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Resection of the mesopancreas in pancreatic head adenocarcinoma: Is it outside of the International Study Group on Pancreatic Surgery definition and consensus statement for standard and extended pancreatectomy?
Letters to the Editors Resection of the mesopancreas in pancreatic head adenocarcinoma: Is it outside of the International Study Group on Pancreatic Surgery definition and consensus statement for standard and extended pancreatectomy?
To the Editors: We read with great interest the articles by the International Study Group on Pancreatic Surgery concerning the consensus statements on the definition of extent of pancreatectomy1 and lymphadenectomy2 in pancreatic adenocarcinoma. According to these statements, the status of the resection margin impacts long-term survival. The so-called ‘‘mesopancreas’’ refers to the retropancreatic tissue, which does not have well-defined anatomic boundaries but represents a site of fusion of peritoneal layers that is connected through its soft tissues and lymphoneurovascular components with the para-aortic area.3 The resection margin at the mesopancreas is the primary site for R1 resection4 after pancreatoduodenectomy for pancreatic head carcinoma. Moreover, epithelial-mesenchymal transition-related processes involved in tumor progression such as tumor budding at the invasive tumor front,5 tumor deposits in the lymphatic basin,6 and a dispersed growth pattern in the tumor periphery7 may impact the prevalence of an R1 resection at the mesopancreatic margin, as well as local failure rates after R0 resection. Total or ‘‘maximal’’ resection of the so-called mesopancreas with para-aortic dissection of the area between superior mesenteric artery (SMA) and celiac trunk (16a2 paraaortic area)8 and circumferential lymphadenectomy of the SMA3,9,10 has been proposed to achieve adequate retropancreatic margin clearance to minimize the likelihood of an R1 resection and local recurrence. The statement of the International Study Group on Pancreatic Surgery on the definition of standard lymphadenectomy did not recommend routine lymphadenectomy around the SMA (only the right side of the SMA) or para-aortic lymphadenectomy, although no consensus was reached on lymphadenectomy of the 16b1 para-aortic area. Locoregional spread of pancreatic carcinoma is characterized not only by lymph node (LN) involvement but also by perineural invasion. Skeletonization of the regional vessels with removal of LNs, lymphoneurovascular structures, and soft tissues was recommended by the Consensus Conference in Castelfranco Veneto, Italy, in 1998.11 Although the goal of mesopancreatic resection is to control the retropancreatic area and the purpose of lymphadenectomy is to evaluate and potentially control the LN basin, the clearance of the para-aortic area during mesopancreatic excision corresponds with neurovascular and soft-tissue clearance during lymphadenectomy of the 16a2-16b1 para-aortic areas, as well as 310 SURGERY
circumferential clearance of the SMA during mesopancreas excision is correspondent with the clearance during lymphadenectomy around the SMA. Extended lymphadenectomy has been shown to be associated with greater R0 resection rates in only a few studies.12,13 In the absence of consensus on the extent of the lymphadenectomy, the definition of involvement of the resection margin, the classification of all sites of the resection margin, and the lack of standardized protocols for pathologic examination of the pancreatoduodenectomy specimens, the impact of extended lymphadenectomy on resection margin status cannot be excluded on the basis of available studies. Moreover, an association between 16b1 para-aortic nodal involvement with an R1 posterior resection margin has been reported,14,15 suggesting para-aortic nodal involvement to be a reflection of local invasion through the mesopancreatic tissues, rather than true second-order nodal involvement.15 Because of the lack of boundaries of the mesopancreas and its continuity with the para-aortic area, the goal of dissection of the 16a2 and 16b1 paraaortic areas as well as the area around the SMA is to control tumor spread along the mesopancreatic resection margin (R-factor) rather than to stage or control the nodal spread (N-factor).16 We propose that the need to achieve an R0 resection entails taking into account mesopancreatic resection when defining the extent of pancreatoduodenectomy for pancreatic head adenocarcinoma. Nadia Peparini, MD, PhD Azienda Sanitaria Locale Roma H- Distretto 3 Ciampino via Mario Cal o , 5–00043, Ciampino, Rome, Italy E-mail: [email protected]
References 1. Hartwig W, Vollmer CM, Fingerhut A, Yeo CJ, Neoptolemos JP, Adham M, et al. Extended pancreatectomy in ductal adenocarcinoma: definition and consensus of the International Study Group for Pancreatic Surgery (ISGPS). Surgery 2014;156:1-14. 2. Tol JA, Gouma DJ, Bassi C, Dervenis C, Montorsi M, Adham M, et al. Definition of a standard lymphadenectomy in surgery for pancreatic ductal adenocarcinoma: a consensus statement by the International Study Group on Pancreatic Surgery (ISGPS). Surgery 2014;156:591-600. 3. Peparini N, Chirletti P. Mesopancreas: a boundless structure, namely R1 risk in pancreaticoduodenectomy for pancreatic head carcinoma. Eur J Surg Oncol 2013;39:1303-8. 4. Gaedcke J, Gunawan B, Grade M, Szoke R, Liersch T, Becker H. The mesopancreas is the primary site for R1 resection in pancreatic head cancer: relevance for clinical trials. Langenbecks Arch Surg 2010;395:451-8. 5. Karamitopoulou E, Zlobec I, Born D, Kondi-Pafiti A, Lykoudis P, Mellou A, et al. Tumor budding is a strong and independent prognostic factor in pancreatic cancer. Eur J Cancer 2013;49:1032-9.
Surgery Volume 158, Number 1
6. Puppa G, Ueno H, Kayahara M, Capelli P, Canzonieri V, Colombari R, et al. Tumor deposits are encountered in advanced colorectal cancer and other adenocarcinomas: an expanded classification with implications for colorectal cancer staging system including a unifying concept of intransit metastases. Mod Pathol 2009;22:410-5. 7. Verbeke CS, Knapp J, Gladhaug IP. Tumor growth is more dispersed in pancreatic head cancers than in rectal cancer: implications for resection margin assessment. Histopathology 2011;59:1111-21. 8. Adham M, Singhirunnusorn J. Surgical technique and results of total mesopancreas excision (TMpE) in pancreatic tumors. Eur J Surg Oncol 2012;38:340-5. 9. Kawabata Y, Tanaka T, Nishi T, Monma H, Yano S, Tajima Y. Appraisal of a total meso-pancreatoduodenum excision with pancreaticoduodenectomy for pancreatic head carcinoma. Eur J Surg Oncol 2012;38:574-9. 10. Aimota T, Mizutani S, Kawano Y, Matsushita A, Yamashita N, Suzuki H. Left posterior approach pancreaticoduodenectomy with total mesopancreas excision and circumferential lymphadenectomy around the superior mesenteric artery for pancreatic head carcinoma. J Nippon Med Sch 2013;80:438-45. 11. Pedrazzoli S, Beger HG, Obertop H, Andren-Sandberg A, Fernandez-Cruz L, Henne-Bruns D, et al. A surgical and pathological based classification of resective treatment of pancreatic cancer. Dig Surg 1999;16:337-45. 12. Riall TS, Cameron JL, Lillemoe KD, Campbell KA, Sauter PK, Coleman J, et al. Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma- part 3: update on 5-year survival. J Gastrointest Surg 2005;9:1191-204. 13. Jang J-Y, Kang MJ, Heo JS, Choi SH, Choi DW, Park SJ, et al. A prospective randomized controlled study comparing outcomes of standard resection and extended resection, including dissection of the nerve plexus and various lymph nodes, in patients with pancreatic head cancer. Ann Surg 2014;259:656-64. 14. Shimada K, Sakamoto Y, Sano T, Kosuge T. The role of paraaortic lymph node involvement on early recurrence and survival after macroscopic curative resection with extended lymphadenectomy for pancreatic carcinoma. J Am Coll Surg 2006;203:345-52. 15. Connor S, Bosonnet L, Ghaneh P, Alexakis N, Hartley M, Campbell F. Survival of patients with periampullary carcinoma is predicted by lymph node 8a but not by lymph node 16b1 status. Br J Surg 2004;91:1592-9. 16. Peparini N. Mesopancreas: a boundless structure,namely the rationale for dissection of the paraaortic area in pancreaticoduodenectomy for pancreatic head carcinoma. World J Gastroenterology 2015;21:2865-70. http://dx.doi.org/10.1016/j.surg.2015.01.003
Reply to ‘‘Resection of the mesopancreas in pancreatic head adenocarcinoma: Is it outside of the International Study Group on Pancreatic Surgery definition and consensus statement for standard and extended pancreatectomy?’’
To the Editors: The members of the International Study Group on Pancreatic Surgery want to thank Dr Peparini for his comments on the consensus papers on extended pancreatectomy1 and lymphadenectomy2 in pancreatic ductal adenocarcinoma. These 2 papers were intended to
Letters to the Editors 311
summarize published evidence on the extent of pancreatectomy and associated lymphadenectomy in the setting of pancreatic cancer resection, with the aim to establish internationally acceptable standards on these 2 issues. Broadly accepted definitions are important to allow the comparison of results of operative and multimodal trials in pancreatic cancer therapy. Dr Peparini commented correctly that extensive resection of the retropancreatic soft tissue, the socalled mesopancreas, which includes lymphoneurovascular tissue, namely also the lymph nodes of the Ln 161b area, is critical to achieve a posterior R0 resection margin status. There is some evidence from retrospective data analyses of prospectively documented patient cohorts that this posterior resection margin effects overall survival.3,4 Various resection techniques have been established to achieve extensive soft tissue clearance in this area.5 Because the mesopancreas includes lymphatic components but does not have well-defined anatomic boundaries, the consensus group intended to include its resection within the standard pancreatectomy definition by using the term ‘‘lymphadenectomy.’’ The consensus group is, therefore, thankful for the clarification of this aspect of the standard and extended pancreatectomy definition. It is surprising to see a call for extensive retropancreatic soft-tissue dissection, including lymphadenectomy in the Ln 16b1 and around the superior mesenteric artery, Ln 14d, and of the 16a2 area with the objective of better R0 resection and survival rates. As indicated in the consensus statement on lymphadenectomy,2 these dissection areas were included in the randomized controlled trials on extended lymphadenectomy. Neither these randomized controlled trials, subsequent meta-analyses,6,7 nor a recent randomized controlled study8 could demonstrate any survival benefit of extended lymphadenectomy combined with pancreatoduodenectomy in patients with pancreatic ductal adenocarcinoma. Therefore, the International Study Group on Pancreatic Surgery did not find enough evidence to recommend the routine inclusion of these lymph node areas in standard lymphadenectomy, although there was a controversial discussion about this issue, as stated.2 The discussion persisted regarding inclusion of Ln 16 area because of the lack of boundaries versus no difference in survival and inclusion of Ln 14d because of more postoperative diarrhea without survival benefit. With the increasing advent of neoadjuvant therapies and the development of more potent tumor drugs or combination therapies that may hinder systemic tumor spread, the relevance of locoregional cancer control may increase in the future. In this context, the uniform application of a generally accepted histopathologic reporting method that includes the evaluation of the various resection margins and detailed lymph node involvement is strongly encouraged.9 We also do realize that pathology staging will be more difficult after neoadjuvant therapy and standards should be adapted.
To the Editors: We read with great interest the articles by the International Study Group on Pancreatic Surgery concerning the consensus statements on the definition of extent of pancreatectomy1 and lymphadenectomy2 in pancreatic adenocarcinoma. According to these statements, the status of the resection margin impacts long-term survival. The so-called ‘‘mesopancreas’’ refers to the retropancreatic tissue, which does not have well-defined anatomic boundaries but represents a site of fusion of peritoneal layers that is connected through its soft tissues and lymphoneurovascular components with the para-aortic area.3 The resection margin at the mesopancreas is the primary site for R1 resection4 after pancreatoduodenectomy for pancreatic head carcinoma. Moreover, epithelial-mesenchymal transition-related processes involved in tumor progression such as tumor budding at the invasive tumor front,5 tumor deposits in the lymphatic basin,6 and a dispersed growth pattern in the tumor periphery7 may impact the prevalence of an R1 resection at the mesopancreatic margin, as well as local failure rates after R0 resection. Total or ‘‘maximal’’ resection of the so-called mesopancreas with para-aortic dissection of the area between superior mesenteric artery (SMA) and celiac trunk (16a2 paraaortic area)8 and circumferential lymphadenectomy of the SMA3,9,10 has been proposed to achieve adequate retropancreatic margin clearance to minimize the likelihood of an R1 resection and local recurrence. The statement of the International Study Group on Pancreatic Surgery on the definition of standard lymphadenectomy did not recommend routine lymphadenectomy around the SMA (only the right side of the SMA) or para-aortic lymphadenectomy, although no consensus was reached on lymphadenectomy of the 16b1 para-aortic area. Locoregional spread of pancreatic carcinoma is characterized not only by lymph node (LN) involvement but also by perineural invasion. Skeletonization of the regional vessels with removal of LNs, lymphoneurovascular structures, and soft tissues was recommended by the Consensus Conference in Castelfranco Veneto, Italy, in 1998.11 Although the goal of mesopancreatic resection is to control the retropancreatic area and the purpose of lymphadenectomy is to evaluate and potentially control the LN basin, the clearance of the para-aortic area during mesopancreatic excision corresponds with neurovascular and soft-tissue clearance during lymphadenectomy of the 16a2-16b1 para-aortic areas, as well as 310 SURGERY
circumferential clearance of the SMA during mesopancreas excision is correspondent with the clearance during lymphadenectomy around the SMA. Extended lymphadenectomy has been shown to be associated with greater R0 resection rates in only a few studies.12,13 In the absence of consensus on the extent of the lymphadenectomy, the definition of involvement of the resection margin, the classification of all sites of the resection margin, and the lack of standardized protocols for pathologic examination of the pancreatoduodenectomy specimens, the impact of extended lymphadenectomy on resection margin status cannot be excluded on the basis of available studies. Moreover, an association between 16b1 para-aortic nodal involvement with an R1 posterior resection margin has been reported,14,15 suggesting para-aortic nodal involvement to be a reflection of local invasion through the mesopancreatic tissues, rather than true second-order nodal involvement.15 Because of the lack of boundaries of the mesopancreas and its continuity with the para-aortic area, the goal of dissection of the 16a2 and 16b1 paraaortic areas as well as the area around the SMA is to control tumor spread along the mesopancreatic resection margin (R-factor) rather than to stage or control the nodal spread (N-factor).16 We propose that the need to achieve an R0 resection entails taking into account mesopancreatic resection when defining the extent of pancreatoduodenectomy for pancreatic head adenocarcinoma. Nadia Peparini, MD, PhD Azienda Sanitaria Locale Roma H- Distretto 3 Ciampino via Mario Cal o , 5–00043, Ciampino, Rome, Italy E-mail: [email protected]
References 1. Hartwig W, Vollmer CM, Fingerhut A, Yeo CJ, Neoptolemos JP, Adham M, et al. Extended pancreatectomy in ductal adenocarcinoma: definition and consensus of the International Study Group for Pancreatic Surgery (ISGPS). Surgery 2014;156:1-14. 2. Tol JA, Gouma DJ, Bassi C, Dervenis C, Montorsi M, Adham M, et al. Definition of a standard lymphadenectomy in surgery for pancreatic ductal adenocarcinoma: a consensus statement by the International Study Group on Pancreatic Surgery (ISGPS). Surgery 2014;156:591-600. 3. Peparini N, Chirletti P. Mesopancreas: a boundless structure, namely R1 risk in pancreaticoduodenectomy for pancreatic head carcinoma. Eur J Surg Oncol 2013;39:1303-8. 4. Gaedcke J, Gunawan B, Grade M, Szoke R, Liersch T, Becker H. The mesopancreas is the primary site for R1 resection in pancreatic head cancer: relevance for clinical trials. Langenbecks Arch Surg 2010;395:451-8. 5. Karamitopoulou E, Zlobec I, Born D, Kondi-Pafiti A, Lykoudis P, Mellou A, et al. Tumor budding is a strong and independent prognostic factor in pancreatic cancer. Eur J Cancer 2013;49:1032-9.
Surgery Volume 158, Number 1
6. Puppa G, Ueno H, Kayahara M, Capelli P, Canzonieri V, Colombari R, et al. Tumor deposits are encountered in advanced colorectal cancer and other adenocarcinomas: an expanded classification with implications for colorectal cancer staging system including a unifying concept of intransit metastases. Mod Pathol 2009;22:410-5. 7. Verbeke CS, Knapp J, Gladhaug IP. Tumor growth is more dispersed in pancreatic head cancers than in rectal cancer: implications for resection margin assessment. Histopathology 2011;59:1111-21. 8. Adham M, Singhirunnusorn J. Surgical technique and results of total mesopancreas excision (TMpE) in pancreatic tumors. Eur J Surg Oncol 2012;38:340-5. 9. Kawabata Y, Tanaka T, Nishi T, Monma H, Yano S, Tajima Y. Appraisal of a total meso-pancreatoduodenum excision with pancreaticoduodenectomy for pancreatic head carcinoma. Eur J Surg Oncol 2012;38:574-9. 10. Aimota T, Mizutani S, Kawano Y, Matsushita A, Yamashita N, Suzuki H. Left posterior approach pancreaticoduodenectomy with total mesopancreas excision and circumferential lymphadenectomy around the superior mesenteric artery for pancreatic head carcinoma. J Nippon Med Sch 2013;80:438-45. 11. Pedrazzoli S, Beger HG, Obertop H, Andren-Sandberg A, Fernandez-Cruz L, Henne-Bruns D, et al. A surgical and pathological based classification of resective treatment of pancreatic cancer. Dig Surg 1999;16:337-45. 12. Riall TS, Cameron JL, Lillemoe KD, Campbell KA, Sauter PK, Coleman J, et al. Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma- part 3: update on 5-year survival. J Gastrointest Surg 2005;9:1191-204. 13. Jang J-Y, Kang MJ, Heo JS, Choi SH, Choi DW, Park SJ, et al. A prospective randomized controlled study comparing outcomes of standard resection and extended resection, including dissection of the nerve plexus and various lymph nodes, in patients with pancreatic head cancer. Ann Surg 2014;259:656-64. 14. Shimada K, Sakamoto Y, Sano T, Kosuge T. The role of paraaortic lymph node involvement on early recurrence and survival after macroscopic curative resection with extended lymphadenectomy for pancreatic carcinoma. J Am Coll Surg 2006;203:345-52. 15. Connor S, Bosonnet L, Ghaneh P, Alexakis N, Hartley M, Campbell F. Survival of patients with periampullary carcinoma is predicted by lymph node 8a but not by lymph node 16b1 status. Br J Surg 2004;91:1592-9. 16. Peparini N. Mesopancreas: a boundless structure,namely the rationale for dissection of the paraaortic area in pancreaticoduodenectomy for pancreatic head carcinoma. World J Gastroenterology 2015;21:2865-70. http://dx.doi.org/10.1016/j.surg.2015.01.003
Reply to ‘‘Resection of the mesopancreas in pancreatic head adenocarcinoma: Is it outside of the International Study Group on Pancreatic Surgery definition and consensus statement for standard and extended pancreatectomy?’’
To the Editors: The members of the International Study Group on Pancreatic Surgery want to thank Dr Peparini for his comments on the consensus papers on extended pancreatectomy1 and lymphadenectomy2 in pancreatic ductal adenocarcinoma. These 2 papers were intended to
Letters to the Editors 311
summarize published evidence on the extent of pancreatectomy and associated lymphadenectomy in the setting of pancreatic cancer resection, with the aim to establish internationally acceptable standards on these 2 issues. Broadly accepted definitions are important to allow the comparison of results of operative and multimodal trials in pancreatic cancer therapy. Dr Peparini commented correctly that extensive resection of the retropancreatic soft tissue, the socalled mesopancreas, which includes lymphoneurovascular tissue, namely also the lymph nodes of the Ln 161b area, is critical to achieve a posterior R0 resection margin status. There is some evidence from retrospective data analyses of prospectively documented patient cohorts that this posterior resection margin effects overall survival.3,4 Various resection techniques have been established to achieve extensive soft tissue clearance in this area.5 Because the mesopancreas includes lymphatic components but does not have well-defined anatomic boundaries, the consensus group intended to include its resection within the standard pancreatectomy definition by using the term ‘‘lymphadenectomy.’’ The consensus group is, therefore, thankful for the clarification of this aspect of the standard and extended pancreatectomy definition. It is surprising to see a call for extensive retropancreatic soft-tissue dissection, including lymphadenectomy in the Ln 16b1 and around the superior mesenteric artery, Ln 14d, and of the 16a2 area with the objective of better R0 resection and survival rates. As indicated in the consensus statement on lymphadenectomy,2 these dissection areas were included in the randomized controlled trials on extended lymphadenectomy. Neither these randomized controlled trials, subsequent meta-analyses,6,7 nor a recent randomized controlled study8 could demonstrate any survival benefit of extended lymphadenectomy combined with pancreatoduodenectomy in patients with pancreatic ductal adenocarcinoma. Therefore, the International Study Group on Pancreatic Surgery did not find enough evidence to recommend the routine inclusion of these lymph node areas in standard lymphadenectomy, although there was a controversial discussion about this issue, as stated.2 The discussion persisted regarding inclusion of Ln 16 area because of the lack of boundaries versus no difference in survival and inclusion of Ln 14d because of more postoperative diarrhea without survival benefit. With the increasing advent of neoadjuvant therapies and the development of more potent tumor drugs or combination therapies that may hinder systemic tumor spread, the relevance of locoregional cancer control may increase in the future. In this context, the uniform application of a generally accepted histopathologic reporting method that includes the evaluation of the various resection margins and detailed lymph node involvement is strongly encouraged.9 We also do realize that pathology staging will be more difficult after neoadjuvant therapy and standards should be adapted.