J Gastrointest Surg DOI 10.1007/s11605-014-2566-5
2014 SSAT POSTER PRESENTATION
Nodal Counts and Lymph Node Ratio Impact Survival After Distal Pancreatectomy for Pancreatic Adenocarcinoma Awais Ashfaq & Barbara A. Pockaj & Richard J. Gray & Thorvardur R. Halfdanarson & Nabil Wasif
Received: 7 May 2014 / Accepted: 30 May 2014 # 2014 The Society for Surgery of the Alimentary Tract
Abstract Background The number of lymph nodes required for accurate staging after distal pancreatectomy for pancreatic adenocarcinoma is unknown. Methods The Surveillance, Epidemiology, and End Results (SEER) database was used to identify 1,473 patients who underwent distal pancreatectomy for pancreatic adenocarcinoma from 1998 to 2010. We evaluated the influence of the total number of lymph nodes examined (NNE) and the lymph node ratio (LNR-positive nodes/total nodes examined) on survival. Results The median NNE was 8. No nodes were examined in 232 (16 %) of the patients, and 843 (57 %) had 10 NNE (16 vs. 20 months and 13 vs. 19 %, respectively, p0.1 (17 vs. 6 %, p=0.002). Discussion Patients with pancreatic cancer undergoing distal pancreatectomy should ideally have at least 11 lymph nodes examined to avoid understaging. For node-positive patients, LNR may be a better prognostic indicator than the total number of positive nodes. Keywords Lymph node . Pancreatic cancer . Distal pancreatectomy . Survival
This study was a poster presentation at the Society for Surgery of the Alimentary Tract during the Digestive Diseases Week (DDW®), May 2014, Chicago, IL. Synopsis We examine the impact of number of lymph nodes examined and lymph node ratio on survival in patients undergoing distal pancreatectomy for pancreatic adenocarcinoma. A. Ashfaq : B. A. Pockaj : R. J. Gray : N. Wasif Section of Surgical Oncology, Department of Surgery, Mayo Clinic, Phoenix, AZ, USA T. R. Halfdanarson Division of Medical Oncology, Mayo Clinic, Phoenix, AZ, USA N. Wasif (*) Department of Surgery, Mayo Clinic, 5777 E Mayo Blvd, Phoenix, AZ 85054, USA e-mail: [email protected]
Introduction Pancreatic cancer is the fourth leading cause of cancer-related death in the USA and results in an estimated 227,000 deaths per year worldwide.1 In 2014, 46,420 new cases were diagnosed, 39,590 of whom would die of their disease.2 Multiple factors have been identified affecting the outcome following pancreatectomy for pancreatic adenocarcinoma, including tumor size, chemotherapy, curative resection, and extent of – locoregional invasion.3 8 Of these, lymph node (LN) status – is one of the most important predictors of survival.9 14 Substantial interest has focused recently on more than just nodal positivity, including the number of positive LN, location of positive LN within the draining nodal basins, and lymph node ratio (LNR), i.e., the ratio between the numbers of positive and examined lymph nodes.15 Lymph node ratio has proven to be a clinically important tool to predict outcome in cancers of the esophagus,16 stomach,17 ampulla of Vater,18,19 small bowel,20 colon,19,21 and even non-gastrointestinal cancers such as breast22 and melanoma. In addition, Japanese – literature23 25 has reported that classification of lymph node
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ratio following gastric cancer resection was superior to current American Joint Committee on Cancer (AJCC) staging, especially with respect to stage migration.26 The recommendations for the number of LN that should be examined range from 11 – to 2027 32 in cases of pancreatectomy and variable LNR categories are discussed in different studies.27,30,33 The number of nodes that need to be examined not only serves as a measure for surgical technique and surgeon experience but is also a surrogate for a thorough pathologic assessment. This enables the patient to be accurately staged and diminish the disparities in survival outcomes. So far, the majority of the data available on the number of LN and LNR following pancreatectomy has been limited to pancreaticoduodenectomy only. The appropriate number of LN needed for staging and the influence of LNR following distal pancreatectomy for pancreatic adenocarcinoma alone are unknown. This is of significance as the regional lymph node basins are different for both operations. The objective of our study was to evaluate a population-based cohort to determine the impact of the total number of lymph nodes examined (NNE) and the lymph node ratio (LNR) on survival in patients undergoing distal pancreatectomy for pancreatic adenocarcinoma.
Methods Surveillance, Epidemiology, and End Results Database The National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) tumor registry database was used for this study. SEER contains over 3 million cases from 17 geographic sites, covering approximately 26% of the US population. SEER Program registries routinely collect data on patient demographics (e.g., age, sex), primary tumor characteristics (e.g., size, extent, grade), nodal staging (number of nodes examined, number of involved nodes), primary operation performed (distal pancreatectomy vs. others), vital status, and survival. The November 2012 update was used for this study, providing information from 1973 to 2010.34 As a population-based study with no patient identifiers involved, our study was exempt from Institutional Research Board review. Study Sample A total of 12,360 patients with pancreatic adenocarcinoma located either in the body or tail of the pancreas, diagnosed between 1998 and 2010, were identified from the SEER database using the International Classification of Disease (ICD) histology classification codes (8000, 8010, 8020, 8021, 8140, 8141, and 8500). Patients who were identified on only autopsy, did not have a histologically confirmed diagnosis, or have AJCC (American Joint Committee on
Cancer) stage IV diseases were excluded. Of the initial cohort, 1,473 underwent distal pancreatectomy for treatment and constituted our final study cohort. Data Collection and Analysis Standard demographic and tumor data were collected including age at diagnosis, sex, race, year of diagnosis, geographical distribution of patients, staging based on AJCC, grade of the tumor, number of lymph nodes examined (NNE), and number of positive lymph nodes. The lymph node ratio (LNR) was calculated by dividing the number of positive LN by NNE in patients who had at least one node examined. Patient characteristics were evaluated using t test for continuous data and chi-square test for categorical variables. Overall survival was used as the primary endpoint, and survival analysis was performed using Kaplan-Meier estimates and log-rank tests. Sensitivity analyses were performed to identify the appropriate cut points for NNE and LNR at which statistical significance in the log-rank tests for overall survival was reached. Multivariable analysis using Cox proportional hazards modeling was used to identify predictors of mortality. Hazard ratios (HR) and 95 % confidence intervals (95 % CI) were reported as appropriate. All statistical tests were twosided, and a p value ≤0.05 was considered to be statistically significant. Statistical analysis was performed using SPSS 17.0 (IBM Corporation).
Results Demographics A total of 1,473 patients were included in the final analysis. There were 771 (52.3 %) women and 702 (47.7 %) men with a mean age of 66±12 years (Table 1). A majority of the patients were white, n=1,180 (80.1 %); 165 (11.2 %) patients were black; and 128 (8.7 %) belonged to other ethnicities. The mean and median tumor sizes were 4.3±2.3 and 4.0 cm, respectively. The majority of the tumors were low grade, n= 829 (56.3 %), and 939 (77.3 %) patients had at least stage IIA disease and above (Table 1). There was a gradual increase in the incidence of distal pancreatectomy for pancreatic adenocarcinoma in the body and tail from 1998 to 2010. Number of Nodes Examined Of the 1,241 patients with complete lymph node staging data available, the median number of LN evaluated was 8 (range 0–85) and 843 (57 %) had ≤10 NNE examined. Of those who had at least one node examined, 628 (50.6 %) had no metastatic lymph node disease compared to 613 (49.4 %) who did
J Gastrointest Surg Table 1 Demographics
Table 2 Characteristics based on the number of lymph nodes examined Characteristic
Number (%) Characteristic
Median age (range) Gender Male Female Race White Black Other Year of diagnosis 1998–2004 2005–2010 Stagea IA IB IIA IIB III Unknown Nodal staging N0 or N1 NX Status of LN obtaineda Negative LN
NX No lymph nodes examined, LN lymph nodes a
Missing data present
Positive LN Unknown Tumor gradea Low High Unknown
NNE 1–10 (%) NNE >10 (%) p value
67 (26–93) 702 (47.7) 771 (52.3) 1,180 (80.1) 165 (11.2) 128 (8.7) 525 (35.6) 948 (64.4) 84 (5.7) 192 (13.0) 303 (20.6) 550 (37.3) 86 (5.8) 258 (17.5) 1,241 (84.2) 232 (15.8) 628 (42.6) 613 (49.3) 233 (15.8)
Year 1998–2004 2005–2010 Age 80 years Mean age (years)±SD Gender Female Male Race White Black Other Stage IA IB IIA IIB III Grade Low High Mean tumor size (cm)±SD
0.331 245 (56.7) 424 (48.9)
187 (43.3) 443 (51.1)
275 (48.0) 308 (52.9) 86 (59.7) 67.3±11.1
298 (52.0) 274 (47.1) 58 (40.3) 65.2±11.9
350 (52.2) 319 (50.7)
320 (47.8) 310 (49.3)
548 (52.6) 72 (48.3) 49 (45.4)
494 (47.4) 77 (51.7) 59 (54.6)
49 (58.3) 105 (54.7) 190 (62.7) 252 (45.9) 57 (66.3)
35 (41.7) 87 (45.3) 113 (37.3) 297 (54.1) 29 (33.7)
411 (54.3) 195 (50.0) 43.8±22.9
346 (45.7) 195 (50.0) 43.6±20.9
0.027*
0.002* 0.311
0.256
0.1 (14 months; p0.1 was 17 and 6 %, respectively (p10 lymph nodes evaluated (21 months; p10 NNE was 13 and 19 %, respectively (p65 years, increasing pathological stage of the tumor, nodal involvement, and higher histological grade. Even after adjusting for competing risk factors, LNR >0.1 remained significantly associated with adverse survival (HR=1.38, 95 % CI 1.10–1.74; p10 0.908 (0.779–1.060) Lymph node ratio (LNR) ≤0.1 1.00 (referent) >0.1 1.383 (1.097–1.742)
0.108
0.013*
0.002* 0.001* 0.001* 0.001*
0.222
0.006*
*p < 0.05 considered significant
positive patients, a LNR of ≤0.1 is associated with improved median and 5-year overall survival. While earlier studies have looked at both LNR and NNE to determine which one of these factors is important to predict prognosis in patients undergoing pancreatectomy,15,26,27,41,43 our data suggests that both of these are important. Our results suggest that the minimal number of evaluated nodes for optimal prognostication in patients with node-negative disease is 11. There was a significant overall median survival difference in patients who had greater than 10 LNs evaluated (17 vs. 21 months; p=0.011). Previous studies15,26,43 have reported that N0 patients need to have at least 10–12 LNs evaluated to accurately predict prognosis in patients undergoing pancreaticoduodenectomy. Huebner et al. reported a worse survival for N0 patients who underwent pancreaticoduodenectomy and had 11 LNs evaluated (HR 1.33, 95 % CI 1.1–1.7; p=0.001).15 In another study, patients with 20 LN groups with 20 LN cohort. Their study revealed that survival was significantly better in the 11– 20 compared with the 1–10 group (median, 20 vs. 15 months,
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respectively, p20 groups (median, 20 vs. 23 months, respectively, p=0.14). Slidell et al.26 found a statistically significant worse survival for patients (pancreaticoduodenectomy 73.6 %, partial pancreatectomy 18.8 %, and total pancreatectomy 5.5 %) with fewer than 12 LNs evaluated, and the difference in survival was 7 months. Similarly, we found that patients undergoing distal pancreatectomy need to have at least 11 LNs evaluated to avoid a negative impact on survival, likely from understaging. We identify several differences between patients who had 1–10 NNE and >10 NNE. Age influenced nodal harvest with 52 % of patients less than 65 years and 40 % older than 80 falling into the >10 NNE category. It is unclear if the reduced nodal count in older patients is intrinsically related to aging or if modification of surgical technique in older patients (less “radical” surgery secondary to surgeon bias) is responsible for this finding. Studies looking at the influence of aging on LN have also shown that lymph nodes can display degenerative changes by replacing the population of immune cells with connective tissue, which may explain low nodal counts.44,45 Geographic variation was also seen in the >10 NNE category for registries reporting to SEER, from 23 % in New Mexico to 67 % in Connecticut (data not shown), suggesting that differences in practice patterns rather than underlying biology may be contributing to this discrepancy. The number of lymph nodes recovered after surgery not only depends on the surgical technique but also the diligence of the staff in the pathology lab in searching for nodes in the surgical specimen. SEER relies on pathology reports submitted by registrars, and we were thus unable to study this point further using registry data given the lack of centralized pathology review. The increasing use of laparoscopic distal pancreatectomy may be associated with lower initial counts of lymph nodes, although published data suggests comparable yields with the open technique once the learning curve has been negotiated.46 Overall, 57 % of our study cohort had ≤10 NNE, suggesting the possibility of understaging in the majority of the population undergoing distal pancreatectomy. Although a trend towards increasing nodal harvest was seen over time, from 30 % in 1998 to 53 % in 2010 (combined figures in Table 2), this was not statistically significant. Nevertheless, this does suggest an increasing awareness of the importance of nodal counts in cancer operations on the pancreas. Finally, the positive impact of >10 NNE on survival was not seen in the multivariable analyses, likely because of the overriding influence of node-positive disease on mortality. LNR has been previously shown to be an important factor – to predict survival in pancreatic cancer.27 29,33 LNR is less susceptible to stage migration and provides a more accurate comparison for patients with N1 disease. As opposed to categorizing patients as N0 or N1, LNR not only provides data regarding the number of positive LNs but also gives an estimate of the adequacy of LNs obtained. However, there is
no consensus on either the best cutoff value for LNR, the method to determine such cutoff, or the total number of LNs needed to achieve an accurate LNR in patients undergoing pancreatectomy.15 Pawlik et al.27 used categories of LNR 0.4 while House et al.47 used LNR of 0.18 to predict survival difference in their patient populations with pancreatic cancer. For patients undergoing distal pancreatectomy, we used sensitivity analyses to determine a LNR cutoff of 0.1 as statistically significant for survival discrimination. Patients with LNR ≤0.1 had a longer median survival compared to patients with LNR >0.1 (19 vs. 14 months; p0.1 appears to be associated with worse survival and may be a better prognostic indicator than the absolute number of positive nodes. Our data provides a guide for what constitutes adequate lymphadenectomy in patients undergoing distal pancreatectomy for pancreatic adenocarcinoma. LNR and NNE should be considered as additional data points in further studies of outcome after curative resection.
Conflicts of Interest No financial disclosures or conflicts of interest for any of the authors.
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J Gastrointest Surg 36. Ludwig MS, Goodman M, Miller DL, Johnstone PA. Postoperative survival and the number of lymph nodes sampled during resection of node-negative non-small cell lung cancer. Chest. 2005;128:15451550 37. Liu KJ, Loewen M, Atten MJ, Millikan K, Tebbit C, Walter RJ. The survival of stage iii gastric cancer patients is affected by the number of lymph nodes removed. Surgery. 2003;134:639-644; discussion 644-636 38. Konety BR, Joslyn SA, O’Donnell MA. Extent of pelvic lymphadenectomy and its impact on outcome in patients diagnosed with bladder cancer: Analysis of data from the surveillance, epidemiology and end results program data base. J Urol. 2003;169:946-950 39. Agrama MT, Reiter D, Cunnane MF, Topham A, Keane WM. Nodal yield in neck dissection and the likelihood of metastases. Otolaryngol Head Neck Surg. 2003;128:185-190 40. Bouvier AM, Haas O, Piard F, Roignot P, Bonithon-Kopp C, Faivre J. How many nodes must be examined to accurately stage gastric carcinomas? Results from a population based study. Cancer. 2002;94:2862-2866 41. Valsangkar NP, Bush DM, Michaelson JS, Ferrone CR, Wargo JA, Lillemoe KD, Fernandez-del Castillo C, Warshaw AL, Thayer SP. N0/n1, pnl, or lnr? The effect of lymph node number on accurate survival prediction in pancreatic ductal adenocarcinoma. J Gastrointest Surg. 2013;17:257-266
42. Murakami Y, Uemura K, Sudo T, Hayashidani Y, Hashimoto Y, Nakashima A, Yuasa Y, Kondo N, Ohge H, Sueda T. Number of metastatic lymph nodes, but not lymph node ratio, is an independent prognostic factor after resection of pancreatic carcinoma. J Am Coll Surg. 2010;211:196-204 43. Hellan M, Sun CL, Artinyan A, Mojica-Manosa P, Bhatia S, Ellenhorn JD, Kim J. The impact of lymph node number on survival in patients with lymph node-negative pancreatic cancer. Pancreas. 2008;37:19-24 44. Hadamitzky C, Spohr H, Debertin AS, Guddat S, Tsokos M, Pabst R. Age-dependent histoarchitectural changes in human lymph nodes: An underestimated process with clinical relevance? J Anat. 2010;216:556-562 45. Lazuardi L, Jenewein B, Wolf AM, Pfister G, Tzankov A, GrubeckLoebenstein B. Age-related loss of naive t cells and dysregulation of t-cell/b-cell interactions in human lymph nodes. Immunology. 2005;114:37-43 46. Borja-Cacho D, Al-Refaie WB, Vickers SM, Tuttle TM, Jensen EH. Laparoscopic distal pancreatectomy. J Am Coll Surg. 2009;209:758765; quiz 800 47. House MG, Gonen M, Jarnagin WR, D’Angelica M, DeMatteo RP, Fong Y, Brennan MF, Allen PJ. Prognostic significance of pathologic nodal status in patients with resected pancreatic cancer. J Gastrointest Surg. 2007;11:1549-1555
2014 SSAT POSTER PRESENTATION
Nodal Counts and Lymph Node Ratio Impact Survival After Distal Pancreatectomy for Pancreatic Adenocarcinoma Awais Ashfaq & Barbara A. Pockaj & Richard J. Gray & Thorvardur R. Halfdanarson & Nabil Wasif
Received: 7 May 2014 / Accepted: 30 May 2014 # 2014 The Society for Surgery of the Alimentary Tract
Abstract Background The number of lymph nodes required for accurate staging after distal pancreatectomy for pancreatic adenocarcinoma is unknown. Methods The Surveillance, Epidemiology, and End Results (SEER) database was used to identify 1,473 patients who underwent distal pancreatectomy for pancreatic adenocarcinoma from 1998 to 2010. We evaluated the influence of the total number of lymph nodes examined (NNE) and the lymph node ratio (LNR-positive nodes/total nodes examined) on survival. Results The median NNE was 8. No nodes were examined in 232 (16 %) of the patients, and 843 (57 %) had 10 NNE (16 vs. 20 months and 13 vs. 19 %, respectively, p0.1 (17 vs. 6 %, p=0.002). Discussion Patients with pancreatic cancer undergoing distal pancreatectomy should ideally have at least 11 lymph nodes examined to avoid understaging. For node-positive patients, LNR may be a better prognostic indicator than the total number of positive nodes. Keywords Lymph node . Pancreatic cancer . Distal pancreatectomy . Survival
This study was a poster presentation at the Society for Surgery of the Alimentary Tract during the Digestive Diseases Week (DDW®), May 2014, Chicago, IL. Synopsis We examine the impact of number of lymph nodes examined and lymph node ratio on survival in patients undergoing distal pancreatectomy for pancreatic adenocarcinoma. A. Ashfaq : B. A. Pockaj : R. J. Gray : N. Wasif Section of Surgical Oncology, Department of Surgery, Mayo Clinic, Phoenix, AZ, USA T. R. Halfdanarson Division of Medical Oncology, Mayo Clinic, Phoenix, AZ, USA N. Wasif (*) Department of Surgery, Mayo Clinic, 5777 E Mayo Blvd, Phoenix, AZ 85054, USA e-mail: [email protected]
Introduction Pancreatic cancer is the fourth leading cause of cancer-related death in the USA and results in an estimated 227,000 deaths per year worldwide.1 In 2014, 46,420 new cases were diagnosed, 39,590 of whom would die of their disease.2 Multiple factors have been identified affecting the outcome following pancreatectomy for pancreatic adenocarcinoma, including tumor size, chemotherapy, curative resection, and extent of – locoregional invasion.3 8 Of these, lymph node (LN) status – is one of the most important predictors of survival.9 14 Substantial interest has focused recently on more than just nodal positivity, including the number of positive LN, location of positive LN within the draining nodal basins, and lymph node ratio (LNR), i.e., the ratio between the numbers of positive and examined lymph nodes.15 Lymph node ratio has proven to be a clinically important tool to predict outcome in cancers of the esophagus,16 stomach,17 ampulla of Vater,18,19 small bowel,20 colon,19,21 and even non-gastrointestinal cancers such as breast22 and melanoma. In addition, Japanese – literature23 25 has reported that classification of lymph node
J Gastrointest Surg
ratio following gastric cancer resection was superior to current American Joint Committee on Cancer (AJCC) staging, especially with respect to stage migration.26 The recommendations for the number of LN that should be examined range from 11 – to 2027 32 in cases of pancreatectomy and variable LNR categories are discussed in different studies.27,30,33 The number of nodes that need to be examined not only serves as a measure for surgical technique and surgeon experience but is also a surrogate for a thorough pathologic assessment. This enables the patient to be accurately staged and diminish the disparities in survival outcomes. So far, the majority of the data available on the number of LN and LNR following pancreatectomy has been limited to pancreaticoduodenectomy only. The appropriate number of LN needed for staging and the influence of LNR following distal pancreatectomy for pancreatic adenocarcinoma alone are unknown. This is of significance as the regional lymph node basins are different for both operations. The objective of our study was to evaluate a population-based cohort to determine the impact of the total number of lymph nodes examined (NNE) and the lymph node ratio (LNR) on survival in patients undergoing distal pancreatectomy for pancreatic adenocarcinoma.
Methods Surveillance, Epidemiology, and End Results Database The National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) tumor registry database was used for this study. SEER contains over 3 million cases from 17 geographic sites, covering approximately 26% of the US population. SEER Program registries routinely collect data on patient demographics (e.g., age, sex), primary tumor characteristics (e.g., size, extent, grade), nodal staging (number of nodes examined, number of involved nodes), primary operation performed (distal pancreatectomy vs. others), vital status, and survival. The November 2012 update was used for this study, providing information from 1973 to 2010.34 As a population-based study with no patient identifiers involved, our study was exempt from Institutional Research Board review. Study Sample A total of 12,360 patients with pancreatic adenocarcinoma located either in the body or tail of the pancreas, diagnosed between 1998 and 2010, were identified from the SEER database using the International Classification of Disease (ICD) histology classification codes (8000, 8010, 8020, 8021, 8140, 8141, and 8500). Patients who were identified on only autopsy, did not have a histologically confirmed diagnosis, or have AJCC (American Joint Committee on
Cancer) stage IV diseases were excluded. Of the initial cohort, 1,473 underwent distal pancreatectomy for treatment and constituted our final study cohort. Data Collection and Analysis Standard demographic and tumor data were collected including age at diagnosis, sex, race, year of diagnosis, geographical distribution of patients, staging based on AJCC, grade of the tumor, number of lymph nodes examined (NNE), and number of positive lymph nodes. The lymph node ratio (LNR) was calculated by dividing the number of positive LN by NNE in patients who had at least one node examined. Patient characteristics were evaluated using t test for continuous data and chi-square test for categorical variables. Overall survival was used as the primary endpoint, and survival analysis was performed using Kaplan-Meier estimates and log-rank tests. Sensitivity analyses were performed to identify the appropriate cut points for NNE and LNR at which statistical significance in the log-rank tests for overall survival was reached. Multivariable analysis using Cox proportional hazards modeling was used to identify predictors of mortality. Hazard ratios (HR) and 95 % confidence intervals (95 % CI) were reported as appropriate. All statistical tests were twosided, and a p value ≤0.05 was considered to be statistically significant. Statistical analysis was performed using SPSS 17.0 (IBM Corporation).
Results Demographics A total of 1,473 patients were included in the final analysis. There were 771 (52.3 %) women and 702 (47.7 %) men with a mean age of 66±12 years (Table 1). A majority of the patients were white, n=1,180 (80.1 %); 165 (11.2 %) patients were black; and 128 (8.7 %) belonged to other ethnicities. The mean and median tumor sizes were 4.3±2.3 and 4.0 cm, respectively. The majority of the tumors were low grade, n= 829 (56.3 %), and 939 (77.3 %) patients had at least stage IIA disease and above (Table 1). There was a gradual increase in the incidence of distal pancreatectomy for pancreatic adenocarcinoma in the body and tail from 1998 to 2010. Number of Nodes Examined Of the 1,241 patients with complete lymph node staging data available, the median number of LN evaluated was 8 (range 0–85) and 843 (57 %) had ≤10 NNE examined. Of those who had at least one node examined, 628 (50.6 %) had no metastatic lymph node disease compared to 613 (49.4 %) who did
J Gastrointest Surg Table 1 Demographics
Table 2 Characteristics based on the number of lymph nodes examined Characteristic
Number (%) Characteristic
Median age (range) Gender Male Female Race White Black Other Year of diagnosis 1998–2004 2005–2010 Stagea IA IB IIA IIB III Unknown Nodal staging N0 or N1 NX Status of LN obtaineda Negative LN
NX No lymph nodes examined, LN lymph nodes a
Missing data present
Positive LN Unknown Tumor gradea Low High Unknown
NNE 1–10 (%) NNE >10 (%) p value
67 (26–93) 702 (47.7) 771 (52.3) 1,180 (80.1) 165 (11.2) 128 (8.7) 525 (35.6) 948 (64.4) 84 (5.7) 192 (13.0) 303 (20.6) 550 (37.3) 86 (5.8) 258 (17.5) 1,241 (84.2) 232 (15.8) 628 (42.6) 613 (49.3) 233 (15.8)
Year 1998–2004 2005–2010 Age 80 years Mean age (years)±SD Gender Female Male Race White Black Other Stage IA IB IIA IIB III Grade Low High Mean tumor size (cm)±SD
0.331 245 (56.7) 424 (48.9)
187 (43.3) 443 (51.1)
275 (48.0) 308 (52.9) 86 (59.7) 67.3±11.1
298 (52.0) 274 (47.1) 58 (40.3) 65.2±11.9
350 (52.2) 319 (50.7)
320 (47.8) 310 (49.3)
548 (52.6) 72 (48.3) 49 (45.4)
494 (47.4) 77 (51.7) 59 (54.6)
49 (58.3) 105 (54.7) 190 (62.7) 252 (45.9) 57 (66.3)
35 (41.7) 87 (45.3) 113 (37.3) 297 (54.1) 29 (33.7)
411 (54.3) 195 (50.0) 43.8±22.9
346 (45.7) 195 (50.0) 43.6±20.9
0.027*
0.002* 0.311
0.256
0.1 (14 months; p0.1 was 17 and 6 %, respectively (p10 lymph nodes evaluated (21 months; p10 NNE was 13 and 19 %, respectively (p65 years, increasing pathological stage of the tumor, nodal involvement, and higher histological grade. Even after adjusting for competing risk factors, LNR >0.1 remained significantly associated with adverse survival (HR=1.38, 95 % CI 1.10–1.74; p10 0.908 (0.779–1.060) Lymph node ratio (LNR) ≤0.1 1.00 (referent) >0.1 1.383 (1.097–1.742)
0.108
0.013*
0.002* 0.001* 0.001* 0.001*
0.222
0.006*
*p < 0.05 considered significant
positive patients, a LNR of ≤0.1 is associated with improved median and 5-year overall survival. While earlier studies have looked at both LNR and NNE to determine which one of these factors is important to predict prognosis in patients undergoing pancreatectomy,15,26,27,41,43 our data suggests that both of these are important. Our results suggest that the minimal number of evaluated nodes for optimal prognostication in patients with node-negative disease is 11. There was a significant overall median survival difference in patients who had greater than 10 LNs evaluated (17 vs. 21 months; p=0.011). Previous studies15,26,43 have reported that N0 patients need to have at least 10–12 LNs evaluated to accurately predict prognosis in patients undergoing pancreaticoduodenectomy. Huebner et al. reported a worse survival for N0 patients who underwent pancreaticoduodenectomy and had 11 LNs evaluated (HR 1.33, 95 % CI 1.1–1.7; p=0.001).15 In another study, patients with 20 LN groups with 20 LN cohort. Their study revealed that survival was significantly better in the 11– 20 compared with the 1–10 group (median, 20 vs. 15 months,
J Gastrointest Surg
respectively, p20 groups (median, 20 vs. 23 months, respectively, p=0.14). Slidell et al.26 found a statistically significant worse survival for patients (pancreaticoduodenectomy 73.6 %, partial pancreatectomy 18.8 %, and total pancreatectomy 5.5 %) with fewer than 12 LNs evaluated, and the difference in survival was 7 months. Similarly, we found that patients undergoing distal pancreatectomy need to have at least 11 LNs evaluated to avoid a negative impact on survival, likely from understaging. We identify several differences between patients who had 1–10 NNE and >10 NNE. Age influenced nodal harvest with 52 % of patients less than 65 years and 40 % older than 80 falling into the >10 NNE category. It is unclear if the reduced nodal count in older patients is intrinsically related to aging or if modification of surgical technique in older patients (less “radical” surgery secondary to surgeon bias) is responsible for this finding. Studies looking at the influence of aging on LN have also shown that lymph nodes can display degenerative changes by replacing the population of immune cells with connective tissue, which may explain low nodal counts.44,45 Geographic variation was also seen in the >10 NNE category for registries reporting to SEER, from 23 % in New Mexico to 67 % in Connecticut (data not shown), suggesting that differences in practice patterns rather than underlying biology may be contributing to this discrepancy. The number of lymph nodes recovered after surgery not only depends on the surgical technique but also the diligence of the staff in the pathology lab in searching for nodes in the surgical specimen. SEER relies on pathology reports submitted by registrars, and we were thus unable to study this point further using registry data given the lack of centralized pathology review. The increasing use of laparoscopic distal pancreatectomy may be associated with lower initial counts of lymph nodes, although published data suggests comparable yields with the open technique once the learning curve has been negotiated.46 Overall, 57 % of our study cohort had ≤10 NNE, suggesting the possibility of understaging in the majority of the population undergoing distal pancreatectomy. Although a trend towards increasing nodal harvest was seen over time, from 30 % in 1998 to 53 % in 2010 (combined figures in Table 2), this was not statistically significant. Nevertheless, this does suggest an increasing awareness of the importance of nodal counts in cancer operations on the pancreas. Finally, the positive impact of >10 NNE on survival was not seen in the multivariable analyses, likely because of the overriding influence of node-positive disease on mortality. LNR has been previously shown to be an important factor – to predict survival in pancreatic cancer.27 29,33 LNR is less susceptible to stage migration and provides a more accurate comparison for patients with N1 disease. As opposed to categorizing patients as N0 or N1, LNR not only provides data regarding the number of positive LNs but also gives an estimate of the adequacy of LNs obtained. However, there is
no consensus on either the best cutoff value for LNR, the method to determine such cutoff, or the total number of LNs needed to achieve an accurate LNR in patients undergoing pancreatectomy.15 Pawlik et al.27 used categories of LNR 0.4 while House et al.47 used LNR of 0.18 to predict survival difference in their patient populations with pancreatic cancer. For patients undergoing distal pancreatectomy, we used sensitivity analyses to determine a LNR cutoff of 0.1 as statistically significant for survival discrimination. Patients with LNR ≤0.1 had a longer median survival compared to patients with LNR >0.1 (19 vs. 14 months; p0.1 appears to be associated with worse survival and may be a better prognostic indicator than the absolute number of positive nodes. Our data provides a guide for what constitutes adequate lymphadenectomy in patients undergoing distal pancreatectomy for pancreatic adenocarcinoma. LNR and NNE should be considered as additional data points in further studies of outcome after curative resection.
Conflicts of Interest No financial disclosures or conflicts of interest for any of the authors.
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