Original Thoracic
597
Prognostic Significance of the Standardized Uptake Value on Positron Emission Tomography in Patients with Multiple Clinical-N0 Lung Cancers Aritoshi Hattori1
Kenji Suzuki1
Takeshi Matsunaga1
1 Department of General Thoracic Surgery, Juntendo University School
of Medicine, Tokyo, Japan
Kazuya Takamochi1
Shiaki Oh1
Address for correspondence Kenji Suzuki, General Thoracic Surgery, Juntendo University School of Medicine, 1-3, 3-chome, Hongo, Bunkyo-ku, Tokyo 113-8432, Japan (e-mail: [email protected]).
Abstract
Keywords
► multiple primary lung cancers ► intrapulmonary metastases ► positron emission tomography ► prognosis
Background While there have been many attempts to differentiate multiple lung cancers (MLCs) using the clinicopathological presentation and molecular profile, there are still some controversies regarding the prognostic factors for MLCs with clinical-N0 status. Patients and Methods Between 1996 and 2012, 131 patients were diagnosed as MLCs pathologically. The main lesion of MLCs was defined as follows: (1) among synchronous lesions, the radiologically denser or larger tumor on thin-section computed tomography (CT) or (2) the second tumor among metachronous lesions. 18F-fluorodeoxyglucose uptake on positron emission tomography (PET) scan was examined to evaluate maximum standardized uptake value (SUVmax) of the main tumor. Results Among 131 patients with clinical-N0 status, 66 were men and 65 were women and they had an average age of 67 years. One-hundred nine patients were diagnosed as MPLCs, and 22 were intrapulmonary metastases (PMs). Based on multivariate analyses, SUVmax was a significant prognostic factor in both synchronous and metachronous clinical-N0 MLCs (p ¼ 0.0060, 0.0451, respectively). Among the overall patients, while pathological diagnosis, maximum tumor dimension, consolidation status, and SUVmax were all significant prognostic factors by a univariate analysis, SUVmax (p ¼ 0.0016) was superior to pathological diagnosis based on the Martini and Melamed classification (p ¼ 0.2258) based on a multivariate analysis. The 5-year survival rate of MPLCs (78.7%) was significantly greater than that of PMs (30.5%) (p ¼ 0.0036). Furthermore, the 5-year survival rate in patients with low SUVmax (91.1%) was far better than that in patients with high SUVmax (17.9%) (p ¼ 0.0001). Conclusion SUVmax on PET was a significant clinical factor that more precisely reflected the prognosis of MLCs with clinical-N0 status, and could be superior to a pathological diagnosis based on the Martini and Melamed classification.
Introduction Recently, there has been a rapid increase in the likelihood of encountering patients with multiple lung cancers (MLCs) due
received July 22, 2014 accepted after revision September 11, 2014 published online December 2, 2014
to the long-term survival of lung cancer patients and improvements in instruments used for early detection, such as thin-section computer tomography (CT) scan and positron
© 2015 Georg Thieme Verlag KG Stuttgart · New York
DOI http://dx.doi.org/ 10.1055/s-0034-1395392. ISSN 0171-6425.
Downloaded by: Universite de Sherbrooke. Copyrighted material.
Thorac Cardiovasc Surg 2015;63:597–603.
Prognostic Significance of SUVmax in Patients with Multiple Lung Cancers emission tomography (PET).1,2 Historically, the Martini and Melamed classification3 is used most often to differentiate between intrapulmonary metastases (PMs) and multiple primary lung cancers (MPLCs). In addition to this valuable criterion, detailed clinical, pathological and genetic/molecular evaluations have been reported to be useful for distinguishing MPLCs from PMs.4–7 However, amid the increasing opportunities to detect small and early-stage lung cancers in daily practice due to improvements in and the routine application of thin-section CT scan, one of the major limitations of the Martini and Melamed classification is that the differential diagnosis between MPLCs and PMs is quite difficult in patients with MLCs, and especially for those in clinicalN0 (c-N0) status. Hence, a consensus has not yet been reached with regard to the preoperative factors that precisely reflect the prognosis for c-N0 multiple lung cancerous lesions. In general, lung cancers that show a wide area of groundgrass opacity (GGO) are considered to have a good prognosis and in most cases their pathologic features are minimally invasive, especially in lung adenocarcinoma.8,9 Furthermore, GGO lesions are considered to have a tendency for multifocal expression but are very rarely metastatic.10–12 On the other hand, radiologically pure-solid nodules are considered to be highly invasive, and postoperative nodal involvement is found in approximately 20% of cases, even in clinical stage IA disease.13,14 Clinically, however, lung cancers exhibit a wide range of grade of malignancies despite their appearances on thin-section CT.15 To address these clinical questions, maximum standardized uptake values (SUVmax) on PET may be helpful clinically for more accurately reflecting the prognosis of MLCs in the preoperative setting, due to previous findings that SUVmax on PET correlates well with cellular proliferation and the aggressiveness of lung cancers.16 In the setting of MLCs, the primary objective of this study was to investigate the clinical factors of MLCs with c-N0 status that more accurately reflect their prognosis.
Hattori et al.
Radiological Findings and Definitions of Multiple Lung Cancers For all 131 patients MLCs, we reviewed the findings of preoperative CT. The size of the tumors was determined preoperatively based on the findings of thin-section CT scan. In addition, all tumors were subsequently evaluated to estimate the extent of GGO lesion in a thin-section CT scan with 2 mm collimation. The lung was photographed with a window level of 500 to 700 H and a window depth of 1,000 to 2,000 H as a “lung window.” The solid component was defined as an area of increased opacification that completely obscured the underlying vascular markings. Ground-grass opacity tumor was defined as an area of a slight, homogeneous increase in density that did not obscure the underlying vascular markings. In the current study, “Solid” tumor was tentatively defined as a tumor in which the ratio of the maximum diameter of consolidation to the maximum tumor diameter (consolidation/tumor ratio, CTR) was equal to 1.0, which only consists of consolidation without GGO radiologically. In contrast, “GGO” tumor was defined as a tumor with 0 CTR < 1.0, which showed pure GGO without a solid component or a tumor with focal nodular opacity that contained both solid and GGO components radiologically. Furthermore, to evaluate the significant prognostic factors in patients with MLCs, we defined the main lesion of MLCs according to the following criteria based on both the duration of tumor detection and the findings of thin-section CT scan in a recent study: (1) among synchronous lesions, the denser tumor, or the larger one when CTR is the same based on thinsection CT findings, (2) among metachronous lesions, second lung tumor detected after resection of the first lung cancers, since these tumors were considered to be a dominant tumor when we decided upon treatment strategies for MLCs. The minimum duration of time, between treatment of the first primary tumor and the appearance of second tumors, that defines metachronous tumors was considered to be 2 years.3
Positron Emission Tomography
Patients and Methods Between 1996 and 2012, 131 patients underwent lung resections and were pathologically diagnosed as MLCs in our institute. For the clinicopathological definition of MPLCs or PMs, our criteria basically relied on the report published by Martini and Melamed.3
Pathological Evaluation With regard to histological studies, all resected specimens were fixed in formalin and sliced at 5 to 10 mm intervals. Both the first and second lung cancers were evaluated microscopically by conventional hematoxylin and eosin staining. All histological materials included in the series were initially assessed by a pathologist at our institute. Basically, PMs were discriminated from MPLCs based on the criteria reported by Martini and Melamed.3 PMs were defined as an independent mass isolated from the primary malignancy with histopathological features identical to the primary tumor and which lacked microscopic features suggesting a primary tumor. Thoracic and Cardiovascular Surgeon
Vol. 63
No. 7/2015
In addition to radiological classifications based on thinsection CT scan, PET was performed and the SUVmax was recorded for the main lesions of all patients with MLCs. In all cases, a PET/CT scan was performed at the Yotsuya Medical Cube (Tokyo, Japan). The technique used for 18F-FDG PET/CT scanning at the Yotsuya Medical Cube was as follows. All patients were asked to fast for at least 6 hours before 18 F-fluorodeoxyglucose (FDG) injection to minimize their blood insulin level and normal tissue glucose uptake. The subjects were injected intravenously with 3.5MBq/kg of 18FFDG, and static emission images were obtained 60 minutes after the injection. Image acquisition was performed using a Discovery ST PET/CT scanner (GE Medical Systems, Waukesha, WI). After CT image acquisition, emission scanning was performed from head to mid-thigh in six bed positions. The acquired PET data were reconstructed to volumetric images with a 2D-OSEM algorithm (2 iterations/15 subsets) incorporating a CT-based attenuation correction. All PET/CT images were interpreted by one or two experienced nuclear medicine radiologists. A workstation (Xeleris; Elegems, Haifa,
Downloaded by: Universite de Sherbrooke. Copyrighted material.
598
Prognostic Significance of SUVmax in Patients with Multiple Lung Cancers
Operation Policy Regarding the operation, a major lung dissection with systemic lymph node dissection was warranted for resectable lung cancer in our institute, whereas intentional segmentectomy is now indicated for part-solid or pure-solid lung cancers 2 cm or smaller. Non-anatomic wedge resection was performed for a few elderly patients or for patients with high cardio-pulmonary risk. However, there are no clear-cut criteria regarding an appropriate operative procedure for MLCs, because it should take several clinical factors into account, such as prior pulmonary resection, cardiopulmonary function, or the presence of contralateral lung lesions. Therefore, sublobar resection is essential procedure for subsolid lesions in patients with MLCs to preserve lung function as much as possible. With regard to the clinical nodal assessment, c-N0 means non-enlarged lymph nodes on CT scan or no uptake on PET/CT. No invasive modalities for mediastinal lymph node staging, such as mediastinoscopy or endobronchial ultrasound-guided transbronchial needle aspiration (EBUS), were used preoperatively in any of these patients in our institute. Intraoperative lymph node dissection or sampling was warranted to confirm the nodal status as much as possible.
Demographic Data and Statistics The medical record of each patient was reviewed with regard to age, sex, pack-year smoking, presence of double cancer, interval between the first and second operations, maximum tumor diameter and CTR based on thin-section CT scan, serum carcinoembryonic antigen level (ng/ml, CEA) and SUVmax on PET of the main lesion. The pathological diagnosis of MPLCs and PMs was also evaluated based on the Martini and Melamed classification.3 A receiver operating characteristic (ROC) curve for predicting the prognosis was generated using SPSS Statistics 21 (SPSS Inc.) by plotting sensitivity versus 1-specificity for various thresholds of several clinical factors. Regarding the method used to select the optimal cutoff value from the ROC curve, we calculated the distance between the point (0, 1) and each observed cutoff point on the ROC curve. The optimal cutoff value was obtained from the point where the distance was minimum. Several clinicopathological factors were investigated to identify factors that significantly reflected the prognosis in patients with c-N0 MLCs. Univariate and multivariate analyses were performed using the Cox proportional hazard model with SPSS Statistics 21 (SPSS Inc.). Forward and backward stepwise procedures were used to determine the combination of factors that were essential for predicting the prognosis. Continuous data are shown as means and standard deviation (SD) for normality. Survival was calculated by the Kaplan-Meier method starting from the date of the last surgery for the MLCs. Statistical analysis was considered to be significant when the probability value was less than 0.05.
599
Results Among 131 surgically resected patients with c-N0 MLCs, 66 were men and 65 were women. The patients ranged in age from 40 to 84 years, with an average of 67 years. With regard to pathological status, 109 were diagnosed as MPLCs, and 22 were PMs. In patients with multiple c-N0 lung cancers, pathological-N0 was found in 123 (94%), pathological-N1 in 4 (3%), and pathological-N2 in 4 (3%), respectively. Furthermore, pathological nodal involvement was revealed in 5 (22.7%) patients of PMs, while 3 (2.7%) patients of MPLCs.
Table 1 Relationships between several clinical factors and pathological status in patients with multiple clinical-N0 lung cancers Clinical factors
Number of patients (%)
Total
131
Downloaded by: Universite de Sherbrooke. Copyrighted material.
Israel) was used for image display and analysis, and the SUVmax of the primary tumor was obtained.
Hattori et al.
Gender Male
66 (50.4%)
Female
65 (49.6%)
Age (y) 70
81 (61.8%)
70 >
50 (38.2%)
Pack-year smoking 20
49 (37.4%)
20 >
82 (62.6%)
Maximum tumor dimension (mm) 30
109 (83.2%)
30
597
Prognostic Significance of the Standardized Uptake Value on Positron Emission Tomography in Patients with Multiple Clinical-N0 Lung Cancers Aritoshi Hattori1
Kenji Suzuki1
Takeshi Matsunaga1
1 Department of General Thoracic Surgery, Juntendo University School
of Medicine, Tokyo, Japan
Kazuya Takamochi1
Shiaki Oh1
Address for correspondence Kenji Suzuki, General Thoracic Surgery, Juntendo University School of Medicine, 1-3, 3-chome, Hongo, Bunkyo-ku, Tokyo 113-8432, Japan (e-mail: [email protected]).
Abstract
Keywords
► multiple primary lung cancers ► intrapulmonary metastases ► positron emission tomography ► prognosis
Background While there have been many attempts to differentiate multiple lung cancers (MLCs) using the clinicopathological presentation and molecular profile, there are still some controversies regarding the prognostic factors for MLCs with clinical-N0 status. Patients and Methods Between 1996 and 2012, 131 patients were diagnosed as MLCs pathologically. The main lesion of MLCs was defined as follows: (1) among synchronous lesions, the radiologically denser or larger tumor on thin-section computed tomography (CT) or (2) the second tumor among metachronous lesions. 18F-fluorodeoxyglucose uptake on positron emission tomography (PET) scan was examined to evaluate maximum standardized uptake value (SUVmax) of the main tumor. Results Among 131 patients with clinical-N0 status, 66 were men and 65 were women and they had an average age of 67 years. One-hundred nine patients were diagnosed as MPLCs, and 22 were intrapulmonary metastases (PMs). Based on multivariate analyses, SUVmax was a significant prognostic factor in both synchronous and metachronous clinical-N0 MLCs (p ¼ 0.0060, 0.0451, respectively). Among the overall patients, while pathological diagnosis, maximum tumor dimension, consolidation status, and SUVmax were all significant prognostic factors by a univariate analysis, SUVmax (p ¼ 0.0016) was superior to pathological diagnosis based on the Martini and Melamed classification (p ¼ 0.2258) based on a multivariate analysis. The 5-year survival rate of MPLCs (78.7%) was significantly greater than that of PMs (30.5%) (p ¼ 0.0036). Furthermore, the 5-year survival rate in patients with low SUVmax (91.1%) was far better than that in patients with high SUVmax (17.9%) (p ¼ 0.0001). Conclusion SUVmax on PET was a significant clinical factor that more precisely reflected the prognosis of MLCs with clinical-N0 status, and could be superior to a pathological diagnosis based on the Martini and Melamed classification.
Introduction Recently, there has been a rapid increase in the likelihood of encountering patients with multiple lung cancers (MLCs) due
received July 22, 2014 accepted after revision September 11, 2014 published online December 2, 2014
to the long-term survival of lung cancer patients and improvements in instruments used for early detection, such as thin-section computer tomography (CT) scan and positron
© 2015 Georg Thieme Verlag KG Stuttgart · New York
DOI http://dx.doi.org/ 10.1055/s-0034-1395392. ISSN 0171-6425.
Downloaded by: Universite de Sherbrooke. Copyrighted material.
Thorac Cardiovasc Surg 2015;63:597–603.
Prognostic Significance of SUVmax in Patients with Multiple Lung Cancers emission tomography (PET).1,2 Historically, the Martini and Melamed classification3 is used most often to differentiate between intrapulmonary metastases (PMs) and multiple primary lung cancers (MPLCs). In addition to this valuable criterion, detailed clinical, pathological and genetic/molecular evaluations have been reported to be useful for distinguishing MPLCs from PMs.4–7 However, amid the increasing opportunities to detect small and early-stage lung cancers in daily practice due to improvements in and the routine application of thin-section CT scan, one of the major limitations of the Martini and Melamed classification is that the differential diagnosis between MPLCs and PMs is quite difficult in patients with MLCs, and especially for those in clinicalN0 (c-N0) status. Hence, a consensus has not yet been reached with regard to the preoperative factors that precisely reflect the prognosis for c-N0 multiple lung cancerous lesions. In general, lung cancers that show a wide area of groundgrass opacity (GGO) are considered to have a good prognosis and in most cases their pathologic features are minimally invasive, especially in lung adenocarcinoma.8,9 Furthermore, GGO lesions are considered to have a tendency for multifocal expression but are very rarely metastatic.10–12 On the other hand, radiologically pure-solid nodules are considered to be highly invasive, and postoperative nodal involvement is found in approximately 20% of cases, even in clinical stage IA disease.13,14 Clinically, however, lung cancers exhibit a wide range of grade of malignancies despite their appearances on thin-section CT.15 To address these clinical questions, maximum standardized uptake values (SUVmax) on PET may be helpful clinically for more accurately reflecting the prognosis of MLCs in the preoperative setting, due to previous findings that SUVmax on PET correlates well with cellular proliferation and the aggressiveness of lung cancers.16 In the setting of MLCs, the primary objective of this study was to investigate the clinical factors of MLCs with c-N0 status that more accurately reflect their prognosis.
Hattori et al.
Radiological Findings and Definitions of Multiple Lung Cancers For all 131 patients MLCs, we reviewed the findings of preoperative CT. The size of the tumors was determined preoperatively based on the findings of thin-section CT scan. In addition, all tumors were subsequently evaluated to estimate the extent of GGO lesion in a thin-section CT scan with 2 mm collimation. The lung was photographed with a window level of 500 to 700 H and a window depth of 1,000 to 2,000 H as a “lung window.” The solid component was defined as an area of increased opacification that completely obscured the underlying vascular markings. Ground-grass opacity tumor was defined as an area of a slight, homogeneous increase in density that did not obscure the underlying vascular markings. In the current study, “Solid” tumor was tentatively defined as a tumor in which the ratio of the maximum diameter of consolidation to the maximum tumor diameter (consolidation/tumor ratio, CTR) was equal to 1.0, which only consists of consolidation without GGO radiologically. In contrast, “GGO” tumor was defined as a tumor with 0 CTR < 1.0, which showed pure GGO without a solid component or a tumor with focal nodular opacity that contained both solid and GGO components radiologically. Furthermore, to evaluate the significant prognostic factors in patients with MLCs, we defined the main lesion of MLCs according to the following criteria based on both the duration of tumor detection and the findings of thin-section CT scan in a recent study: (1) among synchronous lesions, the denser tumor, or the larger one when CTR is the same based on thinsection CT findings, (2) among metachronous lesions, second lung tumor detected after resection of the first lung cancers, since these tumors were considered to be a dominant tumor when we decided upon treatment strategies for MLCs. The minimum duration of time, between treatment of the first primary tumor and the appearance of second tumors, that defines metachronous tumors was considered to be 2 years.3
Positron Emission Tomography
Patients and Methods Between 1996 and 2012, 131 patients underwent lung resections and were pathologically diagnosed as MLCs in our institute. For the clinicopathological definition of MPLCs or PMs, our criteria basically relied on the report published by Martini and Melamed.3
Pathological Evaluation With regard to histological studies, all resected specimens were fixed in formalin and sliced at 5 to 10 mm intervals. Both the first and second lung cancers were evaluated microscopically by conventional hematoxylin and eosin staining. All histological materials included in the series were initially assessed by a pathologist at our institute. Basically, PMs were discriminated from MPLCs based on the criteria reported by Martini and Melamed.3 PMs were defined as an independent mass isolated from the primary malignancy with histopathological features identical to the primary tumor and which lacked microscopic features suggesting a primary tumor. Thoracic and Cardiovascular Surgeon
Vol. 63
No. 7/2015
In addition to radiological classifications based on thinsection CT scan, PET was performed and the SUVmax was recorded for the main lesions of all patients with MLCs. In all cases, a PET/CT scan was performed at the Yotsuya Medical Cube (Tokyo, Japan). The technique used for 18F-FDG PET/CT scanning at the Yotsuya Medical Cube was as follows. All patients were asked to fast for at least 6 hours before 18 F-fluorodeoxyglucose (FDG) injection to minimize their blood insulin level and normal tissue glucose uptake. The subjects were injected intravenously with 3.5MBq/kg of 18FFDG, and static emission images were obtained 60 minutes after the injection. Image acquisition was performed using a Discovery ST PET/CT scanner (GE Medical Systems, Waukesha, WI). After CT image acquisition, emission scanning was performed from head to mid-thigh in six bed positions. The acquired PET data were reconstructed to volumetric images with a 2D-OSEM algorithm (2 iterations/15 subsets) incorporating a CT-based attenuation correction. All PET/CT images were interpreted by one or two experienced nuclear medicine radiologists. A workstation (Xeleris; Elegems, Haifa,
Downloaded by: Universite de Sherbrooke. Copyrighted material.
598
Prognostic Significance of SUVmax in Patients with Multiple Lung Cancers
Operation Policy Regarding the operation, a major lung dissection with systemic lymph node dissection was warranted for resectable lung cancer in our institute, whereas intentional segmentectomy is now indicated for part-solid or pure-solid lung cancers 2 cm or smaller. Non-anatomic wedge resection was performed for a few elderly patients or for patients with high cardio-pulmonary risk. However, there are no clear-cut criteria regarding an appropriate operative procedure for MLCs, because it should take several clinical factors into account, such as prior pulmonary resection, cardiopulmonary function, or the presence of contralateral lung lesions. Therefore, sublobar resection is essential procedure for subsolid lesions in patients with MLCs to preserve lung function as much as possible. With regard to the clinical nodal assessment, c-N0 means non-enlarged lymph nodes on CT scan or no uptake on PET/CT. No invasive modalities for mediastinal lymph node staging, such as mediastinoscopy or endobronchial ultrasound-guided transbronchial needle aspiration (EBUS), were used preoperatively in any of these patients in our institute. Intraoperative lymph node dissection or sampling was warranted to confirm the nodal status as much as possible.
Demographic Data and Statistics The medical record of each patient was reviewed with regard to age, sex, pack-year smoking, presence of double cancer, interval between the first and second operations, maximum tumor diameter and CTR based on thin-section CT scan, serum carcinoembryonic antigen level (ng/ml, CEA) and SUVmax on PET of the main lesion. The pathological diagnosis of MPLCs and PMs was also evaluated based on the Martini and Melamed classification.3 A receiver operating characteristic (ROC) curve for predicting the prognosis was generated using SPSS Statistics 21 (SPSS Inc.) by plotting sensitivity versus 1-specificity for various thresholds of several clinical factors. Regarding the method used to select the optimal cutoff value from the ROC curve, we calculated the distance between the point (0, 1) and each observed cutoff point on the ROC curve. The optimal cutoff value was obtained from the point where the distance was minimum. Several clinicopathological factors were investigated to identify factors that significantly reflected the prognosis in patients with c-N0 MLCs. Univariate and multivariate analyses were performed using the Cox proportional hazard model with SPSS Statistics 21 (SPSS Inc.). Forward and backward stepwise procedures were used to determine the combination of factors that were essential for predicting the prognosis. Continuous data are shown as means and standard deviation (SD) for normality. Survival was calculated by the Kaplan-Meier method starting from the date of the last surgery for the MLCs. Statistical analysis was considered to be significant when the probability value was less than 0.05.
599
Results Among 131 surgically resected patients with c-N0 MLCs, 66 were men and 65 were women. The patients ranged in age from 40 to 84 years, with an average of 67 years. With regard to pathological status, 109 were diagnosed as MPLCs, and 22 were PMs. In patients with multiple c-N0 lung cancers, pathological-N0 was found in 123 (94%), pathological-N1 in 4 (3%), and pathological-N2 in 4 (3%), respectively. Furthermore, pathological nodal involvement was revealed in 5 (22.7%) patients of PMs, while 3 (2.7%) patients of MPLCs.
Table 1 Relationships between several clinical factors and pathological status in patients with multiple clinical-N0 lung cancers Clinical factors
Number of patients (%)
Total
131
Downloaded by: Universite de Sherbrooke. Copyrighted material.
Israel) was used for image display and analysis, and the SUVmax of the primary tumor was obtained.
Hattori et al.
Gender Male
66 (50.4%)
Female
65 (49.6%)
Age (y) 70
81 (61.8%)
70 >
50 (38.2%)
Pack-year smoking 20
49 (37.4%)
20 >
82 (62.6%)
Maximum tumor dimension (mm) 30
109 (83.2%)
30
