Correction
2 Apr 2015: The PLOS ONE Staff (2015) Correction: Early Stage Lung Cancer Detection in Systemic Sclerosis Does Not Portend Survival Benefit: A Cross Sectional Study. PLOS ONE 10(4): e0124225. https://doi.org/10.1371/journal.pone.0124225 View correction
Figures
Abstract
Background
Systemic Sclerosis (SSc) is a rare connective tissue disorder associated with an increased risk of malignancy including lung cancer.
Methods
A single center review of all cases of lung cancer in patients with SSc was conducted. Clinical, radiographic, and detailed pathologic data was collected. Risk factors were compared with our center’s SSc Registry. Cancer characteristics were compared with the National Cancer Institute SEER Cancer Statistics (NCI SEER) data.
Results
17 cases were identified; the majority were females (82%) with the lung cancers diagnosed after the onset of SSc (88%). Tobacco use was identified in 65% of cases. Serologic testing showed 50% of cases were Scl-70 positive. Twelve cases had radiographic evidence of SSc lung involvement, however only 6 had restrictive physiology on pulmonary function testing. Thirteen cases had pulmonary nodules preceding lung cancer. Thirteen of the cancers were adenocarcinoma. Ten underwent molecular mutational profiling: 2/8 had KRAS mutation and 1/10 had EGFR mutation. More of the non-small cell lung cancers were diagnosed at localized disease (56%) than in the NCI SEER database. However, 5 years survival among the stage I cases was 25% versus an expected survival of 54%.
Conclusions
The high proportion of adenocarcinomas seen in our study is different from that reported in the literature. Lung cancers were diagnosed at an early stage, likely due to our center’s practice of radiographic screening for SSc associated lung involvement, however this did not confer a survival advantage. A high proportion of patients who developed lung cancer had interstitial lung disease.
Citation: Katzen JB, Raparia K, Agrawal R, Patel JD, Rademaker A, Varga J, et al. (2015) Early Stage Lung Cancer Detection in Systemic Sclerosis Does Not Portend Survival Benefit: A Cross Sectional Study. PLoS ONE 10(2): e0117829. https://doi.org/10.1371/journal.pone.0117829
Academic Editor: Shervin Assassi, University of Texas Health Science Center at Houston, UNITED STATES
Received: September 29, 2014; Accepted: December 31, 2014; Published: February 17, 2015
Copyright: © 2015 Katzen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Data Availability: All relevant data are within the paper and its tables.
Funding: Funding from the U.S. Department of Health and Human Services-National Institutes of Health-National Cancer Institute (P30CA060553). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Systemic sclerosis (SSc) is a connective tissue disorder characterized by immune dysregulation and accumulation of extracellular matrix constituents resulting in organ dysfunction.[1] Pulmonary involvement is the leading cause of SSc-related mortality. However, cancers as causes of morbidity and mortality are of increasing interest.[2]
A number of population-based SSc cohort studies have reported a significant increase in lung cancer rates; the largest North American study noted an increase that did not reach statistical significance.[3–5] Three recent meta-analyses concluded that patients with SSc have 3–4 fold greater risk of developing lung cancer with males having a higher standardized incident ratio than females.[6–8]
Prior studies of SSc associated lung cancer have identified the presence of the Scl-70 antibody and interstitial lung disease (ILD) as potential risk factors for lung cancer.[9–11] However, radiographic abnormalities and details of pulmonary function testing (PFTs) were not reported. Previous studies describing the histopathology have reported one third to one half of cancers are adenocarcinomas, however, no studies have described the molecular profiles of these cancers, stage at presentation, or outcome.[9,10]
In this cross-sectional analysis, we identify 17 patients with SSc and lung cancer and provide the first description of the immunohistochemical and molecular profile of SSc associated lung cancers.[12,13] In addition, we report the stage of lung cancer at presentation and outcome. Potential risk factors for the development of lung cancer are re-examined, and an analysis of chest imaging and pulmonary function is undertaken.
Materials and Methods
Case ascertainment
The Northwestern University Institutional Review Board granted study approval (STU00075739) and waived the need for informed consent because of the retrospective nature of the study and the data were analyzed anonymously. The Northwestern Memorial Healthcare Electronic Data Warehouse (EDW), an electronic repository of health data, was queried for patients >18 years old with ICD-9 diagnostic codes for SSc or SSc related conditions and for lung cancer or pulmonary nodules. The charts identified were reviewed for confirmation of a diagnosis of SSc by a board certified rheumatologist using the American College of Rheumatology criteria for classification of SSc.[14] Patients with mixed connective tissue disease and localized forms of SSc were excluded from analysis. In cases with slides available for review, lung cancers were confirmed by a board certified pathologist (KR) with expertise in pulmonary pathology. In three additional cases, lung cancers were confirmed by review of pathology reports. Those patients meeting both the criteria for SSc and lung cancer were included as cases.
Data collection
Data abstracted from the medical record included demographics, date of SSc disease onset as defined by first non-Raynaud’s phenomenon diseases manifestation, date of lung cancer diagnosis defined as the date of pathologic diagnosis, chest computed tomography (CT) reports, pulmonary function tests (PFT), serologic markers for SSc, tobacco history (> 5 pack year) and exposure history. PFTs done at Northwestern Memorial Hospital (NMH) were performed in accordance with the American Thoracic Society/European Respiratory Society (ATS/ERS) criteria.[15] All PFT data were reviewed by a board certified pulmonologist (JED) and interpreted according to the ATS/ERS guidelines for interpretation.[16] Chest CT scans were reviewed by a pulmonary radiologist (RA) and classified based on ATS/ERS criteria as consistent with nonspecific interstitial pneumonitis (NSIP), usual interstitial pneumonitis with honeycomb fibrosis (UIP), fibrosis not otherwise specified (nos), or emphysema.[17] Histopathologic and immunohistochemical data were reviewed by a pathologist with an expertise in pulmonary disease in cases with available primary data. Adenocarcinomas were classified according to the International Association for the Study of Lung Cancer (IASLC)/ATS/ERS International Multidisciplinary Lung Adenocarcinoma Classification.[18] The mutational analysis was performed on the deoxyribonucleic acid (DNA) samples extracted from surgically resected, biopsied, or cytologic specimens of lung adenocarcinomas by polymerase chain reaction (PCR) and TrimGens’s Shifted Termination Assay (TrimGens, Sparks, MD) for Kirsten-RAS (KRAS) and Qiagen pyromark 24 sequencer (Valencia, CA) for epidermal growth factor receptor (EGFR) analysis.[19,20]
Statistical Methods
Descriptive statistics were applied. Means, medians, standard deviations and ranges were reported for numeric date. Categorical data were summarized using frequencies and proportions. Risk factors were assessed by comparison between cases and the Northwestern Scleroderma Patient Registry (579 patients). Cancer characteristics were compared with data from the National Institutes of Health, National Cancer Institute, SEER Cancer Statistics (NCI SEER).[21] Proportions were compared using two tailed Fisher Exact Test. Results were exploratory and no attempt to control for Type I error was made.
Results
Demographics
Initial EDW query identified 301 cases meeting criteria for review, and of these 112 cases had lung cancer. Eighty of these cases had Raynaud’s syndrome without SSc, 24 had localized scleroderma, and 8 had other non-SSc connective tissue diseases. Seventeen met the inclusion criteria, 14 females (82%) and 3 males (Table 1). Eight of the 17 cases were in the Northwestern Scleroderma Patient Registry, and 16/17 were seen in the Northwestern Scleroderma Program. The prevalence of lung cancer in the registry was 8/579 (1.4%). The mean age of SSc onset was 48.1 ±12.8 years and the mean age at lung cancer diagnosis was 63.1 ± 8.4 years. In two patients the lung cancer diagnosis predated SSc onset, and in the remaining patients SSc onset preceded lung cancer by 17.3 years (range 2.0 to 43.1 years).
A history of smoking was identified in 11/17 cases (64.7%) compared with 43% of patients in the registry (p = 0.09). The average exposure was 37.6± 22.8 pack-years (py). Three patients were actively smoking at the time of lung cancer diagnosis; the remainder had stopped between 2 and 29 years prior to diagnosis. Two patients had occupational exposure to chemical solvents. One patient received chemotherapy for lymphoma and one had radiation and chemotherapy for a head and neck cancer. Prior to cancer diagnosis, two patients had been treated with cyclophosphamide, one with a tumor necrosis factor inhibitor, one with azathioprine, and three with mycophenolate mofetil.
Systemic Sclerosis
Systemic sclerosis was classified as limited cutaneous (lc) in 13 cases (76%), diffuse cutaneous (dc) in 3 (18%) and SSc/polymyositis overlap in 1 (Table 1). This distribution of disease is similar to that in our SSc registry (63%, 36% and 1% for lc, dc and SSc/myositis overlap respectively) (p = 0.14). Results of serologic testing were available for 15 of 17 cases: 13/15 (87%) antinuclear antibody positive, 7/14 (50%) scl-70 antibody (Scl-70) positive, and 4/15 (27%) anticentromere antibody (ACA) positive. RNA Polymerase III antibody titer (RNA pol) was measured in 10 cases and was positive in 2 (20%). The distribution of positive serologic markers in our registry was 24%, 25% and 22% for ACA, Scl-70 and RNA pol respectively, similar to that reported in the literature.[22] The Scl-70 positive cases were significantly more in cases compared with our registry patients (p = 0.04).
Pulmonary Findings
Sixteen of 17 cases had chest CT imaging available for review, 15 were performed at NMH, 11 were high resolution chest CT (HRCT) (Table 2). The median number of CT scans prior to diagnosis was 3 (range 0–6). Independent review by a pulmonary radiologist identified scleroderma associated lung involvement in 12/15 cases: 9 classified as NSIP, 2 as UIP, 1 as combined fibrosis nos and emphysema (Fig. 1). Thirteen of 16 cases were found to have pulmonary nodules preceding the diagnosis of lung cancer; an additional 2 had cancers diagnosed based on the initial Chest CT scan, and in 1 case available imaging occurred after cancer resection.
All cases had PFTs available for review, 14 were performed at NMH. Six had restrictive impairments (mean forced vital capacity 59%+/-8.7 predicted, range 43–70%) with low diffusing capacity for carbon monoxide (Dlco). All of these cases had radiographic NSIP or UIP. Three cases had obstructive impairments with low DLco (mean forced expiratory volume at 1 second (FEV1) 55%+/-12.7 predicted, range 41–66%), 2 of whom had radiographic emphysema and 1 who had combined emphysema and fibrosis. Four cases had isolated reductions in DLco, 3 of these cases had NSIP and 1 had no radiographic images available. Four cases had normal PFTs, 1 had no radiographic abnormalities but 3 had NSIP. The DLco was reduced in 13 of 16 cases (44% predicted +/- 10.4). Of the six cases with radiographic NSIP who did not have restrictive physiology on PFTs at the time of cancer diagnosis, 2 subsequently developed restriction.
Cancers
Two of the cancers were discovered as incidental masses on imaging, 5 were incidental nodules followed over time, and 10 cases had imaging after complaint of worsening dyspnea, change in cough, or new weight loss. Thirteen of the cancers were adenocarcinoma, 1 adenosquamous, 1 squamous, 1 small cell, and 1 large cell neuroendocrine (Table 3). Of the patients with adenocarcinoma, 4 had a predominant lepidic pattern, 5 had an acinar predominant pattern, and 1 patient had adenocarcinoma with micropapillary features. TTF-1 immunostain was performed in 7 of the adenocarcinomas and stained tumor cells diffusely in 5, focally in 1, and was negative in 1 (Fig. 2). In the 7 resected lung cancers, 5 had visceral pleural invasion (4 stage Ib and 1 with IIIb). Tumor sizes ranged from 1.5 cm to 7.5 cm. Ten of 14 adenocarcinomas underwent molecular mutational profiling: 2/8 had KRAS mutation, 1/10 had EGFR mutation, and 0/5 had ALK rearrangement.
These tumor cells stain positive with TTF-1 (B).
Eight of the non-small cell lung cancers presented at stage I (50%), 3 at Ia and 5 at Ib disease. One case was stage IIb, 2 cases were stage III, and 5 cases were stage IV. NCI SEER data for cancers of the lung and bronchus diagnosed between 2004 and 2010 (n = 268,097) reported that 15% presented with localized disease (stage I or II), 22% with regional disease and 57% with distant metastases. Thus, significantly more of our cases (56%) presented with early stage, localized, disease (p = 0.01). Nine of the 16 cases were alive at the time of data collection, with all seven deaths attributed to progression of cancer or cancer therapy related death. The 5 years survival among the stage I cases that had completed follow-up for 5 years was 25% versus expected survival of 54%.
Discussion
The prevalence of lung cancer in the Northwestern Scleroderma Registry (1.4%) is at the lower range of previously published studies of SSc cohorts, but it is higher than the estimated 2011 prevalence in the US population (SEER). Lung cancer was diagnosed at a younger age than is reported in the SEER database (63yo vs 70yo). The high female predominance of cases likely reflects the high proportion of female patients enrolled in the Northwestern Scleroderma Registry (84% female). Only 65% of our cases had a smoking history, compared to an 80% smoking rate reported in females with lung cancer,[23] and not significantly higher than the smoking rate in our registry. This further supports SSc itself, independent of tobacco, as a risk factor for lung cancer.
Recent publications have shown associations between SSc serology and cancer risk, with the possibility of an immunologic mechanism linking autoantibodies to RNA poI and tumorigenesis.[24,25] The role of RNA pol has not been assessed in prior lung cancer studies. While the low rate of RNA pol measurement in our cohort limits analysis, we did not find a higher rate of this marker in our cases compared with patients in our registry or than reported in the literature. The Scl-70 antibody has also been explored as a risk factor for the development of lung cancer with variable results.[9,10] We did find a significantly higher proportion of positive Scl-70 in our cases than in our registry.
Interstitial lung disease has been reported as a risk factor for lung cancer development in some but not all SSc case series.[9–11] In our cases, a high proportion of patients had ILD, though not all demonstrated restrictive physiology on pulmonary function testing at the time of cancer diagnosis. Thus the high rate of radiographic ILD in our cases may reflect our practice of CT screening for ILD, resulting in recognition of either early ILD prior to the development of restrictive physiology on PFTs or very mild ILD that would otherwise not prompt diagnostic imaging. The variable results reported in the literature may thus reflect different practice patterns with respect to Chest CT screening. This may also be relevant to the stage of lung cancer at presentation in our cohort. Our cases were diagnosed at an earlier stage of disease compared with the general population of lung cancer as represented by the NCI SEER database. The percent of patients diagnosed in stage I (50%) is comparable to patients who underwent low dose Chest CT screening as part of the National Lung Screening Trial (NLST) wherein 58% were stage 1 at diagnosis.[26] Lung nodules were present on 81% of our patients’ CT scans prior to the diagnosis of cancer, and an additional 12.5% were diagnosed with lung cancer based on their initial CT scan. This highlights the importance of screening Chest CT scans in patients with SSc who are actively smoking or who have a history of smoking, and is an area that needs further investigation. Importantly, the NLST included only patients with a tobacco exposure of at least 30 py, an exposure only achieved in 7 of the 11 smokers in this study. While similar to the NSLT screened patients, lung cancers in our cases were found at an earlier stage, unfortunately, this did not confer a survival advantage as it did in the NLST study. In fact, SSc associated lung cancer seems to portend a worse prognosis as indicated by the 5 year survival rates in the early stage lung cancers in our cohort.
The histological pattern of the SSc associated lung cancer in the reported literature is mixed, with an equal predominance of adenocarcinoma and squamous cell carcinoma, and with few cases of small cell carcinoma.[7] In contrast, the majority of patients in our cohort had adenocarcinoma with a predominance of lepidic and acinar patterns. Chronic diffuse fibrotic lung diseases can often show areas of epithelial proliferations including honeycomb change and peribronchiolar metaplasia with and without atypia. These changes have been postulated as an underlying mechanism for the development of adenocarcinoma.[27] Indeed, differentiating these atypical epithelial proliferations from well-differentiated adenocarcinoma can be challenging and features such as monomorphic population with cytologic atypia, architecture complexity of the glandular proliferations, and an invasive growth pattern can be helpful in making an unequivocal diagnosis of adenocarcinoma in such cases. It may be speculated that the predominance of adenocarcinoma in our cases was due to the prevalence of underlying SSc associated inflammation and fibrosis as many of our patients had radiographic evidence of either NSIP or fibrosis on Chest CT scans. In another diffuse lung disease, idiopathic pulmonary fibrosis, an increased risk of lung cancer has been found[28] yet the predominant histopathology has not been adenocarcinoma.[29] Only one study showed a predominance of adenocarcinoma in a subset of cases whose cancers were located within a region of fibrotic lung.[30]
This is the first report of molecular markers in SSc associated lung cancers. The rate of KRAS mutation (2/8) is consistent with the rate of KRAS mutation found in adenocarcinomas in our institution.[31] Only 1/10 had EGFR mutation, which is also in keeping with the expected rate.[32] However interpretation of this data is limited by the small number of cases with molecular markers performed.
Conclusion
Patients with SSc are at increased risk for the development of lung cancer. While the lung cancers in our cases were diagnosed at an early stage, likely due to the practice of screening for ILD, this did not confer a survival advantage; indeed mortality was higher than anticipated in those with stage I cancers. While our results need to be further explored, they do suggest that screening CT scans should be undertaken for all smokers or former smokers regardless of pack year history and that aggressive follow-up of pulmonary nodules in patients with SSc, regardless of tobacco history, is warranted. The high proportion of adenocarcinoma seen in our study is surprising and different from that reported in the literature. Molecular profiling appears to be similar to lung cancers in general.
Acknowledgments
We would like to thank the Northwestern Scleroderma Patient Registry patients and coordinators.
Author Contributions
Analyzed the data: JED AR. Wrote the paper: JBK JED. Designed the study: JBK JED JV JDP. Collected data: JBK JED RA KR.
References
- 1. Gabrielli A, Avvedimento EV, Krieg T (2009) Scleroderma. N Engl J Med 360: 1989–2003. pmid:19420368
- 2. Tyndall AJ, Bannert B, Vonk M, Airo P, Cozzi F, et al. (2010) Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis 69: 1809–1815. pmid:20551155
- 3. Olesen AB, Svaerke C, Farkas DK, Sorensen HT (2010) Systemic sclerosis and the risk of cancer: a nationwide population-based cohort study. Br J Dermatol 163: 800–806. pmid:20854403
- 4. Kuo CF, Luo SF, Yu KH, Chou IJ, Tseng WY, et al. (2012) Cancer risk among patients with systemic sclerosis: a nationwide population study in Taiwan. Scand J Rheumatol 41: 44–49. pmid:22150162
- 5. Derk CT, Rasheed M, Artlett CM, Jimenez SA (2006) A cohort study of cancer incidence in systemic sclerosis. J Rheumatol 33: 1113–1116. pmid:16622904
- 6. Zhang JQ, Wan YN, Peng WJ, Yan JW, Li BZ, et al. (2013) The risk of cancer development in systemic sclerosis: a meta-analysis. Cancer Epidemiol 37: 523–527. pmid:23725641
- 7. Bonifazi M, Tramacere I, Pomponio G, Gabrielli B, Avvedimento EV, et al. (2013) Systemic sclerosis (scleroderma) and cancer risk: systematic review and meta-analysis of observational studies. Rheumatology (Oxford) 52: 143–154. pmid:23175568
- 8. Onishi A, Sugiyama D, Kumagai S, Morinobu A (2013) Cancer incidence in systemic sclerosis: meta-analysis of population-based cohort studies. Arthritis Rheum 65: 1913–1921. pmid:23576072
- 9. Colaci M, Giuggioli D, Sebastiani M, Manfredi A, Vacchi C, et al. (2013) Lung cancer in scleroderma: results from an Italian rheumatologic center and review of the literature. Autoimmun Rev 12: 374–379. pmid:22743031
- 10. Pontifex EK, Hill CL, Roberts-Thomson P (2007) Risk factors for lung cancer in patients with scleroderma: a nested case-control study. Ann Rheum Dis 66: 551–553. pmid:16984943
- 11. Peters-Golden M, Wise RA, Hochberg M, Stevens MB, Wigley FM (1985) Incidence of lung cancer in systemic sclerosis. J Rheumatol 12: 1136–1139. pmid:4093920
- 12. D’Angelo SP, Janjigian YY, Ahye N, Riely GJ, Chaft JE, et al. (2012) Distinct clinical course of EGFR-mutant resected lung cancers: results of testing of 1118 surgical specimens and effects of adjuvant gefitinib and erlotinib. J Thorac Oncol 7: 1815–1822. pmid:23154553
- 13. Roberts PJ, Stinchcombe TE, Der CJ, Socinski MA (2010) Personalized medicine in non-small-cell lung cancer: is KRAS a useful marker in selecting patients for epidermal growth factor receptor-targeted therapy? J Clin Oncol 28: 4769–4777. pmid:20921461
- 14. (1980) Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum 23: 581–590. pmid:7378088
- 15. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, et al. (2005) Standardisation of spirometry. Eur Respir J 26: 319–338. pmid:16055882
- 16. Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, et al. (2005) Interpretative strategies for lung function tests. Eur Respir J 26: 948–968. pmid:16264058
- 17. American Thoracic S, European Respiratory S (2002) American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med 165: 277–304. pmid:11790668
- 18. Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, et al. (2011) International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 6: 244–285. pmid:21252716
- 19. Dufort S, Richard MJ, de Fraipont F (2009) Pyrosequencing method to detect KRAS mutation in formalin-fixed and paraffin-embedded tumor tissues. Anal Biochem 391: 166–168. pmid:19464247
- 20. Rho JK, Choi YJ, Lee JK, Ryoo BY, Na II, et al. (2009) The role of MET activation in determining the sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors. Mol Cancer Res 7: 1736–1743. pmid:19808904
- 21.
Howlader N, Noone A.M., Krapcho M., Garshell J., Miller D., Altekruse S.F., Kosary C.L., Yu M., Ruhl J., Tatalovich Z., Mariotto A., Lewis D.R., Chen H.S., Feuer E.J., Cronin K.A. (eds) (2011) Surveillance, Epidemiology, and End Results (SEER) Cancer Statistics Review, 1975–2011. Bethesda, Md.: National Institutes of Health, National Cancer Institute. https://doi.org/10.1016/j.healun.2014.01.862 pmid:24630406
- 22. Reveille JD, Solomon DH, American College of Rheumatology Ad Hoc Committee of Immunologic Testing G (2003) Evidence-based guidelines for the use of immunologic tests: anticentromere, Scl-70, and nucleolar antibodies. Arthritis Rheum 49: 399–412. pmid:12794797
- 23.
(2004). The Health Consequences of Smoking: A Report of the Surgeon General. Atlanta (GA). pmid:20669512
- 24. Moinzadeh P, Fonseca C, Hellmich M, Shah AA, Chighizola C, et al. (2014) Association of anti-RNA polymerase III autoantibodies and cancer in scleroderma. Arthritis Res Ther 16: R53. pmid:24524733
- 25. Joseph CG, Darrah E, Shah AA, Skora AD, Casciola-Rosen LA, et al. (2014) Association of the autoimmune disease scleroderma with an immunologic response to cancer. Science 343: 152–157. pmid:24310608
- 26. National Lung Screening Trial Research T, Church TR, Black WC, Aberle DR, Berg CD, et al. (2013) Results of initial low-dose computed tomographic screening for lung cancer. N Engl J Med 368: 1980–1991. pmid:23697514
- 27. Vancheri C, Failla M, Crimi N, Raghu G (2010) Idiopathic pulmonary fibrosis: a disease with similarities and links to cancer biology. Eur Respir J 35: 496–504. pmid:20190329
- 28. Hubbard R, Venn A, Lewis S, Britton J (2000) Lung cancer and cryptogenic fibrosing alveolitis. A population-based cohort study. Am J Respir Crit Care Med 161: 5–8. pmid:10619790
- 29. Aubry MC, Myers JL, Douglas WW, Tazelaar HD, Washington Stephens TL, et al. (2002) Primary pulmonary carcinoma in patients with idiopathic pulmonary fibrosis. Mayo Clin Proc 77: 763–770. pmid:12173712
- 30. Park J, Kim DS, Shim TS, Lim CM, Koh Y, et al. (2001) Lung cancer in patients with idiopathic pulmonary fibrosis. Eur Respir J 17: 1216–1219. pmid:11491167
- 31. Raparia K, Villa C, Raj R, Cagle PT (2014) Peripheral Lung Adenocarcinomas With KRAS Mutations Are More Likely to Invade Visceral Pleura. Arch Pathol Lab Med. pmid:25521803
- 32. Villa C, Cagle PT, Johnson M, Patel JD, Yeldandi AV, et al. (2014) Correlation of EGFR Mutation Status With Predominant Histologic Subtype of Adenocarcinoma According to the New Lung Adenocarcinoma Classification of the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society. Arch Pathol Lab Med. pmid:25594725