| Part I. Differentiation of an adenocarcinoma with bronchioloalveolar carcinoma features from the other non-small cell lunger cancers subtypes with metabolic and anatomic characteristics using PET/CT and MSCTPurpose:Since the latest revisions in the WHO/International Association for the Study of Lung Cancer classification in 2004, most adenocarcinomas with aerogenous spread have to be referred to as adenocarcinomas with bronchioloalveolar carcinoma(BAC) features instead of pure BAC because of the presence of a mixed histologic subtype or stromal, nodal, pleural, and vascular invasion. a pure BAC that has no invasive components represents about 3% to 4% of all lung cancers, whereas an adenocarcinoma with BAC features is far more common. F-18 fluorodeoxyglucose (FDG) PET has been shown to be useful to detect pulmonary malignancy. F-18 FDG uptake reflecting the tumor glucose metabolic rate varies widely and depends on the histologic type. Some studies have shown variable uptake including an absence of F-18 FDG uptake in primary BAC, BAC occasionally has been reported to be falsely negative on F-18 FDG PET studies. On the other hand, Fibrotic foci and adenocarcinoma components are usually depicted as consolidation and the BAC component is depicted as a ground-glass opacity on CT scanning. Because an adenocarcinoma with BAC features has BAC components, the goal of our study was to demonstrate the clinical usefulness of combined positron emission tomography/computed tomography(PET/CT) and multislice computed tomography(MSCT) for differentiation an adenocarcinoma with bronchioloalveolar carcinoma(BAC) features from the other non-small cell lung cancers(NSCLCs) subtypes. Methods:This was a retrospective study. One hundred and seventy two patients with focal peripheral lung cancers were included in this study and underwent the PET/CT and MSCT examination. The time interval between MSCT and PET/CT examinations was less than 30 days. Patients who had received prior anticancer treatment were excluded. None of the patients had insulin-dependent diabetes and the serum glucose levels in all patients just before F-18 FDG was injected were less than 120mg/dl. The diagnosis of the lesion was made by surgical histopathology. All patients received a separate thoracic CT examination at our medical center using a 4-detector-row CT(GE Discovery LS) and(or) 16-detector-row CT(GE LightSpeed). The CT examination were obtained with the patients in a supine position and CT images were obtained from the lung apices through the bases. The GE MSCT examination parameters were the following:collimation,4×5.0mm; tube rotation time, 0.8s; pitch,0.75; 300mA; 120 kV. Image data were reconstructed at a slice thickness setting of 5.0mm and(or) collimation,16×1.250mm; tube rotation time,0.8s; pitch, 1.375; 300mA; 120 kV. Image data were reconstructed at a slice thickness setting of 1.250mm. Whole-body or thorthorax imaging was performed using a combined PET/CT scanner (Discovery LS; GE Healthcare). All patients fasted for at least 6h before the PET/CT scan. Sixty minutes after intravenous injection of approximately 555 MBq (15 mCi) of FDG, CT scan was performed from the meatus of the ear to the mid thigh. This PET/CT scanner was used for four-slice multidetector helical CT scan, technical parameters were:a detector row configuration of 4×5 mm,6:1 pitch, gantry rotation speed of 0.8 s, table speed of 30 mm per gantry rotation,140 kVp,80 mA, a slice thickness of 4.25mm. A whole-body PET emission scan for the same axial coverage was performed beginning at the thighs without breath holding, with 5-min acquisition per bed position. After the data acquisition, attenuation correction of the PET emission data was performed by CT-based attenuation correction (CTAC). Image reconstruction was performed with an ordered-subset expectation maximization(OSEM) iterative algorithm (2 iterations,28 subsets). PET image, CT image, and fused PET/CT image were available for review in axial, coronal, and sagittal planes by using the manufacturer's review station (Xeleris, GE Healthcare). After a whole-body PET/CT scan, all patients were operated in our hospital during 3 months. Pathologic specimens were evaluated by an experienced pathologist. The specimens obtained by surgical resection were fixed routinely in formalin and in paraffin. The specimens were stained with hematoxylin and eosin. We categorized NSCLC into an adenocarcinoma with BAC features and the other NSCLCs subtypes according to the WHO/International Association for the Study of Lung Cancer classification in 2004. CT features analyzed included:tumor size and margins features: solid with spiculated, lobulated, smooth margins or ground glass margins(ie, mixed solid). Speculation was defined by the presence of 2-mm or thicker strands extending from the nodule margin into the lung parenchyma without reaching the pleural surface. For measuring tumor size, the MSCT images technical parameters were:pulmonary window setting(window width,1700 Hounsfield units [HU];level,-600HU) and a mediastinal window setting (window width,350HU; level,25HU) and obtain the following information:the maximum dimension of a tumor on pulmonary window setting images (pDmax); the largest dimension perpendicular to the maximum axis on pulmonary window setting images (pDperp); the maximum dimension of a tumor on mediastinal window setting images (mDmax); the largest dimension perpendicular to the maximum axis on mediastinal window setting images (mDperp). The tumor shadow disappearance rate(TDR) was calculated. A small region of interest (ROI) was manually placed on the axial tomograms in correspondence with the visible margins of the lesion in an area of abnormal F-18 FDG uptake. Semiquantitative analysis of the lesion was performed by calculating the SUVmax of the lesion. Univariate and multivariable analyses were performed by the logistic regression procedure to determine the relationship between differentiating an adenocarcinoma with BAC features from the other NSCLCs subtypes and the following clinical or radiologic findings:age; sex; tumor margins features; tumor dimensions (pDmax, mDmax); TDR and SUVmax. One-way ANOVA was used to compare mean measurements between adenocarcinoma with BAC features and the other NSCLCs subtypes. Statistical software (SPSS, version12.0; SPSS Inc) was used for the analysis. Results: All patients underwent successful surgery and pathologic examination confirmed that 39 of 172 patients were proved to adonocarcinomas with BAC features,133 of 172 patients were proved to the other NSCLCs subtypes. Univariate analysis revealed 5 potential factors related to differentiation an adenocarcinoma with BAC features from the other NSCLCs subtypes:speculated margin; mix solid/ground grass; the maximum dimension of a tumor on mediastinal window setting images(mDmax); the tumor shadow disappearance rate(TDR) and SUVmax. Forward LR multivariable logistic regression analysis of SUVmax and CT features showed that SUVmax, mix solid/ground grass and TDR were significant finding in differentiating tumor types (P=0.004, P=0.012 and P<0.001). Other features on CT did not further contribute to the difference of tumor type once SUVmax, mix solid/ground grass and TDR results were utilized. TDR was a more clinically useful factors related to differentiation an adenocarcionoma with BAC features from other NSCLCs subtypes than SUVmax and the other CT features. Conclusions:In the current study, the SUVmax of an adenocarcinoma with BAC features was significantly lower than the SUVmax of the other NSCLCs subtypes. Univariate analysis revealed that SUVmax was an important factors related to differentiation an adenocarcionoma with BAC features from other NSCLCs subtypes. In terms of the CT features, Univariate analysis revealed that mixed solid/ground glass; mDmax; speculated margin and TDR were important CT features that differentiated an adenocarcinoma with BAC features from the other NSCLCs subtypes in the current study. Mixed solid/ground glass tumor was significantly related with an adenocarcinoma with BAC features. CT feature of spiculation margin was not a feature of an adenocarcinoma with BAC features but was seen in other NSCLCs subtypes. This result was in accord with other reports. Other CT findings such as lobulated margin; smooth margin and pDmax could not differentiate an adenocarcinomawith BAC features from the other NSCLC subtypes. The TDR was a new radiologic parameter proposed by Takamochi et al, which was calculated from the tumor shadow sizes on pulmonary window setting images and those on mediastinal window setting images. High-density areas in a tumor shadow on pulmonary window setting images would be preserved on mediastinal window setting images, and hazy increased density areas on pulmonary window setting images would disappear on mediastinal window setting images. TDR might represent the ratio of BAC components to invasive component in a tumor. In the current study, the TDR of an adenocarcinoma with BAC features was significantly higher than the TDR of the other NCSLC subtypes. Univariate analysis revealed that the TDR was more important CT features to differentiate an adenocarcinoma with BAC features from the other NSCLCs subtypes than other CT features, because the TDR was more objective. Although Univariate analysis revealed that speculated margin; mDmax were potential factors related to differentiation an adenocarcionoma with BAC features from the other NSCLCs subtypes, these features were not statistically contributory in the forward LR multivariable logistic regression. The difference in SUVmax, mix solid/ground grass and TDR between an adenocarcinoma with BAC features and the other NSCLCs subtypes were far more significant in the forward LR multivariable logistic analysis and superseded other CT features as useful factors of tumor type. In a word, we could differentiate accurately an adenocarcionoma with BAC features from other NSCLCs subtypes by the combination of the CT features and the SUVmax for NSCLCs. It was well known that the diagnosis of an adenocarcinoma with BAC features was depended on histology, which was the final arbiter. It was difficult to accurately diagnose an adenocarcinoma with BAC features without surgical specimens. In the current study, the SUVmax of an adenocarcinoma with BAC features is significantly lower than the SUVmax of other NSCLCs subtypes, the TDR of an adenocarcinoma with BAC features is significantly higher than the TDR of other NSCLCs subtypes. Moreover, some CT features such as speculated margin; mix solid/ground grass; mDmax are the important CT features to predict the presence of an adenocarcinoma with BAC features. Therefore, we conclude that combined SUVmax and CT features have the potential to differentiate an adenocarcinoma with BAC features from other NSCLCs subtypes at pre-operative stages and even for inoperable patients. PartⅡ. The clinical usefulness value of combined PET/CT and MSCT scan in adenocarcinoma with bronchioloalveolar carcinoma features for evaluating the intrathoracic lymph node metastasesObjective:Bronchioloalveolar carcinoma (BAC) is a subtype of adenocarcinoma and manifests as lepidic growth of tumor cells along the alveoli without stromal, vascular, lymphatic, or pleural invasion. According to this definition, BAC comprises approximately 1%～4% of non-small cell lung cancer (NSCLC). However, Since the latest revisions in the WHO/International Association for the Study of Lung Cancer classification in 2004, most adenocarcinomas with aerogenous spread have to be referred to as adenocarcinomas with BAC features instead of pure BAC because of the presence of a mixed histologic subtype or stromal, nodal, pleural, and vascular invasion. Although pure BAC is uncommon, adenocarcinoma with BAC features is a common tumor. Adenocarcinoma with BAC features comprise approximately～50% of adenocarcinomas. Adenocarcinoma with BAC features seem to be increasing in incidence in the past several years. Moreover, with the introduction of spiral computed tomography (CT) for lung cancer scan and early detection programs, small peripheral lesions are being detected, many of which are adenocarcinoma with BAC features. The original feature of adenocarcinoma with BAC features is the intrapulmonary dissemination of the disease due to bronchial or lymphatic spread, leading to a high frequency of local or regional evolution and a rare metastatic dissemination. To the best of our knowledge, no published study has concentrated on the application of combined integrated positron emission tomography/computed tomography (PET/CT) and multislice computed tomography(MSCT) scan at the level of the intrathoracic lymph node in patients with adenocarcinoma with BAC features. Several investigators have indicated that the maximum□nalyzing□ed uptake value (SUVmax) of the primary tumor is a prognostic factor in patients with NSCLC. Details about adenocarcinoma with BAC features, a histologic subtypes of NSCLC, have not been reported.The goal of our study were to demonstrate the clinical usefulness value of combined positron emission tomography/computed tomography (PET/CT) and multislice computed tomography(MSCT) scan for adenocarcinoma with bronchioloalveolar carcinoma (BAC) features, through evaluating the relationship between the intrathoracic lymph node metastases and maximum standardized uptake value (SUVmax), tumor shadow disappearance rate(TDR), tumor size of the primary tumor and the ratio of BAC component and□nalyzing the correlation of SUVmax, tumor shadow disappearance rate(TDR), tumor size and the ratio of BAC component. Methods:This was a retrospective study. Thirty-nine patients with focal peripheral lung adenocarcinoma with BAC features were included in this study and underwent the PET/CT and MSCT scan. Nineteen patients were women and 20 were men. None of the patients had insulin-dependent diabetes and the serum glucose levels in all patients just before 18F-FDG was injected were less than 120mg/dl. The diagnosis of the lesion was made by surgical histopathology. All patients received a separate thoracic CT examination at our medical center using a 4-detector-row CT(GE Discovery LS) and(or) 16-detector-row CT(GE LightSpeed). The CT examination were obtained with the patients in a supine position and CT images were obtained from the lung apices through the bases. The GE MSCT examination parameters were the following:collimation,4×5.0mm; tube rotation time, 0.8s; pitch,0.75; 300mA; 120 kV. Image data were reconstructed at a slice thickness setting of 5.0mm and(or) collimation,16×1.250mm; tube rotation time,0.8s; pitch, 1.375; 300mA; 120 kV. Image data were reconstructed at a slice thickness setting of 1.250mm.Whole-body imaging was performed using a combined PET/CT scanner (Discovery LS; GE Healthcare; Milwaukee, WI). All patients fasted for at least 6h before the PET/CT scan. Sixty minutes after intravenous injection of approximately 555 MBq (15 mCi) of FDG., CT scan was performed from the meatus of the ear to the mid thigh. This PET/CT scanner was used for four-slice multidetector helical CT scan, technical parameters were:a detector row configuration of 4×5 mm,6:1 pitch, gantry rotation speed of 0.8 s, table speed of 30 mm per gantry rotation,140 kVp,80 mA, a slice thickness of 4.25mm. A whole-body PET emission scan for the same axial coverage was performed beginning at the thighs without breath holding, with 5-min acquisition per bed position. After the data acquisition, attenuation correction of the PET emission data was performed by CT-based attenuation correction (CTAC). Image reconstruction was performed with an ordered-subset expectation maximization(OSEM) iterative algorithm (2 iterations,28 subsets). PET image, CT image, and fused PET/CT image were available for review in axial, coronal, and sagittal planes by using the manufacturer's review station (Xeleris, GE Healthcare). After a whole-body PET/CT scan, all patients were operated in our hospital during 3 months. Surgical procedures included a complete resection of the lesion with the hilar and mediastinal lymph node dissection. Pathologic specimens were evaluated by an experienced pathologist. The specimens obtained by surgical resection were fixed routinely in formalin and in paraffin. The measurement of the ratio of BAC component is as follows in this retrospective study:Five micrometer sections were cut and stained with hematoxylin and eosin. Each slide was observed under ocular field with grid (100 grids per field) and counted to get the ratio of BAC component. The average of BAC component of all slides was then taken for the tumor case. The process was repeated twice, and the final average was used as the ratio of BAC component for a given tumor case. The ratio of BAC component was graded using the following scale:BAC1=1%～24%, BAC2=25%-49%, BAC3=50%～74%, BAC4=75%-99%. For measuring tumor size, the CT images from the PET/CT technical parameters were:pulmonary window setting(window width,1700 Hounsfield units [HU];level,-600HU) and a mediastinal window setting (window width,350HU; level,25HU) and obtain the following information:the maximum dimension of a tumor on pulmonary window setting images (pDmax); the largest dimension perpendicular to the maximum axis on pulmonary window setting images (pDperp); the maximum dimension of a tumor on mediastinal window setting images (mDmax); the largest dimension perpendicular to the maximum axis on mediastinal window setting images (mDperp). The tumor shadow disappearance rate(TDR) was calculated. A small region-of-interest (ROI) was manually placed on the axial tomograms in correspondence with the visible margins of the lesion in an area of abnormal FDG uptake. Semiquantitative analysis of the lesion was performed by calculating the SUVmax of the lesion. To elucidate variables for the prediction of intrathoracic lymph node metastases, we performed logistic regression analyses. The correlation of SUVmax, tumor size and the ratio of BAC components was analysed, using the Bivariate. Statistical software (SPSS, version12.0; SPSS Inc) was used for the analysis. The receiver operating characteristic(ROC) curve and the ROC area, the latter being a parameter to measure how well a certain variable(tumor size, SUVmax and the ratio of BAC component) can assess propensity of intrathoracic lymph node metastases, were analysed by statistical software(MedCalc, version 7.5).Results:All patients underwent successful surgery, and pathologic examination confirmed that 32 of 109excised nodal groups in 17 patients were proved to be positive for malignancy. Univariate analysis revealed 4 potential factors related to intrathoracic lymph node metastases:SUVmax(P=0.008); TDR(P=0.029); mDmax(P=0.046); the ratio of BAC component (P=0.013). The maximum dimension of a tumor on pulmonary window setting images (pDmax, P=0.424) had no significance. An receiver operating characteristic(ROC) curve based on SUVmax, TDR, mDmax and the ratio of BAC component was constructed, the area under curve(AUC) was 82.6%,82.5%,66.0% and 85.8% separately. There was no statistical significance between AUC of SUVmax and AUC of the ratio of BAC component(Z=0.643,P=0.520); There was no statistical significance between AUC of SUVmax and AUC of TDR(Z=0.018,P=0.986); There was no statistical significance between AUC of TDR and AUC of the ratio of BAC component (Z=0.716,P=0.474). The AUC of SUVmax, TDR and AUC of the ratio of BAC component were significant higher than AUC of mDmax(Z=2.114,P=0.035; Z=2.001, P=0.045; Z=2.756, P=0.006).The SUVmax and the ratio of BAC component were significant inverse correlation (r=-0.838, P<0.01). The mDmax and the ratio of BAC component were significant inverse correlation (r=-0.678, P<0.01). The SUVmax and mDmax were significant correlation (r=0.598, P<0.01). The TDR and the SUVmax were significant inverse correlation (r=-0.662, P<0.01). The TDR and the ratio of BAC component were significant correlation(r=0.849, P<0.01). The TDR and the mDmax were significant inverse correlation (r=-0.616, P<0.01). Conclusions: In this study, we calculated ROC for SUVmax to determine the propensity of intrathoracic lymph node metastases. The AUC was 82.6%, suggested that high SUVmax in the primary tumor was followed with a greater propensity to have nodal metastases. According to positive likelihood ratio, a SUVmax cut-off of 7.6 was the best threshold to discriminate lesion with or without intrathoracic lymph node metastases, PET/CT had a sensitivity 72.2%, specificity 90%. Although the revised WHO definition strictly defines BAC as having absolutely no evidence of invasion, adenocarcinoma can display a range of BAC features from predominant BAC with only a small focal area of invasion to a lesion that has BAC features only at the periphery of the tumor. Few studies explore the significance of these differences. The ratio of BAC component in the tumor seems to be controversial. In our study,46% of patients with adenocarcinoma with BAC features had intrathoracic lymph node metastases. But published paper reported that of patients with adenocarcinoma with BAC features,10%～25% have mediastinal nodal involvement.In our study, majority patients with intrathoracic lymph node metastases had low ratio of BAC component, may be this was the reason that our study had high incidence of intrathoracic lymph node metastases. Study limitation was that because there were high correlation among SUVmax, TDR, mDmax, and the ratio of BAC component, multivariate regress of factors with intrathoracic lymph nodes metastasis cannot be analysised. Although the ratio of BAC components is a useful indicator for intrathoracic lymph node metastases, it is difficult to accurately diagnose this indicator without surgical specimens. The SUVmax and TDR obtained by PET/CT and MSCT showed a good correlation with the ratio of BAC components. Moreover, the SUVmax and TDR actually showed a strong correlation with incidence of intrathoracic lymph node metastses of adenocarcinoma with BAC features. Therefore, combined PET/CT and MSCT scan would successfully predict the incidence of intrathoracic lymph node metastases at pre-operative stages and even for inoperable patients. Background:A pure BAC that has no invasive components represents about 3% to 4% of all lung cancers, whereas an adenocarcinoma with BAC features is far more common. An adenocarcinoma with BAC features has a much better prognosis than the other adenocarcinoma subtypes with a similar stage. There are scant studies, which have evaluated the differences in uptake of F-18 FDG combined with MSCT features based on tumor type. Objectives:The goal of our study was to demonstrate the clinical usefulness of combined positron emission tomography/computed tomography(PET/CT) and multislice computed tomography(MSCT) for differentiation an adenocarcinoma with bronchioloalveolar carcinoma(BAC) features from the other non-small cell lung cancers(NSCLCs) subtypes. Methods:This was a retrospective study. One hundred and seventy two patients with focal peripheral lung cancers were included in this study and underwent the PET/CT and MSCT examination. Results:All patients underwent successful surgery and pathologic examination confirmed that 39 of 172 patients were proved to adonocarcinomas with BAC features,133 of 172 patients were proved to the other NSCLCs subtypes. Univariate analysis revealed 5 potential factors related to differentiation an adenocarcinoma with BAC features from the other NSCLCs subtypes:speculated margin; mix solid/ground grass; the maximum dimension of a tumor on mediastinal window setting images(mDmax); the tumor shadow disappearance rate(TDR) and SUVmax. Forward LR multivariable logistic regression analysis of SUVmax and CT features showed that SUVmax, mix solid/ground grass and TDR were significant finding in differentiating tumor types (P=0.004, P=0.012 and P<0.001). Other features on CT did not further contribute to the difference of tumor type once SUVmax, mix solid/ground grass and TDR results were utilized. TDR was a more clinically useful factors related to differentiation an adenocarcionoma with BAC features from other NSCLCs subtypes than SUVmax and the other CT features. Conclusions:Combined SUVmax and CT features have the potential to differentiate an adenocarcinoma with BAC features from the other NSCLCs subtypes. Objective:The goal of our study were to demonstrate the clinical usefulness of positron emission tomography/computed tomography (PET/CT) for adenocarcinoma with bronchioloalveolar carcinoma (BAC) features, through evaluating the relationship between the intrathoracic lymph node metastases and maximum standardized uptake value (SUVmax), tumor size of the primary tumor and the ratio of BAC component and analysing the correlation of SUVmax, tumor size and the ratio of BAC component. Methods:This was a retrospective study. Forty-five patients with focal peripheral lung adenocarcinoma with BAC features were included in this study and underwent the PET/CT scan. Twenty-one patients were women and 24 were men. None of the patients had insulin-dependent diabetes and the serum glucose levels in all patients just before 18F-FDG was injected were less than 120mg/dl. The diagnosis of the lesion was made by surgical histopathology. Results: All patients underwent successful surgery, and pathologic examination confirmed that 34 of 118 excised nodal groups in 18 patients were proved to be positive for malignancy. Univariate analysis revealed 3 potential factors related to intrathoracic lymph node metastases:SUVmax (P=0.002);the ratio of BAC component (P=0.002);maximum dimension of a tumor on mediastinal window setting images (mDmax, P=0.025). The maximum dimension of a tumor on pulmonary window setting images (pDmax, P=0.373) had no significance. An receiver operating characteristic(ROC) curve based on SUVmax, mDmax and the ratio of BAC component was constructed, the area under curve(AUC) was 85.2%,70.3%and 81.5% separately. There was no statistical significance between AUC of SUVmax and AUC of the ratio of BAC component(Z=0.901, P=0.368). The AUC of SUVmax and AUC of the ratio of BAC component were significant higher than AUC of mDmax(Z=2.112,P=0.035; Z=2.016,P=0.042).The SUVmax and the ratio of BAC component were significant inverse correlation (r=-0.85, P<0.01). The mDmax and the ratio of BAC component were significant inverse correlation (r=-0.69, P<0.01). The SUVmax and mDmax were significant correlation (r=0.60, P<0.01). Conclusions: PET/CT would be clinically useful for adenocarcinoma with BAC features, because SUVmax obtained by PET/CT can predict the incidence of intrathoracic lymph node metastases at pre-operative stages and even for inoperable patients. |
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