Surgically Resected Solitary Cavitary Lung Adenocarcinoma: Association Between Clinical, Pathologic, and Radiologic Findings and Prognosis
GENERAL THORACIC
Yukio Watanabe, MD, Masahiko Kusumoto, MD, Akihiko Yoshida, MD, Kenji Suzuki, MD, Hisao Asamura, MD, and Koji Tsuta, MD Divisions of Pathology, Diagnostic Radiology, and Thoracic Surgery, National Cancer Center Hospital, Tokyo; and Department of Thoracic Surgery, Juntendo University School of Medicine, Tokyo, Japan
Background. The incidence of cavitary lung adenocarcinoma has recently increased; despite this, little is known about its clinical features and prognosis. We, therefore, evaluated the clinicopathologic features and prognosis of this malignancy. Methods. Between 1998 and 2007, 2,316 patients without preoperative chemotherapy or radiation therapy underwent surgical resection for primary lung adenocarcinoma. Among these cases, 143 (6.2%) were diagnosed as having cavitary adenocarcinoma based on high-resolution computed tomography scans and were enrolled in our study. Results. Cavitary adenocarcinoma occurred more frequently in patients who were male (p < 0.001); who had a smoking history (p < 0.001), larger tumor size (p < 0.001), a tumor in the lower lobe (p < 0.001), lymph node metastasis (p [ 0.02), advanced tumor stage (p [ 0.04), postoperative recurrence (p < 0.01), and a papillary (p [ 0.02)
or solid predominant tumor pattern (p < 0.01); and who had vascular (p < 0.001), lymphatic (p [ 0.04), or pleural invasion (p < 0.01). Kaplan-Meier analysis revealed that the overall and recurrence-free survival of patients with cavitary adenocarcinoma was significantly shorter than that of patients with noncavitary adenocarcinoma (p < 0.001). Multivariate analysis revealed that cavity formation was an independent prognostic factor in adenocarcinoma (p [ 0.028). Conclusions. Cavitary adenocarcinoma has worse prognostic clinicopathologic characteristics than noncavitary adenocarcinoma. Based on this finding, cavitary and noncavitary adenocarcinoma tumors should be considered separate entities.
C
thus relatively little is known of the detailed clinicoradiographic features of primary lung adenocarcinoma with cavity formation. The aim of the present study was to determine the distinguishing clinicopathologic features and the prognosis of cavitary pulmonary adenocarcinoma.
avities in the lung are often noted on imaging in a variety of pulmonary diseases and present the question of whether the cavity represents a benign or a malignant lesion [1]. The differential diagnosis in such a condition ranges from infection, such as tuberculosis, or an abscess, to malignant tumors, most notably squamous cell carcinoma. Differential diagnosis from among these particular diseases with cavity formation is difficult, even when using the latest radiologic devices [2–4]. Cavitation in a tumor nodule has been reported in 2% to 25% of patients with lung cancer [5, 6]. Compared with noncavitary lung cancer, cavity formation has been found to be more prevalent among male patients and among those with a larger tumor size or squamous cell histology, and is associated with a worse prognosis [5, 7–12]. Owing to the increasing frequency of lung adenocarcinoma, a greater number of cases of cavitary adenocarcinoma have recently been reported [6, 9, 12–14]. However, most previous reports regarding their clinicoradiographic features were based on tumors with squamous cell histology, and Accepted for publication Oct 21, 2014. Address correspondence to Dr Tsuta, Division of Pathology, National Cancer Center Hospital, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan; e-mail: [email protected].
Ó 2015 by The Society of Thoracic Surgeons Published by Elsevier
(Ann Thorac Surg 2015;99:968–74) Ó 2015 by The Society of Thoracic Surgeons
Material and Methods Case Selection The Institutional Review Board of the National Cancer Center Hospital, Tokyo, Japan, approved this study (20100077). Between 1998 and 2007, 2,316 patients who had not received preoperative chemotherapy or radiation therapy underwent surgical resection for primary lung adenocarcinoma at this institute. Among these cases, 143 (6.2%) were diagnosed as having a tumor with cavity formation on high-resolution computed tomography (CT) scans, and the results were analyzed as cavitary adenocarcinoma (Fig 1). All cases were assessed using CT before bronchoscopy or a percutaneous CT-guided biopsy. Staging was based on the criteria of the seventh edition of the tumor, node, and metastasis classification for lung cancer [15]. In this study, the upper limit of the normal value for carcinoembryonic antigen was 5 ng/mL. 0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2014.10.040
Ann Thorac Surg 2015;99:968–74
WATANABE ET AL SOLITARY CAVITARY LUNG ADENOCARCINOMA
969
Fig 1. Flow chart for the selection of cavitary adenocarcinoma patients.
GENERAL THORACIC
Review of CT Images
Histologic Analysis
In all 143 patients, helical technique and additional continual thin section (collimation, 2.0 mm or 1.0 mm) scans were obtained. The CT images were examined by two investigators (Y.W. and M.K.) for tumor cavitation, which was defined as the presence of an air-containing space with a diameter of greater than 5 mm within the primary tumor and which was not identifiable as an airway. Descriptors of tumor location included identification of the affected lung lobe as well as the position of the tumor in the lobe (central versus peripheral). Peripheral tumors were defined as having margins arising from subsegmental or other distal bronchi and bronchioli, based on a previous report [16]. Other tumors were defined as central tumors. With regard to the CT findings of cavitary adenocarcinoma, we investigated the presence of ground-glass opacity, the internal characteristics of the cavity wall (regular or irregular internal contours), and the intratumoral location of cavity formation (centrally located or noncentrally located; Fig 2).
All sections were stained with hematoxylin and eosin. The histopathology specimens were independently examined by two investigators (Y.W. and K.T.). We evaluated vascular invasion, lymphatic invasion, and pleural invasion based on Elastica van Gieson staining. The International Association for the Study of Lung Cancer classifications of lung adenocarcinoma were used to further subdivide tumors into one of the following five predominant patterns: lepidic, papillary, acinar, solid, or micropapillary predominant [17].
Follow-Up and Clinical Outcome Cancer recurrence was carefully divided into three categories according to the site of initial relapse: locoregional, distant, or at both sites simultaneously. Locoregional recurrence was defined as any recurrent disease within the ipsilateral hemithorax, mediastinum, or supraclavicular lymph nodes. All other sites of recurrence were considered distant metastases. Fig 2. High-resolution computed tomographic image showing (A) a noncentrally located cavitary tumor with irregular internal contours, and (B) a centrally located cavitary tumor.
970
WATANABE ET AL SOLITARY CAVITARY LUNG ADENOCARCINOMA
GENERAL THORACIC
Statistical Analysis Statistical analysis was performed using the SPSS Statistics 22 program (IBM Corporation, Armonk, NY). Student’s t test was used to analyze continuous variables, and c2 tests were used to analyze categorical variables. Additional statistical analysis of adenocarcinoma with and without cavity formation among different histologic subtypes was performed using the Fisher exact test. After applying the Bonferroni correction, the level of significance was set at less than 0.00833. Survival curves were calculated using the log rank test. Univariate survival analysis was performed with the log rank test and Cox’s proportional hazard regression. In the multivariate Cox model, stepwise procedures were used to determine the predictors of overall survival. Statistical significance was set at p less than 0.05.
Results Patient Characteristics Cavitary lung adenocarcinoma was detected in both men (n ¼ 97, 67.8%) and women (n ¼ 46, 32.2%). The median age was 63 years (range, 26 to 82). A smoking history was marginally associated with cavitary adenocarcinoma (66.4%). Lymph node metastasis was found in 45 (32.1%) of the 140 tumors (N1 and N2 in 17 patients [12.1%] and 28 patients [20.0%], respectively). Stage I, II, III, and IV tumors were found in 84 (58.7%), 25 (17.5%), 30 (21.0%), and 4 patients (2.8%), respectively.
Computed Tomography Findings Among the 143 cavitary adenocarcinomas, tumors were found in the peripheral area in 127 cases (88.8%), the right side in 83 cases (58.0%), the upper lobe in 55 cases (38.5%), and the lower lobe in 83 cases (58.7%). Cavitary adenocarcinoma occurred more frequently in the lower lobe than the noncavitary form (p < 0.001; Table 1). There were no significant differences with respect to the centrality and laterality of tumor location. A detailed review of the CT characteristics of cavitary formation revealed that peripheral ground-glass opacity was present in 40 cases (28.0%), regular internal contours were present in 19 cases (13.3%) and irregular internal contours were present in 124 cases (86.7%). Intratumoral cavity formation was centrally located in 48 cases (33.6%) and noncentrally located in 95 cases (66.4%).
Histologic Findings The most prevalent histologic subtype in lung adenocarcinoma with cavity formation was the papillary type, in 59 cases (41.3%), followed by the solid type in 30 cases (21.0%), the lepidic type in 15 cases (10.5%), the acinar type in 15 cases (10.5%), and the micropapillary type in 10 cases (7.0%; Table 1). The other findings for cavitary adenocarcinoma were invasive mucinous adenocarcinoma in 8 cases (5.6%), minimally invasive adenocarcinoma in 5 cases (3.5%), and noninvasive adenocarcinoma in 1 case (0.7%). There were also 80 cases (55.9%) of vascular invasion, 65 cases (45.5%) of lymphatic invasion,
Ann Thorac Surg 2015;99:968–74
Table 1. Patient Characteristics in Cavitary Adenocarcinoma and Noncavitary Adenocarcinoma Groups Characteristics Total (n ¼ 2,316) Age, years Median Range >70 years Sex Male Female Smoking history Former or current smoker Never smoker Tumor size, cm Median Range Tumor size >5 cm Tumor location Central Peripheral Operative side Right side Lobar location Lower Other lobe CEA, ng/mL Median Range CEA >5 ng/mL Lymph node metastasis N0 N1 Tumor stage I or II III or IV Postoperative recurrence Predominant pattern Lepidic Papillary Acinar Solid Micropapillary Vascular invasion Lymphatic invasion Pleural invasion
Cavity n (%)
Noncavity n (%)
n ¼ 143
n ¼ 2,173
p Value
GENERAL THORACIC
Yukio Watanabe, MD, Masahiko Kusumoto, MD, Akihiko Yoshida, MD, Kenji Suzuki, MD, Hisao Asamura, MD, and Koji Tsuta, MD Divisions of Pathology, Diagnostic Radiology, and Thoracic Surgery, National Cancer Center Hospital, Tokyo; and Department of Thoracic Surgery, Juntendo University School of Medicine, Tokyo, Japan
Background. The incidence of cavitary lung adenocarcinoma has recently increased; despite this, little is known about its clinical features and prognosis. We, therefore, evaluated the clinicopathologic features and prognosis of this malignancy. Methods. Between 1998 and 2007, 2,316 patients without preoperative chemotherapy or radiation therapy underwent surgical resection for primary lung adenocarcinoma. Among these cases, 143 (6.2%) were diagnosed as having cavitary adenocarcinoma based on high-resolution computed tomography scans and were enrolled in our study. Results. Cavitary adenocarcinoma occurred more frequently in patients who were male (p < 0.001); who had a smoking history (p < 0.001), larger tumor size (p < 0.001), a tumor in the lower lobe (p < 0.001), lymph node metastasis (p [ 0.02), advanced tumor stage (p [ 0.04), postoperative recurrence (p < 0.01), and a papillary (p [ 0.02)
or solid predominant tumor pattern (p < 0.01); and who had vascular (p < 0.001), lymphatic (p [ 0.04), or pleural invasion (p < 0.01). Kaplan-Meier analysis revealed that the overall and recurrence-free survival of patients with cavitary adenocarcinoma was significantly shorter than that of patients with noncavitary adenocarcinoma (p < 0.001). Multivariate analysis revealed that cavity formation was an independent prognostic factor in adenocarcinoma (p [ 0.028). Conclusions. Cavitary adenocarcinoma has worse prognostic clinicopathologic characteristics than noncavitary adenocarcinoma. Based on this finding, cavitary and noncavitary adenocarcinoma tumors should be considered separate entities.
C
thus relatively little is known of the detailed clinicoradiographic features of primary lung adenocarcinoma with cavity formation. The aim of the present study was to determine the distinguishing clinicopathologic features and the prognosis of cavitary pulmonary adenocarcinoma.
avities in the lung are often noted on imaging in a variety of pulmonary diseases and present the question of whether the cavity represents a benign or a malignant lesion [1]. The differential diagnosis in such a condition ranges from infection, such as tuberculosis, or an abscess, to malignant tumors, most notably squamous cell carcinoma. Differential diagnosis from among these particular diseases with cavity formation is difficult, even when using the latest radiologic devices [2–4]. Cavitation in a tumor nodule has been reported in 2% to 25% of patients with lung cancer [5, 6]. Compared with noncavitary lung cancer, cavity formation has been found to be more prevalent among male patients and among those with a larger tumor size or squamous cell histology, and is associated with a worse prognosis [5, 7–12]. Owing to the increasing frequency of lung adenocarcinoma, a greater number of cases of cavitary adenocarcinoma have recently been reported [6, 9, 12–14]. However, most previous reports regarding their clinicoradiographic features were based on tumors with squamous cell histology, and Accepted for publication Oct 21, 2014. Address correspondence to Dr Tsuta, Division of Pathology, National Cancer Center Hospital, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan; e-mail: [email protected].
Ó 2015 by The Society of Thoracic Surgeons Published by Elsevier
(Ann Thorac Surg 2015;99:968–74) Ó 2015 by The Society of Thoracic Surgeons
Material and Methods Case Selection The Institutional Review Board of the National Cancer Center Hospital, Tokyo, Japan, approved this study (20100077). Between 1998 and 2007, 2,316 patients who had not received preoperative chemotherapy or radiation therapy underwent surgical resection for primary lung adenocarcinoma at this institute. Among these cases, 143 (6.2%) were diagnosed as having a tumor with cavity formation on high-resolution computed tomography (CT) scans, and the results were analyzed as cavitary adenocarcinoma (Fig 1). All cases were assessed using CT before bronchoscopy or a percutaneous CT-guided biopsy. Staging was based on the criteria of the seventh edition of the tumor, node, and metastasis classification for lung cancer [15]. In this study, the upper limit of the normal value for carcinoembryonic antigen was 5 ng/mL. 0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2014.10.040
Ann Thorac Surg 2015;99:968–74
WATANABE ET AL SOLITARY CAVITARY LUNG ADENOCARCINOMA
969
Fig 1. Flow chart for the selection of cavitary adenocarcinoma patients.
GENERAL THORACIC
Review of CT Images
Histologic Analysis
In all 143 patients, helical technique and additional continual thin section (collimation, 2.0 mm or 1.0 mm) scans were obtained. The CT images were examined by two investigators (Y.W. and M.K.) for tumor cavitation, which was defined as the presence of an air-containing space with a diameter of greater than 5 mm within the primary tumor and which was not identifiable as an airway. Descriptors of tumor location included identification of the affected lung lobe as well as the position of the tumor in the lobe (central versus peripheral). Peripheral tumors were defined as having margins arising from subsegmental or other distal bronchi and bronchioli, based on a previous report [16]. Other tumors were defined as central tumors. With regard to the CT findings of cavitary adenocarcinoma, we investigated the presence of ground-glass opacity, the internal characteristics of the cavity wall (regular or irregular internal contours), and the intratumoral location of cavity formation (centrally located or noncentrally located; Fig 2).
All sections were stained with hematoxylin and eosin. The histopathology specimens were independently examined by two investigators (Y.W. and K.T.). We evaluated vascular invasion, lymphatic invasion, and pleural invasion based on Elastica van Gieson staining. The International Association for the Study of Lung Cancer classifications of lung adenocarcinoma were used to further subdivide tumors into one of the following five predominant patterns: lepidic, papillary, acinar, solid, or micropapillary predominant [17].
Follow-Up and Clinical Outcome Cancer recurrence was carefully divided into three categories according to the site of initial relapse: locoregional, distant, or at both sites simultaneously. Locoregional recurrence was defined as any recurrent disease within the ipsilateral hemithorax, mediastinum, or supraclavicular lymph nodes. All other sites of recurrence were considered distant metastases. Fig 2. High-resolution computed tomographic image showing (A) a noncentrally located cavitary tumor with irregular internal contours, and (B) a centrally located cavitary tumor.
970
WATANABE ET AL SOLITARY CAVITARY LUNG ADENOCARCINOMA
GENERAL THORACIC
Statistical Analysis Statistical analysis was performed using the SPSS Statistics 22 program (IBM Corporation, Armonk, NY). Student’s t test was used to analyze continuous variables, and c2 tests were used to analyze categorical variables. Additional statistical analysis of adenocarcinoma with and without cavity formation among different histologic subtypes was performed using the Fisher exact test. After applying the Bonferroni correction, the level of significance was set at less than 0.00833. Survival curves were calculated using the log rank test. Univariate survival analysis was performed with the log rank test and Cox’s proportional hazard regression. In the multivariate Cox model, stepwise procedures were used to determine the predictors of overall survival. Statistical significance was set at p less than 0.05.
Results Patient Characteristics Cavitary lung adenocarcinoma was detected in both men (n ¼ 97, 67.8%) and women (n ¼ 46, 32.2%). The median age was 63 years (range, 26 to 82). A smoking history was marginally associated with cavitary adenocarcinoma (66.4%). Lymph node metastasis was found in 45 (32.1%) of the 140 tumors (N1 and N2 in 17 patients [12.1%] and 28 patients [20.0%], respectively). Stage I, II, III, and IV tumors were found in 84 (58.7%), 25 (17.5%), 30 (21.0%), and 4 patients (2.8%), respectively.
Computed Tomography Findings Among the 143 cavitary adenocarcinomas, tumors were found in the peripheral area in 127 cases (88.8%), the right side in 83 cases (58.0%), the upper lobe in 55 cases (38.5%), and the lower lobe in 83 cases (58.7%). Cavitary adenocarcinoma occurred more frequently in the lower lobe than the noncavitary form (p < 0.001; Table 1). There were no significant differences with respect to the centrality and laterality of tumor location. A detailed review of the CT characteristics of cavitary formation revealed that peripheral ground-glass opacity was present in 40 cases (28.0%), regular internal contours were present in 19 cases (13.3%) and irregular internal contours were present in 124 cases (86.7%). Intratumoral cavity formation was centrally located in 48 cases (33.6%) and noncentrally located in 95 cases (66.4%).
Histologic Findings The most prevalent histologic subtype in lung adenocarcinoma with cavity formation was the papillary type, in 59 cases (41.3%), followed by the solid type in 30 cases (21.0%), the lepidic type in 15 cases (10.5%), the acinar type in 15 cases (10.5%), and the micropapillary type in 10 cases (7.0%; Table 1). The other findings for cavitary adenocarcinoma were invasive mucinous adenocarcinoma in 8 cases (5.6%), minimally invasive adenocarcinoma in 5 cases (3.5%), and noninvasive adenocarcinoma in 1 case (0.7%). There were also 80 cases (55.9%) of vascular invasion, 65 cases (45.5%) of lymphatic invasion,
Ann Thorac Surg 2015;99:968–74
Table 1. Patient Characteristics in Cavitary Adenocarcinoma and Noncavitary Adenocarcinoma Groups Characteristics Total (n ¼ 2,316) Age, years Median Range >70 years Sex Male Female Smoking history Former or current smoker Never smoker Tumor size, cm Median Range Tumor size >5 cm Tumor location Central Peripheral Operative side Right side Lobar location Lower Other lobe CEA, ng/mL Median Range CEA >5 ng/mL Lymph node metastasis N0 N1 Tumor stage I or II III or IV Postoperative recurrence Predominant pattern Lepidic Papillary Acinar Solid Micropapillary Vascular invasion Lymphatic invasion Pleural invasion
Cavity n (%)
Noncavity n (%)
n ¼ 143
n ¼ 2,173
p Value
