Abstract

Background: Sarcoidosis patients show dysregulated immune function, which may be related to subsequent cancer. We examined here the overall and specific cancer risks among Swedish subjects who had been hospitalized for sarcoidosis.

Methods: A sarcoidosis research database was created by identifying hospitalized sarcoidosis patients from the Swedish Hospital Discharge Register and by linking them with the Cancer Registry. Standardized incidence ratios (SIRs) were calculated for cancers in sarcoidosis patients compared with subjects without sarcoidosis.

Results: A total of 10 037 patients were hospitalized for sarcoidosis during years 1964–2004. Among them 1045 patients developed subsequent cancer, giving an overall SIR of 1.40 and 1.18 for cancer diagnosed later than 1 year of follow-up. A significant excess was noted for skin (squamous cell), kidney and nonthyroid endocrine tumors and additionally for non-Hodgkin's lymphoma and leukemia. Patients with multiple hospitalizations showed high risks.

Conclusions: A 40% overall excess incidence of cancer was noted among sarcoidosis patients, but the increase was confined mainly to the first year after hospitalization. However, the increased risks of skin cancer and non-Hodgkin's lymphoma and leukemia, especially for those with multiple hospitalizations or hospitalized at old age, call for clinical attention.

introduction

Sarcoidosis is a systemic disorder affecting people at all ages but most frequently in young adults. Sarcoidosis is characterized by mononuclear cell infiltrates and granuloma formation in the lymph nodes, lung, skin and eye [1, 2]. The average incidence in the world is reported to be 16 per 100 000 in men and 19 per 100 000 in women, with the highest incidence of 60 per 100 000 individuals in the Nordic countries [3, 4]. Familial history is an established risk factor for sarcoidosis but the reported relative risks vary widely from 5 to 70 [5, 6]. Genetic studies have shown that some major histocompatibility complex alleles and tumor necrosis factor (TNF) polymorphisms are associated with an increased risk of sarcoidosis [7–9]. The causes of sarcoidosis are not known [2]. The disease is usually characterized by an increased macrophage and CD4 T-cell activation, whereas sarcoidosis patients also show suppressed response to antigen challenges [10]. The coexistent of hyper- and hypoactivity indicates a state of anergy in the immune system. Many sarcoidosis patients recover without any therapy [2]. In other patients, especially for those with severe, progressive and organ-threatening diseases, corticosteroids have been the standard treatment. Antimalarial and cytotoxic agents have been the conventional steroid-sparing reagents for sarcoidosis. Recent medication for chronic disease targets TNF-α, including pentoxifylline, thalidomide and specific TNF-α blockers [2].

The association between sarcoidosis and malignant tumors has been examined in a few previous studies [11–15] on the basis of the hypothesis that dysregulated immune functions could lead to an increased cancer risk, as shown in asthma, rheumatoid arthritis and psoriasis [16–18]. However, the results on sarcoidosis have been inconsistent [12, 13]. We carried out here a longitudinal cohort study to quantify the subsequent overall and specific cancer risks in hospitalized sarcoidosis patients, using the Swedish nationwide registers. The present study is the largest one reported, covering 10 037 patients and allowing a separate analysis of patients with multiple hospitalizations and thus with severe sarcoidosis.

patients and methods

We used the Swedish Hospital Discharge Register, founded in 1964–1965 by the National Board of Health and Welfare with a complete national wide coverage since 1987, to create a cohort of sarcoidosis patients. These patients were retrieved from the registry according to the seventh (1964–1968 code 138.00–138.10), eighth (1969–1986 code 135), ninth (1987–1996 code 135), and 10th International Classification of Disease (ICD) code (1997– code D86). A total of 10 037 patients were identified in the registry. The study cohort was linked to the national Swedish Cancer Registry, founded in 1958 with close to 100% coverage, to ascertain all incident cancers from the start of follow-up until 31 December 2004. The Cancer Registry used a four-digit code according to ICD-7 to identify malignant tumors during the study period. Additional linkages were carried out to the national census data to obtain individual occupational status, the national Registry of Causes of Death to identify date of death and the Emigration Registry to identify date of emigration. All linkages were carried out by the use of an individual national identification number that is assigned to each person in Sweden for their lifetime. This number was replaced by a serial number for each person in order to provide anonymity.

Person-years were calculated from the last hospitalization for sarcoidosis until diagnosis of cancer, death, emigration or closing date (31 December 2004), whichever came first. The follow-up time was divided into four periods: <1, 1–4, 5–9 and ≥10 years. Standardized incidence ratios (SIRs) were calculated as the ratio of observed to expected number of cases. The expected numbers were calculated by the incidence rates for all individuals without a history of sarcoidosis, and the rates were standardized by 5-year age, gender, period (5-year group), socioeconomic status and residential area [19]. For cancers of the female reproductive system, age at first childbirth and parity was also standardized. The 95% confidence intervals of the SIR were calculated assuming a Poisson distribution, and they were rounded to the nearest two decimals [19]. All analyses were carried out using the SAS statistical package (version 9.1; SAS Institute, Cary, NC). The ethics committee at Karolinska Institute, Stockholm, Sweden, approved this study.

results

A total of 10 037 patients were hospitalized in Sweden for sarcoidosis during years 1964–2004; among them 6992 patients (70%) were hospitalized only once and 3045 patients (30%) had multiple hospital visits. The follow-up time ranged from 0 to 40 years, with a median follow-up of 12 years. A total of 1045 patients developed subsequent cancer after being hospitalized for sarcoidosis, giving an overall SIR of 1.40 and an SIR of 1.18 for cancer diagnosed later than 1 year of the last hospitalization (all 1+), as shown in Table 1. Only those cancer sites with at least 10 cases during the whole follow-up period were listed. The risk for lung cancer and Hodgkin's disease was very high during the first year, probably because of a concomitant diagnosis. Thus, we show the data for the whole follow-up period and 1+, respectively. The overall risk of cancers in the stomach, colon, liver, lung, skin (squamous cell) and nonthyroid endocrine glands and of lymphoma (Hodgkin's and non-Hodgkin's) and leukemia was significantly increased. However, excluding cancer cases during the first year after hospitalization, the significant excess was noted only for kidney, skin (squamous cell) and nonthyroid endocrine tumors and for non-Hodgkin's lymphoma and leukemia. No specific endocrine gland sites showed a significant increase. For specific subtypes of leukemia, the risk for myeloid leukemia was significantly increased (SIR 2.19). A significantly decreased SIR was noted for bladder cancer (0.60).

Table 1.

SIR for subsequent cancer in patients hospitalized for sarcoidosis by follow-up time

Cancer site Follow-up interval (years) 
<1 1–4 5–9 ≥10 All All 1+ 
SIR 95% CI SIR 95% CI SIR 95% CI SIR 95% CI SIR 95% CI SIR 95% CI 
Upper aerodigestive tract 1.41 0.00–8.08 1.56 0.41–4.04 0.66 0.06–2.41 15 1.60 0.89–2.65 22 1.40 0.88–2.13 21 1.40 0.87–2.15 
Stomach 6.43 2.75–12.74 1.84 0.78–3.64 1.64 0.70–3.25 11 0.83 0.41–1.49 35 1.48 1.03–2.06 27 1.20 0.79–1.75 
Colon 14 5.65 3.08–9.51 14 1.56 0.85–2.62 15 1.38 0.77–2.28 33 0.96 0.66–1.34 76 1.34 1.05–1.67 62 1.14 0.87–1.46 
Rectum 1.46 0.14–5.35 0.81 0.21–2.09 1.01 0.36–2.21 20 1.03 0.63–1.60 32 1.01 0.69–1.43 30 0.99 0.67–1.42 
Liver 9.08 4.12–17.32 0.84 0.16–2.48 0.94 0.24–2.43 17 1.40 0.82–2.25 33 1.58 1.08–2.21 24 1.20 0.77–1.79 
Pancreas 6.33 2.28–13.88 0.88 0.17–2.61 1.98 0.85–3.93 0.68 0.29–1.35 25 1.24 0.80–1.84 19 0.99 0.59–1.55 
Lung 42 18.42 13.27–24.92 15 1.83 1.02–3.03 16 1.60 0.91–2.61 18 0.55 0.33–0.87 91 1.71 1.38–2.10 49 0.96 0.71–1.27 
Breast 1.07 0.38–2.34 25 1.19 0.77–1.76 30 1.19 0.80–1.71 64 0.89 0.68–1.13 125 1.01 0.84–1.20 119 1.01 0.83–1.20 
Cervix   1.08 0.20–3.20 1.08 0.20–3.19 1.29 0.51–2.67 13 1.11 0.59–1.90 13 1.18 0.63–2.03 
Endometrium 1.56 0.15–5.75 1.27 0.46–2.78 1.27 0.50–2.63 14 0.88 0.48–1.49 29 1.06 0.71–1.53 27 1.04 0.68–1.51 
Ovary 3.47 0.90–8.97 1.19 0.38–2.81 1.07 0.34–2.53 17 1.46 0.85–2.34 31 1.43 0.97–2.03 27 1.32 0.87–1.92 
Prostate 12 3.41 1.75–5.97 21 1.77 1.09–2.71 0.63 0.28–1.20 68 1.09 0.85–1.39 110 1.20 0.98–1.44 98 1.11 0.90–1.35 
Kidney 8.52 3.86–16.25 1.32 0.42–3.10 1.14 0.36–2.68 21 1.68 1.04–2.57 40 1.84 1.31–2.50 31 1.50 1.02–2.13 
Urinary bladder 0.71 0.00–4.06 0.40 0.04–1.47 0.83 0.26–1.95 12 0.58 0.30–1.02 20 0.60 0.37–0.93 19 0.60 0.36–0.94 
Melanoma   1.45 0.58–3.01 10 1.74 0.83–3.20 17 1.00 0.58–1.61 34 1.18 0.82–1.65 34 1.23 0.85–1.72 
Skin, squamous cell 4.82 1.52–11.33 13 3.44 1.82–5.90 15 3.13 1.74–5.17 26 1.47 0.96–2.15 59 2.16 1.64–2.79 54 2.05 1.54–2.68 
Nervous system 5.55 2.20–11.50 0.44 0.04–1.60 1.15 0.41–2.52 18 1.30 0.77–2.07 33 1.33 0.91–1.87 26 1.10 0.72–1.62 
Thyroid gland 11.23 2.92–29.04 2.33 0.44–6.90 2.89 0.75–7.47 0.32 0.00–1.81 12 1.94 1.00–3.39 1.37 0.59–2.71 
Endocrine glands 10 13.04 6.21–24.06 2.49 0.99–5.17 1.54 0.48–3.61 12 1.36 0.70–2.39 34 2.18 1.51–3.04 24 1.62 1.03–2.41 
Non-Hodgkin's lymphoma 30 21.50 14.49–30.73 19 3.72 2.24–5.82 13 2.07 1.10–3.56 16 0.79 0.45–1.29 78 2.36 1.87–2.95 48 1.52 1.12–2.02 
Hodgkin's disease 18 82.13 48.57–130.05 4.01 0.76–11.87     21 6.79 4.20–10.40 1.04 0.20–3.09 
Myeloma 4.17 0.39–15.35   1.91 0.50–4.93 1.23 0.53–2.44 14 1.29 0.71–2.18 12 1.16 0.60–2.03 
Leukemia 4.62 0.87–13.67 1.71 0.44–4.42 2.61 1.03–5.40 12 1.56 0.80–2.74 26 1.95 1.27–2.86 23 1.81 1.15–2.72 
Myeloid leukemia 2.81 0.00–16.14 2.34 0.44–6.93 4.09 1.47–8.96 1.46 0.52–3.20 16 2.22 1.26–3.61 15 2.19 1.22–3.61 
All 202 5.96 5.17–6.85 184 1.50 1.30–1.74 199 1.38 1.19–1.58 460 1.03 0.94–1.13 1045 1.40 1.31–1.48 843 1.18 1.10–1.26 
Cancer site Follow-up interval (years) 
<1 1–4 5–9 ≥10 All All 1+ 
SIR 95% CI SIR 95% CI SIR 95% CI SIR 95% CI SIR 95% CI SIR 95% CI 
Upper aerodigestive tract 1.41 0.00–8.08 1.56 0.41–4.04 0.66 0.06–2.41 15 1.60 0.89–2.65 22 1.40 0.88–2.13 21 1.40 0.87–2.15 
Stomach 6.43 2.75–12.74 1.84 0.78–3.64 1.64 0.70–3.25 11 0.83 0.41–1.49 35 1.48 1.03–2.06 27 1.20 0.79–1.75 
Colon 14 5.65 3.08–9.51 14 1.56 0.85–2.62 15 1.38 0.77–2.28 33 0.96 0.66–1.34 76 1.34 1.05–1.67 62 1.14 0.87–1.46 
Rectum 1.46 0.14–5.35 0.81 0.21–2.09 1.01 0.36–2.21 20 1.03 0.63–1.60 32 1.01 0.69–1.43 30 0.99 0.67–1.42 
Liver 9.08 4.12–17.32 0.84 0.16–2.48 0.94 0.24–2.43 17 1.40 0.82–2.25 33 1.58 1.08–2.21 24 1.20 0.77–1.79 
Pancreas 6.33 2.28–13.88 0.88 0.17–2.61 1.98 0.85–3.93 0.68 0.29–1.35 25 1.24 0.80–1.84 19 0.99 0.59–1.55 
Lung 42 18.42 13.27–24.92 15 1.83 1.02–3.03 16 1.60 0.91–2.61 18 0.55 0.33–0.87 91 1.71 1.38–2.10 49 0.96 0.71–1.27 
Breast 1.07 0.38–2.34 25 1.19 0.77–1.76 30 1.19 0.80–1.71 64 0.89 0.68–1.13 125 1.01 0.84–1.20 119 1.01 0.83–1.20 
Cervix   1.08 0.20–3.20 1.08 0.20–3.19 1.29 0.51–2.67 13 1.11 0.59–1.90 13 1.18 0.63–2.03 
Endometrium 1.56 0.15–5.75 1.27 0.46–2.78 1.27 0.50–2.63 14 0.88 0.48–1.49 29 1.06 0.71–1.53 27 1.04 0.68–1.51 
Ovary 3.47 0.90–8.97 1.19 0.38–2.81 1.07 0.34–2.53 17 1.46 0.85–2.34 31 1.43 0.97–2.03 27 1.32 0.87–1.92 
Prostate 12 3.41 1.75–5.97 21 1.77 1.09–2.71 0.63 0.28–1.20 68 1.09 0.85–1.39 110 1.20 0.98–1.44 98 1.11 0.90–1.35 
Kidney 8.52 3.86–16.25 1.32 0.42–3.10 1.14 0.36–2.68 21 1.68 1.04–2.57 40 1.84 1.31–2.50 31 1.50 1.02–2.13 
Urinary bladder 0.71 0.00–4.06 0.40 0.04–1.47 0.83 0.26–1.95 12 0.58 0.30–1.02 20 0.60 0.37–0.93 19 0.60 0.36–0.94 
Melanoma   1.45 0.58–3.01 10 1.74 0.83–3.20 17 1.00 0.58–1.61 34 1.18 0.82–1.65 34 1.23 0.85–1.72 
Skin, squamous cell 4.82 1.52–11.33 13 3.44 1.82–5.90 15 3.13 1.74–5.17 26 1.47 0.96–2.15 59 2.16 1.64–2.79 54 2.05 1.54–2.68 
Nervous system 5.55 2.20–11.50 0.44 0.04–1.60 1.15 0.41–2.52 18 1.30 0.77–2.07 33 1.33 0.91–1.87 26 1.10 0.72–1.62 
Thyroid gland 11.23 2.92–29.04 2.33 0.44–6.90 2.89 0.75–7.47 0.32 0.00–1.81 12 1.94 1.00–3.39 1.37 0.59–2.71 
Endocrine glands 10 13.04 6.21–24.06 2.49 0.99–5.17 1.54 0.48–3.61 12 1.36 0.70–2.39 34 2.18 1.51–3.04 24 1.62 1.03–2.41 
Non-Hodgkin's lymphoma 30 21.50 14.49–30.73 19 3.72 2.24–5.82 13 2.07 1.10–3.56 16 0.79 0.45–1.29 78 2.36 1.87–2.95 48 1.52 1.12–2.02 
Hodgkin's disease 18 82.13 48.57–130.05 4.01 0.76–11.87     21 6.79 4.20–10.40 1.04 0.20–3.09 
Myeloma 4.17 0.39–15.35   1.91 0.50–4.93 1.23 0.53–2.44 14 1.29 0.71–2.18 12 1.16 0.60–2.03 
Leukemia 4.62 0.87–13.67 1.71 0.44–4.42 2.61 1.03–5.40 12 1.56 0.80–2.74 26 1.95 1.27–2.86 23 1.81 1.15–2.72 
Myeloid leukemia 2.81 0.00–16.14 2.34 0.44–6.93 4.09 1.47–8.96 1.46 0.52–3.20 16 2.22 1.26–3.61 15 2.19 1.22–3.61 
All 202 5.96 5.17–6.85 184 1.50 1.30–1.74 199 1.38 1.19–1.58 460 1.03 0.94–1.13 1045 1.40 1.31–1.48 843 1.18 1.10–1.26 

Bold type: 95% CI does not include 1.00; underline type: 99% CI does not include 1.00.

CI, confidence interval; SIR, standardized incidence ratio.

Multiple hospitalizations may reflect the disease severity, and we examined cancer risk among sarcoidosis patients by the number of hospitalizations (Table 2). The patients diagnosed with cancers during the first year of follow-up were excluded from the analysis; the follow-up was started from the last hospitalization. The overall SIR was 1.14 for sarcoidosis patients who have been hospitalized once, and it was increased to 1.29 for those with two and more hospitalizations. The SIR was higher for almost all the cancer sites when sarcoidosis patients had multiple hospitalizations, with the highest risk of 3.13 for myeloid leukemia.

Table 2.

SIR for subsequent cancer in sarcoidosis patients by number of hospitalizations

Cancer site Number of hospitalizations 
≥2 
SIR 95% CI SIR 95% CI 
Upper aerodigestive tract 15 1.41 0.79–2.34 1.38 0.50–3.02 
Stomach 18 1.13 0.67–1.79 1.37 0.62–2.62 
Colon 42 1.09 0.78–1.47 20 1.28 0.78–1.98 
Rectum 20 0.93 0.57–1.44 10 1.14 0.54–2.11 
Liver 14 0.99 0.54–1.66 10 1.72 0.82–3.18 
Pancreas 15 1.10 0.61–1.82 0.72 0.19–1.87 
Lung 34 0.94 0.65–1.32 15 1.01 0.56–1.67 
Breast 94 1.07 0.87–1.31 25 0.82 0.53–1.21 
Cervix 0.97 0.41–1.92 1.84 0.58–4.33 
Endometrium 18 0.95 0.56–1.50 1.28 0.58–2.44 
Ovary 20 1.32 0.81–2.04 1.31 0.52–2.71 
Prostate 68 1.12 0.87–1.42 30 1.09 0.73–1.55 
Kidney 22 1.49 0.93–2.27 1.50 0.68–2.86 
Urinary bladder 15 0.67 0.38–1.11 0.42 0.11–1.10 
Melanoma 20 0.99 0.60–1.53 14 1.89 1.03–3.18 
Skin, squamous cell 32 1.72 1.18–2.43 22 2.86 1.79–4.34 
Nervous system 23 1.33 0.84–2.00 0.47 0.09–1.40 
Thyroid gland 1.62 0.64–3.36 0.66 0.00–3.76 
Endocrine glands 18 1.66 0.98–2.63 1.49 0.54–3.26 
Non-Hodgkin's lymphoma 31 1.37 0.93–1.95 17 1.88 1.09–3.02 
Hodgkin's disease 0.95 0.09–3.48 1.32 0.00–7.56 
Myeloma 0.95 0.38–1.97 1.67 0.53–3.93 
Leukemia 15 1.64 0.92–2.71 2.25 0.96–4.46 
Myeloid leukemia 1.82 0.83–3.47 3.13 1.12–6.85 
All 583 1.14 1.05–1.23 260 1.29 1.14–1.45 
Cancer site Number of hospitalizations 
≥2 
SIR 95% CI SIR 95% CI 
Upper aerodigestive tract 15 1.41 0.79–2.34 1.38 0.50–3.02 
Stomach 18 1.13 0.67–1.79 1.37 0.62–2.62 
Colon 42 1.09 0.78–1.47 20 1.28 0.78–1.98 
Rectum 20 0.93 0.57–1.44 10 1.14 0.54–2.11 
Liver 14 0.99 0.54–1.66 10 1.72 0.82–3.18 
Pancreas 15 1.10 0.61–1.82 0.72 0.19–1.87 
Lung 34 0.94 0.65–1.32 15 1.01 0.56–1.67 
Breast 94 1.07 0.87–1.31 25 0.82 0.53–1.21 
Cervix 0.97 0.41–1.92 1.84 0.58–4.33 
Endometrium 18 0.95 0.56–1.50 1.28 0.58–2.44 
Ovary 20 1.32 0.81–2.04 1.31 0.52–2.71 
Prostate 68 1.12 0.87–1.42 30 1.09 0.73–1.55 
Kidney 22 1.49 0.93–2.27 1.50 0.68–2.86 
Urinary bladder 15 0.67 0.38–1.11 0.42 0.11–1.10 
Melanoma 20 0.99 0.60–1.53 14 1.89 1.03–3.18 
Skin, squamous cell 32 1.72 1.18–2.43 22 2.86 1.79–4.34 
Nervous system 23 1.33 0.84–2.00 0.47 0.09–1.40 
Thyroid gland 1.62 0.64–3.36 0.66 0.00–3.76 
Endocrine glands 18 1.66 0.98–2.63 1.49 0.54–3.26 
Non-Hodgkin's lymphoma 31 1.37 0.93–1.95 17 1.88 1.09–3.02 
Hodgkin's disease 0.95 0.09–3.48 1.32 0.00–7.56 
Myeloma 0.95 0.38–1.97 1.67 0.53–3.93 
Leukemia 15 1.64 0.92–2.71 2.25 0.96–4.46 
Myeloid leukemia 1.82 0.83–3.47 3.13 1.12–6.85 
All 583 1.14 1.05–1.23 260 1.29 1.14–1.45 

Bold type: 95% CI does not include 1.00; underline type: 99% CI does not include 1.00.

CI, confidence interval; SIR, standardized incidence ratio.

For patients with a single hospitalization, we calculated the cancer risk by the age at hospitalization (Table 3). For cancer sites with an increased SIR, a late age at hospitalization (≥50 years) was associated with a high risk. The highest risk was noted for myeloid leukemia with an SIR of 2.86 for patients hospitalized older than age 49 years.

Table 3.

SIR for subsequent cancer in sarcoidosis patients hospitalized once by age at hospitalization

Cancer site Age at hospitalization (years) 
<50 ≥50 
SIR 95% CI SIR 95% CI 
Upper aerodigestive tract 1.06 0.38–2.33 1.81 0.82–3.45 
Stomach 0.87 0.28–2.05 13 1.28 0.68–2.19 
Colon 11 0.78 0.39–1.39 31 1.27 0.86–1.80 
Rectum 0.46 0.12–1.19 16 1.25 0.71–2.04 
Liver 1.04 0.33–2.45 0.96 0.44–1.83 
Pancreas 1.38 0.55–2.87 0.93 0.40–1.84 
Lung 0.42 0.17–0.87 27 1.40 0.92–2.04 
Breast 43 0.97 0.70–1.30 51 1.18 0.88–1.55 
Cervix 0.62 0.12–1.83 1.47 0.46–3.45 
Endometrium 0.66 0.21–1.56 13 1.13 0.60–1.94 
Ovary 10 1.44 0.68–2.65 10 1.22 0.58–2.25 
Prostate 33 1.25 0.86–1.75 35 1.02 0.71–1.42 
Kidney 0.91 0.33–2.00 16 1.97 1.12–3.20 
Urinary bladder 0.72 0.28–1.49 0.64 0.27–1.27 
Melanoma 0.69 0.31–1.32 11 1.53 0.76–2.74 
Skin, squamous cell 0.94 0.34–2.05 26 2.13 1.39–3.13 
Nervous system 10 0.94 0.45–1.74 13 1.95 1.03–3.34 
Thyroid gland 1.54 0.40–3.99 1.74 0.33–5.15 
Endocrine glands 1.44 0.61–2.85 10 1.90 0.91–3.51 
Non-Hodgkin's lymphoma 10 0.94 0.45–1.74 21 1.76 1.09–2.70 
Hodgkin's disease 1.43 0.13–5.24   
Myeloma 0.70 0.07–2.59 1.11 0.35–2.61 
Leukemia 1.13 0.36–2.67 10 2.11 1.01–3.90 
Myeloid leukemia 0.80 0.08–2.59 2.86 1.13–5.93 
All 222 0.94 0.82–1.07 361 1.31 1.18–1.45 
Cancer site Age at hospitalization (years) 
<50 ≥50 
SIR 95% CI SIR 95% CI 
Upper aerodigestive tract 1.06 0.38–2.33 1.81 0.82–3.45 
Stomach 0.87 0.28–2.05 13 1.28 0.68–2.19 
Colon 11 0.78 0.39–1.39 31 1.27 0.86–1.80 
Rectum 0.46 0.12–1.19 16 1.25 0.71–2.04 
Liver 1.04 0.33–2.45 0.96 0.44–1.83 
Pancreas 1.38 0.55–2.87 0.93 0.40–1.84 
Lung 0.42 0.17–0.87 27 1.40 0.92–2.04 
Breast 43 0.97 0.70–1.30 51 1.18 0.88–1.55 
Cervix 0.62 0.12–1.83 1.47 0.46–3.45 
Endometrium 0.66 0.21–1.56 13 1.13 0.60–1.94 
Ovary 10 1.44 0.68–2.65 10 1.22 0.58–2.25 
Prostate 33 1.25 0.86–1.75 35 1.02 0.71–1.42 
Kidney 0.91 0.33–2.00 16 1.97 1.12–3.20 
Urinary bladder 0.72 0.28–1.49 0.64 0.27–1.27 
Melanoma 0.69 0.31–1.32 11 1.53 0.76–2.74 
Skin, squamous cell 0.94 0.34–2.05 26 2.13 1.39–3.13 
Nervous system 10 0.94 0.45–1.74 13 1.95 1.03–3.34 
Thyroid gland 1.54 0.40–3.99 1.74 0.33–5.15 
Endocrine glands 1.44 0.61–2.85 10 1.90 0.91–3.51 
Non-Hodgkin's lymphoma 10 0.94 0.45–1.74 21 1.76 1.09–2.70 
Hodgkin's disease 1.43 0.13–5.24   
Myeloma 0.70 0.07–2.59 1.11 0.35–2.61 
Leukemia 1.13 0.36–2.67 10 2.11 1.01–3.90 
Myeloid leukemia 0.80 0.08–2.59 2.86 1.13–5.93 
All 222 0.94 0.82–1.07 361 1.31 1.18–1.45 

Bold type: 95% CI does not include 1.00; underline type: 99% CI does not include 1.00.

CI, confidence interval; SIR, standardized incidence ratio.

To study periodic effects in respect to the changing therapeutic regimens and diagnosis criteria, we analyzed cancer risk among sarcoidosis patients who were hospitalized in the 1970s, 1980s and 1990s (Table 4), respectively. Since maximally 14 years could be followed up for hospitalization in the 1990s, analyses were limited to cancers diagnosed 1–14 years after the last hospitalization. For sarcoidosis patients with a single hospitalization, the overall SIR was marginally higher among patients hospitalized in the 1990s. The highest risk (3.51) was noted for squamous cell skin carcinoma when patients were hospitalized in the 1990s. We tested for the significance of the temporal trends, and the risk for stomach cancer showed a decreased temporal pattern.

Table 4.

SIR for subsequent cancer in sarcoidosis patients by hospitalization period

Cancer site 1970s 1980s 1990s 
SIR 95% CI SIR 95% CI SIR 95% CI 
Upper aerodigestive tract 1.44 0.57–2.98 0.62 0.06–2.29 1.66 0.16–6.09 
Esophagus   0.82 0.00–4.73   
Stomach** 11 1.52 0.75–2.72 0.88 0.23–2.27 0.63 0.00–3.60 
Colon 19 1.14 0.68–1.78 13 1.05 0.56–1.81 1.10 0.35–2.59 
Rectum 11 1.18 0.59–2.12 0.59 0.15–1.53 0.78 0.07–2.88 
Liver 0.96 0.35–2.10 0.92 0.24–2.38   
Pancreas 0.99 0.36–2.18 1.43 0.52–3.14 1.36 0.13–5.01 
Lung 12 0.74 0.38–1.29 13 1.17 0.62–2.01 1.41 0.51–3.08 
Breast 36 0.96 0.67–1.33 31 1.08 0.73–1.54 17 1.58 0.92–2.53 
Cervix 1.36 0.43–3.21 0.43 0.00–2.44 1.13 0.00–6.46 
Endometrium 1.02 0.43–2.01 1.27 0.54–2.51 0.87 0.08–3.19 
Ovary 10 1.50 0.71–2.77 0.85 0.22–2.19 1.24 0.12–4.57 
Prostate 29 1.06 0.71–1.52 23 1.29 0.81–1.93 0.88 0.35–1.81 
Kidney 1.23 0.52–2.43 1.79 0.76–3.54 1.26 0.12–4.63 
Urinary bladder 0.70 0.28–1.44 0.88 0.32–1.93   
Melanoma 11 1.26 0.62–2.25 0.61 0.16–1.57 1.13 0.21–3.34 
Skin, squamous cell 14 1.69 0.92–2.85 0.84 0.26–1.97 3.51 1.50–6.95 
Nervous system 12 1.62 0.84–2.85 1.10 0.40–2.41 0.47 0.00–2.69 
Thyroid gland 1.05 0.10–3.86 0.76 0.00–4.38 4.08 0.39–15.02 
Endocrine glands 1.28 0.46–2.79 2.02 0.80–4.19 1.60 0.15–5.90 
Non-Hodgkin's lymphoma 10 1.04 0.50–1.92 11 1.51 0.75–2.71 2.50 0.99–5.19 
Hodgkin's disease 2.18 0.21–8.02     
Myeloma 1.57 0.49–3.68 0.43 0.00–2.49   
Leukemia 1.77 0.70–3.66 1.40 0.37–3.63 2.80 0.53–8.30 
Myeloid leukemia 1.86 0.48–4.81 1.29 0.12–4.76 5.19 0.98–15.35 
All 258 1.15 1.01–1.30 169 1.05 0.90–1.23 78 1.27 1.00–1.59 
Cancer site 1970s 1980s 1990s 
SIR 95% CI SIR 95% CI SIR 95% CI 
Upper aerodigestive tract 1.44 0.57–2.98 0.62 0.06–2.29 1.66 0.16–6.09 
Esophagus   0.82 0.00–4.73   
Stomach** 11 1.52 0.75–2.72 0.88 0.23–2.27 0.63 0.00–3.60 
Colon 19 1.14 0.68–1.78 13 1.05 0.56–1.81 1.10 0.35–2.59 
Rectum 11 1.18 0.59–2.12 0.59 0.15–1.53 0.78 0.07–2.88 
Liver 0.96 0.35–2.10 0.92 0.24–2.38   
Pancreas 0.99 0.36–2.18 1.43 0.52–3.14 1.36 0.13–5.01 
Lung 12 0.74 0.38–1.29 13 1.17 0.62–2.01 1.41 0.51–3.08 
Breast 36 0.96 0.67–1.33 31 1.08 0.73–1.54 17 1.58 0.92–2.53 
Cervix 1.36 0.43–3.21 0.43 0.00–2.44 1.13 0.00–6.46 
Endometrium 1.02 0.43–2.01 1.27 0.54–2.51 0.87 0.08–3.19 
Ovary 10 1.50 0.71–2.77 0.85 0.22–2.19 1.24 0.12–4.57 
Prostate 29 1.06 0.71–1.52 23 1.29 0.81–1.93 0.88 0.35–1.81 
Kidney 1.23 0.52–2.43 1.79 0.76–3.54 1.26 0.12–4.63 
Urinary bladder 0.70 0.28–1.44 0.88 0.32–1.93   
Melanoma 11 1.26 0.62–2.25 0.61 0.16–1.57 1.13 0.21–3.34 
Skin, squamous cell 14 1.69 0.92–2.85 0.84 0.26–1.97 3.51 1.50–6.95 
Nervous system 12 1.62 0.84–2.85 1.10 0.40–2.41 0.47 0.00–2.69 
Thyroid gland 1.05 0.10–3.86 0.76 0.00–4.38 4.08 0.39–15.02 
Endocrine glands 1.28 0.46–2.79 2.02 0.80–4.19 1.60 0.15–5.90 
Non-Hodgkin's lymphoma 10 1.04 0.50–1.92 11 1.51 0.75–2.71 2.50 0.99–5.19 
Hodgkin's disease 2.18 0.21–8.02     
Myeloma 1.57 0.49–3.68 0.43 0.00–2.49   
Leukemia 1.77 0.70–3.66 1.40 0.37–3.63 2.80 0.53–8.30 
Myeloid leukemia 1.86 0.48–4.81 1.29 0.12–4.76 5.19 0.98–15.35 
All 258 1.15 1.01–1.30 169 1.05 0.90–1.23 78 1.27 1.00–1.59 

Bold type: 95% CI does not include 1.00; underline type: 99% CI does not include 1.00.

**

P value for trend test is <0.01.

CI, confidence interval; SIR, standardized incidence ratio.

discussion

In this population-based study, 10 037 sarcoidosis patients were identified from the Swedish Hospital Discharge Register with a follow-up until year 2004. Overall, a 40% excess incidence of cancers was noted, and the risk was still above the unity (1.18) when excluding cases diagnosed during the first year of follow-up. This excess was largely attributed to squamous cell skin cancer and non-Hodgkin's lymphoma and leukemia.

The advantages of the present study include the larger number of patients from a nationwide population, its prospective design and completeness of follow-up of sarcoidosis patients. All the data were from nationwide databases guaranteeing reliable information. One limitation of this study is that some of the findings may be due to chance because of multiple comparisons. Another limitation is the lack of information on medication and treatment. However, the analysis of temporal trends compensated partly for this because medication has partly changed over time. Moreover, the data from this study are not directly applicable to all patients with sarcoidosis because hospitalized patients probably represent a severe and chronic clientele.

Cancer risk among sarcoidosis patients has been examined in previous studies. A suggestive association between lymphoma and sarcoidosis was reported in Denmark on the basis of five sarcoidosis patients among 1500 malignant lymphoma patients in the 1970s [20]. The subsequent study using the Danish Sarcoidosis Registry supported this association [12]. However, the recent Danish study on 555 sarcoidosis patients failed to confirm the increased occurrence of malignancies [13]. A UK study on the basis of 1153 incident sarcoidosis patients provided no evidence of increased risk of malignancy, with the exception of skin cancer [14]. Askling et al. [11] reported an increased SIR of 1.3 for all cancers on the basis of 8541 hospitalized sarcoidosis patients followed up to year 1994 in Sweden, in a population partially overlapping with the present one. The cases diagnosed during the first year of follow-up were excluded in that study. Besides lymphoma, many other cancers, such as stomach, colon, liver and skin caners and leukemia, showed increase after diagnosis of sarcoidosis.

In the present study, a significantly increased overall risk of cancer was noted for hospitalized sarcoidosis patients, which was in line with the previous Swedish study [11]. The highest risk in our study was noted during the first year after last hospitalization for sarcoidosis, which could be due to lead time bias because of concomitant diagnosis. The risk (all 1+) was marginally increased, but this could be an underestimation because the accuracy of diagnosis of cancers was not compromised by lead time bias, rather the diagnosis was shifted earlier. For specific cancers, the risk of non-Hodgkin's lymphoma was significantly increased, which was in line with the study of Askling et al. and some other, but not all, previous studies [11, 14, 21–23]. Non-Hodgkin's lymphoma is one of the hallmarks of dysregulated immunity. Another hallmark, squamous cell skin cancer was also a significantly increased risk after sarcoidosis, which is in line with the evidence that sarcoidosis patients have dysregulated immune function [1, 11, 14, 24]. The excess of melanoma among sarcoidosis patients with multiple hospital visits could also be related to dysregulated immunity. The previous observed cancer sites from the study of Askling et al., including stomach, colon, lung and liver cancers, were confirmed in the present study. Lung cancer was increased during the first year of follow-up but the risk was significantly decreased after 10 years of follow-up, which could be explained by the reverse association between sarcoidosis and smoking [25, 26]. Evidence for this reverse association was supported by the decreased risk of bladder cancer. Among the subtypes of leukemia, only myeloid leukemia showed an increase after sarcoidosis. The risk remained high (2.19) even after we excluded myeloid leukemia diagnosed during the first year of follow-up, indicating it may be a true biological association. The significant increase in kidney cancer after diagnosis of sarcoidosis has not been reported before. A possible explanation could be that malignant kidney cancer may produce a local sarcoid reaction and initiate the manifestations of sarcoidosis [15]. Although the risks of nonthyroid endocrine tumors were significantly increased, the risk for specific sites was not of significance, which should be clarified in further studies.

As a novel design, we analyzed the patient population by the number of hospital visits, using this as a surrogate for disease severity and chronicity. The overall cancer risk was associated with the number of hospitalizations. The excesses in skin (melanoma and squamous cell) cancer and non-Hodgkin's lymphoma and leukemia were most pronounced for patients with multiple hospitalizations. The highest risk of 3.13 was noted for myeloid leukemia among patients with multiple hospitalizations. Multiple hospitalizations witness about the severity of sarcoidosis but, additionally, the highly increased risk of skin cancer and non-Hodgkin's lymphoma and leukemia should be an extra concern, which may call for medical surveillance.

For all the cancer sites with an increased risk, hospitalization at ages older than 49 years was associated with a high risk; we have no specific explanation to the age-dependent cancer risk. Although hospitalization may be several years later than the onset of sarcoidosis, hospital visit normally depends on the severity of the disease and not on the age of onset. The diagnostic criteria and treatment for sarcoidosis patients have changed during the follow-up period and we examined the temporal trends of cancer development among these patients. For most specific cancers, the risk did not change during the study periods because of the sparseness of individual cancers, which limited our conclusion. However, the increased risk of skin squamous cell carcinoma at the end of the study period calls for clinical attention.

In summary, a 40% overall excess incidence of cancer was noted among sarcoidosis patients, but the increase was confined mainly to the first year after hospitalization. However, for specific cancers, such as squamous cell carcinoma of the skin and non-Hodgkin's lymphoma and leukemia, the increases were still significant for patients diagnosed later than 1 year after hospitalization, especially for those with multiple hospitalizations. A late age at hospitalization was associated with a high risk, which calls for clinical attention.

funding

The Deutsche Krebshilfe (107406); the Swedish Cancer Society (CAN/2007/479); the European Union (LSHC-CT-2004-503465); the Swedish Council for Working Life and Social Research (2005-0039).

Conflicts of interest: None.

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