Letters to the Editor
Lymph Node/Tumor SUVmax Ratio Can Predict Metastasis to Mediastinal Lymph Nodes in Lung Cancer Patients To the Editor: We were interested to read the article by Evison et al.1 published in the January 2015 issue of Journal of Thoracic Oncology. We appreciated the idea of proposing a risk stratification model for negative lymph nodes by endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) in lung cancer patients. The proposed model increased the negative predictive value of EBUSTBNA from 91%2 to approximately 99%. We believe that this model can help to discriminate patients that may directly proceed to curative treatment after a negative EBUS-TBNA. On the basis of this model, an EBUS-TBNA negative lymph node needs no further evaluation if the lymph node maximum standardized uptake value (SUVmax) is lower than 4, the SUVmax ratio between lymph node and primary tumor (LN/T SUVmax) is lower than 0.4, and the lymph node has homogeneous echogenecity during ultrasonographic assessment.1 In the absence of distant metastasis, proper staging of mediastinum is of great importance for identification of patients who are candidates for radical curative therapies. Although positron emission tomography/computed tomography (PET/CT) can never replace pathological staging, it is regarded as the most accurate imaging modality for nodal staging. However, there are a significant number of false positivity (underlying inflammatory processes, such as immune reaction because of presence of tumor, obstructive Address for correspondence: Deniz Koksal, Department of Chest Diseases, Hacettepe University Medical Faculty, Sihhiye 06100, Altindag/Ankara, Turkey. E-mail: dckoksal@ gmail.com DOI: 10.1097/JTO.0000000000000510 Copyright © 2015 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/15/1005-0e32
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Journal of Thoracic Oncology ® • Volume 10, Number 5, May 2015
pneumonia, anthracosis, or granulomatous inflammation) and false negativity (microscopic metastasis beyond spatial resolution of PET/CT). In the literature, there are different declared PET positivity criteria for a lymph node, but are not well validated.3 A SUVmax level higher than the mediastinal blood pool is associated with increased probability of malignancy and higher sensitivity, but lower specificity.1,4 Using a cutoff level as “SUVmax higher than 2.5” is sometimes low for predicting malignancy because of common inflammatory conditions. In the study by Evison et al., using a SUVmax value higher than 4 to indicate PET positivity leads to a diagnostic performance as follows: sensitivity, 89.9%; specificity, 89.6%; negative predictive value, 85.8%; positive predictive value 92.6%, and diagnostic accuracy 89.8%.1 A LN/T SUVmax ratio was first defined by Cerfolio et al. as a universal predictor of lymph node metastasis to eliminate the variation of SUVmax among different PET scanners. They documented that a ratio of 0.56 or higher predicts the node to be malignant with a chance of 94%.5 After that study, we proposed a level of 0.2, which is lower than the study by Cerfolio et al. This low ratio was probably because of our study population who were early stage cases directly referred to surgical resection. None of them have a lymph node larger than 1 cm in short axis diameter on CT. Besides, we considered a lymph node as positive if there was a fluoro-deoxy-d-glucose (FDG) uptake higher than the surrounding mediastinal tissue. Therefore the number of pathologically positive lymph nodes was extremely low (%14).4 Evison et al. is the first who suggested a LN/T SUV max ratio of 0.4 and validated it. We think that using such a LN/T SUVmax ratio instead of a SUVmax threshold can be important for tumors with low FDG activities. A tumor with a low FDG activity (for example low-grade adenocarcinomas) might have a metastatic lymph node with low FDG activity. We wonder if Evison et al. realized such cases in their study group especially in EBUS-TBNA positive cases. Deniz Koksal, MD Department of Chest Diseases
Hacettepe University Medical Faculty Ankara, Turkey Ozlem Ozmen, MD Department of Nuclear Medicine Ataturk Chest Diseases and Chest Surgery Education and Research Hospital Ankara, Turkey REFERENCES 1. Evison M, Morris J, Martin J, et al. Nodal staging in lung cancer: a risk stratification model for lymph nodes classified as negative by EBUSTBNA. J Thorac Oncol 2015;10:126–133. 2. Silvestri GA, Gonzalez AV, Jantz MA, et al. Methods for staging non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143(5 Suppl):e211S–e250S. 3. Nguyen P, Bhatt M, Bashirzadeh F, et al. Comparison of objective criteria and expert visual interpretation to classify benign and malignant hilar and mediastinal nodes on 18-F FDG PET/CT. Respirology 2015;20:129–137. 4. Koksal D, Demirag F, Bayiz H, et al. The correlation of SUVmax with pathological characteristics of primary tumor and the value of Tumor/ Lymph node SUVmax ratio for predicting metastasis to lymph nodes in resected NSCLC patients. J Cardiothorac Surg 2013;8:63. 5. Cerfolio RJ, Bryant AS. Ratio of the maximum standardized uptake value on FDG-PET of the mediastinal (N2) lymph nodes to the primary tumor may be a universal predictor of nodal malignancy in patients with non small-cell lung cancer. Ann Thorac Surg 2007;83:1826–1830.
Reply to: “Lymph Node/Tumor SUVmax Ratio Can Predict Metastasis to Mediastinal Lymph Nodes in Lung Cancer Patients” In Response: We welcome the correspondence from Professor Koksal and Dr. Ozmen in regard to our manuscript published in the Journal of Thoracic Oncology. In particular, we welcome the opportunity to correspond with some of the first authors to investigate the potential value of the “standardized uptake value
Copyright © 2015 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology ® • Volume 10, Number 5, May 2015
(SUV) ratio”; the ratio of maximum SUV between the primary tumor and mediastinal lymph nodes, on positron emission computed tomography (CT), in lung cancer patients. It was the previous work of Koksal et al. and Cerfolio et al. that sparked our own interest in the SUV ratio as a potential predictor of false-negative nodal sampling with endobronchial ultrasound-guided transbronchial needle aspiration (EBUSTBNA). In our study, the SUV ratio proved to be a powerful predictor of nodal malignancy and false-negative EBUS-TBNA and is a key element of our risk stratification model. Professor Koksal specifically asks about our experience with indeterminate 18-F-fluorodeoxyglucose (FDG) avidity tumors, for example, lepidic-type adenocarcinomas, and the usefulness of the SUV ratio in such circumstances. We use the term “indeterminate” to describe an SUVmax above that of the background mediastinal blood pool but lacking the significant FDG avidity normally associated with malignancy. Our first comment is that, in our experience, it is rare to undertake EBUS mediastinal staging in such circumstances. Lowgrade adenocarcinomas are usually peripheral ground-glass opacities on CT imaging with no or indeterminate FDG uptake and normal hilar and mediastinal nodes radiologically. These tumors are often biologically indolent tumors, and therefore, nodal spread is less common. As per the American College of Chest Physicians Staging Guidelines,1 peripheral tumors with low or indeterminate FDG avidity and normal hilar/mediastinal nodes radiologically do not require pathological nodal staging and can proceed directly to resection, assuming adequate fitness because the prevalence of nodal metastases is low. The prevalence of nodal metastases in our study was much higher as it predominantly included patients with N2/3 nodal disease on CT (376 of 509 patients, 74%). Address for correspondence: Matthew Evison, MRCP, North West Lung Centre, University Hospital South Manchester, Southmoor Road, Manchester, M23 9LT, United Kingdom. E-mail: [email protected] DOI: 10.1097/JTO.0000000000000511 Copyright © 2015 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/15/1005-0e32
It is uncommon for low-grade adenocarcinomas to present in such a way and are therefore under-represented in this study. This is reflected in the number of patients with an indeterminate primary tumor SUVmax; only 15 of 509 patients had a primary tumor SUVmax less than 4.0, and just four patients had an SUVmax less than 2.5. From these 15 patients, 11 patients had both indeterminate FDG avidity in the primary tumor and indeterminate avidity in the lymph nodes sampled by EBUS-TBNA. Ten of these tumors were adenocarcinomas plus one non-small-cell lung cancer not otherwise specified. The SUV ratio in all of the sampled lymph nodes was greater than 40% and ranged from 45% to 175%. In three cases, EBUSTBNA confirmed N2/3 metastases. In the remaining eight cases, in which the EBUS-TBNA was negative, there were two false-negatives where nodal metastases were subsequently diagnosed and six true-negatives. The risk stratification model indicated seven out of the eight cases of negative EBUS were high risk for false-negative sampling, suggesting the need for further pathological sampling and two of seven were ultimately proven to be false-negative. In summary, the SUV ratio does seem to be a useful indicator of the risk of nodal metastases in indeterminate FDG avidity tumors with indeterminate SUV FDG avidity in mediastinal lymph nodes. The risk stratification model, we presented in our study, therefore encompasses this clinical scenario and remains relevant to this patient group. We acknowledge the small number of such patients in our study and as such, our comments need be interpreted with this in mind. We would also stress the importance of using this risk stratification model for lymph nodes sampled with EBUS and deemed negative. It cannot replace pathological staging and has only been derived and validated in this setting. Matthew Evison, MRCP Philip Crosbie, PhD Richard Booton, PhD North West Lung Centre University Hospital South Manchester Manchester, United Kingdom The University of Manchester Manchester, United Kingdom
Copyright © 2015 by the International Association for the Study of Lung Cancer
Letters to the Editor
REFERENCES 1. Silvestri GA, Gonzalez AV, Jantz MA, et al. Methods for staging non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143(5 Suppl):e211S–e250S.
MET-Mutated NSCLC with Major Response to Crizotinib To the Editor: MET abnormalities, including overexpression, amplification, and mutation, have been described in nonsmall-cell lung cancer (NSCLC). Ou et al.1 reported in Journal of Thoracic Oncology in 2011 a patient with de novo MET amplification and a rapid and durable response to the oral ALK and MET inhibitor, crizotinib. The utility of MET amplification as a predictive marker was recently confirmed in a larger case series, but there have been no data regarding the clinical significance of MET mutations in NSCLC. We treated a 76-year-old female diagnosed with metastatic squamous cell carcinoma of the lung in April 2014. She was a former light smoker and quit tobacco use more than 30 years ago. Extended mutation analysis was performed, revealing a MET D1010H mutation and MDM2 amplification (Foundation Medicine, Cambridge, MA). She was initially treated with a combination of a novel MMP9 inhibitor, carboplatin, and paclitaxel and had progressive disease after three cycles. Treatment was then changed to gemcitabine, but after one cycle symptomatic disease progression occurred in the lung and bone and at a painful right
Address for correspondence: Jonathan W. Goldman, MD, The David Geffen School of Medicine, University of California, Los Angeles, 2020 Santa Monica Boulevard, Suite 600, Santa Monica, California 90404. E-mail: [email protected]. DOI: 10.1097/JTO.0000000000000491 Copyright © 2015 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/15/1005-0e33
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Lymph Node/Tumor SUVmax Ratio Can Predict Metastasis to Mediastinal Lymph Nodes in Lung Cancer Patients To the Editor: We were interested to read the article by Evison et al.1 published in the January 2015 issue of Journal of Thoracic Oncology. We appreciated the idea of proposing a risk stratification model for negative lymph nodes by endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) in lung cancer patients. The proposed model increased the negative predictive value of EBUSTBNA from 91%2 to approximately 99%. We believe that this model can help to discriminate patients that may directly proceed to curative treatment after a negative EBUS-TBNA. On the basis of this model, an EBUS-TBNA negative lymph node needs no further evaluation if the lymph node maximum standardized uptake value (SUVmax) is lower than 4, the SUVmax ratio between lymph node and primary tumor (LN/T SUVmax) is lower than 0.4, and the lymph node has homogeneous echogenecity during ultrasonographic assessment.1 In the absence of distant metastasis, proper staging of mediastinum is of great importance for identification of patients who are candidates for radical curative therapies. Although positron emission tomography/computed tomography (PET/CT) can never replace pathological staging, it is regarded as the most accurate imaging modality for nodal staging. However, there are a significant number of false positivity (underlying inflammatory processes, such as immune reaction because of presence of tumor, obstructive Address for correspondence: Deniz Koksal, Department of Chest Diseases, Hacettepe University Medical Faculty, Sihhiye 06100, Altindag/Ankara, Turkey. E-mail: dckoksal@ gmail.com DOI: 10.1097/JTO.0000000000000510 Copyright © 2015 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/15/1005-0e32
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Journal of Thoracic Oncology ® • Volume 10, Number 5, May 2015
pneumonia, anthracosis, or granulomatous inflammation) and false negativity (microscopic metastasis beyond spatial resolution of PET/CT). In the literature, there are different declared PET positivity criteria for a lymph node, but are not well validated.3 A SUVmax level higher than the mediastinal blood pool is associated with increased probability of malignancy and higher sensitivity, but lower specificity.1,4 Using a cutoff level as “SUVmax higher than 2.5” is sometimes low for predicting malignancy because of common inflammatory conditions. In the study by Evison et al., using a SUVmax value higher than 4 to indicate PET positivity leads to a diagnostic performance as follows: sensitivity, 89.9%; specificity, 89.6%; negative predictive value, 85.8%; positive predictive value 92.6%, and diagnostic accuracy 89.8%.1 A LN/T SUVmax ratio was first defined by Cerfolio et al. as a universal predictor of lymph node metastasis to eliminate the variation of SUVmax among different PET scanners. They documented that a ratio of 0.56 or higher predicts the node to be malignant with a chance of 94%.5 After that study, we proposed a level of 0.2, which is lower than the study by Cerfolio et al. This low ratio was probably because of our study population who were early stage cases directly referred to surgical resection. None of them have a lymph node larger than 1 cm in short axis diameter on CT. Besides, we considered a lymph node as positive if there was a fluoro-deoxy-d-glucose (FDG) uptake higher than the surrounding mediastinal tissue. Therefore the number of pathologically positive lymph nodes was extremely low (%14).4 Evison et al. is the first who suggested a LN/T SUV max ratio of 0.4 and validated it. We think that using such a LN/T SUVmax ratio instead of a SUVmax threshold can be important for tumors with low FDG activities. A tumor with a low FDG activity (for example low-grade adenocarcinomas) might have a metastatic lymph node with low FDG activity. We wonder if Evison et al. realized such cases in their study group especially in EBUS-TBNA positive cases. Deniz Koksal, MD Department of Chest Diseases
Hacettepe University Medical Faculty Ankara, Turkey Ozlem Ozmen, MD Department of Nuclear Medicine Ataturk Chest Diseases and Chest Surgery Education and Research Hospital Ankara, Turkey REFERENCES 1. Evison M, Morris J, Martin J, et al. Nodal staging in lung cancer: a risk stratification model for lymph nodes classified as negative by EBUSTBNA. J Thorac Oncol 2015;10:126–133. 2. Silvestri GA, Gonzalez AV, Jantz MA, et al. Methods for staging non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143(5 Suppl):e211S–e250S. 3. Nguyen P, Bhatt M, Bashirzadeh F, et al. Comparison of objective criteria and expert visual interpretation to classify benign and malignant hilar and mediastinal nodes on 18-F FDG PET/CT. Respirology 2015;20:129–137. 4. Koksal D, Demirag F, Bayiz H, et al. The correlation of SUVmax with pathological characteristics of primary tumor and the value of Tumor/ Lymph node SUVmax ratio for predicting metastasis to lymph nodes in resected NSCLC patients. J Cardiothorac Surg 2013;8:63. 5. Cerfolio RJ, Bryant AS. Ratio of the maximum standardized uptake value on FDG-PET of the mediastinal (N2) lymph nodes to the primary tumor may be a universal predictor of nodal malignancy in patients with non small-cell lung cancer. Ann Thorac Surg 2007;83:1826–1830.
Reply to: “Lymph Node/Tumor SUVmax Ratio Can Predict Metastasis to Mediastinal Lymph Nodes in Lung Cancer Patients” In Response: We welcome the correspondence from Professor Koksal and Dr. Ozmen in regard to our manuscript published in the Journal of Thoracic Oncology. In particular, we welcome the opportunity to correspond with some of the first authors to investigate the potential value of the “standardized uptake value
Copyright © 2015 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology ® • Volume 10, Number 5, May 2015
(SUV) ratio”; the ratio of maximum SUV between the primary tumor and mediastinal lymph nodes, on positron emission computed tomography (CT), in lung cancer patients. It was the previous work of Koksal et al. and Cerfolio et al. that sparked our own interest in the SUV ratio as a potential predictor of false-negative nodal sampling with endobronchial ultrasound-guided transbronchial needle aspiration (EBUSTBNA). In our study, the SUV ratio proved to be a powerful predictor of nodal malignancy and false-negative EBUS-TBNA and is a key element of our risk stratification model. Professor Koksal specifically asks about our experience with indeterminate 18-F-fluorodeoxyglucose (FDG) avidity tumors, for example, lepidic-type adenocarcinomas, and the usefulness of the SUV ratio in such circumstances. We use the term “indeterminate” to describe an SUVmax above that of the background mediastinal blood pool but lacking the significant FDG avidity normally associated with malignancy. Our first comment is that, in our experience, it is rare to undertake EBUS mediastinal staging in such circumstances. Lowgrade adenocarcinomas are usually peripheral ground-glass opacities on CT imaging with no or indeterminate FDG uptake and normal hilar and mediastinal nodes radiologically. These tumors are often biologically indolent tumors, and therefore, nodal spread is less common. As per the American College of Chest Physicians Staging Guidelines,1 peripheral tumors with low or indeterminate FDG avidity and normal hilar/mediastinal nodes radiologically do not require pathological nodal staging and can proceed directly to resection, assuming adequate fitness because the prevalence of nodal metastases is low. The prevalence of nodal metastases in our study was much higher as it predominantly included patients with N2/3 nodal disease on CT (376 of 509 patients, 74%). Address for correspondence: Matthew Evison, MRCP, North West Lung Centre, University Hospital South Manchester, Southmoor Road, Manchester, M23 9LT, United Kingdom. E-mail: [email protected] DOI: 10.1097/JTO.0000000000000511 Copyright © 2015 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/15/1005-0e32
It is uncommon for low-grade adenocarcinomas to present in such a way and are therefore under-represented in this study. This is reflected in the number of patients with an indeterminate primary tumor SUVmax; only 15 of 509 patients had a primary tumor SUVmax less than 4.0, and just four patients had an SUVmax less than 2.5. From these 15 patients, 11 patients had both indeterminate FDG avidity in the primary tumor and indeterminate avidity in the lymph nodes sampled by EBUS-TBNA. Ten of these tumors were adenocarcinomas plus one non-small-cell lung cancer not otherwise specified. The SUV ratio in all of the sampled lymph nodes was greater than 40% and ranged from 45% to 175%. In three cases, EBUSTBNA confirmed N2/3 metastases. In the remaining eight cases, in which the EBUS-TBNA was negative, there were two false-negatives where nodal metastases were subsequently diagnosed and six true-negatives. The risk stratification model indicated seven out of the eight cases of negative EBUS were high risk for false-negative sampling, suggesting the need for further pathological sampling and two of seven were ultimately proven to be false-negative. In summary, the SUV ratio does seem to be a useful indicator of the risk of nodal metastases in indeterminate FDG avidity tumors with indeterminate SUV FDG avidity in mediastinal lymph nodes. The risk stratification model, we presented in our study, therefore encompasses this clinical scenario and remains relevant to this patient group. We acknowledge the small number of such patients in our study and as such, our comments need be interpreted with this in mind. We would also stress the importance of using this risk stratification model for lymph nodes sampled with EBUS and deemed negative. It cannot replace pathological staging and has only been derived and validated in this setting. Matthew Evison, MRCP Philip Crosbie, PhD Richard Booton, PhD North West Lung Centre University Hospital South Manchester Manchester, United Kingdom The University of Manchester Manchester, United Kingdom
Copyright © 2015 by the International Association for the Study of Lung Cancer
Letters to the Editor
REFERENCES 1. Silvestri GA, Gonzalez AV, Jantz MA, et al. Methods for staging non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143(5 Suppl):e211S–e250S.
MET-Mutated NSCLC with Major Response to Crizotinib To the Editor: MET abnormalities, including overexpression, amplification, and mutation, have been described in nonsmall-cell lung cancer (NSCLC). Ou et al.1 reported in Journal of Thoracic Oncology in 2011 a patient with de novo MET amplification and a rapid and durable response to the oral ALK and MET inhibitor, crizotinib. The utility of MET amplification as a predictive marker was recently confirmed in a larger case series, but there have been no data regarding the clinical significance of MET mutations in NSCLC. We treated a 76-year-old female diagnosed with metastatic squamous cell carcinoma of the lung in April 2014. She was a former light smoker and quit tobacco use more than 30 years ago. Extended mutation analysis was performed, revealing a MET D1010H mutation and MDM2 amplification (Foundation Medicine, Cambridge, MA). She was initially treated with a combination of a novel MMP9 inhibitor, carboplatin, and paclitaxel and had progressive disease after three cycles. Treatment was then changed to gemcitabine, but after one cycle symptomatic disease progression occurred in the lung and bone and at a painful right
Address for correspondence: Jonathan W. Goldman, MD, The David Geffen School of Medicine, University of California, Los Angeles, 2020 Santa Monica Boulevard, Suite 600, Santa Monica, California 90404. E-mail: [email protected]. DOI: 10.1097/JTO.0000000000000491 Copyright © 2015 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/15/1005-0e33
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