Ann Thorac Surg 2014;97:2228–34
Prognostic Significance of Lymph Node Counts in Operable Esophageal Cancer To the Editor: We read with interest the article by Hsu and colleagues [1] regarding the prognostic significance of negative lymph node count in operable esophageal cancer. The authors conclude that the total number of negative lymph nodes prognosticate long-term outcomes of resection for esophageal cancer. We commend the authors on their excellent study, but we have some comments regarding their conclusions. The authors explain the superior survival of patients with higher numbers of negative lymph nodes based on either stage migration (which they subsequently argue against) or that the ‘negative’ lymph nodes harbor occult metastases. However, we are puzzled about the authors’ inclusion of factors such as tumor location, grade, and surgical approach, but not lymph node ratio (LNR). Several studies [2–4] have shown that LNR is an independent prognostic factor in resected esophageal cancer. The authors’ results can be explained by a lower LNR having better prognosis than a higher LNR. The authors’ claims would have had more credence if they had shown in a multivariate analysis including LNR as one of the covariates that the total number of negative lymph nodes remained a significant prognostic factor. Our lack of enthusiasm for the use of either of these prognostic factors is a result of the variability in detecting negative lymph nodes in resected specimens and the inevitable breakage of lymph nodes during surgery. The number of dissected lymph nodes varies considerably depending on the diligence of the individual grossing the specimen. Our experience has been that the total and negative lymph node counts are much higher when the surgeon (rather than the pathologist) grosses the lymph nodes. Similarly, we find that a number of the mediastinal nodes are broken during surgical dissection, leading to falsely high lymph node counts. With such wide variability in the nodal counts, “independent prognostic factors” such as the number of negative lymph nodes and the lymph node ratio are unlikely to be reproducible across centers, and even within the same center. The least variability occurs with the number of positive nodes; therefore, we should stick to this number in any attempt to prognosticate based on lymph node counts. Pallavi Purwar, MS Supriya Bambarkar, DNB Sabita Jiwnani, MS, MRCS C. S. Pramesh, MS, FRCS Division of Thoracic Oncology Department of Surgical Oncology Tata Memorial Hospital, Parel Mumbai 400012, India e-mail: [email protected]
Ó 2014 by The Society of Thoracic Surgeons Published by Elsevier Inc
2229
References 1. Hsu PK, Huang CS, Wang BY, Wu YC, Chou TY, Hsu WH. The prognostic value of the number of negative lymph nodes in esophageal cancer patients after transthoracic resection. Ann Thorac Surg. 2013;96:995–1001. 2. He Z, Wu S, Li Q, Lin Q, Xu J. Use of the metastatic lymph node ratio to evaluate the prognosis of esophageal cancer patients with node metastasis following radical esophagectomy. PLoS One. 2013;8:e73446. 3. Hou X, Wei JC, Xu Y, Luo RZ, Fu JH, Zhang LJ, Lin P, Yang HX. The positive lymph node ratio predicts long-term survival in patients with operable thoracic esophageal squamous cell carcinoma in China. Ann Surg Oncol. 2013;20: 1653–9. 4. Bhamidipati CM, Stukenborg GJ, Thomas CJ, Lau CL, Kozower BD, Jones DR. Pathologic lymph node ratio is a predictor of survival in esophageal cancer. Ann Thorac Surg. 2012;94:1643–51.
Reply To the Editor: We appreciate the interest of Purwar and colleagues [1] in our article [2]. We totally agree with their comments on the prognostic significance of lymph node ratio (LNR). Indeed, our previous report has identified LNR as a significant predictor for survival in esophageal cancer patients [3]. Whereas both total lymph node count and LNR include positive lymph nodes, which is associated with pathologic tumor stage, the number of negative lymph nodes is independent of tumor stage. Therefore, we focused on the number of negative lymph nodes in our study. The multivariate analysis indicated that the two non-interacting variables, positive lymph node number (N stages) and negative lymph node number, were both independent prognostic factors. As for the inevitable breakage of lymph nodes, we know that a thorough pathological examination of lymph node depends on how surgeons dissect the nodes during the operation and how pathologists examine the specimens. Therefore, we suggest en bloc lymph node dissection, in which the lymph nodes are removed along with the adjacent fat tissue to prevent fragmentation, rather than piece by piece. The pathological examination protocol is important as well. In the methods proposed by Ramirez and colleagues [4], the fragmented lymph nodes were pieced together and examined by light microscopy to determine if they were lymph nodes. The lymph nodes were identified by their rounded contour and the presence of a capsule, sub-capsular sinus, and lymphoid follicles. Similarly, we also determine the lymph node number under microscopy, rather than count the number grossly. The meticulous and labor intensive pathological examination is the solution to decrease the confounding effect by the fragmentation of lymph nodes. If there is wide variability in counting “total” and “negative” lymph node number, the pathological N stage would be inaccurate since the positive lymph nodes may be broken during dissection as well. Po-Kuei Hsu, MD Division of Thoracic Surgery, Department of Surgery Taipei Veterans General Hospital Taipei, Taiwan School of Medicine National Yang-Ming University Taipei, Taiwan
0003-4975/$36.00
MISCELLANEOUS
2. Seder CW, Allen MS, Cassivi SD, et al. Stage IIIA non-small cell lung cancer: morbidity and mortality of three distinct multimodality regimens. Ann Thorac Surg 2013;95:1708–16. 3. Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomized controlled trial. Lancet 2009;374:379–86. 4. Bradley JD, R Paulus, R Komaki, et al. A randomized phase III comparison of standard-dose (60 Gy) versus high-dose (74 Gy) conformal chemoradiotherapy with or without cetuximab for stage III non-small cell lung cancer: results on radiation dose in RTOG 0617. ASCO, 2013 (abstract).
CORRESPONDENCE
Prognostic Significance of Lymph Node Counts in Operable Esophageal Cancer To the Editor: We read with interest the article by Hsu and colleagues [1] regarding the prognostic significance of negative lymph node count in operable esophageal cancer. The authors conclude that the total number of negative lymph nodes prognosticate long-term outcomes of resection for esophageal cancer. We commend the authors on their excellent study, but we have some comments regarding their conclusions. The authors explain the superior survival of patients with higher numbers of negative lymph nodes based on either stage migration (which they subsequently argue against) or that the ‘negative’ lymph nodes harbor occult metastases. However, we are puzzled about the authors’ inclusion of factors such as tumor location, grade, and surgical approach, but not lymph node ratio (LNR). Several studies [2–4] have shown that LNR is an independent prognostic factor in resected esophageal cancer. The authors’ results can be explained by a lower LNR having better prognosis than a higher LNR. The authors’ claims would have had more credence if they had shown in a multivariate analysis including LNR as one of the covariates that the total number of negative lymph nodes remained a significant prognostic factor. Our lack of enthusiasm for the use of either of these prognostic factors is a result of the variability in detecting negative lymph nodes in resected specimens and the inevitable breakage of lymph nodes during surgery. The number of dissected lymph nodes varies considerably depending on the diligence of the individual grossing the specimen. Our experience has been that the total and negative lymph node counts are much higher when the surgeon (rather than the pathologist) grosses the lymph nodes. Similarly, we find that a number of the mediastinal nodes are broken during surgical dissection, leading to falsely high lymph node counts. With such wide variability in the nodal counts, “independent prognostic factors” such as the number of negative lymph nodes and the lymph node ratio are unlikely to be reproducible across centers, and even within the same center. The least variability occurs with the number of positive nodes; therefore, we should stick to this number in any attempt to prognosticate based on lymph node counts. Pallavi Purwar, MS Supriya Bambarkar, DNB Sabita Jiwnani, MS, MRCS C. S. Pramesh, MS, FRCS Division of Thoracic Oncology Department of Surgical Oncology Tata Memorial Hospital, Parel Mumbai 400012, India e-mail: [email protected]
Ó 2014 by The Society of Thoracic Surgeons Published by Elsevier Inc
2229
References 1. Hsu PK, Huang CS, Wang BY, Wu YC, Chou TY, Hsu WH. The prognostic value of the number of negative lymph nodes in esophageal cancer patients after transthoracic resection. Ann Thorac Surg. 2013;96:995–1001. 2. He Z, Wu S, Li Q, Lin Q, Xu J. Use of the metastatic lymph node ratio to evaluate the prognosis of esophageal cancer patients with node metastasis following radical esophagectomy. PLoS One. 2013;8:e73446. 3. Hou X, Wei JC, Xu Y, Luo RZ, Fu JH, Zhang LJ, Lin P, Yang HX. The positive lymph node ratio predicts long-term survival in patients with operable thoracic esophageal squamous cell carcinoma in China. Ann Surg Oncol. 2013;20: 1653–9. 4. Bhamidipati CM, Stukenborg GJ, Thomas CJ, Lau CL, Kozower BD, Jones DR. Pathologic lymph node ratio is a predictor of survival in esophageal cancer. Ann Thorac Surg. 2012;94:1643–51.
Reply To the Editor: We appreciate the interest of Purwar and colleagues [1] in our article [2]. We totally agree with their comments on the prognostic significance of lymph node ratio (LNR). Indeed, our previous report has identified LNR as a significant predictor for survival in esophageal cancer patients [3]. Whereas both total lymph node count and LNR include positive lymph nodes, which is associated with pathologic tumor stage, the number of negative lymph nodes is independent of tumor stage. Therefore, we focused on the number of negative lymph nodes in our study. The multivariate analysis indicated that the two non-interacting variables, positive lymph node number (N stages) and negative lymph node number, were both independent prognostic factors. As for the inevitable breakage of lymph nodes, we know that a thorough pathological examination of lymph node depends on how surgeons dissect the nodes during the operation and how pathologists examine the specimens. Therefore, we suggest en bloc lymph node dissection, in which the lymph nodes are removed along with the adjacent fat tissue to prevent fragmentation, rather than piece by piece. The pathological examination protocol is important as well. In the methods proposed by Ramirez and colleagues [4], the fragmented lymph nodes were pieced together and examined by light microscopy to determine if they were lymph nodes. The lymph nodes were identified by their rounded contour and the presence of a capsule, sub-capsular sinus, and lymphoid follicles. Similarly, we also determine the lymph node number under microscopy, rather than count the number grossly. The meticulous and labor intensive pathological examination is the solution to decrease the confounding effect by the fragmentation of lymph nodes. If there is wide variability in counting “total” and “negative” lymph node number, the pathological N stage would be inaccurate since the positive lymph nodes may be broken during dissection as well. Po-Kuei Hsu, MD Division of Thoracic Surgery, Department of Surgery Taipei Veterans General Hospital Taipei, Taiwan School of Medicine National Yang-Ming University Taipei, Taiwan
0003-4975/$36.00
MISCELLANEOUS
2. Seder CW, Allen MS, Cassivi SD, et al. Stage IIIA non-small cell lung cancer: morbidity and mortality of three distinct multimodality regimens. Ann Thorac Surg 2013;95:1708–16. 3. Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomized controlled trial. Lancet 2009;374:379–86. 4. Bradley JD, R Paulus, R Komaki, et al. A randomized phase III comparison of standard-dose (60 Gy) versus high-dose (74 Gy) conformal chemoradiotherapy with or without cetuximab for stage III non-small cell lung cancer: results on radiation dose in RTOG 0617. ASCO, 2013 (abstract).
CORRESPONDENCE
