Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 1  |  Page : 240-244

Correlation between epidermal growth factor receptor mutation and histologic subtypes or characteristics of computed tomography findings in patients with resected pulmonary adenocarcinoma


1 Department of Thoracic Surgery, Jinan Center Hospital Affiliated Shandong University, Shandong 250013, P.R. China
2 Department of Urology, Jinan Center Hospital of Jinan, Jinan, Shandong 250013, P.R. China
3 Department of Thoracic Surgery, Qianfo Shan Hospital of Shandong, Jinan, Shandong 250021, P.R. China
4 Department of Anesthesiology, Jinan Center Hospital of Jinan, Jinan, Shandong 250013, P.R. China
5 Department of Thoracic Surgery, Provincial Hospital Affiliated Shandong University, Shandong University, Jinan, Shandong 250021, P.R. China

Date of Web Publication8-Mar-2018

Correspondence Address:
Dr. Zhongmin Peng
Department of Thoracic Surgery, Provincial Hospital Affiliated to Shandong University, Shandong University, 324 Jingwu Road, Jinan, Shandong 250021
P.R. China
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.183178

Rights and Permissions
 > Abstract 

Objective: To investigate the correlation between epidermal growth factor receptor (EGFR) mutation and the histologic subtypes features or computed tomography (CT) findings in patients with resected pulmonary adenocarcinoma.
Materials and Methods: We retrospectively reviewed 153 patients underwent surgical resected pulmonary adenocarcinoma. EGFR mutations were detected using the amplification refractory mutation system. Histologic subtype was classified according to the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society pulmonary adenocarcinoma classification. Characteristics of CT in the tumor were retrospectively analyzed, and compared to mutation-negative cohort.
Results: EGFR mutations were found in 67 (43.79%) cases. The prevalent histologic subtypes of invasive adenocarcinoma were acinar predominant adenocarcinoma (33.99%), papillary predominant adenocarcinoma (24.18%), micropapillary predominant adenocarcinoma (MPA; 18.95%), solid predominant adenocarcinoma (11.76%), and lepidic predominant adenocarcinoma (LPA; 11.11%). EGFR mutations were correlated with the MPA and LPA subtypes (P = 0.009 and P = 0.018) and was correlated with the air bronchograms (P = 0.008). EGFR mutations were independently associated with other CT characteristics including ground-glass opacity/tumor ratio (P = 0.054).
Conclusions: Correlation exists between EGFR mutations and histologic subtypes of invasive adenocarcinoma or air bronchograms on CT images, which could use to predict EGFR mutation status in patients with pulmonary adenocarcinoma.

Keywords: Computed tomography, epidermal growth factor receptor mutation, International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification, pulmonary adenocarcinoma


How to cite this article:
Wang D, Yan N, Yang X, Ge Y, Xu D, Shao G, Peng Z. Correlation between epidermal growth factor receptor mutation and histologic subtypes or characteristics of computed tomography findings in patients with resected pulmonary adenocarcinoma. J Can Res Ther 2018;14:240-4

How to cite this URL:
Wang D, Yan N, Yang X, Ge Y, Xu D, Shao G, Peng Z. Correlation between epidermal growth factor receptor mutation and histologic subtypes or characteristics of computed tomography findings in patients with resected pulmonary adenocarcinoma. J Can Res Ther [serial online] 2018 [cited 2021 Jun 24];14:240-4. Available from: https://www.cancerjournal.net/text.asp?2018/14/1/240/183178


 > Introduction Top


Lung and bronchus cancer is a common malignant tumor and a major public health problem worldwide.[1] In 2014, there were an estimated 224,210 new cases with lung and bronchus cancer in the United States and an estimated 159,260 cases death.[1] China is the most populous country of lung cancer in the world; it contains 19% of the world population with 35.78% of all newly diagnosed lung cancer cases and 37.56% of lung cancer deaths worldwide.[2],[3] It is estimated that in 2015, the total number of new cases of lung cancer will reach 733,300.[2] Pulmonary adenocarcinoma accounts for approximately 45% of all lung cancers.[4]

It was thought that the major cause of pulmonary adenocarcinoma is gene mutations, including epidermal growth factor receptor (EGFR), anaplastic large cell lymphoma (anaplastic lymphoma kinase) fusion gene, K-ras oncogene.[5],[6] Those discovery provides new therapeutic strategies for lung cancer. Important progress was made by using the EGFR-tyrosine kinase inhibitor (TKI) for treating the pulmonary adenocarcinoma harboring EGFR-activating mutations.[6],[7] This was supported by results from the Iressa Pan-Asia Study clinical trial.[8]

It was demonstrated that pulmonary adenocarcinoma harboring EGFR-activating mutations are correlated with clinical characteristics such as smoking status, gender, and ethnicity.[9],[10] Since the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS) and European Respiratory Society (ERS) reported a new lung adenocarcinoma classification (IASLC/ATS/ERS classification), several groups have validated its association with prognosis in early stage disease.[11] The new histologic classification was intended to incorporate our knowledge in oncologic, biologic, radiologic, surgical, and pathologic management to better favoring the diagnosis and treatment of lung adenocarcinoma. There have been a few studies evaluating the correlation between radiologic characteristics of pulmonary adenocarcinoma and EGFR mutations.[5],[6],[7] However, the relationship between EGFR mutation and the histologic subtypes of pulmonary adenocarcinoma according to the new classification is unclear. Furthermore, it is unclear whether a correlation exists between EGFR-activating mutations and computed tomography (CT) characteristics of patients who underwent surgical resected pulmonary adenocarcinoma.

To clarify the correlation between EGFR mutations and radiologic or histologic features in patients who underwent surgical resected pulmonary adenocarcinoma, we performed this retrospective study.


 > Materials and Methods Top


Patient eligibility

From January 2012 to December 2014, we consecutively collected 153 specimens from patients resected with pulmonary adenocarcinoma at Department of Thoracic Surgery in Shandong University. Histological subtypes were determined according to IASLC/ATS/ERS classification.[11] Lung cancer staging was performed for all patients according to the seventh tumor node metastasis staging classification.[12],[13] The tumor histology and tumor content in all cases were reviewed and confirmed by at least two pathologists. Subjects eligible in this study had to meet the following criteria: pathologically confirmed lung adenocarcinoma and sufficient tissue for comprehensive mutational analyses. This study was approved by the Institutional Review Board of Provincial Hospital Affiliated Shandong University. Written informed consent was obtained from all patients.

Histological evaluation

All resected specimens were formalin fixed, stained with hematoxylin and eosin in the routine manner. Each of the slides was examined independently by three specialists. Histological classification was according to the IASLC/ATS/ERS classification of lung adenocarcinoma. According to the IASLC/ATS/ERS criteria, each tumor was reviewed using comprehensive histologic subtype, recording the percentage in 5% increments for each histologic component. Tumors were classified as adenocarcinomas in situ (AIS), minimally invasive adenocarcinomas (MIA), and invasive adenocarcinomas. In which, invasive adenocarcinomas were further subdivided into lepidic predominant adenocarcinoma (LPA), papillary predominant adenocarcinoma (PPA), acinar predominant adenocarcinoma (APA), micropapillary predominant adenocarcinoma (MPA), solid predominant adenocarcinoma (SPA), invasive mucinous adenocarcinoma and others (including colloid adenocarcinoma and fetal adenocarcinoma). The predominant pattern is defined as the one with the largest percentage.

Computed tomography findings

CT was performed using helical or multi-detector scanners. Conventional CT images were obtained serially with 7–10 mm section thickness and 7–10 mm section spacing. High-resolution images targeted to the tumor were obtained serially with 1–2-mm section thickness and 1–2 mm section spacing. All CT images were reviewed by two independent clinicians who were unaware of the status of histologic subtype and EGFR mutation. Ground-glass opacity (GGO) was defined as a hazy increase in lung attenuation, without obscuring the underlying bronchial or vascular structures.[14] The GGO ratio of the tumor (GGO/tumor ratio; G/T ratio) was calculated as (Dggo− Dsol)/Dggo, where Dggo was the largest area of the tumor including the GGO, and Dsol was the largest solid area of the tumor excluding the GGO.[15] Discrepancies between the observers were resolved by discussion and recording of the measurements agreed. In addition, the presence of obvious pleural indentations or concave, spicula, lobulation or notch, and vascular convergences were assessed.

Epidermal growth factor receptor mutation analysis

Tumor samples were obtained. After tumor DNA extraction, molecular analysis of EGFR was performed using the amplification refractory mutation system with formalin-fixed paraffin embedded archival tissue blocks obtained during surgical excision of the tumors. The examination was followed the methods of Newton et al.[16]

Statistical analysis

Associations between mutations and histologic or radiologic features were analyzed by using the Pearson's Chi-squared test or Fisher's exact test. Characteristics associated with mutations with P < 0.05 were included in a multivariate logistic model. All the statistical analyses were conducted in the SPSS 20.0 for Windows (SPSS Inc., Chicago, IL, USA). P <0.05 were considered statistically significant.


 > Results Top


Clinicopathological characteristics of patients

The clinicopathological characteristics of the patients are shown in [Table 1]. The mean age was 58.5 ± 12.5 years in the current cohort. There were 66 men and 87 women. Of the 153 patients, 97 patients were never smokers, and 56 were former or current smokers. Sixty-seven patients were found to harbor EGFR mutation, accounting for 43.79% of all the cases. In the present cohort, none of the specimens met the criteria proposed for AIS and MIA. Of the 153 invasive adenocarcinoma cases, 38 were PPA, 52 were APA, 29 were MPA, 18 were SPA, 17 were LPA subtypes. The prevalent histologic subtypes of invasive adenocarcinoma were APA (34%), PPA (24%), MPA (19%), SPA (12%), and LPA (11%).
Table 1: Clinicopathological characteristics in patients with lung adenocarcinoma of patients

Click here to view


Correlation between epidermal growth factor receptor mutation and clinicopathologic characteristics

EGFR mutation was found in 67 (44%) cases including 47 women and 20 men. Among them, 50 patients had never smoked. We compared the clinicopathological characteristics between the patients harboring EGFR mutation and EGFR wild-type. The frequency of EGFR mutations in women was significantly more than in men (P = 0.003). In patients who had a history of smoking, the frequency of EGFR mutations were significantly more than that of wild-type EGFR (P = 0.011).

Correlation between epidermal growth factor receptor mutations and pathologic subtype of invasive adenocarcinoma

EGFR mutations were correlated with the MPA and LPA subtypes (P = 0.009 and P = 0.018) [Table 2]. EGFR mutations were independently associated with other subtypes of invasive adenocarcinoma.
Table 2: Correlations between predominant histologic subtypes of lung adenocarcinoma and epidermal growth factor receptor mutation

Click here to view


Correlation between epidermal growth factor receptor mutation and computed tomography findings

Although it was observed EGFR mutation in GGO (+) group (15 of 27 cases) and GGO (−) group (52 of 126 cases), EGFR mutation was independently associated with GGO (P = 0.175) [Table 3]. Furthermore, EGFR mutation was independent associated with G/T ratio (P = 0.054), speculation (P = 0.182), notch (P = 0.765), pleural indentation (P = 0.492), and vascular convergence (P = 0.892) [Table 3]. It was observed the correlation existed between EGFR mutation and the air bronchograms. EGFR mutations in air bronchograms (+) group were significantly more than in air bronchograms (−) group (P = 0.008) [Table 3].
Table 3: Correlations between computed tomography findings and epidermal growth factor receptor gene mutation

Click here to view



 > Discussion Top


In this study, we demonstrate that correlation exists between EGFR mutations and histologic subtypes of invasive adenocarcinoma or air bronchograms on CT images. The incidence of EGFR mutations in patients with lung adenocarcinoma was 43.79% (67/153). There was a significant correlation between EGFR mutation status and gender (P = 0.003) and nonsmoking status (P = 0.011). EGFR mutations were positively associated with nonsmoking status in patients underwent surgical resected pulmonary adenocarcinoma (P = 0.011). Consistent with a previous study,[9] EGFR mutations were more frequently in female patients and never smoked patients.

Although several previous studies have been examined the relationship between EGFR mutations and predominant histologic subtype,[17],[18],[19],[20] the findings in the relationship were conflict and the percentages of each lung adenocarcinoma subtypes were differently reported. Zhang et al.[19] investigated 349 cases of lung adenocarcinoma and found that EGFR mutations were more frequent in APA subtype of pulmonary adenocarcinoma. Shim et al.[20] examined 107 cases of resected lung adenocarcinomas and found that EGFR mutations were more common in MPA and LPA subtypes (P = 0.02, and P = 0.002, respectively). Song et al.,[18] examined 161 cases resected lung adenocarcinomas and found that EGFR mutations were 67 cases (41.6%) and that EGFR mutations were more closely associated with the MPA subtype (P = 0.0068) and LPA (P = 0.005), and were significant lower in the SPA subtype than in others (P = 0.04). Sun et al.[17] Investigated 102 cases of resected lung adenocarcinoma and found that EGFR mutations were 39 cases (38.2%) and that EGFR mutations were more closely associated with MPA subtypes (P = 0.0026), and were less frequent in the SPA subtype than in others (P = 0.0508). Here, our study showed that the most frequent subtypes of invasive adenocarcinoma were APA (34%), followed by PPA (24%), MPA (19%), SPA (12%), and LPA (11%). Furthermore, we showed EGFR mutations to be more common in MPA and LPA subtypes than in others (P = 0.009 and P = 0.018), suggesting a correlation existed between EGFR mutations and MPA and LPA subtypes.

There were only few reports evaluated the association between EGFR mutation status and characteristics of CT imaging of lung adenocarcinoma. Yano et al.[21] reported that a high ratio of GGO components may predict the presence of EGFR mutations, and that EGFR mutation frequency was significantly higher in patients who had a GGO ratio ≥50% and a tumor diameter ≤3 cm, compared with the patients who had a GGO ratio of <50% and a tumor diameter of ≤3 cm. Glynn et al.,[22] found no correlation between morphological features on a CT scan and the presence of EGFR or KRAS mutations. Sugano et al.[15] also reported that no significant association was found between GGO and EGFR mutations (P = 0.07), the EGFR mutation occurred more frequently in male patients GGO (+) than in those GGO (−) (P = 0.04). Lee et al.[23] examined 161 cases of consecutive patients and found that GGO volume percentage in tumors with exon 21 missense mutation was significantly higher than that with EGFR wild-type and exon 19 mutated tumors. Here, we showed that EGFR mutation was an independent association with GGO (P = 0.175), although the EGFR mutation occurred more frequently in patients with GGO than in those without GGO. Our study only included 27 cases presented GGO, expanding the original sample to a larger sample size in the future will validate the conclusion. Furthermore, we found that EGFR mutations occur more frequently the patients with a G/T ratio ≥50% than in those with a G/T ratio <50%, but the difference was not statistically significant (P = 0.054). This is consistent with the findings published by Sugano et al.,[8] Furthermore, there was no correlation between EGFR mutation and speculation, notch, pleural indentation, or vascular convergence. It was observed the correlation existed between EGFR mutation and the air bronchograms. EGFR mutations in air bronchograms (+) group were significantly more frequent than in air bronchograms (−) group (P = 0.008).

Our present study may have several limitations in accurately evaluating the correlation between EGFR mutation and histologic subtypes. First, the study is a retrospective study, and we did not perform the survival analysis. However, numerous studies have demonstrated EGFR-TKI therapy achieved promising successes in nonsmall cell lung cancer patients harboring EGFR active mutations, significantly prolonging patients' survival.[8],[10],[24] Second, the sample size was not relatively large, the sample size of histologic subtypes was not evenly distributed. None of the specimens met the criteria proposed for AIS and MIA. It suggests a further prospective study accumulated a large sample size.


 > Conclusion Top


We found correlations between EGFR mutation and histologic subtypes or characteristics of CT findings. EGFR mutations were correlated with the micropapillary and lepidic predominant subtypes and were correlated with the air bronchograms. This information may be used to predict EGFR mutation status in patients with pulmonary adenocarcinoma. In addition, it is worth to investigate the correction between EGFR mutation and histologic subtypes or CT features in other histological subtypes of lung cancer in the future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

1.
Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64:9-29.  Back to cited text no. 1
    
2.
Chen W, Zheng R, Zeng H, Zhang S. Epidemiology of lung cancer in China. Thorac Cancer 2015;6:209-15.  Back to cited text no. 2
    
3.
Zhou C. Lung cancer molecular epidemiology in China: Recent trends. Transl Lung Cancer Res 2014;3:270-9.  Back to cited text no. 3
    
4.
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;32:810-27.  Back to cited text no. 4
    
5.
Shi Y, Li J, Zhang S, Wang M, Yang S, Li N, et al. Molecular epidemiology of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology – Mainland China subset analysis of the PIONEER study. PLoS One 2015;10:e0143515.  Back to cited text no. 5
    
6.
Dong YJ, Cai YR, Zhou LJ, Su D, Mu J, Chen XJ, et al. Association between the histological subtype of lung adenocarcinoma, EGFR/KRAS mutation status and the ALK rearrangement according to the novel IASLC/ATS/ERS classification. Oncol Lett 2016;11:2552-8.  Back to cited text no. 6
    
7.
Jiang R, Wang X, Li K. Predictive and prognostic value of preoperative serum tumor markers is EGFR mutation-specific in resectable non-small-cell lung cancer. Oncotarget 2016. doi: 10.18632/oncotarget.8662.  Back to cited text no. 7
    
8.
Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947-57.  Back to cited text no. 8
    
9.
Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 2004;304:1497-500.  Back to cited text no. 9
    
10.
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;350:2129-39.  Back to cited text no. 10
    
11.
Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, et al. International association for the study of lung cancer/American thoracic society/European respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011;6:244-85.  Back to cited text no. 11
    
12.
Greaves SM, Brown K, Garon EB, Garon BL. The new staging system for lung cancer: Imaging and clinical implications. J Thorac Imaging 2011;26:119-31.  Back to cited text no. 12
    
13.
van Meerbeeck JP, Janssens A. The seventh tumour-node-metastasis staging system for lung cancer: Sequel or prequel? EJC Suppl 2013;11:150-8.  Back to cited text no. 13
    
14.
Aoki T, Nakata H, Watanabe H, Nakamura K, Kasai T, Hashimoto H, et al. Evolution of peripheral lung adenocarcinomas: CT findings correlated with histology and tumor doubling time. AJR Am J Roentgenol 2000;174:763-8.  Back to cited text no. 14
    
15.
Sugano M, Shimizu K, Nakano T, Kakegawa S, Miyamae Y, Kaira K, et al. Correlation between computed tomography findings and epidermal growth factor receptor and KRAS gene mutations in patients with pulmonary adenocarcinoma. Oncol Rep 2011;26:1205-11.  Back to cited text no. 15
    
16.
Newton CR, Graham A, Heptinstall LE, Powell SJ, Summers C, Kalsheker N, et al. Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS). Nucleic Acids Res 1989;17:2503-16.  Back to cited text no. 16
    
17.
Sun Y, Yu X, Shi X, Hong W, Zhao J, Shi L. Correlation of survival and EGFR mutation with predominant histologic subtype according to the new lung adenocarcinoma classification in stage IB patients. World J Surg Oncol 2014;12:148.  Back to cited text no. 17
    
18.
Song Z, Zhu H, Guo Z, Wu W, Sun W, Zhang Y. Correlation of EGFR mutation and predominant histologic subtype according to the new lung adenocarcinoma classification in Chinese patients. Med Oncol 2013;30:645.  Back to cited text no. 18
    
19.
Zhang Y, Sun Y, Pan Y, Li C, Shen L, Li Y, et al. Frequency of driver mutations in lung adenocarcinoma from female never-smokers varies with histologic subtypes and age at diagnosis. Clin Cancer Res 2012;18:1947-53.  Back to cited text no. 19
    
20.
Shim HS, Lee da H, Park EJ, Kim SH. Histopathologic characteristics of lung adenocarcinomas with epidermal growth factor receptor mutations in the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society lung adenocarcinoma classification. Arch Pathol Lab Med 2011;135:1329-34.  Back to cited text no. 20
    
21.
Yano M, Sasaki H, Kobayashi Y, Yukiue H, Haneda H, Suzuki E, et al. Epidermal growth factor receptor gene mutation and computed tomographic findings in peripheral pulmonary adenocarcinoma. J Thorac Oncol 2006;1:413-6.  Back to cited text no. 21
    
22.
Glynn C, Zakowski MF, Ginsberg MS. Are there imaging characteristics associated with epidermal growth factor receptor and KRAS mutations in patients with adenocarcinoma of the lung with bronchioloalveolar features? J Thorac Oncol 2010;5:344-8.  Back to cited text no. 22
    
23.
Lee HJ, Kim YT, Kang CH, Zhao B, Tan Y, Schwartz LH, et al. Epidermal growth factor receptor mutation in lung adenocarcinomas: Relationship with CT characteristics and histologic subtypes. Radiology 2013;268:254-64.  Back to cited text no. 23
    
24.
Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011;12:735-42.  Back to cited text no. 24
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  >Abstract>Introduction>Materials and Me...>Results>Discussion>Conclusion>Article Tables
  In this article
>References

 Article Access Statistics
    Viewed2207    
    Printed65    
    Emailed0    
    PDF Downloaded105    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]