Accepted Manuscript CT features of epidermal growth factor receptor mutated adenocarcinoma of the lung: Comparison with non mutated adenocarcinoma Mizue Hasegawa, MD, PhD, Fumikazu Sakai, MD, PhD, Rinako Ishikawa, MD, PhD, Fumiko Kimura, MD, PhD, Hironori Ishida, MD, PhD, Kunihiko Kobayashi, MD, PhD PII:
S1556-0864(16)00429-9
DOI:
10.1016/j.jtho.2016.02.010
Reference:
JTHO 119
To appear in:
Journal of Thoracic Oncology
Received Date: 1 December 2015 Revised Date:
17 February 2016
Accepted Date: 17 February 2016
Please cite this article as: Hasegawa M, Sakai F, Ishikawa R, Kimura F, Ishida H, Kobayashi K, CT features of epidermal growth factor receptor mutated adenocarcinoma of the lung: Comparison with non mutated adenocarcinoma, Journal of Thoracic Oncology (2016), doi: 10.1016/j.jtho.2016.02.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
(a) Title:
Comparison with non mutated adenocarcinoma.
SC
(b) Author`s names and affiliations:
Rinako Ishikawa, MD, PhD 2) Fumiko Kimura, MD, PhD 1)
TE D
Hironori Ishida, MD, PhD 3)
M AN U
Mizue Hasegawa, MD, PhD 1)4) Fumikazu Sakai, MD, PhD 1)
RI PT
CT features of epidermal growth factor receptor mutated adenocarcinoma of the lung:
EP
Kunihiko Kobayashi, MD, PhD 2)
AC C
1) Saitama International Medical Center, Saitama Medical University, department of diagnostic radiology
2) Saitama International Medical Center, Saitama Medical University, department of respiratory medicine 3) Saitama International Medical Center, Saitama Medical University, department of thoracic surgery
ACCEPTED MANUSCRIPT
4) Tokyo Women’s Medical University, Yachiyo Medical Center, department of
RI PT
respiratory medicine
(c) Corresponding author:
SC
Name: Mizue Hasegawa
Address: Department of Diagnostic Radiology, Saitama International Medical Center,
Post code: 350-1298
Fax; +81-042-984-4220
TE D
Phone; +81-042-984-4111
Email: hasemizue@yahoo/co.jp
AC C
EP
Disclosure of funding: none
(d) Address for reprints: Same as (c)
(e) All sources of support: None
M AN U
Saitama Medical University, 1397-1 Hidaka, Saitama, Japan
ACCEPTED MANUSCRIPT
Disclosures of funding from NIH; Wellcome Trust; HHMI; and others:
AC C
EP
TE D
M AN U
SC
RI PT
None
ACCEPTED MANUSCRIPT
Introduction: The purpose of this study was to analyze the high resolution computed tomography (HRCT) features of lung carcinoma based on epidermal growth factor
RI PT
receptor (EGFR) mutation status.
Methods: Two hundred and sixty-three consecutive cases of lung adenocarcinoma
SC
diagnosed at our institution between January 2010 and December 2011 were enrolled in the study. All patients underwent HRCT and analysis of EGFR mutation status. The
M AN U
HRCT findings were retrospectively analyzed for tumor size, multiple bilateral lung metastases, convergence of surrounding structures, surrounding ground-glass opacity, prominent peribronchovascular extension, air bronchogram, notch, pleural indentation,
TE D
spiculation, cavity, and pleural effusions.
Results: EGFR mutations were demonstrated in 103 patients (39.2%), the remaining
EP
160 patients (60.8%) had non-mutated type. Compared with the non-mutated group, the
AC C
mutated group had significantly higher frequencies of multiple bilateral lung metastases (p = 0.0152), convergence of surrounding structures (p < 0.0001), ground glass opacity (p = 0.0011), and notch (p = 0.0428); but significantly lower frequencies of cavitation (p = 0.0004) and pleural effusions (p = 0.0064). The frequencies of the other CT findings were similar between the two groups. The devised prediction HRCT score for EGFR mutation was 78.4% sensitive and 70.4% specific.
ACCEPTED MANUSCRIPT
Conclusion: EGFR-mutated adenocarcinoma showed significantly higher frequencies of multiple bilateral lung metastases, convergence of surrounding structures, surrounding
RI PT
ground glass opacity, and notch at HRCT compared with EGFR non-mutated type. Conversely, EGFR-mutated adenocarcinoma showed cavity and pleural effusions less
Key words: epidermal
growth
factor
M AN U
SC
frequently than the non-mutated type.
receptor
AC C
EP
TE D
tomography
mutation;
lung
adenocarcinoma;
computed
ACCEPTED MANUSCRIPT
Introduction Lung cancer is one of the leading causes of death worldwide. Adenocarcinoma is one
RI PT
of the most common histologic subtypes of lung cancer. Since the discovery of somatic epidermal growth factor receptor (EGFR) mutations, targeted therapies have
SC
dramatically improved survival rates for patients with lung cancer, especially
M AN U
adenocarcinoma (1-4). Adenocarcinoma, non-smoking status, female sex, and Asian ethnicity were described as predictors of EGFR mutation (5-7) that enable efficient plans for earlier diagnosis and treatment.
Several studies have attempted to describe the relationship between computed
TE D
tomography (CT) findings and EGFR mutation status. Lee et al have reported that the volume of ground glass opacity (GGO) attenuation was significantly higher in
EP
adenocarcinoma with EGFR mutation of exon 21 missense (8). Togashi et al reported
AC C
that EGFR-mutated adenocarcinoma tends to develop diffuse and random pulmonary metastases compared with the wild type (9). However, the relationship between EGFR-mutated adenocarcinoma and CT scan features has not been fully elucidated. In the field of lung cancer, there has been a recent increase in the identification of new gene mutations for targeted therapy, including anaplastic lymphoma kinase (ALK), ROS-1, and RET (10-12). Yamamoto et al have reported that non-small cell lung cancer
1
ACCEPTED MANUSCRIPT
(NSCLC) with ALK rearrangement was associated with CT scan characteristics of central tumor location, absence of pleural tail, and large pleural effusion (13). With
RI PT
regard to cost effectiveness and early planning of treatment, prediction of gene mutation from CT findings may be valuable. In this study, we aimed to analyze the differences in
Materials and Methods
M AN U
SC
CT findings between EGFR-mutated and non-mutated lung adenocarcinoma.
This retrospective study was approved by our institutional review board, who waived
of patient anonymity.
EP
Patient selection
TE D
the need for informed consent due to the non-invasive nature of the study and because
AC C
Consecutive patients (median age, 66 years; range, 38–90 years; N = 263, 156 men, 107 women) who had pathologically-confirmed diagnoses of primary lung adenocarcinoma at Saitama International Medical Center between January 2010 and December 2011 were enrolled in this study. All patients were Japanese and had no prior diagnosis or treatment for lung cancer. Patients with active malignancies in other organs, including apparent recurrent or residual tumor; patients with recurrent lung cancer;
2
ACCEPTED MANUSCRIPT
patients without pathologic confirmation of adenocarcinoma, including adenosquamous carcinoma; and patients with inadequate samples for sequencing were excluded from
RI PT
this study. Non-smoking status was defined as lifetime exposure to less than 100
SC
cigarettes. All patients underwent chest CT and analysis of EGFR mutation status.
M AN U
Analysis of EGFR status
All patients were analyzed for EGFR mutation status using histology or cytology specimens. The mutation status of EGFR exons 18, 19, 20, and 21 was examined with
PCR) clamp (14).
EP
CT imaging protocol
TE D
the peptide nucleic acid-locked nucleic acid polymerase chain reaction (PNA-LNA
AC C
All patients underwent chest CT scan, either at our institution or at a previous institution, within 2 months before histology or cytology examination. At our institution, CT was performed using scanners with 64-detector rows (Light Speed VCT; GE Medical Systems, Milwaukee, USA) or 16-detector rows (Bright speed; GE Medical Systems), with the following parameters: detector collimation, 1–5 mm; beam pitch, 1–5; rotation time, 0.5–1.0 second; tube voltage, 120 kVp; and tube current, 150–200
3
ACCEPTED MANUSCRIPT
mA. Contiguous images of 5-mm thickness were constructed from the lung apex to base, followed by reconstruction with high-resolution kernel covering of contiguous 1-mm
RI PT
slices of the primary tumor. Contrast study was done on 256 cases at our institution.
Seven cases underwent CT scan at previous institutions using a similar image protocol
SC
with different kinds of commercially available and state-of-the-art scanners. The
M AN U
frequency of positive EGFR mutation status was not statistically different between patients who underwent CT at our institution (38.3%, 98/256) and those who underwent
CT interpretation
TE D
CT at previous institutions (71.4%, 5/7).
The CT images were independently analyzed by one chest radiologist (F.S.) and one
EP
pulmonologist (M.H.), with experience of 38 years and 14 years, respectively. The
AC C
radiologist (F.S.) was blinded to the results of EGFR mutation status; whereas the pulmonologist (M.H.) had access to the data on EGFR mutation status of all enrolled patients. In order to avoid bias, at least 6 months interval was provided before CT interpretation. Interpretation of CT images was done on mediastinal window (M: 20 to 40. W: 300) and lung window (M: -500 to -700 W: 1500 to 2000) using picture archiving and communication system. The images were analyzed for the following
4
ACCEPTED MANUSCRIPT
points: longest and shortest diameters on the largest axial surface of the primary tumor, multiple bilateral lung metastases, convergence of surrounding structures, surrounding
indentation, spiculation, cavity, and pleural effusion (Fig. 1).
RI PT
GGO, prominent peribronchovascular extension, air bronchogram, notch, pleural
SC
Multiple bilateral lung metastases were defined as more than 10 lesions in both lung
M AN U
fields. Convergence of surrounding structures pertained to vessels, bronchi, bronchioles, or pleura around the primary tumor. Surrounding GGO was delineated based on a clearly defined border with the normal lung parenchyma and was classified on a 4-point scale, depending on the percentage of the GGO component on the largest axial surface
TE D
of the tumor (1: 1%–25%; 2: 25%–50%; 3: 50%–75%; 4: >75%). Prominent peribronchovascular extension of the primary lesion was defined as tumor involvement
EP
of the lymphatic channels, which was recognized on CT as longitudinal extensions of
AC C
the tumor; thickening of the bronchovascular bundle; or perilymphatic satellite lesions. Air bronchogram was defined as a branching or tubular air density surrounded by consolidation without prominent bronchial dilation. Cavity was indicated by the presence of round or oval air density in the tumor with relatively thick wall; markedly dilated tubular lucencies with extensive bronchial dilation within the tumor were considered as cavity. Tumors arising on a cyst wall or air densities caused by
5
ACCEPTED MANUSCRIPT
pre-existing structures, such as bullae or blebs, were excluded from this category. When
consensus.
SC
Comparison of EGFR mutation status and CT findings
RI PT
interpretations of two observers were different, a discussion was made to reach a final
M AN U
The CT findings of EGFR-mutated and non-mutated groups were compared. We had to exclude 19 patients from the CT analysis because of passive atelectasis from massive pleural effusion that obscured the primary tumor. Therefore, 263 patients were evaluated
points.
EP
Statistical analyses
TE D
for the presence of pleural effusion and 244 patients were evaluated for the remaining
AC C
Patient and CT characteristics of the study population were expressed as median (range) for non-parametric variables, and as frequency and percentage for categorical variables. Interobserver agreement was assessed by the kappa coefficient. The CT scan variables were compared between the two groups using univariate (Fisher’s exact test or Chi-square test) and multivariate (multiple logistic regression) analyses. Before performing multiple logistic regression analysis, variables were selected by a stepwise
6
ACCEPTED MANUSCRIPT
method. A prediction tool for positive EGFR mutation was devised from the total scores of each
RI PT
CT finding on multiple logistic regression analysis; a cut-off value was determined by receiver operating characteristic (ROC) analysis. Values of p < 0.05 were considered
SC
significant. All statistical analyses were performed using commercially available
M AN U
software programs (JMP 9; SAS Institute Inc., Cary, NC, USA or StatMate 4; Atoms, Tokyo, Japan).
Results
TE D
Clinical characteristics of the study population The clinical characteristics of the patients are shown in Table 1. The 263 patients had a
EP
median age of 66 years (range, 38–90 years); 156 were men, 107 were women. EGFR
AC C
mutation was positive in 103 (39.0%) patients (44 men, 59 women), who had a median age of 68 years (range, 38–86 years). Specifically, the EGFR mutations were on exon 21 in 51 patients (49.5%), exon 19 in 50 patients (48.5%), and exon 18 in 2 patients (1.9%). There was no EGFR exon 20 mutation observed in this study. Non-mutated type adenocarcinoma was seen in 160 (61%) patients (112 men, 48 women) who had a median age of 69 years (range, 38–90 years). The percentage of smokers was 45.0% in
7
ACCEPTED MANUSCRIPT
the EGFR-mutated group and 74.4% in the non-mutated group. The proportions of
compared with those in the non-mutated group.
SC
Interobserver agreement of CT interpretation
RI PT
women and non-smoking status were significantly higher in the EGFR-mutated group
M AN U
Concordance rates between the two observers were almost perfect, with kappa coefficients ranging between 0.89 and 1.0.
1) Pleural effusion
TE D
Relevance of EGFR mutation and CT findings
Pleural effusion was observed in 45 patients, but was negative in 218 patients. Among
EP
45 patients with pleural effusion, 9 (20%) were positive for EGFR mutation, whereas 36
AC C
(80%) had non-mutated adenocarcinoma. Among 218 patients without pleural effusion, 94 (43.1%) were positive for EGFR mutation, whereas 124 (56.9%) had non-mutated adenocarcinoma. Overall, the frequency of pleural effusion was significantly higher in the non-mutated group than the EGFR-mutated group (p = 0.0064). 2) Tumor size The average size of primary lesions was similar between the EGFR-mutated group and
8
ACCEPTED MANUSCRIPT
the non-mutated group (29.2 mm vs. 34.7 mm, p = 0.1953) (Table 1). 3) CT findings of the primary lesions
RI PT
The CT findings of the primary lesions were evaluated in 244 patients without passive atelectasis from massive pleural effusion (Table 2). Compared with the non-mutated
SC
group, the mutated group had significantly higher frequencies of multiple bilateral lung
M AN U
metastases (univariate, p = 0.0258; multivariate, p = 0.0152); convergence of surrounding vessels (univariate, p
S1556-0864(16)00429-9
DOI:
10.1016/j.jtho.2016.02.010
Reference:
JTHO 119
To appear in:
Journal of Thoracic Oncology
Received Date: 1 December 2015 Revised Date:
17 February 2016
Accepted Date: 17 February 2016
Please cite this article as: Hasegawa M, Sakai F, Ishikawa R, Kimura F, Ishida H, Kobayashi K, CT features of epidermal growth factor receptor mutated adenocarcinoma of the lung: Comparison with non mutated adenocarcinoma, Journal of Thoracic Oncology (2016), doi: 10.1016/j.jtho.2016.02.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
(a) Title:
Comparison with non mutated adenocarcinoma.
SC
(b) Author`s names and affiliations:
Rinako Ishikawa, MD, PhD 2) Fumiko Kimura, MD, PhD 1)
TE D
Hironori Ishida, MD, PhD 3)
M AN U
Mizue Hasegawa, MD, PhD 1)4) Fumikazu Sakai, MD, PhD 1)
RI PT
CT features of epidermal growth factor receptor mutated adenocarcinoma of the lung:
EP
Kunihiko Kobayashi, MD, PhD 2)
AC C
1) Saitama International Medical Center, Saitama Medical University, department of diagnostic radiology
2) Saitama International Medical Center, Saitama Medical University, department of respiratory medicine 3) Saitama International Medical Center, Saitama Medical University, department of thoracic surgery
ACCEPTED MANUSCRIPT
4) Tokyo Women’s Medical University, Yachiyo Medical Center, department of
RI PT
respiratory medicine
(c) Corresponding author:
SC
Name: Mizue Hasegawa
Address: Department of Diagnostic Radiology, Saitama International Medical Center,
Post code: 350-1298
Fax; +81-042-984-4220
TE D
Phone; +81-042-984-4111
Email: hasemizue@yahoo/co.jp
AC C
EP
Disclosure of funding: none
(d) Address for reprints: Same as (c)
(e) All sources of support: None
M AN U
Saitama Medical University, 1397-1 Hidaka, Saitama, Japan
ACCEPTED MANUSCRIPT
Disclosures of funding from NIH; Wellcome Trust; HHMI; and others:
AC C
EP
TE D
M AN U
SC
RI PT
None
ACCEPTED MANUSCRIPT
Introduction: The purpose of this study was to analyze the high resolution computed tomography (HRCT) features of lung carcinoma based on epidermal growth factor
RI PT
receptor (EGFR) mutation status.
Methods: Two hundred and sixty-three consecutive cases of lung adenocarcinoma
SC
diagnosed at our institution between January 2010 and December 2011 were enrolled in the study. All patients underwent HRCT and analysis of EGFR mutation status. The
M AN U
HRCT findings were retrospectively analyzed for tumor size, multiple bilateral lung metastases, convergence of surrounding structures, surrounding ground-glass opacity, prominent peribronchovascular extension, air bronchogram, notch, pleural indentation,
TE D
spiculation, cavity, and pleural effusions.
Results: EGFR mutations were demonstrated in 103 patients (39.2%), the remaining
EP
160 patients (60.8%) had non-mutated type. Compared with the non-mutated group, the
AC C
mutated group had significantly higher frequencies of multiple bilateral lung metastases (p = 0.0152), convergence of surrounding structures (p < 0.0001), ground glass opacity (p = 0.0011), and notch (p = 0.0428); but significantly lower frequencies of cavitation (p = 0.0004) and pleural effusions (p = 0.0064). The frequencies of the other CT findings were similar between the two groups. The devised prediction HRCT score for EGFR mutation was 78.4% sensitive and 70.4% specific.
ACCEPTED MANUSCRIPT
Conclusion: EGFR-mutated adenocarcinoma showed significantly higher frequencies of multiple bilateral lung metastases, convergence of surrounding structures, surrounding
RI PT
ground glass opacity, and notch at HRCT compared with EGFR non-mutated type. Conversely, EGFR-mutated adenocarcinoma showed cavity and pleural effusions less
Key words: epidermal
growth
factor
M AN U
SC
frequently than the non-mutated type.
receptor
AC C
EP
TE D
tomography
mutation;
lung
adenocarcinoma;
computed
ACCEPTED MANUSCRIPT
Introduction Lung cancer is one of the leading causes of death worldwide. Adenocarcinoma is one
RI PT
of the most common histologic subtypes of lung cancer. Since the discovery of somatic epidermal growth factor receptor (EGFR) mutations, targeted therapies have
SC
dramatically improved survival rates for patients with lung cancer, especially
M AN U
adenocarcinoma (1-4). Adenocarcinoma, non-smoking status, female sex, and Asian ethnicity were described as predictors of EGFR mutation (5-7) that enable efficient plans for earlier diagnosis and treatment.
Several studies have attempted to describe the relationship between computed
TE D
tomography (CT) findings and EGFR mutation status. Lee et al have reported that the volume of ground glass opacity (GGO) attenuation was significantly higher in
EP
adenocarcinoma with EGFR mutation of exon 21 missense (8). Togashi et al reported
AC C
that EGFR-mutated adenocarcinoma tends to develop diffuse and random pulmonary metastases compared with the wild type (9). However, the relationship between EGFR-mutated adenocarcinoma and CT scan features has not been fully elucidated. In the field of lung cancer, there has been a recent increase in the identification of new gene mutations for targeted therapy, including anaplastic lymphoma kinase (ALK), ROS-1, and RET (10-12). Yamamoto et al have reported that non-small cell lung cancer
1
ACCEPTED MANUSCRIPT
(NSCLC) with ALK rearrangement was associated with CT scan characteristics of central tumor location, absence of pleural tail, and large pleural effusion (13). With
RI PT
regard to cost effectiveness and early planning of treatment, prediction of gene mutation from CT findings may be valuable. In this study, we aimed to analyze the differences in
Materials and Methods
M AN U
SC
CT findings between EGFR-mutated and non-mutated lung adenocarcinoma.
This retrospective study was approved by our institutional review board, who waived
of patient anonymity.
EP
Patient selection
TE D
the need for informed consent due to the non-invasive nature of the study and because
AC C
Consecutive patients (median age, 66 years; range, 38–90 years; N = 263, 156 men, 107 women) who had pathologically-confirmed diagnoses of primary lung adenocarcinoma at Saitama International Medical Center between January 2010 and December 2011 were enrolled in this study. All patients were Japanese and had no prior diagnosis or treatment for lung cancer. Patients with active malignancies in other organs, including apparent recurrent or residual tumor; patients with recurrent lung cancer;
2
ACCEPTED MANUSCRIPT
patients without pathologic confirmation of adenocarcinoma, including adenosquamous carcinoma; and patients with inadequate samples for sequencing were excluded from
RI PT
this study. Non-smoking status was defined as lifetime exposure to less than 100
SC
cigarettes. All patients underwent chest CT and analysis of EGFR mutation status.
M AN U
Analysis of EGFR status
All patients were analyzed for EGFR mutation status using histology or cytology specimens. The mutation status of EGFR exons 18, 19, 20, and 21 was examined with
PCR) clamp (14).
EP
CT imaging protocol
TE D
the peptide nucleic acid-locked nucleic acid polymerase chain reaction (PNA-LNA
AC C
All patients underwent chest CT scan, either at our institution or at a previous institution, within 2 months before histology or cytology examination. At our institution, CT was performed using scanners with 64-detector rows (Light Speed VCT; GE Medical Systems, Milwaukee, USA) or 16-detector rows (Bright speed; GE Medical Systems), with the following parameters: detector collimation, 1–5 mm; beam pitch, 1–5; rotation time, 0.5–1.0 second; tube voltage, 120 kVp; and tube current, 150–200
3
ACCEPTED MANUSCRIPT
mA. Contiguous images of 5-mm thickness were constructed from the lung apex to base, followed by reconstruction with high-resolution kernel covering of contiguous 1-mm
RI PT
slices of the primary tumor. Contrast study was done on 256 cases at our institution.
Seven cases underwent CT scan at previous institutions using a similar image protocol
SC
with different kinds of commercially available and state-of-the-art scanners. The
M AN U
frequency of positive EGFR mutation status was not statistically different between patients who underwent CT at our institution (38.3%, 98/256) and those who underwent
CT interpretation
TE D
CT at previous institutions (71.4%, 5/7).
The CT images were independently analyzed by one chest radiologist (F.S.) and one
EP
pulmonologist (M.H.), with experience of 38 years and 14 years, respectively. The
AC C
radiologist (F.S.) was blinded to the results of EGFR mutation status; whereas the pulmonologist (M.H.) had access to the data on EGFR mutation status of all enrolled patients. In order to avoid bias, at least 6 months interval was provided before CT interpretation. Interpretation of CT images was done on mediastinal window (M: 20 to 40. W: 300) and lung window (M: -500 to -700 W: 1500 to 2000) using picture archiving and communication system. The images were analyzed for the following
4
ACCEPTED MANUSCRIPT
points: longest and shortest diameters on the largest axial surface of the primary tumor, multiple bilateral lung metastases, convergence of surrounding structures, surrounding
indentation, spiculation, cavity, and pleural effusion (Fig. 1).
RI PT
GGO, prominent peribronchovascular extension, air bronchogram, notch, pleural
SC
Multiple bilateral lung metastases were defined as more than 10 lesions in both lung
M AN U
fields. Convergence of surrounding structures pertained to vessels, bronchi, bronchioles, or pleura around the primary tumor. Surrounding GGO was delineated based on a clearly defined border with the normal lung parenchyma and was classified on a 4-point scale, depending on the percentage of the GGO component on the largest axial surface
TE D
of the tumor (1: 1%–25%; 2: 25%–50%; 3: 50%–75%; 4: >75%). Prominent peribronchovascular extension of the primary lesion was defined as tumor involvement
EP
of the lymphatic channels, which was recognized on CT as longitudinal extensions of
AC C
the tumor; thickening of the bronchovascular bundle; or perilymphatic satellite lesions. Air bronchogram was defined as a branching or tubular air density surrounded by consolidation without prominent bronchial dilation. Cavity was indicated by the presence of round or oval air density in the tumor with relatively thick wall; markedly dilated tubular lucencies with extensive bronchial dilation within the tumor were considered as cavity. Tumors arising on a cyst wall or air densities caused by
5
ACCEPTED MANUSCRIPT
pre-existing structures, such as bullae or blebs, were excluded from this category. When
consensus.
SC
Comparison of EGFR mutation status and CT findings
RI PT
interpretations of two observers were different, a discussion was made to reach a final
M AN U
The CT findings of EGFR-mutated and non-mutated groups were compared. We had to exclude 19 patients from the CT analysis because of passive atelectasis from massive pleural effusion that obscured the primary tumor. Therefore, 263 patients were evaluated
points.
EP
Statistical analyses
TE D
for the presence of pleural effusion and 244 patients were evaluated for the remaining
AC C
Patient and CT characteristics of the study population were expressed as median (range) for non-parametric variables, and as frequency and percentage for categorical variables. Interobserver agreement was assessed by the kappa coefficient. The CT scan variables were compared between the two groups using univariate (Fisher’s exact test or Chi-square test) and multivariate (multiple logistic regression) analyses. Before performing multiple logistic regression analysis, variables were selected by a stepwise
6
ACCEPTED MANUSCRIPT
method. A prediction tool for positive EGFR mutation was devised from the total scores of each
RI PT
CT finding on multiple logistic regression analysis; a cut-off value was determined by receiver operating characteristic (ROC) analysis. Values of p < 0.05 were considered
SC
significant. All statistical analyses were performed using commercially available
M AN U
software programs (JMP 9; SAS Institute Inc., Cary, NC, USA or StatMate 4; Atoms, Tokyo, Japan).
Results
TE D
Clinical characteristics of the study population The clinical characteristics of the patients are shown in Table 1. The 263 patients had a
EP
median age of 66 years (range, 38–90 years); 156 were men, 107 were women. EGFR
AC C
mutation was positive in 103 (39.0%) patients (44 men, 59 women), who had a median age of 68 years (range, 38–86 years). Specifically, the EGFR mutations were on exon 21 in 51 patients (49.5%), exon 19 in 50 patients (48.5%), and exon 18 in 2 patients (1.9%). There was no EGFR exon 20 mutation observed in this study. Non-mutated type adenocarcinoma was seen in 160 (61%) patients (112 men, 48 women) who had a median age of 69 years (range, 38–90 years). The percentage of smokers was 45.0% in
7
ACCEPTED MANUSCRIPT
the EGFR-mutated group and 74.4% in the non-mutated group. The proportions of
compared with those in the non-mutated group.
SC
Interobserver agreement of CT interpretation
RI PT
women and non-smoking status were significantly higher in the EGFR-mutated group
M AN U
Concordance rates between the two observers were almost perfect, with kappa coefficients ranging between 0.89 and 1.0.
1) Pleural effusion
TE D
Relevance of EGFR mutation and CT findings
Pleural effusion was observed in 45 patients, but was negative in 218 patients. Among
EP
45 patients with pleural effusion, 9 (20%) were positive for EGFR mutation, whereas 36
AC C
(80%) had non-mutated adenocarcinoma. Among 218 patients without pleural effusion, 94 (43.1%) were positive for EGFR mutation, whereas 124 (56.9%) had non-mutated adenocarcinoma. Overall, the frequency of pleural effusion was significantly higher in the non-mutated group than the EGFR-mutated group (p = 0.0064). 2) Tumor size The average size of primary lesions was similar between the EGFR-mutated group and
8
ACCEPTED MANUSCRIPT
the non-mutated group (29.2 mm vs. 34.7 mm, p = 0.1953) (Table 1). 3) CT findings of the primary lesions
RI PT
The CT findings of the primary lesions were evaluated in 244 patients without passive atelectasis from massive pleural effusion (Table 2). Compared with the non-mutated
SC
group, the mutated group had significantly higher frequencies of multiple bilateral lung
M AN U
metastases (univariate, p = 0.0258; multivariate, p = 0.0152); convergence of surrounding vessels (univariate, p
