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Original Research: Diffuse Lung Disease |

Sarcoidosis and Cancer RiskSarcoidosis and Cancer Risk: Systematic Review and Meta-analysis of Observational Studies FREE TO VIEW

Martina Bonifazi, MD; Francesca Bravi, PhD; Stefano Gasparini, MD, FCCP; Carlo La Vecchia, MD; Armando Gabrielli, MD; Athol U. Wells, MD; Elisabetta A. Renzoni, MD
Author and Funding Information

From the Department of Epidemiology (Dr Bonifazi), Istituto di Ricerche Farmacologiche Mario Negri-Istituto di Ricovero e Cura a carattere Scientifico (IRCCS), Milan, Italy; Department of Clinical Sciences and Community Health (Drs Bravi and La Vecchia), Università Degli Studi di Milano, Milan, Italy; Department of Biomedical Sciences and Public Health (Dr Gasparini) and Department of Clinical and Molecular Sciences (Dr Gabrielli), Università Politecnica delle Marche, Ancona, Italy; and Interstitial Lung Disease Unit (Drs Wells and Renzoni), Royal Brompton Hospital, Royal Brompton & Harefield NHS Foundation Trust, London, England.

CORRESPONDENCE TO: Martina Bonifazi, MD, Department of Epidemiology, Istituto di Ricerche Farmacologiche Mario Negri-IRCCS, Via La Masa 19, 20256 Milan, Italy; e-mail: martina.bonifazi@marionegri.it


FUNDING/SUPPORT: This work has been partly supported by the “Fondazione di Medicina Molecolare e Terapia Cellulare” (Università Politecnica delle Marche, Ancona), the Italian Association for Cancer Research [Grant 10068 to Istituto di Ricerche Farmacologiche Mario Negri-IRCCS], and by the NIHR Respiratory Disease Biomedical Research Unit at Royal Brompton & Harefield NHS Foundation Trust and Imperial College London.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(3):778-791. doi:10.1378/chest.14-1475
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BACKGROUND:  An increased cancer risk in patients with sarcoidosis has been suggested, although results are conflicting in a number of case-control and cohort studies. We conducted a systematic review of all available data and performed a meta-analysis to better define and quantify the association between sarcoidosis and cancer.

METHODS:  We searched Medline and Embase for all original articles on cancer and sarcoidosis published up to January 2013. Two independent authors reviewed all titles/abstracts to identify studies according to predefined selection criteria. We derived summary estimates using a random-effects model and reported them as relative risk (RR). Publication bias was evaluated using a funnel plot and was quantified by the Egger test.

RESULTS:  Sixteen original studies, involving > 25,000 patients, were included in the present review. The summary RR to develop all invasive cancers was 1.19 (95% CI, 1.07-1.32). The results for selected cancer sites indicated a significantly increased risk of skin (RR, 2.00; 95% CI, 1.69-2.36), hematopoietic (RR, 1.92; 95% CI, 1.41-2.62), upper digestive tract (RR, 1.73; 95% CI, 1.07-2.79), kidney (RR, 1.55; 95% CI, 1.21-1.99), liver (RR, 1.79; 95% CI, 1.03-3.11), and colorectal cancers (RR, 1.33; 95% CI, 1.07-1.67). There was no evidence of publication bias for all cancers (P = .9), nor for any specific cancer site.

CONCLUSIONS:  The present meta-analysis suggests a significant, though moderate, association between sarcoidosis and malignancy.

Figures in this Article

Sarcoidosis is a multisystem chronic condition of unknown etiology, characterized by persistent granulomatous inflammation, which mainly affects the intrathoracic lymph nodes and the lungs, although any organ can be involved.1 The incidence of sarcoidosis varies according to race and to latitude, suggesting a role for both environmental and genetic susceptibility, including human leukocyte antigen class 2 and cytokine polymorphisms.2 The interplay between genetic and environmental factors is likely to define not only the risk for the disease, but also the spectrum of clinical phenotypes and prognosis.3

An increased incidence of cancer in patients with sarcoidosis compared with the general population has been suggested by several case reports and series.4 However, case-control and cohort studies, conducted to properly address this issue, have reported conflicting results.5 An overall excess risk has been reported in a number of studies, although estimates varied considerably,5,6 and data on selected cancer sites were often inconsistent. On the other hand, other studies have not detected any increased risk.

Therefore, we conducted a systematic review of all available data and performed a meta-analysis to better explore and quantify the association between sarcoidosis and cancer.

We followed the guidelines developed by the Meta-analysis of Observational Studies in Epidemiology (MOOSE) group.7 We searched Medline and Embase for all original articles of observational studies on cancer and sarcoidosis published up to January 2013, using a combination of free text and medical subject heading (MESH)/Emtree terms related to sarcoidosis, cancer, and observational studies. The electronic search was supplemented by hand searching the bibliography of relevant articles.

The following criteria were established for inclusion: (1) cohort study of patients with sarcoidosis reporting relative risk (RRs) and the corresponding CIs or sufficient information to calculate them; (2) case-control study of cancer estimating the ORs relative to a history of sarcoidosis. Exclusion criteria were: (1) diagnosis of cancer preceding the diagnosis of sarcoidosis; (2) non-English full text.

Two independent authors (M. B. and F. B.) first reviewed all titles/abstracts to identify potentially relevant articles. They then performed the study selection, based on a full-text review, according to inclusion/exclusion criteria. Disagreements were resolved by discussion. When manuscript full texts were unretrievable, the corresponding authors were contacted directly.

The two reviewers independently extracted information on study design, country, sex, number of subjects (cases, controls, or cohort size), duration of follow-up, cancer sites considered, years between diagnosis of sarcoidosis and cancer (when available), variables adjusted for in the analysis, RR estimates, and the corresponding 95% CIs.

Forest plots were generated by using random-effects models to derive all meta-analytic estimates.8 Heterogeneity among studies was assessed by using the χ2 test,8 defining a significant heterogeneity as a P value < .10, whereas inconsistency was quantified using the I2 statistic.9 A sensitivity analysis was performed to verify the influence of studies including coincident cancer cases (diagnosed within the first year from diagnosis of sarcoidosis) on the summary estimates. Publication bias was evaluated using the funnel plot10 and was quantified by the Egger test.11

After removing duplicates between the two data sources, the search identified 1,469 references (Fig 1). The initial screening, based on titles/abstracts, led to the exclusion of 1,375 papers because they were not relevant (eg, laboratory studies, case reports, review articles), and the remaining 94 articles were retrieved for detailed full-text evaluation. Thirty-two were case reports/series, 16 were review articles, and 30 were observational studies not fulfilling the inclusion criteria, such as studies on mortality, prevalence, or those addressing the risk of sarcoidosis in patients with cancer.

Figure Jump LinkFigure 1 –  Flowchart of study selection.Grahic Jump Location

Thus, 16 original studies were included in the present review. Their main characteristics are given in Table 1.5,6,1224 Ten were cohort studies, and six were case-control studies. Only eight studies reported “overall” cancer risk, whereas specific cancer site rates are reported in all the selected studies (Table 1). In the majority of studies, the variables adjusted for in statistical analyses were age, sex, and calendar period.

Table Graphic Jump Location
TABLE 1 ]  Case-Control and Cohort Studies on Sarcoidosis and Cancer Risk Included in the Meta-analysis

All = overall; Bl = bladder; Br = breast; C = colon; Ce = cervix; CLL = chronic lymphocytic leukemia; E = eye; EG = endocrine gland; En = endometrium; ENT = nose and throat; F = female; GB = gallbladder; Ge = genital; HCL = hairy cell leukemia; HL = Hodgkin lymphoma; K = kidney; L = lung; Le = leukemia; LI = large intestine; Lp = lip; Lv = liver; Lx = larynx; Ly = lymphoma; M = male; Me = melanoma; MF = male and female; MPN = myeloproliferative neoplasm; Mt = mouth; My = myeloma; Na = nasal; NHL = non-Hodgkin’s lymphoma; NLL = nonlymphocytic leukemia; NMS = nonmelanoma skin cancer; NS = nervous system; OC = oral cavity; Oe = esophagus; Or = oropharynx; Ot = other; Ov = ovarian; P = pancreas; Ph = pharynx; Pr = prostate; PR = person at risk; PY = person-year; R = rectal; SI = small intestine; Sk = skin; St = stomach; Te = testicular; Th = thyroid; Uc = corpus of uterus; UD = upper digestive; UK = United Kingdom; Un = unspecified; USA = United States of America; Ut = uterus.

a 

The number of cancer cases refers to all cancer cases diagnosed in each study, including site-specific cancer cases.

b 

This is a case-control study comparing rates of sarcoidosis between 418 cases with hairy cell leukemia and 160,086 control subjects. The exact number of patients with both sarcoidosis and cancer (cancer cases) was not specified in the full text, but was less than five, while there were 167 control cases that had sarcoidosis. Thus, it was not possible to calculate the overall number of patients with sarcoidosis.

Figure 2 provides the study-specific and summary RRs for “overall” invasive cancers, overall and according to sex and time since diagnosis. This was based on eight cohort studies (the remaining two cohort studies evaluated specific cancer sites but not overall cancers) including 27,268 patients with sarcoidosis and 1,952 cancer cases. The overall RR was 1.19 (95% CI, 1.07-1.32). A significant heterogeneity (P = .002) was detected, although all studies, except two, gave a RR above unity, significant in most cases (Fig 2A). The RRs according to sex, derived from three cohorts, were 1.39 (95% CI, 1.25-1.54) for men and 1.20 (95% CI, 1.07-1.34) for women, in the absence of significant heterogeneity among studies (Fig 2B). Forest plots by time since diagnosis showed a significantly higher risk of malignancies up to the 10th year from the first diagnosis of sarcoidosis, with a RR of 1.41 (95% CI, 1.27-1.56) until the fourth year, and a RR of 1.31 (95% CI, 1.15-1.48) between the fifth and ninth year (Fig 2C). Afterward, the RR was no longer significant (RR, 1.06; 95% CI, 0.93-1.21). Furthermore, the sensitivity analysis, excluding studies that included patients diagnosed with cancer within the first year, did not substantially change the overall result (RR, 1.17; 95% CI, 1.06-1.30).

Figure Jump LinkFigure 2 –  A-C, Study-specific and pooled RRs and 95% CIs for all invasive cancers in patients with sarcoidosis, overall (A) and according to sex (B) and time since diagnosis (C). Only studies providing overall cancer rates are included in this figure.5,6,1215 Den = Denmark; Jap = Japan; RR = relative risk; Swe = Sweden; UK = United Kingdom; USA = United States.Grahic Jump Location

Figure 3 gives the forest plots for hematologic malignancies, overall and by subtypes. The overall RR, derived from 15 investigations (seven case-control and eight cohort studies), including 27,602 patients with sarcoidosis and 316 cancer cases, of all hematologic neoplasms was 1.92 (95% CI, 1.41-2.62). The results were above unity in 12 studies, although there was significant heterogeneity (P < .0001). According to selected subtypes, the highest risk was found for Hodgkin’s lymphoma (RR, 2.91; 95% CI, 1.21-6.98), with significant heterogeneity among the six studies included (P = .001). The overall risk of lymphoma, evaluated in 12 studies (four case-control and eight cohort studies), was 1.88 (95% CI, 1.18-3.01) and there was a high interstudy heterogeneity (P < .0001); the RR for non-Hodgkin’s lymphoma was 1.43 (95% CI, 1.03-1.99). A significant increased risk was observed for leukemia (RR, 2.03; 95% CI, 1.55-2.66). There was no association between sarcoidosis and myeloma (RR, 1.04; 95% CI, 0.70-1.56), though the estimate was based on three studies only.

Figure Jump LinkFigure 3 –  Study-specific and summary RRs for hematologic cancers in patients with sarcoidosis, overall and by subtypes. See Figure 2 legend for expansion of abbreviations.Grahic Jump Location

Figure 4 shows study-specific and summary RRs for skin cancers, overall and by subtype. Based on seven investigations, including 21,500 patients with sarcoidosis and 207 cancer cases, there was an overall excess risk (RR, 2.00; 95% CI, 1.69-2.36), and no heterogeneity among studies was detected (P = .4). The RRs were 1.64 (95% CI, 1.16-2.31) for melanoma and 2.29 (95% CI, 1.88-2.78) for nonmelanoma skin cancer, in the absence of significant interstudy heterogeneity (P = .2 and P = .6).

Figure Jump LinkFigure 4 –  Study-specific and summary RRs for skin cancers in patients with sarcoidosis. See Figure 2 legend for expansion of abbreviations.Grahic Jump Location

Figure 5 gives the forest plot for lung cancer risk, derived from eight cohort studies, including 27,268 patients with sarcoidosis and 153 cancer cases. Although RR was slightly above unity, no significant association was found (RR, 1.20; 95% CI, 0.84-1.71), and there was a high heterogeneity among studies (P = .007). The RRs by time since diagnosis were 1.73 (95% CI, 1.05-2.85) until the fourth year, 1.53 (95% CI, 0.87-2.68) between the fifth and ninth years, and 0.48 (95% CI, 0.34-0.67) from the 10th year onward.

Figure Jump LinkFigure 5 –  Study-specific and summary RRs for lung cancer in patients with sarcoidosis. See Figure 2 legend for expansion of abbreviations.Grahic Jump Location

Study-specific and summary RRs for upper digestive tract, kidney, liver, and colorectal cancers are provided in Figure 6. Seven cohort studies, involving 26,115 patients with sarcoidosis, evaluated the association with upper digestive tract, kidney, and liver cancers. The RRs were 1.73 (95% CI, 1.07-2.79) for upper digestive tract cancer, 1.55 (95% CI, 1.21-1.99) for kidney cancer, and 1.33 (95% CI, 1.07-1.67) for colorectal cancer. Liver cancer risk was investigated in six cohort studies including 21,246 patients, and the overall RR was 1.79 (95% CI, 1.03-3.11).

Figure Jump LinkFigure 6 –  A-D, Study-specific and summary RRs for upper digestive (A), kidney (B), liver (C), and colorectal (D) cancers in patients with sarcoidosis. See Figure 2 legend for expansion of abbreviations.Grahic Jump Location

The RRs and the corresponding 95% CI for other cancer sites analyzed (bladder, breast, cervix/uterus, ovary, pancreas, prostate, and stomach) are given in Table 2. Bladder cancer risk was significantly reduced in patients with sarcoidosis (RR, 0.65; 95% CI, 0.45-0.92), while no association was found between the remaining explored sites and sarcoidosis. We did not find evidence of publication bias for all cancers (P = .861), nor for any specific cancer site.

Table Graphic Jump Location
TABLE 2 ]  Summary of Pooled RRs and 95% CIs for All Invasive Cancers and All Sites Explored

df = degrees of freedom; RR = relative risk.

a 

Statistically significant RR.

The present meta-analysis, the first, to our knowledge, on sarcoidosis and cancer risk, involving > 25,000 patients from various countries worldwide, suggests a significant association between sarcoidosis and malignancy. The results for selected cancer sites indicated an approximately twofold higher risk of developing skin and hematopoietic cancers. There was also a significant, although moderate, association with upper digestive tract, kidney, liver, and colorectal cancer. Although significant heterogeneity across studies was observed for several cancer sites, most of the RRs derived from individual data were significantly above unity and there was no evidence of publication bias.

Several mechanisms have been proposed to explain the relationship between sarcoidosis and cancer. These include chronic inflammation, immune dysfunction, shared etiologic agents, and genetic susceptibility to both cancer and autoimmune diseases.5,25 In sarcoidosis, a systemic inflammatory state, beyond the local granulomatous response, is demonstrated by persistently high levels of peripheral blood inflammatory markers, such as the erythrocyte sedimentation rate and IL-6.2628 A role for chronic inflammation in carcinogenesis has been established.29 In fact, the inflammatory pathway promotes tumor development and stimulates angiogenesis, involving cytokines such as macrophage migratory inhibitory factor, tumor necrosis factor-α, IL-6, and transforming growth factor-β, which are major intracellular and intercellular mediators in the inflammatory tumor microenvironment.30,31 Moreover, chronic inflammation subverts adaptive immunity, potentially leading to reduced immunosurveillance.30 Despite the presence of upregulated cellular immune activity within granulomatous tissues, patients with sarcoidosis often express paradoxical suppression of their peripheral immune responses,26 and evidence of reduced cellular immunity, such as clinical anergy to specific skin test antigens, is commonly found in sarcoidosis.28 Decreased function of blood dendritic cells and impairment of T-cell activity have also been proposed as potential mechanisms.28

An increased risk of cancer has been observed in autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and scleroderma.3234 Although sarcoidosis is not currently viewed as a classic autoimmune disorder, these conditions share intrinsic immune dysfunction and systemic chronic inflammation, further suggesting a potential role of these pathologic mechanisms in carcinogenesis.35 Most autoimmune diseases are significantly associated with hematologic malignancies, as the persistent stimulation of the immune system, as well as the exposure to immunomodulatory treatments, seem to contribute to malignant lymphoproliferation.36,37 The significant association between lymphoma and sarcoidosis confirms a long-standing anecdotal suspicion of linkage between the two conditions, captured by a review of all published cases and small series in 2010,38 although this report did not satisfy criteria for inclusion in meta-analysis.

With reference to solid malignancies, an increased cancer risk has been suggested for organs specifically targeted by the inflammatory condition.36 In sarcoidosis, this applies to skin, kidney, and liver, as granulomatous inflammation often affects these organs. However, no association was found between sarcoidosis and lung cancer, although lung tissue inflammation leading to chronic scarring has been suggested as a further risk factor for carcinogenesis.34 Unfortunately, none of the included studies reported the prevalence of fibrotic interstitial disease in their cohorts, and, thus, it is difficult to assess its role on lung cancer overall estimates. However, data from literature suggest that < 20% of patients with sarcoidosis present a fibrotic parenchymal involvement,39 partly supporting our finding. Another explanation could be the higher prevalence of nonsmokers among patients with sarcoidosis. In fact, observational studies have reported a negative association between tobacco smoking and sarcoidosis risk, suggesting a protective role of a smoking habit on the onset of disease.4042 Moreover, another tobacco-related cancer, such as bladder cancer, was significantly reduced in patients with sarcoidosis. However, further analyzing lung cancer risk by time since diagnosis, there was a significant excess risk within the first 5 years of follow-up, which progressively decreased afterward, until it became significantly lower than expected in the general population beyond 10 years from diagnosis. Possible explanations include a higher biologic activity of the disease during the first years, which could in itself play a relevant role for carcinogenesis, and the evidence that patients, when previously smokers, usually quit smoking after the diagnosis, but some years are needed to lower lung cancer risk.13,42,43

The association between sarcoidosis and upper digestive and colorectal cancers is more difficult to explain, as these sites are not recognized as common targets of disease, although subclinical involvement could be underdiagnosed. Furthermore, from the information available, it was not possible to identify which types of cancer were increased. However, the fact that GI mucosa is rich in mucosa-associated lymphoid tissue, likely to be involved in the context of sarcoidosis, could predispose to carcinogenesis.44

Although an association between sarcoidosis and testis cancer has been suggested by several case reports and series, in most cases, a diagnosis of malignancy was previous or concomitant to that of sarcoidosis.4547 The only two studies that prospectively evaluated testis cancer risk in patients with sarcoidosis reported no significant association.14,15 As testis cancer is the leading solid tumor in young adult men48 and the first peak of sarcoidosis incidence occurs in subjects aged < 35 years, the association observed could be casual rather than causal.

The present meta-analysis has potential limitations, related to the heterogeneity in sample size and design, including case-selection criteria. Moreover, in most of the investigations, data were retrieved from record-linkage between various health-care databases, such as hospital discharge datasets and national registers, usually not reporting information on relevant covariates or clinical details. As a consequence, information on organ-specific involvements in sarcoidosis, as well as relevant confounding or modifying factors, such as smoking habit and previous immunosuppressive therapies, could not be evaluated. The lack of data on immunosuppressive drugs deserves careful consideration. Immunosuppressive agents may themselves increase cancer rates, especially hematologic and skin cancers. However, the majority of data refer to transplant patients receiving lifelong, high-dosage therapies,49 while systematic reviews on the associations between cancer risk and immunomodulatory treatments in other clinical settings (eg, rheumatoid arthritis, inflammatory bowel diseases) report conflicting results5052 for drugs such as methotrexate and azathioprine, the nonsteroidal agents most commonly prescribed in sarcoidosis.53 Moreover, only a minority of patients with sarcoidosis requires nonsteroidal immunosuppressive therapies, used by most only in steroid-refractory cases or in the presence of steroid-associated adverse effects.53 Therefore, it is unlikely that this potential bias has largely influenced our pooled estimates, although it should be taken into account in the interpretation of results.

Other potential sources of bias include the selection of reference cohorts and the increased medical surveillance bias, due to the closer observation of patients with sarcoidosis compared with the general population. As sarcoidosis is often self-limiting, this is more likely to affect the first years of follow-up, leading to potential overestimates of summary RR. To further explore this issue, a sensitivity analysis was performed to verify the influence of studies including cancer cases diagnosed within the first year from diagnosis of sarcoidosis. These cases were more likely to be concurrent rather than subsequent and they could have been detected as a result of an initial closer surveillance. However, the overall RR did not substantially change (RR, 1.17; 95% CI, 1.06-1.30). On the other hand, data on long-term estimates showed that all cancer risk was no longer significant from the 10th year onward (RR, 1.06; 95% CI, 0.93-1.21). However, only five studies provided data by years since diagnosis, with conflicting results with regards to all cancer risk, and insufficient long-term data to perform a proper meta-analysis for selected cancer sites, including hematologic, liver, colorectal, kidney, and skin cancer risks.5,12,13,15 Therefore, it is difficult to definitely assess whether and how much the surveillance bias really affected our results. Moreover, most of the cancer types identified at increased risk, if untreated, tend to progress and, thus, it is likely that they would have been detected even outside of a close “screening.”

A further potential source of selection bias is the inclusion of hospitalized patients in several of the studies. Because of differences in the selection criteria used to detect sarcoidosis in the 16 included studies, it is not possible to ascertain what proportion of patients was hospitalized “for” rather than “with” sarcoidosis. Patients hospitalized “with” sarcoidosis would by definition have higher comorbidities, and therefore potentially higher cancer rates than the general population. However, in that case, a link with common cancers rather than with selected rarer (eg, hematologic, liver, kidney) cancer sites would have been expected. Moreover, the fact that the mean age (in years) at “diagnosis” was below 50 in the majority of studies makes the possibility of a substantial proportion of morbidities (other than sarcoidosis) in this population less likely.

In conclusion, the present study, based on > 25,000 patients with sarcoidosis worldwide, assesses and quantifies the association between sarcoidosis and cancer, particularly for skin and hematologic neoplasms. Further studies on disease-related predictors of cancer development in patients with sarcoidosis, such as different clinical phenotypes, degrees of severity, and organ involvement, would be useful to identify high-risk subjects and better understand potential underlying mechanisms. Studies to refine the identification of high-risk subjects would enhance the cost-effectiveness of active surveillance of these patients for early detection of selected cancers, allowing the development of specific guidelines to define modalities and timing of screening.

Author contributions: M. B. and F. B. had full access to all of the data in the study, and they take full responsibility for the integrity of all of the data and the accuracy of the data analysis. M. B. and E. A. R. contributed substantially to study conception and design and data acquisition, analysis, and interpretation, drafted the submitted article, revised it critically for important intellectual content, and provided final approval of the version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; F. B. contributed substantially to data acquisition, analysis, and interpretation, revised the submitted article critically for important intellectual content and provided final approval of the version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; S. G. contributed substantially to study conception and design and data interpretation, revised the submitted article for important intellectual content and provided final approval of the version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; C. L. V. contributed substantially to data conception, analysis, and interpretation, revised the submitted article critically for important intellectual content and provided final approval of the version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; A. G. contributed substantially to data interpretation, revised the submitted article critically for important intellectual content and provided final approval of the version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; and A. U. W. contributed to study design and data analysis and interpretation, revised the submitted article critically for important intellectual content and provided final approval of the version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.

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Alexandrescu DT, Kauffman CL, Ichim TE, Riordan NH, Kabigting F, Dasanu CA. Cutaneous sarcoidosis and malignancy: An association between sarcoidosis with skin manifestations and systemic neoplasia. Dermatol Online J. 2011;17(1):2. [PubMed]
 
Mathew S, Bauer KL, Fischoeder A, Bhardwaj N, Oliver SJ. The anergic state in sarcoidosis is associated with diminished dendritic cell function. J Immunol. 2008;181(1):746-755. [CrossRef] [PubMed]
 
Sahashi K, Ina Y, Takada K, Sato T, Yamamoto M, Morishita M. Significance of interleukin 6 in patients with sarcoidosis. Chest. 1994;106(1):156-160. [CrossRef] [PubMed]
 
Alexandrescu DT, Riordan NH, Ichim TE, et al. On the missing link between inflammation and cancer. Dermatol Online J. 2011;17(1):10. [PubMed]
 
Candido J, Hagemann T. Cancer-related inflammation. J Clin Immunol. 2013;33(suppl 1):S79-S84. [CrossRef] [PubMed]
 
Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454(7203):436-444. [CrossRef] [PubMed]
 
Conroy H, Mawhinney L, Donnelly SC. Inflammation and cancer: macrophage migration inhibitory factor (MIF)—the potential missing link. QJM. 2010;103(11):831-836. [CrossRef] [PubMed]
 
Smitten AL, Simon TA, Hochberg MC, Suissa S. A meta-analysis of the incidence of malignancy in adult patients with rheumatoid arthritis. Arthritis Res Ther. 2008;10(2):R45. [CrossRef] [PubMed]
 
Bernatsky S, Ramsey-Goldman R, Labrecque J, et al. Cancer risk in systemic lupus: an updated international multi-centre cohort study. J Autoimmun. 2013;42:130-135. [CrossRef] [PubMed]
 
Bonifazi M, Tramacere I, Pomponio G, et al. Systemic sclerosis (scleroderma) and cancer risk: systematic review and meta-analysis of observational studies. Rheumatology (Oxford). 2013;52(1):143-154. [CrossRef] [PubMed]
 
Wahlström J, Dengjel J, Persson B, et al. Identification of HLA-DR-bound peptides presented by human bronchoalveolar lavage cells in sarcoidosis. J Clin Invest. 2007;117(11):3576-3582. [CrossRef] [PubMed]
 
Franks AL, Slansky JE. Multiple associations between a broad spectrum of autoimmune diseases, chronic inflammatory diseases and cancer. Anticancer Res. 2012;32(4):1119-1136. [PubMed]
 
Javierre BM, Esteller M, Ballestar E. Epigenetic connections between autoimmune disorders and haematological malignancies. Trends Immunol. 2008;29(12):616-623. [CrossRef] [PubMed]
 
Papanikolaou IC, Sharma OP. The relationship between sarcoidosis and lymphoma. Eur Respir J. 2010;36(5):1207-1209. [CrossRef] [PubMed]
 
Baughman RP, Teirstein AS, Judson MA, et al; Case Control Etiologic Study of Sarcoidosis (ACCESS) research group. Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med. 2001;164(10 pt 1):1885-1889. [CrossRef] [PubMed]
 
Newman LS, Rose CS, Bresnitz EA, et al; ACCESS Research Group. A case control etiologic study of sarcoidosis: environmental and occupational risk factors. Am J Respir Crit Care Med. 2004;170(12):1324-1330. [CrossRef] [PubMed]
 
Valeyre D, Soler P, Clerici C, et al. Smoking and pulmonary sarcoidosis: effect of cigarette smoking on prevalence, clinical manifestations, alveolitis, and evolution of the disease. Thorax. 1988;43(7):516-524. [CrossRef] [PubMed]
 
Douglas JG, Middleton WG, Gaddie J, et al. Sarcoidosis: a disorder commoner in non-smokers? Thorax. 1986;41(10):787-791. [CrossRef] [PubMed]
 
Harf RA, Ethevenaux C, Gleize J, Perrin-Fayolle M, Guerin JC, Ollagnier C. Reduced prevalence of smokers in sarcoidosis. Results of a case-control study. Ann N Y Acad Sci. 1986;465:625-631. [CrossRef] [PubMed]
 
McGhee JR, Fujihashi K. Inside the mucosal immune system. PLoS Biol. 2012;10(9):e1001397. [CrossRef] [PubMed]
 
Paparel P, Devonec M, Perrin P, et al. Association between sarcoidosis and testicular carcinoma: a diagnostic pitfall. Sarcoidosis Vasc Diffuse Lung Dis. 2007;24(2):95-101. [PubMed]
 
Rayson D, Burch PA, Richardson RL. Sarcoidosis and testicular carcinoma. Cancer. 1998;83(2):337-343. [CrossRef] [PubMed]
 
Tjan-Heijnen VC, Vlasveld LT, Pernet FP, Pauwels P, De Mulder PH. Coincidence of seminoma and sarcoidosis: a myth or fact? Ann Oncol. 1998;9(3):321-325. [CrossRef] [PubMed]
 
Cook MB, Chia VM, Berndt SI, et al. Genetic contributions to the association between adult height and testicular germ cell tumors. Int J Epidemiol. 2011;40(3):731-739. [CrossRef] [PubMed]
 
Corthay A. Does the immune system naturally protect against cancer? Front Immunol. 2014;5(5):197. [PubMed]
 
Beyaert R, Beaugerie L, Van Assche G, et al. Cancer risk in immune-mediated inflammatory diseases (IMID). Mol Cancer. 2013;12(1):98. [CrossRef] [PubMed]
 
Salliot C, van der Heijde D. Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research. Ann Rheum Dis. 2009;68(7):1100-1104. [CrossRef] [PubMed]
 
Masunaga Y, Ohno K, Ogawa R, Hashiguchi M, Echizen H, Ogata H. Meta-analysis of risk of malignancy with immunosuppressive drugs in inflammatory bowel disease. Ann Pharmacother. 2007;41(1):21-28. [CrossRef] [PubMed]
 
Cremers JP, Drent M, Bast A, et al. Multinational evidence-based World Association of Sarcoidosis and Other Granulomatous Disorders recommendations for the use of methotrexate in sarcoidosis: integrating systematic literature research and expert opinion of sarcoidologists worldwide. Curr Opin Pulm Med. 2013;19(5):545-561. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Flowchart of study selection.Grahic Jump Location
Figure Jump LinkFigure 2 –  A-C, Study-specific and pooled RRs and 95% CIs for all invasive cancers in patients with sarcoidosis, overall (A) and according to sex (B) and time since diagnosis (C). Only studies providing overall cancer rates are included in this figure.5,6,1215 Den = Denmark; Jap = Japan; RR = relative risk; Swe = Sweden; UK = United Kingdom; USA = United States.Grahic Jump Location
Figure Jump LinkFigure 3 –  Study-specific and summary RRs for hematologic cancers in patients with sarcoidosis, overall and by subtypes. See Figure 2 legend for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 4 –  Study-specific and summary RRs for skin cancers in patients with sarcoidosis. See Figure 2 legend for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 5 –  Study-specific and summary RRs for lung cancer in patients with sarcoidosis. See Figure 2 legend for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 6 –  A-D, Study-specific and summary RRs for upper digestive (A), kidney (B), liver (C), and colorectal (D) cancers in patients with sarcoidosis. See Figure 2 legend for expansion of abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Case-Control and Cohort Studies on Sarcoidosis and Cancer Risk Included in the Meta-analysis

All = overall; Bl = bladder; Br = breast; C = colon; Ce = cervix; CLL = chronic lymphocytic leukemia; E = eye; EG = endocrine gland; En = endometrium; ENT = nose and throat; F = female; GB = gallbladder; Ge = genital; HCL = hairy cell leukemia; HL = Hodgkin lymphoma; K = kidney; L = lung; Le = leukemia; LI = large intestine; Lp = lip; Lv = liver; Lx = larynx; Ly = lymphoma; M = male; Me = melanoma; MF = male and female; MPN = myeloproliferative neoplasm; Mt = mouth; My = myeloma; Na = nasal; NHL = non-Hodgkin’s lymphoma; NLL = nonlymphocytic leukemia; NMS = nonmelanoma skin cancer; NS = nervous system; OC = oral cavity; Oe = esophagus; Or = oropharynx; Ot = other; Ov = ovarian; P = pancreas; Ph = pharynx; Pr = prostate; PR = person at risk; PY = person-year; R = rectal; SI = small intestine; Sk = skin; St = stomach; Te = testicular; Th = thyroid; Uc = corpus of uterus; UD = upper digestive; UK = United Kingdom; Un = unspecified; USA = United States of America; Ut = uterus.

a 

The number of cancer cases refers to all cancer cases diagnosed in each study, including site-specific cancer cases.

b 

This is a case-control study comparing rates of sarcoidosis between 418 cases with hairy cell leukemia and 160,086 control subjects. The exact number of patients with both sarcoidosis and cancer (cancer cases) was not specified in the full text, but was less than five, while there were 167 control cases that had sarcoidosis. Thus, it was not possible to calculate the overall number of patients with sarcoidosis.

Table Graphic Jump Location
TABLE 2 ]  Summary of Pooled RRs and 95% CIs for All Invasive Cancers and All Sites Explored

df = degrees of freedom; RR = relative risk.

a 

Statistically significant RR.

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Anderson LA, Engels EA. Autoimmune conditions and hairy cell leukemia: an exploratory case-control study. J Hematol Oncol. 2010;3(35):35. [CrossRef] [PubMed]
 
Hemminki K, Liu X, Ji J, Försti A, Sundquist J, Sundquist K. Effect of autoimmune diseases on risk and survival in female cancers. Gynecol Oncol. 2012;127(1):180-185. [CrossRef] [PubMed]
 
Tanimoto Y, Kataoka M. Sarcoidosis and malignancy [in Japanese]. Jpn J Chest Dis. 2013;72(8):838-845.
 
Alexandrescu DT, Kauffman CL, Ichim TE, Riordan NH, Kabigting F, Dasanu CA. Cutaneous sarcoidosis and malignancy: An association between sarcoidosis with skin manifestations and systemic neoplasia. Dermatol Online J. 2011;17(1):2. [PubMed]
 
Mathew S, Bauer KL, Fischoeder A, Bhardwaj N, Oliver SJ. The anergic state in sarcoidosis is associated with diminished dendritic cell function. J Immunol. 2008;181(1):746-755. [CrossRef] [PubMed]
 
Sahashi K, Ina Y, Takada K, Sato T, Yamamoto M, Morishita M. Significance of interleukin 6 in patients with sarcoidosis. Chest. 1994;106(1):156-160. [CrossRef] [PubMed]
 
Alexandrescu DT, Riordan NH, Ichim TE, et al. On the missing link between inflammation and cancer. Dermatol Online J. 2011;17(1):10. [PubMed]
 
Candido J, Hagemann T. Cancer-related inflammation. J Clin Immunol. 2013;33(suppl 1):S79-S84. [CrossRef] [PubMed]
 
Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454(7203):436-444. [CrossRef] [PubMed]
 
Conroy H, Mawhinney L, Donnelly SC. Inflammation and cancer: macrophage migration inhibitory factor (MIF)—the potential missing link. QJM. 2010;103(11):831-836. [CrossRef] [PubMed]
 
Smitten AL, Simon TA, Hochberg MC, Suissa S. A meta-analysis of the incidence of malignancy in adult patients with rheumatoid arthritis. Arthritis Res Ther. 2008;10(2):R45. [CrossRef] [PubMed]
 
Bernatsky S, Ramsey-Goldman R, Labrecque J, et al. Cancer risk in systemic lupus: an updated international multi-centre cohort study. J Autoimmun. 2013;42:130-135. [CrossRef] [PubMed]
 
Bonifazi M, Tramacere I, Pomponio G, et al. Systemic sclerosis (scleroderma) and cancer risk: systematic review and meta-analysis of observational studies. Rheumatology (Oxford). 2013;52(1):143-154. [CrossRef] [PubMed]
 
Wahlström J, Dengjel J, Persson B, et al. Identification of HLA-DR-bound peptides presented by human bronchoalveolar lavage cells in sarcoidosis. J Clin Invest. 2007;117(11):3576-3582. [CrossRef] [PubMed]
 
Franks AL, Slansky JE. Multiple associations between a broad spectrum of autoimmune diseases, chronic inflammatory diseases and cancer. Anticancer Res. 2012;32(4):1119-1136. [PubMed]
 
Javierre BM, Esteller M, Ballestar E. Epigenetic connections between autoimmune disorders and haematological malignancies. Trends Immunol. 2008;29(12):616-623. [CrossRef] [PubMed]
 
Papanikolaou IC, Sharma OP. The relationship between sarcoidosis and lymphoma. Eur Respir J. 2010;36(5):1207-1209. [CrossRef] [PubMed]
 
Baughman RP, Teirstein AS, Judson MA, et al; Case Control Etiologic Study of Sarcoidosis (ACCESS) research group. Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med. 2001;164(10 pt 1):1885-1889. [CrossRef] [PubMed]
 
Newman LS, Rose CS, Bresnitz EA, et al; ACCESS Research Group. A case control etiologic study of sarcoidosis: environmental and occupational risk factors. Am J Respir Crit Care Med. 2004;170(12):1324-1330. [CrossRef] [PubMed]
 
Valeyre D, Soler P, Clerici C, et al. Smoking and pulmonary sarcoidosis: effect of cigarette smoking on prevalence, clinical manifestations, alveolitis, and evolution of the disease. Thorax. 1988;43(7):516-524. [CrossRef] [PubMed]
 
Douglas JG, Middleton WG, Gaddie J, et al. Sarcoidosis: a disorder commoner in non-smokers? Thorax. 1986;41(10):787-791. [CrossRef] [PubMed]
 
Harf RA, Ethevenaux C, Gleize J, Perrin-Fayolle M, Guerin JC, Ollagnier C. Reduced prevalence of smokers in sarcoidosis. Results of a case-control study. Ann N Y Acad Sci. 1986;465:625-631. [CrossRef] [PubMed]
 
McGhee JR, Fujihashi K. Inside the mucosal immune system. PLoS Biol. 2012;10(9):e1001397. [CrossRef] [PubMed]
 
Paparel P, Devonec M, Perrin P, et al. Association between sarcoidosis and testicular carcinoma: a diagnostic pitfall. Sarcoidosis Vasc Diffuse Lung Dis. 2007;24(2):95-101. [PubMed]
 
Rayson D, Burch PA, Richardson RL. Sarcoidosis and testicular carcinoma. Cancer. 1998;83(2):337-343. [CrossRef] [PubMed]
 
Tjan-Heijnen VC, Vlasveld LT, Pernet FP, Pauwels P, De Mulder PH. Coincidence of seminoma and sarcoidosis: a myth or fact? Ann Oncol. 1998;9(3):321-325. [CrossRef] [PubMed]
 
Cook MB, Chia VM, Berndt SI, et al. Genetic contributions to the association between adult height and testicular germ cell tumors. Int J Epidemiol. 2011;40(3):731-739. [CrossRef] [PubMed]
 
Corthay A. Does the immune system naturally protect against cancer? Front Immunol. 2014;5(5):197. [PubMed]
 
Beyaert R, Beaugerie L, Van Assche G, et al. Cancer risk in immune-mediated inflammatory diseases (IMID). Mol Cancer. 2013;12(1):98. [CrossRef] [PubMed]
 
Salliot C, van der Heijde D. Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research. Ann Rheum Dis. 2009;68(7):1100-1104. [CrossRef] [PubMed]
 
Masunaga Y, Ohno K, Ogawa R, Hashiguchi M, Echizen H, Ogata H. Meta-analysis of risk of malignancy with immunosuppressive drugs in inflammatory bowel disease. Ann Pharmacother. 2007;41(1):21-28. [CrossRef] [PubMed]
 
Cremers JP, Drent M, Bast A, et al. Multinational evidence-based World Association of Sarcoidosis and Other Granulomatous Disorders recommendations for the use of methotrexate in sarcoidosis: integrating systematic literature research and expert opinion of sarcoidologists worldwide. Curr Opin Pulm Med. 2013;19(5):545-561. [CrossRef] [PubMed]
 
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