Annals of Oncology
\noriginal article doi:10.1093\/annonc\/mdr333
\nAutoimmune disease and subsequent digestive tract
\ncancer by histology
\nK. Hemminki
\n1,2
\n*, X. Liu
\n2
\n, J. Ji
\n2
\n, J. Sundquist
\n1,3
\n& K. Sundquist
\n2
\n1
\nDivision of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany;
\n2
\nCenter for Primary Health Care Research, Lund
\nUniversity, Malmo\u00a8, Sweden;
\n3
\nStanford Prevention Research Center, Stanford University School of Medicine, Stanford, USA
\nReceived 21 March 2011; accepted 1 June 2011
\nBackground: Dysregulation of the immune function in autoimmune diseases could potentially lead to cancer
\ndevelopment and there is definite evidence linking some autoimmune mechanisms with cancer. We analyzed
\nsystematically the occurrence of histology-specific digestive tract cancers in patients diagnosed with 33 different
\nautoimmune diseases in order to address the question of shared susceptibility.
\nPatients and methods: Standardized incidence ratios (SIRs) were calculated for subsequent digestive tract
\ncancers up to the year 2008 and in patients hospitalized for autoimmune disease after the year 1964.
\nResults: Myasthenia gravis associated with five different cancers with SIRs ranging from 1.35 to 2.78. Pernicious
\nanemia, Crohn disease, ulcerative colitis, systemic lupus erythematosis and psoriasis were also associated with
\ncancers at multiple sites. Rheumatoid arthritis associated with no cancer and the standardized incidence ratio was
\ndecreased for colon adenocarcinoma, also in ankylosing spondylitis patients.
\nConclusions: Increased risks of cancer were observed in patients with several autoimmune diseases. Myasthenia
\ngravis and pernicious anemia were associated with many cancers; this is possibly related to immunosuppressant
\nmedication in myasthenia gravis. The decreased risks in colon and rectal adenocarcinomas in rheumatoid arthritis and
\nankylosing spondylitis suggest underlying inflammatory mechanisms as the risks may have been suppressed by the
\nuse of anti-inflammatory medication.
\nKey words: cancer, digestive tract, autoimmune disease
\nintroduction
\nCancer risk is vastly increased in immune deficiency conditions
\nand immunosuppressed patients [1]. A normal immune system
\ncan act against tumor formation at multiple levels. It can eliminate
\nand suppress microbial infections and it can resolve inflammation
\nbefore it becomes chronic and tumor promoting. Transformed
\ncells express tumor-specific antigens, which are recognized by
\ntumor immune surveillance and subsequently eliminated. Thus,
\ndysregulation of the immune function in conditions such as
\nautoimmune diseases could potentially lead to cancer
\ndevelopment. Autoimmune diseases, which affect \u00015% to 10% of
\nthe population in the developed countries, include some common
\ndiseases, such as rheumatoid arthritis and autoimmune
\nthyroiditis, and many rare ones [2]. For unknown reasons, many
\nautoimmune diseases are more common in women than in men.
\nThere are also large ethnic differences in their prevalence.
\nAutoimmune diseases are often defined as clinical syndromes
\ncaused by the activation of T cells or B cells, or both, in the absence
\nof an ongoing infection or other discernible cause [3]. These cells
\nrecognize specific foreign antigens but even in healthy individuals,
\nthey possess a low level of autoreactivity toward own (self or auto)
\nantigens. In autoimmune diseases, autoreactivity is increased
\neither systemically (as in systemic lupus erythematosus) or organ
\nspecifically (type 1 diabetes). The diseases are diagnosed on the
\nbasis of various criteria, such as clinical symptoms or signs and by
\nspecific types of autoantibodies. Genetic epidemiological studies
\nhave demonstrated that genetic factors are crucial determinants of
\nsusceptibility to autoimmune disease [3].
\nMany previous studies have shown associations between
\nautoimmune diseases and cancer, particularly lymphomas and
\nmyeloma [4, 5]. However, many of the previous studies have
\nfocused on a single or a few autoimmune diseases and cancers, and
\nmost have covered small populations. As an exception, a recent
\nlarge study reported alimentary tract cancers after hospitalization
\nfor autoimmune diseases in 4.5 million USA male veterans [6]. In
\nthe present follow-up study, we examined digestive tract cancer
\nrisks in those who had been hospitalized for an autoimmune
\ndisease, covering the total Swedish population of 9 million. The
\nmajor differences to the USA study are that the present population
\nincluded also women and children. Moreover, 27 autoimmune
\ndiseases were covered by both studies but we included 6 additional
\ndiseases. The present study included tumor histologies to examine
\nwhether the many autoimmune diseases affect a specific histology.
\nmaterials and methods
\nAll the registers used in this study were nationwide, covering the whole
\npopulation of Sweden over a defined period of time (9.0 million in 2005).
\no r i g i n a l
\na r t i c l e
\n*Correspondence to: K. Hemminki, Division of Molecular Genetic Epidemiology, German
\nCancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg,
\nGermany. Tel: +49-6221-421800; Fax: +49-6221-421810; E-mail: k.hemminki@dkfz.de
\n\u00aa The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
\nAll rights reserved. For permissions, please email: journals.permissions@oup.com
\nAnnals of Oncology Advance Access published August 2, 2011
\n at Gesellschaft f?r Biotechnologische Forschung on August 17, 2011 annonc.oxfordjournals.org Downloaded from The research database used for this study is a subset of the national MigMed
\n2 datasets at the Center for Primary Health Care Research, Lund University,
\nMalmo\u00a8, Sweden. Data on autoimmune diseases were obtained from the
\nSwedish Hospital Discharge Register that records complete data on all
\ndischarges with dates of hospitalization and diagnoses in some regions since
\n1964 and nationwide since 1986. The International Classification of
\nDiseases codes used were described earlier [7, 8]. We did not want to be
\nrestrictive in including diseases into the present study. Rather, we wanted to
\ninclude diseases such as multiple sclerosis and amyotrophic lateral sclerosis
\neven though some consider these neurodegenerative rather than
\nautoimmune diseases. A total of 33 diseases were covered. However, five of
\nthem had less than five cases for any cancer and data are not shown for
\nthese diseases that were autoimmune hemolytic anemia, chorea minor,
\ndiscoid lupus erythematosus, lupoid hepatitis and Reiter disease; these
\ndiseases were not significantly associated with any cancer. The linkages were
\ncarried out by the use of an individual national identification number that
\nis assigned to each person in Sweden for their lifetime. This number was
\nreplaced by a serial number for each person in order to provide anonymity.
\nCancers were obtained from the nationwide Swedish Cancer Registry.
\nPerson-years of follow-up were calculated from date of discharge with the
\nfirst main diagnosis of autoimmune disease until diagnosis of cancer, death,
\nemigration, or closing date, 31 December 2008. In control studies to
\ncheck for the possibility of surveillance bias in patients who underwent
\ntreatment, the follow-up was started from the last hospitalization.
\nStandardized incidence ratios (SIRs) were calculated as the ratio of observed
\n(O) to expected (E) number of cases. Expected numbers were calculated for
\nanyone not hospitalized for autoimmune disease. The expected numbers
\nwere calculated as age (5-year groups), sex, period (5-year groups), region
\nand socioeconomic status-specific standard incidence rates. An additional
\nadjustment, because of potential confounding, was made for hospitalization
\nfor obesity using codes ICD-7 = 287.00, 287.09; ICD-8 = 277.99; ICD-9 =
\n278A; ICD-10= E65-E68 (26). A total of 30 020 individuals had been
\nhospitalized for obesity. Similar adjustments were made for smoking using
\nhospitalization for chronic obstructive pulmonary disease as a surrogate
\nwith 260 243 individuals affected (codes: ICD-7 = 500\u2013502; ICD-8 = 490\u2013
\n493; ICD-9 = 490\u2013496; ICD-10= J40\u2013J49), and alcohol using alcoholisms as
\na surrogate (codes: ICD-9 = 303; ICD-10 = F10.1\u2013F10.9) with 181 862
\nindividuals affected, respectively. Assuming a Poisson distribution, 95%
\nconfidence intervals (95% CI) were calculated.
\nThe study was approved by the regional ethical review board at Lund.
\nresults
\nTable 1 shows the risks of upper digestive tract, esophageal and
\nstomach cancers after 28 autoimmune diseases; five
\nautoimmune diseases had less than five cases even for the most
\ncommon cancers and they were excluded but none of the
\nresults were significant. The first column shows the personyears at risk for autoimmune disease patients. The risks of
\nupper digestive tract squamous cell carcinoma (SCC) were
\nincreased after hospitalization for seven autoimmune diseases
\nwith an overall standardized incidence ratio (SIR) of 1.37; the
\nhighest risks were seen for systemic lupus erythematosus (2.86)
\nand pernicious anemia (2.17). Esophageal adenocarcinoma was
\nonly increased in localized scleroderma (5.77) and
\npolymyosistis\/dermatomyositis patients (16.58), both
\ndiagnosed in three patients. Esophageal SCC was more
\ncommon in the present population than was adenocarcinoma
\nand it was increased in patients diagnosed with pernicious
\nanemia (5.62), Addison disease (5.54) and myasthenia gravis
\n(2.78); the overall SIR was 1.67. Stomach adenocarcinoma was
\nincreased in seven patient groups, with the highest risks in
\npatients with pernicious anemia (4.09) and immune
\nthrombocytopenic purpura (3.04). Pernicious anemia and
\nmyasthenia gravis were associated with increases in three of the
\nstudied cancers in Table 1.
\nSmall intestinal adenocarcinoma is a rare cancer but the
\noverall SIR was 2.33 (Table 2). Very high risks were noted for
\nCrohn disease (11.05) and pernicious anemia (7.64); the SIR for
\nulcerative colitis was 4.10. Colon and rectal adenocarcinomas
\nwere increased in Crohn disease (2.76 and 1.83) and ulcerative
\ncolitis patients (3.13 and 1.94) and also in chronic rheumatic
\nheart disease and myasthenia gravis patients. Both cancers were
\ndecreased in ankylosing spondylitis (0.55 and 0.35) patients
\nand colon cancer was also decreased in rheumatoid arthritis
\npatients (0.70). Anal cancer is a rare cancer with SCC histology;
\nit was increased in systemic lupus erythematosus (7.18),
\nsarcoidosis (3.51) and psoriasis patients (3.18).
\nGastrointestinal carcinoids occur mainly in the stomach,
\nsmall intestine and colorectum (Table 3). Particularly high risks
\nfor stomach carcinoids were observed in patients with primary
\nbiliary cirrhosis (78.29), pernicious anemia (46.67), type 1
\ndiabetes (39.21) and rheumatoid arthritis (5.38); the overall SIR
\nwas 4.53. Crohn disease and ulcerative colitis patients were at
\na risk of small intestinal (7.33 and 3.31) and colorectal
\ncarcinoids (8.18 and 7.32). Small intestinal carcinoids were also
\nincreased in sarcoidosis patients (3.67). In order to assess the
\neffect of lead time bias, the risks for carcinoid tumors were
\nanalyzed in two follow-up periods after the last hospitalization:
\n\u00a32 years and >2 years. Small intestinal and colorectal carcinoids
\nwere highly increase within 2 years of hospitalization and the
\nonly SIR that was significant in the >2 period was that for
\ncolorectal carcinoids in Crohn disease patients (N = 15, SIR =
\n1.95, 95% CI 1.09\u20133.22).
\nThe present data indicated cancer risks after the first
\nhospitalization for an autoimmune disease. The analyses were
\nrepeated considering cancer after last hospitalization for an
\nautoimmune disease; the case numbers were fewer but the SIRs
\nwere essentially unchanged.
\ndiscussion
\nA follow-up study of the present design may raise a number of
\ntechnical queries. Diagnostics should be of high quality because
\nmost of the patients would have been treated in specialist
\ndepartments and the indicated diagnosis was the one on which
\nthe patients were discharged. Coverage is another issue that
\ndepends, e.g. on the severity of the condition. We have
\ndiscussed diagnostic accuracy and coverage in many previous
\npapers on familial clustering of autoimmune diseases in Sweden
\n[9\u201312]. Severe debilitating conditions, such as Graves disease,
\ntype 1 diabetes mellitus, Crohn disease, ulcerative colitis,
\nrheumatoid arthritis and celiac disease, lead to hospitalization
\nat one point or another in Sweden. In contrast, Hashimoto
\ndisease\/hypothyroidism is an example of a disease with a low
\ndegree of hospitalization.
\nAnother issue relating to the interpretation of the results is
\nthe lead time bias, i.e. the possibility of earlier diagnosis of any
\nother disease, such as cancer, in patients with chronic disease
\noriginal article Annals of Oncology
\n2 | Hemminki et al.
\n at Gesellschaft f?r Biotechnologische Forschung on August 17, 2011 annonc.oxfordjournals.org Downloaded from and frequent medical contacts. The Swedish Cancer Registry
\nrecords all new cases of cancer and close to 100% of the cases
\nare histologically or cytologically confirmed. Thus, the lead
\ntime bias would only shift the diagnoses earlier as the
\ndiagnostic accuracy is not compromised. Benign tumors,
\nparticularly carcinoids in the present study, are of particular
\nconcern because they are usually indolent tumors diagnosed
\nincidentally at medical examination conducted for other
\npurposes [13, 14]. As all the observed risks were much higher
\nimmediately after hospitalization for autoimmune diseases, it is
\nTable 1. Risk of cancers of the upper digestive tract, esophagus and stomach after a specified autoimmune disease
\nAutoimmune disease (case
\nnumber)
\nUpper digestive tract Esophageal
\nadenocarcinoma
\nEsophageal SCC Stomach
\nadenocarcinoma
\nPyrs O SIR 95% CI O SIR 95% CI O SIR 95% CI O SIR 95% CI
\nDigestive tract involvement
\nAnkylosing spondylitis
\n(5173)
\n92 881 14 1.05 0.57\u20131.77 5 2.99 0.94\u20137.03 2 0.73 0.07\u20132.70 13 0.92 0.49\u20131.57
\nCeliac disease (4124) 67 572 1 0.75 0.00\u20134.32 0 1 3.38 0.00\u201319.37 0
\nCrohn disease (28 349) 488 461 58 1.32 1.00\u20131.71 3 0.60 0.11\u20131.77 9 1.00 0.45\u20131.90 43 0.87 0.63\u20131.17
\nImmune
\nthrombocytopenic
\npurpura (1709)
\n28 310 2 1.36 0.13\u20135.01 0 1 3.13 0.00\u201317.92 6 3.04 1.09\u20136.66
\nLocalized scleroderma
\n(3128)
\n63 257 7 1.38 0.55\u20132.86 3 5.77 1.09\u201317.09 1 0.87 0.00\u20135.01 11 1.56 0.70\u20132.55
\nPernicious anemia
\n(11 839)
\n68 625 34 2.17 1.50\u20133.03 3 1.45 0.27\u20134.28 23 5.62 3.56\u20138.44 108 4.09 3.36\u20134.94
\nPolyarteritis nodosa
\n(12 046)
\n94 093 23 1.19 0.75\u20131.78 4 1.59 0.41\u20134.12 8 1.51 0.64\u20132.99 35 1.02 0.71\u20131.42
\nPrimary biliary cirrhosis
\n(835)
\n7110 1 0.85 0.00\u20134.86 0 0 2 1.29 0.12\u20134.75
\nSarcoidosis (9053) 136 747 16 0.95 0.54\u20131.54 0 2 0.54 0.05\u20131.98 31 1.45 0.98\u20132.06
\nSjo\u00a8gren syndrome (3769) 46 309 7 1.30 0.51\u20132.69 1 1.69 0.00\u20139.67 3 2.26 0.43\u20136.68 12 1.42 0.73\u20132.48
\nSystemic lupus
\nerythematosus (5318)
\n62 007 16 2.86 1.63\u20134.65 0 2 1.52 0.14\u20135.60 10 1.20 0.57\u20132.21
\nSystemic sclerosis (1195) 8199 1 0.94 0.00\u20135.40 0 0 2 1.32 0.12\u20134.87
\nUlcerative colitis (16 363) 15 883 17 1.14 0.66\u20131.83 2 1.08 0.10\u20133.97 1 0.32 0.00\u20131.81 15 0.88 0.49\u20131.45
\nNo digestive tract involvement
\nAddison disease (1594) 21 314 2 0.84 0.08\u20133.08 0 3 5.54 1.05\u201316.41 9 2.74 1.24\u20135.23
\nAmyotrophic lateral
\nsclerosis (4262)
\n19 135 2 0.74 0.07\u20132.70 0 0 4 0.96 0.25\u20132.49
\nBehcet disease (2860) 51 636 9 1.40 0.64\u20132.67 1 1.34 0.00\u20137.67 0 11 1.66 0.83\u20132.99
\nChronic rheumatic heart
\ndisease (16 770)
\n133 597 30 1.10 0.74\u20131.58 5 1.42 0.45\u20133.33 5 0.74 0.23\u20131.73 59 1.40 1.07\u20131.81
\nDiabetes mellitus type I
\n(20 554)
\n323 086 5 1.70 0.54\u20134.00 0 1 4.59 0.00\u201326.33 5 2.64 0.83\u20136.21
\nGrave\/hyperthyroidism
\n(36 240)
\n468 161 66 1.36 1.05\u20131.73 2 0.40 0.04\u20131.48 9 0.75 0.34\u20131.42 103 1.31 1.07\u20131.59
\nHashimoto\/hypothroidism
\n(10 682)
\n100 612 20 1.70 1.04\u20132.63 2 1.56 0.15\u20135.75 6 1.95 0.70\u20134.28 26 1.34 0.87\u20131.96
\nMultiple sclerosis (12 553) 157 915 19 1.13 0.68\u20131.77 2 1.08 0.10\u20133.97 2 0.55 0.55\u20132.03 12 0.55 0.28\u20130.97
\nMyasthenia gravis (17 974) 286 399 104 1.66 1.36\u20132.02 11 1.29 0.64\u20132.31 41 2.78 2.00\u20133.78 117 1.38 1.14\u20131.65
\nPolymyalgia rheumatica
\n(14 745)
\n172 528 23 0.79 0.50\u20131.18 4 1.08 0.28\u20132.80 6 0.81 0.29\u20131.79 63 1.45 1.11\u20131.85
\nPolymyositis\/
\ndermatomyositis (1256)
\n11 188 2 1.32 0.12\u20134.86 3 16.58 3.13\u201349.07 2 5.52 0.52\u201320.30 6 2.74 0.99\u20136.01
\nPsoriasis (15 592) 222 027 59 1.78 1.36\u20132.30 6 1.62 0.58\u20133.54 25 3.36 2.17\u20134.96 49 1.28 0.94\u20131.69
\nRheumatic fever (3458) 65 040 14 1.48 0.81\u20132.49 0 3 1.48 0.28\u20134.39 16 1.50 0.86\u20132.44
\nRheumatoid arthritis
\n(26 937)
\n23 5491 38 1.07 0.76\u20131.47 9 2.12 0.96\u20134.03 13 1.44 0.76\u20132.46 60 1.07 0.82\u20131.38
\nWegener granulomatosis
\n(945)
\n9398 4 2.84 0.74\u20137.34 0 0 1 0.45 0.00\u20132.59
\nAll (290 665) 3 606 353 599 1.37 1.26\u20131.48 65 1.24 0.96\u20131.58 172 1.67 1.43\u20131.94 833 1.36 1.27\u20131.46
\nCI, confidence interval; O, observed number of cases; SIR, standardized incidence ratio; Pyrs, person years.
\nAnnals of Oncology
\noriginal article
\ndoi:10.1093\/annonc\/mdr333 | 3
\n at Gesellschaft f?r Biotechnologische Forschung on August 17, 2011 annonc.oxfordjournals.org Downloaded from likely that the findings were due to lead time bias or
\noverdiagnosis [15]. Carcinoids are rare tumors at most
\ngastrointestinal sites and the results would be only marginally
\naffected if histology was not considered. However, the
\nexceptionally high risks of stomach carcinoids after pernicious
\nanemia (46.67) and primary biliary cirrhoses (78.29) would have
\ninfluenced stomach cancer risks; after pernicious anemia all
\nstomach cancer SIRs would have been 4.53, instead of 4.09 for
\nadenocarcinoma and after primary biliary cirrhoses, 2.35 for all
\nstomach cancer and 1.29 for adenocarcinoma. The small
\nintestine was an exceptional site because there carcinoids
\noutnumbered adenocarcinomas. Pernicious anemia was strongly
\nassociated with small intestinal adenocarcinoma only (7.64).
\nPrevious Swedish studies have also noted the high risk of
\ncarcinoid tumors in patients with pernicious anemia [16, 17].
\nThe above example on carcinoids shows the importance of
\nconsidering histology. Another example is provided by
\nesophageal tumors. Albeit the case numbers were small, none of
\nthe six autoimmune diseases appeared to be associated with
\nboth histological types of esophageal cancer. None of these six
\nincreases were found in the USA study that did not consider
\nhistology [6]. Similarly, rectal and anal cancers differ in
\nhistology. Again, none of the seven autoimmune diseases with
\nan increased risk of cancer at these sites showed a concordant
\nincrease. For the four autoimmune diseases that associated with
\nrectal adenocarcinoma in our study, only ulcerative colitis was
\nalso associated in the USA study that considered rectum and
\nanus together [6]; the USA study found an association with
\nsarcoidosis, which in our study associated with anal cancer
\nonly.
\nTable 2. Risk of cancers of the small intestine, colon, rectum and anus after a specified autoimmune disease
\nAutoimmune disease Small intestinal adenocarcinoma Colon adenocarcinoma Rectal adenocarcinoma Anus SCC
\nPyrs O SIR 95% CI O SIR 95% CI O SIR 95% CI O SIR 95% CI
\nDigestive tract involvement
\nAnkylosing spondylitis 92 881 0 17 0.55 0.32\u20130.88 7 0.35 0.14\u20130.73 2 2.01 0.19\u20137.41
\nCeliac disease 67 572 1 10.70 0.00\u201361.31 9 2.05 0.93\u20133.90 1 0.42 0.00\u20132.39 0
\nCrohn disease 488 461 32 11.05 7.55\u201315.62 340 2.76 2.48\u20133.07 132 1.83 1.53\u20132.17 8 1.66 0.71\u20133.29
\nImmune
\nthrombocytopenic
\npurpura
\n28 310 0 13 2.61 1.39\u20134.48 3 1.11 0.21\u20133.28 0
\nLocalized scleroderma 63 257 0 29 1.35 0.90\u20131.94 9 0.83 0.38\u20131.58 2 2.11 0.20\u20137.77
\nPernicious anemia 68 625 9 7.64 3.46\u201314.56 72 1.16 0.91\u20131.46 35 1.04 0.72\u20131.44 3 1.86 0.35\u20135.50
\nPolyarteritis nodosa 94 093 2 1.15 0.11\u20134.23 106 1.13 0.92\u20131.36 55 1.15 0.87\u20131.50 4 1.50 0.39\u20133.89
\nPrimary biliary cirrhosis 7110 0 8 1.64 0.70\u20133.24 3 1.21 0.23\u20133.59 1 5.42 0.00\u201331.06
\nSarcoidosis 136 747 2 1.65 0.16\u20136.05 73 1.30 1.02\u20131.63 34 1.09 0.75\u20131.52 7 3.51 1.39\u20137.27
\nSjo\u00a8gren syndrome 46 309 0 29 1.21 0.81\u20131.73 11 0.90 0.45\u20131.62 0
\nSystemic lupus
\nerythematosus
\n62 007 0 38 1.59 1.13\u20132.19 10 0.82 0.39\u20131.51 7 7.18 2.85\u201314.88
\nSystemic sclerosis 8199 0 7 1.55 0.61\u20133.20 0 0
\nUlcerative colitis 15 883 4 4.10 1.07\u201310.61 133 3.13 2.62\u20133.71 49 1.94 1.43\u20132.56 4 2.72 0.71\u20137.03
\nNo digestive tract involvement
\nAddison disease 21 314 0 5 0.57 0.18\u20131.34 7 1.49 0.59\u20133.08 0
\nAmyotrophic lateral
\nsclerosis
\n19 135 1 5.84 0.00\u201333.46 13 1.50 0.80\u20132.58 4 0.79 0.21\u20132.05 0
\nBehcet disease 51 636 0 14 0.92 0.50\u20131.55 10 1.09 0.52\u20132.01 1 2.07 0.00\u201311.88
\nChronic rheumatic heart
\ndisease
\n133 597 3 1.54 0.29\u20134.56 126 1.26 1.05\u20131.50 71 1.29 1.01\u20131.63 5 1.83 0.58\u20134.31
\nDiabetes mellitus type I 323 086 0 4 0.96 0.25\u20132.49 5 2.06 0.65\u20134.84 0
\nGrave\/hyperthyroidism 468 161 5 1.08 0.34\u20132.54 248 1.06 0.93\u20131.20 130 1.12 0.94\u20131.33 12 1.33 0.68\u20132.32
\nHashimoto\/hypothroidism 100 612 2 1.77 0.17\u20136.51 63 1.07 0.82\u20131.37 15 0.52 0.29\u20130.87 1 0.48 0.00\u20132.76
\nMultiple sclerosis 157 915 2 1.62 0.15\u20135.96 62 1.09 0.84\u20131.40 23 0.73 0.46\u20131.10 2 0.88 0.08\u20133.23
\nMyasthenia gravis 286 399 1 0.28 0.00\u20131.61 233 1.35 1.18\u20131.53 159 1.49 1.26\u20131.74 5 1.25 0.39\u20132.94
\nPolymyalgia rheumatica 172 528 4 1.69 0.44\u20134.36 114 0.94 0.78\u20131.13 55 0.86 0.65\u20131.12 3 0.79 0.15\u20132.34
\nPolymyositis\/
\ndermatomyositis
\n11 188 1 9.02 0.00\u201351.70 10 1.83 0.87\u20133.38 4 1.34 0.35\u20133.47 0
\nPsoriasis 222 027 1 0.49 0.00\u20132.81 112 2.19 0.98\u20131.44 65 1.23 0.95\u20131.56 10 3.18 1.52\u20135.88
\nRheumatic fever 65 040 1 1.88 0.00\u201310.77 28 1.19 0.79\u20131.73 10 0.69 0.33\u20131.27 0
\nRheumatoid arthritis 235 491 4 1.33 0.34\u20133.43 109 0.70 0.58\u20130.85 64 0.80 0.62\u20131.02 3 0.59 0.11\u20131.76
\nWegener granulomatosis 9398 0 7 1.35 0.54\u20132.80 3 1.06 0.20\u20133.14 0
\nAll 3 606 353 75 2.33 1.83\u20132.92 2026 1.30 1.24\u20131.35 979 1.15 1.08\u20131.22 80 1.55 1.23\u20131.93
\nCI, confidence interval; O, observed number of cases; SIR, standardized incidence ratio; Pyrs, person years.
\noriginal article Annals of Oncology
\n4 | Hemminki et al.
\n at Gesellschaft f?r Biotechnologische Forschung on August 17, 2011 annonc.oxfordjournals.org Downloaded from Some autoimmune diseases were associated with many
\ncancers, excluding carcinoid tumors. Myasthenia gravis
\nassociated with five cancers with SIRs ranging from 1.35 to
\n2.78 (upper digestive tract, esophageal SCC, stomach
\nadenocarcinoma and colon and rectal adenocarcinomas);
\npernicious anemia associated with four cancers with SIRs
\nranging from 2.17 to 7.64 (upper digestive tract, esophageal
\nSCC, stomach adenocarcinoma and small intestinal
\nadenocarcinoma); Crohn disease associated with four sites and
\nulcerative colitis, systemic lupus erythematosis and psoriasis
\nassociated each with three sites. A common disease, rheumatoid
\narthritis associated with no cancer. However, rheumatoid
\narthritis is an old age disease with a relatively short follow-up
\ntime; consequently, the numbers of person-years at risk for
\nrheumatoid arthritis were only less than half compared with
\nCrohn and Graves diseases.
\nThe finding on pernicious anemia being associated with
\nupper gastrointestinal cancers ranging from oral cavity to small
\nintestine has been reported by others [6, 16, 17]. Pernicious
\nanemia is caused by a gradual loss of gastric parietal cells
\nthrough autoimmune destruction and subsequent inability to
\nabsorb vitamin B12. The increased risk of stomach cancer has
\nbeen ascribed to a chronic inflammation in the course of an
\natrophic gastritis but the effects appear to be widespread as the
\npresent risks were higher for small intestinal adenocarcinoma
\nand esophageal SCC than for gastric adenocarcinoma.
\nIncreased risks of cancer have been reported also at sites outside
\nthe gastrointestinal tract [6, 16].
\nThe multiple cancers diagnosed after myasthenia gravis are
\nnovel findings based on a cohort study. However, it is well
\nknown that myasthenia gravis patients have frequently benign
\nand malignant thymomas [18, 19]. There are many reports on
\nTable 3. Risk of carcinoid tumors in the stomach, small intestine and colorectum after a specified autoimmune disease
\nAutoimmune disease Stomach Small intestine Colorectum
\nPyrs O SIR 95% CI O SIR 95% CI O SIR 95% CI
\nDigestive tract involvement
\nAnkylosing spondylitis 92 881 0 1 0.82 0.00\u20134.72 2 2.35 0.22\u20138.63
\nCeliac disease 67 572 0 0 0
\nCrohn disease 488 461 2 2.46 0.23\u20139.04 33 7.33 5.04\u201310.31 39 8.18 5.82\u201311.19
\nImmune
\nthrombocytopenic
\npurpura
\n28 310 0 0 0
\nLocalized scleroderma 63 257 0 3 4.32 0.81\u201312.79 1 1.38 0.00\u20137.91
\nPernicious anemia 68 625 12 46.67 24.00\u201381.78 4 2.16 0.56\u20135.59 0
\nPolyarteritis nodosa 94 093 0 3 1.15 0.22\u20133.40 1 0.73 0.00\u20134.21
\nPrimary biliary cirrhosis 7110 2 78.29 7.38\u2013287.91 0 0
\nSarcoidosis 136 747 1 3.11 0.00\u201317.80 7 3.67 1.46\u20137.61 3 2.11 0.40\u20136.25
\nSjo\u00a8gren syndrome 46 309 1 8.30 0.00\u201347.57 0 1 1.81 0.00\u201310.36
\nSystemic lupus
\nerythematosus
\n62 007 0 1 1.35 0.00\u20137.73 0
\nSystemic sclerosis 8199 0 1 7.23 0.00\u201341.44 0
\nUlcerative colitis 15 883 1 3.80 0.00\u201321.80 5 3.31 1.04\u20137.79 11 7.32 3.63\u201313.14
\nNo digestive tract involvement
\nAddison disease 21 314 0 0 1 4.38 0.00\u201325.10
\nAmyotrophic lateral
\nsclerosis
\n19 135 0 1 3.53 0.00\u201320.24 0
\nBehcet disease 51 636 0 2 3.51 0.33\u201312.90 0
\nChronic rheumatic heart
\ndisease
\n133 597 1 2.27 0.00\u201313.01 3 0.97 0.18\u20132.87 0
\nDiabetes mellitus type I 323 086 3 39.21 7.39\u2013116.06 0 3 1.25 0.24\u20133.70
\nGrave\/hyperthyroidism 468 161 2 1.65 0.16\u20136.05 10 1.44 0.69\u20132.66 5 0.85 0.27\u20132.00
\nHashimoto\/hypothroidism 100 612 2 6.93 0.65\u201325.48 2 1.20 0.11\u20134.40 3 2.39 0.45\u20137.09
\nMultiple sclerosis 157 915 0 2 1.03 0.10\u20133.78 2 1.15 0.11\u20134.22
\nMyasthenia gravis 286 399 3 3.68 0.69\u201310.90 4 0.68 0.18\u20131.75 3 0.96 0.18\u20132.83
\nPolymyalgia rheumatica 172 528 2 3.43 0.32\u201312.60 8 2.23 0.95\u20134.41 6 2.69 0.97\u20135.90
\nPolymyositis\/
\ndermatomyositis
\n11 188 0 1 5.75 0.00\u201332.97 0
\nPsoriasis 222 027 1 1.90 0.00\u201310.88 6 1.88 0.68\u20134.11 2 0.83 0.08\u20133.04
\nRheumatic fever 65 040 0 1 1.16 0.00\u20136.64 0
\nRheumatoid arthritis 235 491 4 5.38 1.40\u201313.91 7 1.52 0.60\u20133.15 4 1.33 0.35\u20133.43
\nWegener granulomatosis 9398 0 0 0
\nAll 3 606 353 37 4.53 3.19\u20136.26 105 2.10 1.72\u20132.54 87 2.22 1.78\u20132.74
\nCI, confidence interval; O, observed number of cases; SIR, standardized incidence ratio; Pyrs, person years.
\nAnnals of Oncology
\noriginal article
\ndoi:10.1093\/annonc\/mdr333 | 5
\n at Gesellschaft f?r Biotechnologische Forschung on August 17, 2011 annonc.oxfordjournals.org Downloaded from patient series on extrathymic tumors in myasthenia gravis
\npatients with or without thymoma. In the latter patient group,
\nan excess of squamous cell skin cancer has been reported [19].
\nMyasthenia gravis is diagnosed earlier than many other
\nautoimmune diseases, the mean ages have been 34.9 years for
\nwomen and 48.5 years for men in Sweden [18]. In Sweden, as
\nelsewhere, a large proportion of patients receive an
\nimmunosuppressive therapy with either azathioprine or
\nciclosporin, two known human carcinogens [18, 19]. These
\ndrugs are used in some other autoimmune diseases but rarely
\nfor equally long periods. To test for the possible effect of
\nmedication, a case-only study compared myasthenia gravis
\npatients with and without extrathymic malignancies [20]. The
\ntherapies by these drugs showed a borderline association with
\nextrathymic neoplasms in univariate analysis but no longer in
\nmultivariate analysis. Whether the present associations at five
\nsites are related to autoimmunity or medication remain to be
\nestablished.
\nTo our knowledge, only a Danish study has previously
\nanalyzed anal cancers in autoimmune diseases patients, with
\nsomewhat lower case numbers than in the present study [21].
\nBoth studies found a significant and equal risk (3.1) for
\npsoriasis but the present associations with sarcoidosis and
\nsystemic lupus erythematosus were not significant in the
\nDanish study, albeit over 1.00. Addison disease was associated
\nwith an increased risk of esophageal SCC and stomach
\nadenocarcinoma. The risks were above unity in the USA study
\nbut not significant [6].
\nIn studies involving multiple comparisons, chance findings
\nare an issue. It is, however, noteworthy that only five
\nsignificant decreases were observed and three of them are
\nprobably true findings. The decreased risks of colon and rectal
\nadenocarcinomas in ankylosing spondylitis and rheumatoid
\narthritis may be related to the prolonged use of
\nanti-inflammatory medication. According to a recent joint
\nanalysis of randomized trials on a daily use of aspirin, a >5
\nyear use reduced colorectal cancer mortality to about one half
\n[22]. An equal reduction of esophageal cancer mortality was
\nobserved but no reduction was apparent in the present study.
\nAs anti-inflammatory medication is used in many
\nautoimmune diseases, and some effects, at least for colorectal
\ncancer, may have been masked by the beneficial effects of the
\ntreatment.
\nIn conclusion, increased risks of digestive tract
\nadenocarcinoma and SCC were observed in patients with
\nhospitalization for some autoimmune diseases. Myasthenia
\ngravis and pernicious anemia were associated with many
\ncancers, in myasthenia gravis probably related to
\nimmunosuppressant medication. The decreased risks in colon
\nand rectal adenocarcinomas in ankylosing spondylitis and
\nrheumatoid arthritis suggest inflammatory mechanisms to the
\nobserved risks as these were alleviated by the assumed use of
\nanti-inflammatory medication.
\nfunding
\nSupported by the Swedish Council for Working Life and Social
\nResearch, the Swedish Cancer Society and Deutsche Krebshilfe.
\nThe funding sources had no influence on the study
\ndisclosure
\nThe authors declare no conflicts of interest.
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\noriginal article Annals of Oncology
\n6 | Hemminki et al.
\n at Gesellschaft f?r Biotechnologische Forschung on August 17, 2011 annonc.oxfordjournals.org Downloaded from <\/p>\n","protected":false},"excerpt":{"rendered":"