EDITORIAL
Lymphadenectomy for Pancreatic Neuroendocrine Tumors: Is That the Relevant Debate? Cristina R. Ferrone, MD
P
ancreatic neuroendocrine tumors (PNETs) represent approximately 3% of primary pancreatic neoplasms, with approximately 1000 new cases per year in the United States.1 The natural history of these malignancies is poorly defined and understood, which contributes to why there are 3 commonly used staging systems. Most often, these tumors are classified by the 2010 WHO (World Health Organization) staging system, which relies on size, metastases, mitotic rate, perineural invasion, angioinvasion, and Ki67.2 The lesions classified as well-differentiated by the WHO are a heterogeneous group, which are further divided into low- and intermediate-grade lesions on the basis of proliferative rate, as measured by mitoses and the Ki67 labeling index. Many groups have tried to simplify the WHO staging system by focusing on size, metastases, number of mitoses, necrosis, and/or CK19 staining.3,4 Ellison and colleagues5 compared a staging system entirely based on the grade (as measured by Ki67 index) with the 2 existing staging systems: AJCC (2010 American Joint Committee on Cancer) and ENETS (2006 European Neuroendocrine Tumor Society). This novel staging system uses grade to predict overall survival (OS). Tumor size, lymph node involvement, and distant metastases did not improve the model’s prognostic ability. In contrast to the work by Ellison and colleagues, where lymph node status is not a prognostic factor, Hashim and colleagues6 report that a lymphadenectomy is essential when treating PNETs. By retrospectively examining the data of 136 patients who underwent pancreatic resection and lymphadenectomy, both lymph node metastases and Ki67 more than 20% were predictors of recurrence-free survival. Predictors of OS were an R1 resection and Ki67 more than 20%. On the basis of these 2 studies and the results reported by others, the role of lymphadenectomy in the treatment of PNETs remains unclear. Many physicians looking for guidance use the NCCN (National Comprehensive Cancer Network) guidelines, which recommend a lymph node dissection for lesions larger than 2 cm in size. Although no one would debate that knowing the lymph node status improves the staging of the patient, it is not clear whether a lymphadenectomy has any effect on OS.7–9 Would leaving positive lymph nodes behind decrease a patient’s survival? Doubtful, because we have no evidence to support an improved survival with a lymph node dissection in any other gastrointestinal cancer, including gastric cancer.10 Without a lymphadenectomy, a more limited operation can be performed. As expected, a more limited operation has been associated with decreased operative time, blood loss, serious postoperative complications, length of hospital stay, and risk of postoperative diabetes/pancreatic insufficiency.11 For operations in which 44% of patients have 1 or more complications,12 can we justify a lymphadenectomy that may increase the morbidity and mortality further? If the prognostic information is deemed essential, we may want to consider sentinel lymph node biopsies, similar to other cancers, as one method of potentially reducing morbidity. Because the “oncological” resection including the draining lymph node basins seems to be prognostic, rather than therapeutic, can we justify the morbidity? Yes, if surveillance or survival could be improved. Accurate staging has several advantages—it sets expectations for patients and identifies recurrent disease via optimal surveillance strategies. Currently, postresection surveillance has not been standardized. If surveillance schedules were improved and standardized, the expense and morbidity of blood work and imaging could be reduced. The NCCN guidelines recommend surveillance at 3 to 12 months in the first year and then every 6 to 12 months for a maximum of 10 years. These are very broad time frames, with patients potentially being subject to anywhere from 11 to 24 imaging studies over the course of 11 years. More imaging studies may lead to earlier detection of metastases. However, does an earlier intervention for recurrent disease in asymptomatic patients improve survival? Small retrospective series advocate for metastasectomy for PNETs, but there are significant biases when selecting patients, making conclusions difficult. These series have contributed
From the Division of General Surgery, Massachusetts General Hospital, Boston, MA. Disclosure: The author declares no conflicts of interest. Reprints: Cristina R. Ferrone, MD, Division of General Surgery, Massachusetts General Hospital, 15 Parkman St, WANG 460, Boston, MA 02114. E-mail: [email protected]. C 2014 by Lippincott Williams & Wilkins Copyright ISSN: 0003-4932/14/25902-0213 DOI: 10.1097/SLA.0000000000000533
Annals of Surgery r Volume 259, Number 2, February 2014
www.annalsofsurgery.com | 213
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Annals of Surgery r Volume 259, Number 2, February 2014
Ferrone
to the NCCN guidelines, which recommend resection for localized locoregional recurrent disease and cytotoxic or targeted therapy for metastatic disease. Although the role of lymphadenectomy is an important question, a more significant question is which PNETs should be resected. With improved and more frequent radiological imaging, smaller and smaller PNETs are identified. No guidelines have been established for observation versus resection when small, asymptomatic, nonfunctioning PNETs are identified. This has resulted in significant variation in the treatment patterns across the country. Because PNETs are slow growing, many have questioned whether surgical resection is impacting the natural history of the disease. In an attempt to demonstrate the therapeutic role of surgical resection, Tseng and colleagues13 used the SEER (Surveillance, Epidemiology, and End Results) database to compare patients with PNETs who underwent resection with those who did not undergo resection. Patients who underwent resection (310/425) had a significantly longer OS. Although there are limitations in the SEER database, it does provide some evidence in favor of surgical resection. Does that mean all PNETs should be resected regardless of size? The risk of lymph node metastases increases with lesions larger than 1.5 to 2 cm,6,14 and the hazard of death increases for tumors larger than 3 cm.5,15 Are we comfortable with observing nonfunctioning PNETs smaller than 2 cm? 3 cm? 1.5 cm? Bilimoria and colleagues16 analyzed 9821 patients with “malignant” PNETs from the National Cancer Database and determined that US patients who did not have metastases were more likely to undergo a pancreatic resection if they were younger than 55 years, had a pancreatic tail lesion, had a lesion 4 cm or smaller, and presented to a high-volume hospital/academic center.16 These data are limited because patients with “benign” lesions are not included in the National Cancer Database. However, on the basis of these data, patients with larger tumors are not being resected, which is contrary to what the literature recommends. There are currently no practice guidelines for nonfunctioning PNETs. A consensus conference to establish treatment guidelines, similar to what was done for pancreatic cystic lesions, is desperately needed. If we do not standardize resection criteria based on the size and type of resection, along with more specific surveillance guidelines, it will be difficult to improve the treatment of patients with PNETs. In addition, with the advent of more treatment options using targeted agents, we need to standardize what we do as a surgical community to make progress in the treatment of these patients. As a medical community, we are obligated to develop consensus guidelines for patients with nonfunctioning PNETs.
214 | www.annalsofsurgery.com
REFERENCES 1. Fesinmeyer MD, Austin MA, Li CI, et al. Differences in survival by histologic type of pancreatic cancer. Cancer Epidemiol Biomarkers Prev. 2005;14:1766– 1773. 2. Rindi G, Arnold R, Bosman FT, et al. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: Bosman TF, Carneiro F, Hruban RH, Theise ND, et al., eds. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon, France: International Agency for Research on Cancer; 2010:13. 3. Ferrone CR, Tang LH, Tomlinson J, et al. Determining prognosis in patients with pancreatic endocrine neoplasms: can the WHO classification system be simplified? J Clin Oncol. 2007;25:5609–5615. 4. Deshpande V, Fernandez-del Castillo C, Muzikansky A, et al. Cytokeratin 19 is a powerful predictor of survival in pancreatic endocrine tumors. Am J Surg Pathol. 2004;28:1145–1153. 5. Ellison T WC, Shi C, Cameron JL, et al. A single institution’s 26-year experience with non-functional pancreatic neuroendocrine tumors: a validation of current staging systems and a new prognostic nomogram. Ann Surg. 2014;259:204–212. 6. Hashim YM, Trinkaus KM, Linehan DC, et al. Regional lymphadenectomy is indicated in the surgical treatment of pancreatic neuroendocrine tumors (PNETs). Ann Surg. 2014;259:197–203. 7. Bilimoria KY, Talamonti MS, Tomlinson JS, et al.: Prognostic score predicting survival after resection of pancreatic neuroendocrine tumors: analysis of 3851 patients. Ann Surg. 2008;247:490–500. 8. Kazanjian KK, Reber HA, Hines OJ. Resection of pancreatic neuroendocrine tumors: results of 70 cases. Arch Surg. 2006;141:765–769. 9. Tomassetti P, Campana D, Piscitelli L, et al. Endocrine pancreatic tumors: factors correlated with survival. Ann Oncol. 2005;16:1806– 1810. 10. Songun I, Putter H, Kranenbarg EM, et al. Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial. Lancet Oncol. 2010;11:439–449. 11. Cauley CE, Pitt HA, Ziegler KM, et al. Pancreatic enucleation: improved outcomes compared to resection. J Gastrointest Surg. 2012;16:1347– 1353. 12. Haynes AB, Deshpande V, Ingkakul T, et al. Implications of incidentally discovered, nonfunctioning pancreatic endocrine tumors: short-term and longterm patient outcomes. Arch Surg. 2011;146:534–538. 13. Hill JS, McPhee JT, McDade TP, et al. Pancreatic neuroendocrine tumors: the impact of surgical resection on survival. Cancer. 2009;115:741– 751. 14. Kim MJ, Choi DW, Choi SH, et al. Surgical strategies for non-functioning pancreatic neuroendocrine tumours. Br J Surg. 2012;99:1562–1568. 15. Ekeblad S, Skogseid B, Dunder K, et al. Prognostic factors and survival in 324 patients with pancreatic endocrine tumor treated at a single institution. Clin Cancer Res. 2008;14:7798–7803. 16. Bilimoria KY, Tomlinson JS, Merkow RP, et al. Clinicopathologic features and treatment trends of pancreatic neuroendocrine tumors: analysis of 9,821 patients. J Gastrointest Surg. 2007;11:1460–1467.
C 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Lymphadenectomy for Pancreatic Neuroendocrine Tumors: Is That the Relevant Debate? Cristina R. Ferrone, MD
P
ancreatic neuroendocrine tumors (PNETs) represent approximately 3% of primary pancreatic neoplasms, with approximately 1000 new cases per year in the United States.1 The natural history of these malignancies is poorly defined and understood, which contributes to why there are 3 commonly used staging systems. Most often, these tumors are classified by the 2010 WHO (World Health Organization) staging system, which relies on size, metastases, mitotic rate, perineural invasion, angioinvasion, and Ki67.2 The lesions classified as well-differentiated by the WHO are a heterogeneous group, which are further divided into low- and intermediate-grade lesions on the basis of proliferative rate, as measured by mitoses and the Ki67 labeling index. Many groups have tried to simplify the WHO staging system by focusing on size, metastases, number of mitoses, necrosis, and/or CK19 staining.3,4 Ellison and colleagues5 compared a staging system entirely based on the grade (as measured by Ki67 index) with the 2 existing staging systems: AJCC (2010 American Joint Committee on Cancer) and ENETS (2006 European Neuroendocrine Tumor Society). This novel staging system uses grade to predict overall survival (OS). Tumor size, lymph node involvement, and distant metastases did not improve the model’s prognostic ability. In contrast to the work by Ellison and colleagues, where lymph node status is not a prognostic factor, Hashim and colleagues6 report that a lymphadenectomy is essential when treating PNETs. By retrospectively examining the data of 136 patients who underwent pancreatic resection and lymphadenectomy, both lymph node metastases and Ki67 more than 20% were predictors of recurrence-free survival. Predictors of OS were an R1 resection and Ki67 more than 20%. On the basis of these 2 studies and the results reported by others, the role of lymphadenectomy in the treatment of PNETs remains unclear. Many physicians looking for guidance use the NCCN (National Comprehensive Cancer Network) guidelines, which recommend a lymph node dissection for lesions larger than 2 cm in size. Although no one would debate that knowing the lymph node status improves the staging of the patient, it is not clear whether a lymphadenectomy has any effect on OS.7–9 Would leaving positive lymph nodes behind decrease a patient’s survival? Doubtful, because we have no evidence to support an improved survival with a lymph node dissection in any other gastrointestinal cancer, including gastric cancer.10 Without a lymphadenectomy, a more limited operation can be performed. As expected, a more limited operation has been associated with decreased operative time, blood loss, serious postoperative complications, length of hospital stay, and risk of postoperative diabetes/pancreatic insufficiency.11 For operations in which 44% of patients have 1 or more complications,12 can we justify a lymphadenectomy that may increase the morbidity and mortality further? If the prognostic information is deemed essential, we may want to consider sentinel lymph node biopsies, similar to other cancers, as one method of potentially reducing morbidity. Because the “oncological” resection including the draining lymph node basins seems to be prognostic, rather than therapeutic, can we justify the morbidity? Yes, if surveillance or survival could be improved. Accurate staging has several advantages—it sets expectations for patients and identifies recurrent disease via optimal surveillance strategies. Currently, postresection surveillance has not been standardized. If surveillance schedules were improved and standardized, the expense and morbidity of blood work and imaging could be reduced. The NCCN guidelines recommend surveillance at 3 to 12 months in the first year and then every 6 to 12 months for a maximum of 10 years. These are very broad time frames, with patients potentially being subject to anywhere from 11 to 24 imaging studies over the course of 11 years. More imaging studies may lead to earlier detection of metastases. However, does an earlier intervention for recurrent disease in asymptomatic patients improve survival? Small retrospective series advocate for metastasectomy for PNETs, but there are significant biases when selecting patients, making conclusions difficult. These series have contributed
From the Division of General Surgery, Massachusetts General Hospital, Boston, MA. Disclosure: The author declares no conflicts of interest. Reprints: Cristina R. Ferrone, MD, Division of General Surgery, Massachusetts General Hospital, 15 Parkman St, WANG 460, Boston, MA 02114. E-mail: [email protected]. C 2014 by Lippincott Williams & Wilkins Copyright ISSN: 0003-4932/14/25902-0213 DOI: 10.1097/SLA.0000000000000533
Annals of Surgery r Volume 259, Number 2, February 2014
www.annalsofsurgery.com | 213
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Annals of Surgery r Volume 259, Number 2, February 2014
Ferrone
to the NCCN guidelines, which recommend resection for localized locoregional recurrent disease and cytotoxic or targeted therapy for metastatic disease. Although the role of lymphadenectomy is an important question, a more significant question is which PNETs should be resected. With improved and more frequent radiological imaging, smaller and smaller PNETs are identified. No guidelines have been established for observation versus resection when small, asymptomatic, nonfunctioning PNETs are identified. This has resulted in significant variation in the treatment patterns across the country. Because PNETs are slow growing, many have questioned whether surgical resection is impacting the natural history of the disease. In an attempt to demonstrate the therapeutic role of surgical resection, Tseng and colleagues13 used the SEER (Surveillance, Epidemiology, and End Results) database to compare patients with PNETs who underwent resection with those who did not undergo resection. Patients who underwent resection (310/425) had a significantly longer OS. Although there are limitations in the SEER database, it does provide some evidence in favor of surgical resection. Does that mean all PNETs should be resected regardless of size? The risk of lymph node metastases increases with lesions larger than 1.5 to 2 cm,6,14 and the hazard of death increases for tumors larger than 3 cm.5,15 Are we comfortable with observing nonfunctioning PNETs smaller than 2 cm? 3 cm? 1.5 cm? Bilimoria and colleagues16 analyzed 9821 patients with “malignant” PNETs from the National Cancer Database and determined that US patients who did not have metastases were more likely to undergo a pancreatic resection if they were younger than 55 years, had a pancreatic tail lesion, had a lesion 4 cm or smaller, and presented to a high-volume hospital/academic center.16 These data are limited because patients with “benign” lesions are not included in the National Cancer Database. However, on the basis of these data, patients with larger tumors are not being resected, which is contrary to what the literature recommends. There are currently no practice guidelines for nonfunctioning PNETs. A consensus conference to establish treatment guidelines, similar to what was done for pancreatic cystic lesions, is desperately needed. If we do not standardize resection criteria based on the size and type of resection, along with more specific surveillance guidelines, it will be difficult to improve the treatment of patients with PNETs. In addition, with the advent of more treatment options using targeted agents, we need to standardize what we do as a surgical community to make progress in the treatment of these patients. As a medical community, we are obligated to develop consensus guidelines for patients with nonfunctioning PNETs.
214 | www.annalsofsurgery.com
REFERENCES 1. Fesinmeyer MD, Austin MA, Li CI, et al. Differences in survival by histologic type of pancreatic cancer. Cancer Epidemiol Biomarkers Prev. 2005;14:1766– 1773. 2. Rindi G, Arnold R, Bosman FT, et al. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: Bosman TF, Carneiro F, Hruban RH, Theise ND, et al., eds. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon, France: International Agency for Research on Cancer; 2010:13. 3. Ferrone CR, Tang LH, Tomlinson J, et al. Determining prognosis in patients with pancreatic endocrine neoplasms: can the WHO classification system be simplified? J Clin Oncol. 2007;25:5609–5615. 4. Deshpande V, Fernandez-del Castillo C, Muzikansky A, et al. Cytokeratin 19 is a powerful predictor of survival in pancreatic endocrine tumors. Am J Surg Pathol. 2004;28:1145–1153. 5. Ellison T WC, Shi C, Cameron JL, et al. A single institution’s 26-year experience with non-functional pancreatic neuroendocrine tumors: a validation of current staging systems and a new prognostic nomogram. Ann Surg. 2014;259:204–212. 6. Hashim YM, Trinkaus KM, Linehan DC, et al. Regional lymphadenectomy is indicated in the surgical treatment of pancreatic neuroendocrine tumors (PNETs). Ann Surg. 2014;259:197–203. 7. Bilimoria KY, Talamonti MS, Tomlinson JS, et al.: Prognostic score predicting survival after resection of pancreatic neuroendocrine tumors: analysis of 3851 patients. Ann Surg. 2008;247:490–500. 8. Kazanjian KK, Reber HA, Hines OJ. Resection of pancreatic neuroendocrine tumors: results of 70 cases. Arch Surg. 2006;141:765–769. 9. Tomassetti P, Campana D, Piscitelli L, et al. Endocrine pancreatic tumors: factors correlated with survival. Ann Oncol. 2005;16:1806– 1810. 10. Songun I, Putter H, Kranenbarg EM, et al. Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial. Lancet Oncol. 2010;11:439–449. 11. Cauley CE, Pitt HA, Ziegler KM, et al. Pancreatic enucleation: improved outcomes compared to resection. J Gastrointest Surg. 2012;16:1347– 1353. 12. Haynes AB, Deshpande V, Ingkakul T, et al. Implications of incidentally discovered, nonfunctioning pancreatic endocrine tumors: short-term and longterm patient outcomes. Arch Surg. 2011;146:534–538. 13. Hill JS, McPhee JT, McDade TP, et al. Pancreatic neuroendocrine tumors: the impact of surgical resection on survival. Cancer. 2009;115:741– 751. 14. Kim MJ, Choi DW, Choi SH, et al. Surgical strategies for non-functioning pancreatic neuroendocrine tumours. Br J Surg. 2012;99:1562–1568. 15. Ekeblad S, Skogseid B, Dunder K, et al. Prognostic factors and survival in 324 patients with pancreatic endocrine tumor treated at a single institution. Clin Cancer Res. 2008;14:7798–7803. 16. Bilimoria KY, Tomlinson JS, Merkow RP, et al. Clinicopathologic features and treatment trends of pancreatic neuroendocrine tumors: analysis of 9,821 patients. J Gastrointest Surg. 2007;11:1460–1467.
C 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
