroderma patients.

We conclude that contrary to previous studies,the present study did not show evidence of a significantlyincreased incidence of cancer in patients with sclero-derma. Among individual cancers, only the liver cancerrate was increased, although the significance of thatfinding was questionable because of the small number ofcases and the wide confidence interval. The precisematching, as well as the population-based nature of the

case cohort, may account for our findings and supportstheir validity.

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