EGFR mutational status of primary Lung Adenocarcinoma in an Indian cohort based on 2015 WHO classification of lung tumors.
Keywords:
EGFR mutation, Lung cancer, Histology, Adenocarcinoma, WHO classification, India.Abstract
Background: Epidermal growth factor receptor (EGFR) mutations have been known to be associated with adenocarcinoma, women, non- smokers and East-Asian ethnicity. This study was aimed to characterize the frequency of EGFR mutations and their association with histologic subtypes in primary lung adenocarcinoma in an Indian cohort.
Methods: Two seventy-four cases were categorized using 2015 WHO classification of lung tumors. The frequency of each histologic subtype and cell type was correlated with EGFR exon sequences in a subset of 120 cases using polymerase chain reaction (PCR) gene sequencing.
Results: The predominant biopsy categories in 274 cases were acinar 167(61%), solid 63(23%), mucinous 19(7%), lepidic 11(4%) and others 14(5%). EGFR mutations were detected in 49/120 (40.8%) including 3/5(60%) lepidic, 4/9(44.4%) papillary, 29/68(42.7%) acinar, 10/24(41.7%) solid and 1/13(7.7%) mucinous subtypes and were significantly associated with the cuboidal cell type (p=0.01). These mutations were common in women and non-smokers, although not statistically significant. Exon 19 mutations predominated in 36/49(73.4%). The majority, 213/263 (81%), were thyroid transcription factor 1(TTF-1) positive. The polygonal cell type and the solid subtype were frequent amongst stage IV tumors and smokers.
Conclusions: EGFR mutations were most frequently seen with the lepidic and papillary subtypes, not associated with the mucinous subtype, more common in women and non-smokers and significantly associated with the cuboidal cell type.
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DOI:Â 10.21276/APALM.1372
References
1. Behera D. Epidemiology of lung cancer-Global and Indian perspective. J Indian Acad Clin Med. 2012;13:131–7.
2. Pikor LA, Ramnarine VR, Lam S, Lam WL. Genetic alterations defining NSCLC subtypes and their therapeutic implications. Lung Cancer Amst Neth. 2013 Nov;82(2):179–89.
3. Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger K, Yatabe Y, et al. Diagnosis of Lung Cancer in Small Biopsies and Cytology: Implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society Classification. Arch Pathol Lab Med. 2013 May;137(5):668–84.
4. Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger K, Yatabe Y, et al. Diagnosis of Lung Adenocarcinoma in Resected Specimens: Implications of the 2011 International Association for
the Study of Lung Cancer/American Thoracic Society/European Respiratory Society Classification. Arch Pathol Lab Med. 2013 May;137(5):685–705.
5. Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB, et al. The 2015 World Health Organization Classification of Lung Tumors. J Thorac Oncol. 2015 Sep 1;10(9):1243–60.
6. Travis WD. Pathology & Genetics: Tumours of the Lung, Pleura, Thymus, and Heart [Internet]. Vol. 7. Iarc; 2004 [cited 2013 Nov 15].
7. Tsao M-S, Sakurada A, Cutz J-C, Zhu C-Q, Kamel-Reid S, Squire J, et al. Erlotinib in lung cancer—molecular and clinical predictors of outcome. N Engl J Med. 2005;353(2):133–144.
8. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, et al. AJCC cancer staging manual. 2010. Vol 17th Ed N Y Springer. 2010;
9. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004 May 20;350(21):2129–39.
10. Bhatt AD, Pai R, Rebekah G, Nehru GA, Dhananjayan S, Samuel A, et al. Clinicopathologic features of non-small cell lung cancer in India and correlation with epidermal growth factor receptor mutational status. Indian J Cancer. 2013 Jun;50(2):94–101.
11. Maturu VN, Singh N, Bal A, Gupta N, Das A, Behera D. Relationship of epidermal growth factor receptor activating mutations with histologic subtyping according to International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society 2011 adenocarcinoma classification and their impact on overall survival. Lung India Off Organ Indian Chest Soc. 2016;33(3):257.
12. Sahoo R, Harini VV, Babu VC, Patil Okaly GV, Rao S, Nargund A, et al. Screening for EGFR mutations in lung cancer, a report from India. Lung Cancer Amst Neth. 2011 Sep;73(3):316–9.
13. Veldore VH, Rao RM, Kakara S, Pattanayak S, Tejaswi R, Sahoo R, et al. Epidermal growth factor receptor mutation in non-small-cell lung carcinomas: a retrospective analysis of 1036 lung cancer specimens from a network of tertiary cancer care centers in India. Indian J Cancer. 2013 Jun;50(2):87–93.
14. Moorjani P, Thangaraj K, Patterson N, Lipson M, Loh P-R, Govindaraj P, et al. Genetic evidence for recent population mixture in India. Am J Hum Genet. 2013;93(3):422–438.
15. Raparia K, Villa C, DeCamp MM, Patel JD, Mehta MP. Molecular profiling in non-small cell lung cancer: a step toward personalized medicine. Arch Pathol Lab Med. 2013 Apr;137(4):481–91.
16. Motoi N, Szoke J, Riely GJ, Seshan VE, Kris MG, Rusch VW, et al. Lung adenocarcinoma: modification of the 2004 WHO mixed subtype to include the major histologic subtype suggests correlations between papillary and micropapillary adenocarcinoma subtypes, EGFR mutations and gene expression analysis. Am J Surg Pathol. 2008;32(6):810.
17. Yoshizawa A, Sumiyoshi S, Sonobe M, Kobayashi M, Fujimoto M, Kawakami F, et al. Validation of the IASLC/ATS/ERS lung adenocarcinoma classification for prognosis and association with EGFR and KRAS gene mutations: analysis of 440 Japanese patients. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer. 2013 Jan;8(1):52–61.
18. Sun P-L, Seol H, Lee HJ, Yoo SB, Kim H, Xu X, et al. High incidence of EGFR mutations in Korean men smokers with no intratumoral heterogeneity of lung adenocarcinomas: correlation with histologic subtypes, EGFR/TTF-1 expressions, and clinical features. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer. 2012 Feb;7(2):323–30.
19. Tsao M-S, Marguet S, Le Teuff G, Lantuejoul S, Shepherd FA, Seymour L, et al. Subtype classification of lung adenocarcinoma predicts benefit from adjuvant chemotherapy in patients undergoing complete resection. J Clin Oncol. 2015;33(30):3439–3446.
20. D’Angelo SP, Pietanza MC, Johnson ML, Riely GJ, Miller VA, Sima CS, et al. Incidence of EGFR exon 19 deletions and L858R in tumor specimens from men and cigarette smokers with lung adenocarcinomas. J Clin Oncol. 2011;29(15):2066–2070.
21. Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac Oncol. 2013;8(7):823–859.
22. Leary AF, de Castro DG, Nicholson AG, Ashley S, Wotherspoon A, O’Brien ME, et al. Establishing an EGFR mutation screening service for non-small cell lung cancer–Sample quality criteria and candidate histological predictors. Eur J Cancer. 2012;48(1):61–67.
23. Okada A, Shimmyo T, Hashimoto T, Kobayashi Y, Miyagi Y, Ishikawa Y, et al. Predictive advantage of a cell type classification for pulmonary adenocarcinoma coupled with data for p53, K-ras and EGFR alterations. Cancer Sci. 2010 Jul 1;101(7):1745–53.
24. Yoshizawa A, Motoi N, Riely GJ, Sima CS, Gerald WL, Kris MG, et al. Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases. Mod Pathol Off J U S Can Acad Pathol Inc. 2011 May;24(5):653–64.
2. Pikor LA, Ramnarine VR, Lam S, Lam WL. Genetic alterations defining NSCLC subtypes and their therapeutic implications. Lung Cancer Amst Neth. 2013 Nov;82(2):179–89.
3. Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger K, Yatabe Y, et al. Diagnosis of Lung Cancer in Small Biopsies and Cytology: Implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society Classification. Arch Pathol Lab Med. 2013 May;137(5):668–84.
4. Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger K, Yatabe Y, et al. Diagnosis of Lung Adenocarcinoma in Resected Specimens: Implications of the 2011 International Association for
the Study of Lung Cancer/American Thoracic Society/European Respiratory Society Classification. Arch Pathol Lab Med. 2013 May;137(5):685–705.
5. Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB, et al. The 2015 World Health Organization Classification of Lung Tumors. J Thorac Oncol. 2015 Sep 1;10(9):1243–60.
6. Travis WD. Pathology & Genetics: Tumours of the Lung, Pleura, Thymus, and Heart [Internet]. Vol. 7. Iarc; 2004 [cited 2013 Nov 15].
7. Tsao M-S, Sakurada A, Cutz J-C, Zhu C-Q, Kamel-Reid S, Squire J, et al. Erlotinib in lung cancer—molecular and clinical predictors of outcome. N Engl J Med. 2005;353(2):133–144.
8. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, et al. AJCC cancer staging manual. 2010. Vol 17th Ed N Y Springer. 2010;
9. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004 May 20;350(21):2129–39.
10. Bhatt AD, Pai R, Rebekah G, Nehru GA, Dhananjayan S, Samuel A, et al. Clinicopathologic features of non-small cell lung cancer in India and correlation with epidermal growth factor receptor mutational status. Indian J Cancer. 2013 Jun;50(2):94–101.
11. Maturu VN, Singh N, Bal A, Gupta N, Das A, Behera D. Relationship of epidermal growth factor receptor activating mutations with histologic subtyping according to International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society 2011 adenocarcinoma classification and their impact on overall survival. Lung India Off Organ Indian Chest Soc. 2016;33(3):257.
12. Sahoo R, Harini VV, Babu VC, Patil Okaly GV, Rao S, Nargund A, et al. Screening for EGFR mutations in lung cancer, a report from India. Lung Cancer Amst Neth. 2011 Sep;73(3):316–9.
13. Veldore VH, Rao RM, Kakara S, Pattanayak S, Tejaswi R, Sahoo R, et al. Epidermal growth factor receptor mutation in non-small-cell lung carcinomas: a retrospective analysis of 1036 lung cancer specimens from a network of tertiary cancer care centers in India. Indian J Cancer. 2013 Jun;50(2):87–93.
14. Moorjani P, Thangaraj K, Patterson N, Lipson M, Loh P-R, Govindaraj P, et al. Genetic evidence for recent population mixture in India. Am J Hum Genet. 2013;93(3):422–438.
15. Raparia K, Villa C, DeCamp MM, Patel JD, Mehta MP. Molecular profiling in non-small cell lung cancer: a step toward personalized medicine. Arch Pathol Lab Med. 2013 Apr;137(4):481–91.
16. Motoi N, Szoke J, Riely GJ, Seshan VE, Kris MG, Rusch VW, et al. Lung adenocarcinoma: modification of the 2004 WHO mixed subtype to include the major histologic subtype suggests correlations between papillary and micropapillary adenocarcinoma subtypes, EGFR mutations and gene expression analysis. Am J Surg Pathol. 2008;32(6):810.
17. Yoshizawa A, Sumiyoshi S, Sonobe M, Kobayashi M, Fujimoto M, Kawakami F, et al. Validation of the IASLC/ATS/ERS lung adenocarcinoma classification for prognosis and association with EGFR and KRAS gene mutations: analysis of 440 Japanese patients. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer. 2013 Jan;8(1):52–61.
18. Sun P-L, Seol H, Lee HJ, Yoo SB, Kim H, Xu X, et al. High incidence of EGFR mutations in Korean men smokers with no intratumoral heterogeneity of lung adenocarcinomas: correlation with histologic subtypes, EGFR/TTF-1 expressions, and clinical features. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer. 2012 Feb;7(2):323–30.
19. Tsao M-S, Marguet S, Le Teuff G, Lantuejoul S, Shepherd FA, Seymour L, et al. Subtype classification of lung adenocarcinoma predicts benefit from adjuvant chemotherapy in patients undergoing complete resection. J Clin Oncol. 2015;33(30):3439–3446.
20. D’Angelo SP, Pietanza MC, Johnson ML, Riely GJ, Miller VA, Sima CS, et al. Incidence of EGFR exon 19 deletions and L858R in tumor specimens from men and cigarette smokers with lung adenocarcinomas. J Clin Oncol. 2011;29(15):2066–2070.
21. Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac Oncol. 2013;8(7):823–859.
22. Leary AF, de Castro DG, Nicholson AG, Ashley S, Wotherspoon A, O’Brien ME, et al. Establishing an EGFR mutation screening service for non-small cell lung cancer–Sample quality criteria and candidate histological predictors. Eur J Cancer. 2012;48(1):61–67.
23. Okada A, Shimmyo T, Hashimoto T, Kobayashi Y, Miyagi Y, Ishikawa Y, et al. Predictive advantage of a cell type classification for pulmonary adenocarcinoma coupled with data for p53, K-ras and EGFR alterations. Cancer Sci. 2010 Jul 1;101(7):1745–53.
24. Yoshizawa A, Motoi N, Riely GJ, Sima CS, Gerald WL, Kris MG, et al. Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases. Mod Pathol Off J U S Can Acad Pathol Inc. 2011 May;24(5):653–64.
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25-10-2017
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Ravi PY, Korula A, Jeyaseelan V, Sakthi D, Pai R. EGFR mutational status of primary Lung Adenocarcinoma in an Indian cohort based on 2015 WHO classification of lung tumors. Ann of Pathol and Lab Med [Internet]. 2017 Oct. 25 [cited 2024 Nov. 19];4(5):A487-495. Available from: https://pacificejournals.com/journal/index.php/apalm/article/view/apalm1372
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Copyright (c) 2017 Priyanka Yogendra Ravi, Anila Korula, Visalakshi Jeyaseelan, Dhananjayan Sakthi, Rekha Pai
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