Background:
Pancreatic ductal adenocarcinoma is a highly malignant tumor with relatively poor survival. Surgery is the first choice for treating patients with early pancreatic cancer. However, the surgical approach and the extent of resection for patients with pancreatic cancer are currently controversial.
Methods:
The authors optimized the procedure of standard pancreaticoduodenectomy to selective extended dissection (SED), which is based on the extrapancreatic nerve plexus potentially invaded by the tumor. The authors retrospectively analyzed the clinicopathological data of patients with pancreatic adenocarcinoma who underwent radical surgery in our center from 2011 to 2020. Patients who underwent standard dissection (SD) were matched 2:1 to those who underwent SED using propensity score matching. The log-rank test and Cox regression model were used to analyze survival data. In addition, statistical analyses were performed for the perioperative complications, postoperative pathology, and recurrence pattern.
Results:
A total of 520 patients were included in the analysis. Among patients with extrapancreatic perineural invasion (EPNI), disease-free survival was significantly longer in those who received SED than in those who received SD (14.5 months vs. 10 months, P<0.05). The incidence of metastasis in No. 9 and No. 14 lymph nodes was significantly higher in patients with EPNI. In addition, there was no significant difference in the incidence rate of perioperative complications between the two surgical procedures.
Conclusion:
Compared with SD, SED exhibits a significant prognostic benefit for patients with EPNI. The SED procedure aiming at specific nerve plexus dissection displayed particular efficacy and safety in resectable pancreatic ductal adenocarcinoma patients.
Keywords: extended dissection, pancreatic cancer, perineural invasion, whipple procedure
Introduction
Highlights
Selective extended dissection (SED) is a novel surgical procedure, which is based on the extrapancreatic nerve plexus potentially invaded by the tumor in a patient with pancreatic head cancer.
SED can significantly improve the disease-free survival of patients with extrapancreatic perineural invasion.
SED can reduce the possibility of postoperative regional recurrence.
The positive rate of No. 9 and No. 14 lymph nodes was higher in patients with extrapancreatic perineural invasion, and routinely extended dissection was recommended.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors which had become the third leading cause of death among cancers in 20221. Often for patients with regional lesions, surgery is the only potential curative option, even though early recurrence after radical resection is extremely high. The importance of extended dissection in patients with resectable pancreatic cancer still remained undefined. Several randomized controlled trials, as well as some retrospective studies have proved that comparing with standard dissection (SD), patients underwent extended dissection exhibited no significant survival benefit2–5. In addition, the prognosis of patients with resectable pancreatic cancer can be improved by total neoadjuvant therapy, including preoperative radio-chemotherapy, radical dissection, and postoperative radio-chemotherapy6,7. This treatment concept may impair the importance of radical surgery in multidisciplinary treatment, while emphasize the role of perioperative chemoradiotherapy. Nevertheless, the procedure of operation and extent of resection are still the focused area of research. On the one hand, radical dissection is the most efficient treatment to eliminate the primary tumor burden, so that patients’ symptoms such as jaundice and pain, could be relieved or eliminated. On the other hand, postoperative pathology can provide a complete pathological stage and molecular typing, which can provide the foundation for subsequent treatment.
For the standard operation in patients with pancreatic head cancer, the whipple procedure, the optimal extent of resection had been still controversial8. The results of several clinical trials showed that extended dissection did not significantly influence the long-term prognosis in patients received radical dissection. However, the surgical procedure and extent of resection in clinical trials is hardly reflective of a real-world situation. Firstly, a comprehensive evaluation based on the general state, physical state, preoperative laboratory value, and imaging examination are needed to determine whether patients should receive extended dissection. In addition, the extent of resection should be adapted according to the anatomical subsites of the tumors and their biological characteristics9. Therefore, for patients with pancreatic head cancer, the extent of resection cannot be a single unified model. In summary, we aimed to identify patients with resectable pancreatic cancer who might benefit from extended surgery.
Extrapancreatic nerve invasion (EPNI) is a malignant biologicals behavior of PDAC, as well as a risk factor of prognosis for patients10,11. Our previous studies have shown that preoperative enhanced-contrast CT yielded a high diagnosis sensitivity and specificity on EPNI. In addition, tumors that arise at different anatomic sites of the pancreas potentially invaded different nerve plexus12. In this study, we proposed a novel surgical procedure of selective extended dissection (SED) focusing on dissecting the nerve plexus selectively based on the nerve plexus potentially invaded by tumor. On the one hand, the ‘selective’ of SED refers to the selection of the region of nerve plexus. According to the classification of preoperative imaging perineural invasion, the nerve plexus with potential invasion should be dissected. The ‘selective’ of SED, on the other hand, refers to the selection of patients most likely to derive benefit from extended dissection, according to EPNI. Extended dissection is just performed in patients with EPNI, as shown by preoperative imaging examination, while SD is performed in patients without EPNI. In order to perform an accurate and comprehensive dissection of the nerve plexus, different arterial approaches were combined with extended dissection. On the basis of the normalization of the surgical procedure, the patients who received SED underwent long-termed follow-up to evaluate the efficacy and safety of this procedure.
Method
Study population and data collection
We reviewed the medical records of patients who were admitted to our center from January 2011 to December 2019 from the medical database of our center. The inclusion criteria are as follows: Patients of any age diagnosed as resectable pancreatic cancer were pathologically diagnosed as PDAC after surgery. Patients received radical surgery and had complete photos or videos of the operation. Patients had no history of cancer including pancreatic cancer. Exclusion criteria: The operation records and related photo or video data could not reflect the surgical approach and the extent of resection or surgical rule violation. Patients with incomplete clinical, pathological, imaging, and follow-up information. An unresectable condition or metastasis was found during surgery. The diagnosis of resectable pancreatic cancer and postoperative chemotherapy regimen were based on the guidelines of National Comprehensive Cancer Network (NCCN) guidelines13. The postoperative specimens were evaluated according to AJCC criteria (8th edition)14. This retrospective study met the ethical guidelines of the Declaration of Helsinki and was approved by the Ethics Committee of our center (bc2023010).
Surgical procedure
According to the extent of nerve invasion in patients with pancreatic cancer and the development of the pancreas during embryogenesis, we classified the patients into three types and determined the scope of resection. For type I EPNI, the tumor is located in the dorsal pancreatic head or pancreatic neck, which tends to invade extrapancreatic nerve plexus 1 (PLX1) surrounding the celiac trunk (CT). Type II refers to the tumor located in the ventral head of the pancreas (uncinate process of the pancreas), and the tumor tends to be invaded in the extrapancreatic nerve plexus 2 (PLX2) surrounding the superior mesenteric artery (SMA). Type III is a pancreatic tumor prone to comprehensively invade PLX1 and PLX2. Different surgical techniques were developed for different types, which are as follows.
For the patients with type I EPNI, we focused on an extended dissection of PLX1 during surgery. The detailed extent of nerve fibers, lymph nodes, and soft tissue are shown in Figure 1A and Supplementary Figure 1a, Supplemental Digital Content 2, http://links.lww.com/JS9/A503. Following the Cattell-Braasch maneuver, the gastrocolic ligament and the greater omentum were dissected until the head of the pancreas is fully exposed and mobilized. Soft tissues along the inferior border of the pancreas was released to expose the anterior wall of the superior mesenteric vein (SMV) and portal vein (PV). Then, soft tissue along the left side of the SMV were dissected to exposed SMA. After the transection of the pancreatic neck, the mesopancreas along the right lateral of the SMA were separated, and the arterial segments between the root of the SMA and the horizontal at the inferior border of the pancreas were exposed. Then, PLX1 was exposed between SMV and SMA. Lymph nodes and nerve plexus bearing soft tissues along the celiac axis (CA), SMA, and SMV/PV was completely dissected (TRIANGLE operation). And then No. 8a (the CHA), No. 9 (the CA), and No. 12 (portal hilum) lymph nodes were removed en bloc, and the arterial adventitia of CHA, CA (left side), and SMA (root part of the artery) were resected.
Figure 1.
The diagram for the extent of extrapancreatic nerve plexus and lymph nodes of selective extended dissection (SED): A. type I extrapancreatic perineural invasion (EPNI), B. type II EPNI and C. type III EPNI. The yellow region was the nerve plexus should be dissected and orange dots refer to the lymph nodes. CHA, common hepatic artery; CT, celiac trunk; PLX I, extrapancreatic nerve plexus I; PLX II, extrapancreatic nerve plexus II; SA, spleen artery; SV, spleen vein; SMA, superior mesenteric artery; SMV, superior mesenteric vein.
For the situation of type II, the tumor was closely related to the PLX2. A left-posterior artery approach was performed. The Treitz ligament was dissected to expose the SMA. After the proximal jejunum was dissected and overturns to the right, the SMA was rotated counterclockwise. The first jejunal artery (J1A) was isolated and ligated at its root either on the SMA or on the common trunk with the inferior pancreaticoduodenal artery (IPDA). Then, the mesojejunum around the IPDA and J1A and the left hemicircle nerve plexus of SMA were dissected. Through a Cattell-Braasch maneuver performed15, the root of SMA was isolated above the left renal vein. After that, SMV was completely isolated from the right of the SMA, and the right hemicircle nerve plexus of SMA was dissected. At this point, the PLX2 and No. 14 lymph nodes surrounding the SMA have been dissected.
Patients with type III EPNI were considered concurrent invasion of the tumor to both PLX1 and PLX2. The extent of resection included lymph nodes, nerve plexus and soft tissue along the entire circumference of SMA as well as the Heidelberg Triangle. In addition to this, CHA and right side of SMA, were skeletonized.
In routine extended dissection (RED), on the basis of SD, the CHA lymph nodes (No. 8), CT lymph nodes (No. 9), SMA lymph nodes (No. 14), and para-aortic lymph nodes between CT and inferior mesenteric artery (No.16a2, No.16b1) were dissected. All the soft tissues around the hepatoduodenal ligament were completely dissected and skeletonized. The nerve plexus or ganglion on the right hemicircle of the celiac trunk and the peripheral nerve plexus along the entire circumference of SMA were dissected2.
Clinicopathologic data
Clinical, pathological, and imaging information were entered into the pancreatic cancer database by two independent researchers. Surgical videos and photos were collected by researchers who were not involved in the operation and uploaded to the database of pancreatic cancer. Follow-up information was uploaded to the database after regular telephone follow-up by the follow-up team of our center. The above patients’ clinical, imaging, and pathological information were collected from the pancreatic cancer database. Contrast-enhanced CT evaluated the EPNI of all the patients. The pathological data of the patients were mainly concerned with the EPNI. The diagnosis and subtypes of imaging PNI was based on the criteria proposed in our previous studies. Pathologically, the diagnostic criterion of EPNI is a nerve plexus invaded by tumor tissue was no surrounding benign pancreatic tissue (islet of Langerhans, pancreatic acini, or benign pancreatic ductles)16. In addition, the dissected nerve plexus during surgery was pathologically examined in patients who received SED. In addition, the shortest distance between the tumor boundary and the adventitia of the CT and SMA on enhanced-contrast CT was less than 6.5 mm as the diagnostic criteria for imaging PNI12.
Study design and statistical methods
The propensity score matching method matched patients undergoing SED and patients undergoing SD according to sex, age, 8th AJCC stage, pathological grade, and serum CA19-9 level in a 1:2 ratio. The nearest matching method was used, and the caliper value was set at 0.05. In the matched cohort, the standardized mean difference of each index was less than 0.1, as shown in Supplementary Figure 2, Supplemental Digital Content 2, http://links.lww.com/JS9/A503
The measurement data were described by mean, SD, median, and interquartile range, while count data was described as the number of cases and percentage. Statistical analysis was performed on the matched cohort, and the t-test or Mann–Whitney U test was used for measurement data. Categorical data were analyzed by the χ 2-test or Fisher’s exact test. All statistical analyses were performed R and R Studio software (version 1.4.1106.0). The applied packages include tableone, matching, survey, reshape2, ggplot2, survival, and survfit. In this study, P<0.05 was considered statistically significant. This work has been reported in line with strengthening the reporting of cohort studies in surgery (STROCSS) criteria17, Supplemental Digital Content 1, http://links.lww.com/JS9/A502.
Result
Comparison of baseline information between the two groups
According to the established criteria, 735 cases were included, 118 cases were excluded, and 612 patients were finally included, as shown in Figure 2. Patients were followed through the death date or the last follow-up date (31 December 2022), and the median follow-up time overall was 46 months (interquartile range, 40–60 months). We compared the clinicopathological data between the SD group and the SED group. Significant differences were noted between the two groups in terms of AJCC stage, pathological grade, vascular invasion rate, and R0 resection rate, as well as the number of cases between the two groups (shown in Supplementary Table 1, Supplemental Digital Content 2, http://links.lww.com/JS9/A503). For the cohort after matching, differences between the two groups of patients in the above clinicopathological characteristics were eliminated, as shown in Table 1. The matched cohort consisted of 243 patients, 162 cases in the SD group, and 81 cases in the SED group.
Figure 2.
Flow chart of patient enrollment and exclusion.
Table 1.
Comparison of basic information between SD and SED group in matched cohort.
| SD | SED | P | |
|---|---|---|---|
| 162 | 81 | ||
| Sex (%) | |||
| Female | 76 (46.9) | 40 (49.4) | 0.820 |
| Male | 86 (53.1) | 41 (50.6) | |
| Age (%) | |||
| ≤60 | 71 (43.8) | 36 (44.4) | >0.999 |
| >60 | 91 (56.2) | 45 (55.6) | |
| Tumor size (%) | |||
| <=4 | 108 (66.7) | 59 (72.8) | 0.406 |
| >4 | 54 (33.3) | 22 (27.2) | |
| P stage (%) | |||
| I/IIa | 54 (33.3) | 22 (27.2) | 0.406 |
| IIb/III | 108 (66.7) | 59 (72.8) | |
| Positive LN ratio (%) | |||
| ≤0.02 | 76 (46.9) | 35 (43.2) | 0.682 |
| >0.02 | 86 (53.1) | 46 (56.8) | |
| Soft tissue invasion (%) | |||
| Negative | 36 (22.2) | 18 (22.2) | >0.999 |
| Positive | 126 (77.8) | 63 (77.8) | |
| Vessel invasion (%) | |||
| Negative | 137 (84.6) | 69 (85.2) | >0.999 |
| Positive | 25 (15.4) | 12 (14.8) | |
| Differentiation (%) | |||
| Poor | 30 (18.5) | 16 (19.8) | 0.954 |
| Well | 132 (81.5) | 65 (80.2) | |
| CA19-9 (%) | |||
| ≤172.8 U/ml | 74 (45.7) | 40 (49.4) | 0.683 |
| >172.8 U/ml | 88 (54.3) | 41 (50.6) | |
| CEA (%) | |||
| ≤3.54 ng/ml | 85 (52.5) | 41 (50.6) | 0.892 |
| >3.54 ng/ml | 77 (47.5) | 40 (49.4) | |
| Nerve invasion (%) | |||
| Negative | 42 (25.9) | 21 (25.9) | >0.999 |
| Positive | 120 (74.1) | 60 (74.1) | |
| IPNI (%) | |||
| iPNI (-) | 67 (41.4) | 35 (43.2) | 0.890 |
| iPNI (+) | 95 (58.6) | 46 (56.8) | |
| Postoperative chemotherapy (%) | |||
| No | 46 (28.4) | 23 (28.4) | >0.999 |
| Yes | 116 (71.6) | 58 (71.6) | |
| Curability (%) | |||
| R0 | 94 (58.0) | 47 (58.0) | >0.999 |
| R1 | 68 (42.0) | 34 (42.0) | |
CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; iPNI, imaging Perineural Invasion; LN, lymph node; SD, Standard Dissection; SED, Selective Extended dissection.
Survival analysis and subgroup analysis
In the matched cohort, patients had no significant difference in DFS and OS between the SED group and the SD group (DFS: P=0.393; OS: P=0.650), as shown in Figure 3A. In the subgroup of patients without EPNI indicated by preoperative enhanced-contrast CT, no significant difference in DFS and OS was indicated between the two groups (DFS: P=0.210; OS: P=0.404), as shown in Figure 3B. However, in the subgroup of patients with EPNI, SED group had a significantly better DFS than that of SD group (median DFS: 14.5 months vs. 11 months, P=0.032), while there was no significant difference in OS between the two groups, as shown in Figure 3C. Thus, patients with EPNI, the SED can significantly prolong the DFS of patients. However, this effect was not significant in patients without EPNI.
Figure 3.
K-M curve for patients underwent selective extended dissection (SED) and standard dissection (SD): A. in the total cohort, B: in patients without extrapancreatic perineural invasion (EPNI) and C: in patients with EPNI.
Cox regression analysis for the matched cohort showed that tumors larger than 4 cm, AJCC stages IIb to III, and R1 resection were independent risk factors for DFS and OS, as shown in Table 2. In addition, tumor size larger than 4 cm, lymph node positive rate greater than 0.02, and R1 resection are independent risk factors for OS, as shown in Table 3. Although in Cox hazard regression models, SED was not a protective factor for the prognosis of patients with pancreatic cancer. These results demonstrate that SED is of great significance for patients with potential EPNI, which is significantly able to improve the DFS of patients. However, in patients without EPNI, the improvement of survival for extended dissection was not significant.
Table 2.
Univariate and multivariate cox regression model for DFS in matched cohort.
| Univariate analysis | Multivariate analysis | |||
|---|---|---|---|---|
| HR (95% CI for HR) | P | HR (95% CI for HR) | P | |
| Sex | ||||
| Female/Male | 0.934 (0.715–1.219) | 0.615 | ||
| Age | ||||
| ≤60/>60 | 0.874 (0.668–1.140) | 0.317 | ||
| Tumor size | ||||
| ≤4/4 cm | 1.632 (1.228–2.170) | <0.001 | 2.050 (1.506–2.791) | <0.001 |
| 8th AJCC stage | ||||
| I, IIa/IIb,III | 1.406 (1.055–1.874) | 0.020 | 1.892 (1.343-2.665) | <0.001 |
| Positive LN ratio | ||||
| ≤0.02/0.02 | 1.462 (1.071–1.997) | 0.017 | 1.264 (0.899–1.777) | 0.178 |
| Soft tissue invasion | ||||
| Negative/Positive | 1.033 (0.752–1.420) | 0.840 | ||
| Vessel invasion | ||||
| Negative/Positive | 1.021 (0.698–1.493) | 0.916 | ||
| Differentiation | ||||
| Poor/Well | 0.816 (0.580–1.147) | 0.241 | ||
| CA19-9 | ||||
| ≤200/>200 U/ml | 1.297 (0.994–1.694) | 0.056 | ||
| CEA | ||||
| ≤3.5/>3.5 ng/ml | 0.973 (0.746–1.270) | 0.842 | ||
| iPNI | ||||
| Negative/Positive | 1.048 (0.800–1.374) | 0.732 | ||
| Postoperative chemotherapy | ||||
| No/Yes | 0.796 (0.594–1.065) | 0.125 | ||
| Curability | ||||
| R0/R1 | 1.414 (1.081–1.850) | 0.012 | 1.739 (1.311–2.305) | <0.001 |
AJCC, American Joint Committee on Cancer Staging; CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; HR, hazard ratio; iPNI, imaging perineural invasion; LN, lymph node.
Table 3.
Univariate and multivariate analysis of OS in matched cochort.
| Univariate analysis | Mutivariate analysis | ||||
|---|---|---|---|---|---|
| HR (95% CI for HR) | P | HR (95% CI for HR) | P | ||
| Sex | |||||
| Female/Male | 0.789 (0.591–1.055) | 0.110 | |||
| Age | |||||
| ≤60/>60 | 0.787 (0.589–1.052) | 0.105 | |||
| Tumor Size | |||||
| ≤4/4 cm | 1.780 (1.317–2.406) | <0.001 | 1.859 (1.373–2.517) | <0.001 | |
| p stage | |||||
| I, IIa/IIb,III | 1.370 (1.000–1.877) | 0.050 | |||
| LN ratio | |||||
| ≤0.02/0.02 | 1.589 (1.145–2.207) | 0.006 | 1.775 (1.271–2.478) | 0.001 | |
| Soft tissue invasion | |||||
| Negative/Positive | 1.150 (0.810–1.634) | 0.434 | |||
| Vessel invasion | |||||
| Negative/Positive | 1.296 (0.880–1.908) | 0.190 | |||
| Differentiation | |||||
| Poor/Well | 0.775 (0.539–1.113) | 0.168 | |||
| CA19-9 | |||||
| ≤200/>200 U/ml | 1.234 (0.923–1.652) | 0.156 | |||
| CEA | |||||
| ≤3.5/>3.5 ng/ml | 0.807 (0.603–1.081) | 0.150 | |||
| EPNI | |||||
| Negative/Positive | 1.155 (0.857–1.556) | 0.343 | |||
| Postoperative chemotherapy | |||||
| No/Yes | 0.772 (0.564–1.056) | 0.105 | |||
| Curability | |||||
| R0/R1 | 1.441 (1.077–1.928) | 0.014 | 1.561 (1.162–2.098) | 0.003 | |
| Surgical approach | |||||
| SD/SED | 0.931 (0.681–1.271) | 0.650 | |||
AJCC, American Joint Committee on Cancer Staging; CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; EPNI, extrapancreatic perineural invasion; HR, hazard ratio; LN, lymph node.
Postoperative pathology analysis
According to the statistical analysis of postoperative pathology in the matched cohort, it can be concluded that EPNI is highly correlated with metastasis of No. 9 and No. 14 lymph nodes. In the EPNI positive group, the positive rate of lymph nodes in No. 14c or No. 14d (28.6%) was significantly higher than that in the EPNI negative group (3.4%). It is worth nothing that the positive rate of No. 9 lymph nodes (38.9%) was also significantly higher than that in the EPNI negative group (9.1%), as shown in Table 4. In addition, the pathological examination of the surgical specimens for the PLX1 and PLX2 further confirmed the diagnostic value of contrast-enhanced CT in pathological EPNI. There was no significant difference in prognosis between patients with positive and negative No. 9 lymph nodes, as shown in Figure 4A. The patients with negative No. 14 lymph nodes showed a markedly better prognosis than those of the negative patients, as shown in Figures 4B and C.
Table 4.
Comparison of lymph node metastasis between EPNI positive and negative patients after operation.
| Overall | EPNI (-) | EPNI (+) | P | |
|---|---|---|---|---|
| 96 | 40 | 56 | ||
| Positive LN (%) | ||||
| <=3 | 60 (62.5) | 28 (70.0) | 32 (57.1) | 0.285 |
| >3 | 36 (37.5) | 12 (30.0) | 24 (42.9) | |
| LN dissection (%) | ||||
| <=24 | 54 (56.2) | 26 (65.0) | 28 (50.0) | 0.211 |
| >24 | 42 (43.8) | 14 (35.0) | 28 (50.0) | |
| Type (%) | ||||
| I | 32 (33.3) | 11 (27.5) | 21 (37.5) | 0.545 |
| II | 38 (39.6) | 18 (45.0) | 20 (35.7) | |
| III | 26 (27.1) | 11 (27.5) | 15 (26.8) | |
| PLX1 (%) | 28 (56.0) | 2 (14.3) | 26 (72.2) | 0.001 |
| PLX2 (%) | 30 (54.5) | 4 (20.0) | 26 (74.3) | <0.001 |
| EPNI (%) | 47 (49.0) | 6 (15.0) | 41 (73.2) | <0.001 |
| No. 14.ab (%) | 17 (17.7) | 4 (10.0) | 13 (23.2) | 0.161 |
| No. 14.cd (%) | 11 (17.2) | 1 (3.4) | 10 (28.6) | 0.020 |
| No. 9 (%) | 16 (27.6) | 2 (9.1) | 14 (38.9) | 0.031 |
| No. 8a (%) | 39 (40.6) | 15 (37.5) | 24 (42.9) | 0.752 |
| No.8p (%) | 22 (22.9) | 9 (22.5) | 13 (23.2) | >0.999 |
| No.7 (%) | 7 (7.3) | 3 (7.5) | 4 (7.1) | >0.999 |
| No. 5 (%) | 9 (9.4) | 4 (10.0) | 5 (8.9) | >0.999 |
| No. 6 (%) | 6 (6.2) | 4 (10.0) | 2 (3.6) | 0.392 |
| No.13 (%) | 46 (47.9) | 19 (47.5) | 27 (48.2) | >0.999 |
| No.17 (%) | 38 (39.6) | 16 (40.0) | 22 (39.3) | >0.999 |
EPNI, extrapancreatic perineural invasion; LN, lymph node; PLX1, extrapancreatic perineural invasion 1; PLX2, extrapancreatic perineural invasion 2.
Figure 4.
Comparison of K-M curve between patients with and without regional lymph nodes metastasis: A. No. 9 lymph nodes, B. No. 14a or No. 14b lymph nodes and C. No. 14c and No. 14d lymph nodes.
Postoperative complications and recurrence pattern
There was no significant difference in the incidence of postoperative pancreatic fistula, biliary fistula, delayed gastric emptying, gastrointestinal fistula, abdominal infection, and postoperative hemorrhage between the two groups. However, the incidence of postoperative diarrhea in patients undergoing SED (23.5%) was higher than that in patients undergoing SD (8.6%). In addition, no significant differences were indicated in operation time, hospital stay, intraoperative blood loss, vascular reconstruction and combined organ resection between the two groups, as shown in Table 5. Comparing the postoperative recurrence pattern between the two groups, we found that patients who underwent SED (8.6%) had a lower peritoneal metastasis than those who underwent standard radical resection (21.6%). There were no significant differences in the incidence of stump recurrence, abdominal cavity metastasis, liver metastasis, lung metastasis, and bone metastasis, as shown in Table 6.
Table 5.
Perioperative complications were compared between the two groups.
| Overall | SD | SED | P | |
|---|---|---|---|---|
| 243 | 162 | 81 | ||
| Operation time (median [IQR]) | 291.92 [223.98, 334.18] | 296.17 [231.13, 334.22] | 285.86 [212.54, 333.19] | 0.519 |
| <=291.9 | 121 (49.8) | 79 (48.8) | 42 (51.9) | 0.751 |
| >291.9 | 122 (50.2) | 83 (51.2) | 39 (48.1) | |
| Intraoperative bleeding (median [IQR]) | 380.00 [270.00, 530.00] | 380.00 [250.00, 517.50] | 410.00 [280.00, 560.00] | 0.171 |
| <=380 | 122 (50.2) | 84 (51.9) | 38 (46.9) | 0.555 |
| >380 | 121 (49.8) | 78 (48.1) | 43 (53.1) | |
| Intraoperative transfusion (median [IQR]) | 0.00 [0.00, 500.00] | 0.00 [0.00, 500.00] | 0.00 [0.00, 500.00] | 0.904 |
| Combined devisceration (%) | 13 ( 5.3) | 9 (5.6) | 4 (4.9) | |
| Vascular reconstruction (%) | 21 ( 8.6) | 15 (9.3) | 6 (7.4) | |
| HLOS (mean (standard deviation)) | 20.15 (9.26) | 20.43 (9.47) | 19.59 (8.84) | 0.509 |
| <=19 | 125 (51.4) | 81 (50.0) | 44 (54.3) | 0.618 |
| >19 | 118 (48.6) | 81 (50.0) | 37 (45.7) | |
| Pancreatic fistula (%) | ||||
| No | 149 (61.3) | 95 (58.6) | 54 (66.7) | 0.393 |
| Biochemical fistula | 77 (31.7) | 56 (34.6) | 21 (25.9) | |
| Grade B | 17 (7.0) | 11 (6.8) | 6 (7.4) | |
| Bile fistula (%) | 58 (23.9) | 36 (22.2) | 22 (27.2) | 0.489 |
| Gastrointestinal fistula (%) | 11 (4.5) | 7 (4.3) | 4 (4.9) | >0.999 |
| DGE (%) | 29 (11.9) | 19 (11.7) | 10 (12.3) | >0.999 |
| Diarrhea (%) | 33 (13.6) | 14 (8.6) | 19 (23.5) | 0.003 |
| Postoperative bleeding (%) | 22 (9.1) | 14 (8.6) | 8 (9.9) | 0.937 |
DGE, delayed gastric emptying; HLOS, hospital length of stay; IQR, interquartile range; SD, standard dissection; SED, selective extended dissection.
Table 6.
Comparison of postoperative recurrence pattern between SD and SED.
| Overall | SD | SED | P | |
|---|---|---|---|---|
| 243 | 162 | 81 | ||
| Residual pancreas (%) | 5 (2.1) | 5 (3.1) | 0 (0.0) | 0.263 |
| Liver metastasis (%) | 89 (36.6) | 64 (39.5) | 25 (30.9) | 0.239 |
| Lung metastasis (%) | 32 (13.2) | 22 (13.6) | 10 (12.3) | 0.947 |
| Bone metastasis (%) | 7 (2.9) | 2 (1.2) | 5 (6.2) | 0.078 |
| Peritoneal metastasis (%) | 42 (17.3) | 35 (21.6) | 7 (8.6) | 0.019 |
| Retroperitoneal lymph nodes metastasis (%) | 70 (28.8) | 53 (32.7) | 17 (21.0) | 0.080 |
SD, standard dissection; SED, selective extended dissection.
Comparison between SED and RED
We compared survival between patients who underwent SED and RED. In the original cohort, the proportion of patients receiving postoperative chemotherapy was significantly higher in the SED group than in the RED group (67.7 vs. 29.3%, P<0.001). There was no significant difference in other clinicopathological data between the two groups, as shown in supplementary Table 2, Supplemental Digital Content 2, http://links.lww.com/JS9/A503. In addition, SED had a significantly better DFS than those in the RED group (14 months vs. 9 months), while there was no significant difference in OS between the two groups (21 months vs. 18 months), as shown in supplementary Figure 3A, Supplemental Digital Content 2, http://links.lww.com/JS9/A503. Among patients with EPNI, DFS, and OS in SED group were significantly better than those in the SD group, as shown in supplementary Figure 3B, Supplemental Digital Content 2, http://links.lww.com/JS9/A503. However, among patients without EPNI, there was no significant difference in DFS and OS between the two groups, as shown in supplementary Figure 3C, Supplemental Digital Content 2, http://links.lww.com/JS9/A503. In addition, the operation time (median: 282.29 min vs. 306.88 min) and HLOS (19.43 days vs. 27.63 days) were significantly higher in the RED group, as shown in supplementary Table 3, Supplemental Digital Content 2, http://links.lww.com/JS9/A503. The incidence of DEG after surgery as well as diarrhea was significantly higher in the RED group than in the SED group, as shown in supplementary Table 3, Supplemental Digital Content 2, http://links.lww.com/JS9/A503. The RED group had a significantly higher incidence of postoperative liver metastases than those in the SED group, as shown in supplementary Table 4, Supplemental Digital Content 2, http://links.lww.com/JS9/A503.
Discussion
Previous studies have shown that EPNI is a risk factor for the prognosis of pancreatic cancer. EPNI is closely related to a variety of malignant biological behaviors, such as lymph node metastasis and liver metastasis18,19. The extent of surgical resection for patients with EPNI and the dissection of the extrapancreatic nerve plexus is still controversial. Inoue et al.20 proposed a surgical technique for aggressive pancreatic head tumors in which an en bloc resection of the nerve plexus was performed around the SMA on the right hemicircumference. Qian et al.9 also put forward a similar point of view and confirmed that No. 14 lymph node metastasis is likely to occur in ventral pancreatic cancer. This surgical technique can dissect the mesopancreas and soft tissue around SMA for the tumor located in the pancreatic uncinate process. However, this approach cannot be applied in this situation for malignant tumors located in the dorsal head and neck of the pancreas that are prone to invade CA/CHA and PLX1. Hackert et al. proposed the Heidelberg technique, which focuses on extended dissection of soft tissue with presumed tumor invasion within the PV/SMV, CA, and SMA boundary triangles21. This technique highlights the CA and SMA dissection in the right hemiperimetric region. However, there is no clear conclusion on whether the mesojejunum around J1A and IPDA needs to be dissected. Nagakawa et al. proposed a surgical resection method based on SMA’s peripheral nerve and fibrous tissue structure. They emphasized that preserving three regions without nerve and fibrous tissue branches can effectively reduce the incidence of postoperative serious adverse events while ensuring the R0 resection rate22. Previous studies about extended dissection of pancreaticoduodenectomy have always made uniform requirements for the scope of dissection. There is a lack of reasonable classification methods and a reasonable definition of the dissection scope for different types. Previous randomized controlled trials have concluded that there is no significant difference in OS benefit between the extended radical resection group and the standard radical resection group2,4,5,23. However, we believe that extended extrapancreatic nerve plexus dissection is beneficial for pancreatic cancer patients with EPNI. Therefore, we proposed the concept of SED. Compared with a merely ‘anatomical’ margin achieved by SD, a more radical ‘biological’ R0 margin is crucial for those PDAC patients with EPNI. On the one hand, PD with extended dissection on extrapancreatic nerve plexus can be benefit on patients diagnosed with imaging EPNI, whereas patients considered to have no EPNI before surgery should undergo SD to avoid a variety of postoperation complications. The selection, on the other hand, is to identify the extent of dissection. Depending on the type of imaging EPNI, the extrapancreatic nerve plexus that might be invaded by the tumor was accurately removed through SED technic; while for patients without imaging EPNI, SD was a more favorable approach. Our data have concluded that SED could improve the DFS of patients with EPNI, but barely show significance for patients without EPNI. Furthermore, SED has relatively lower retroperitoneal lymph node metastasis rates, residual pancreatic recurrence, and peritoneal seeding compared with SD. Therefore, we believe that expanded dissection with a focus on the nerve plexus can reduce the possibility of local and regional recurrence. The incidence of postoperative complications in the extended dissection group was similar to that in the SD group. Although the incidence of diarrhea in the extended dissection group was higher than in the SD group, most patients who received medical treatment had significant relief of diarrhea symptoms. Thus, SED has relatively favorable efficacy and safety.
Previous studies have shown that regional lymph node metastasis is a prognostic risk factor in patients with pancreatic cancer24–26. Current standards for lymph node dissection in standard radical resection of pancreatic cancer require No. 5, No. 6, No. 8a, No. 12b1, No. 12b2, 12C, No. 13a, No. 13b, right side of No. 14a, right side of 14b lymph node, No. 17a, and No.17b lymph nodes27. Qian et al.9 have confirmed that No. 14 lymph node metastasis is likely to occur in ventral pancreatic cancer and they recommended routine dissection of No. 14c, No. 14d lymph nodes in patients with malignancies of the pancreatic uncinate process. Our data suggested that the positive rate of No. 14c and No. 14d was significantly higher in patients with type II and III EPNI (PLX2 potentially invaded by the tumor). The patients with No. 14 lymph nodes metastasis exhibited a significantly poor prognosis. In addition, for patients with type I and III EPNI (PLX1 potentially invaded by the tumor), the positive rate of No. 9 lymph nodes was significantly higher than that in patients with negative EPNI. Therefore, routine dissection of No. 9 lymph nodes is recommended for patients with preoperatively considered PLX1 invaded, while dissection of No. 14 lymph nodes was performed in patients with PLX2 involvement. The SED approach may meet the requirement of selective extended lymphadenectomy including both No. 9 and No. 14 lymph nodes. On the one hand, SED was meaningful for the prolong of patients DFS; on the other hand, it would markedly improve the amount of collected lymph nodes so that a more accurate pathological staging could be performed.
Compared with SED, the incidence of delayed gastric emptying and diarrhea was significantly higher in the RED group. These are highly associated with excessive extrapancreatic nerve fiber dissection as well as the skeletonization of blood vessels. Postoperative adjuvant therapy was delayed or abandoned because of long-term nutritional disorders and poor physical status. These are the reasons why the proportion of patients in the RED group receiving adjuvant chemotherapy is significantly lower than that in the SED group. In addition, vascular injury caused by dissection of the perivascular soft tissue and adventitia may damage the local function of chemotherapy drugs. We believe that these may partly explain the worse prognosis of patients in the RED group. Therefore, even for resectable pancreatic cancer, timely and standardized postoperative adjuvant therapy is an important factor to improve the prognosis of patients. Although RED has a larger extent of dissection than SED, excessive dissection leads to poor physical status, which affects the postoperative treatment and is not conducive to the prognosis of patients. In conclusion, SED is a balance between SD and RED, which can accurately dissect the nerve and soft tissue potentially involved by the tumor, and also ensure the normal organ function of the patient to a great extent.
Regarding the R0 resection rate, there was no significant difference between patients in the SED group (42.0%) and those in the SD group (42.0%). Kaltenmeier et al. showed that the R1 resection rate was 14.4% in patients with pancreatic cancer, based on the resection margin cleared by more than 1 mm, and R1 resection margin was a risk factor for the prognosis28. Chang et al. showed that R1 resection rates were 51.5, 53.7, and 57.5%, respectively, based on the standard of 1 mm, 1.5 mm, and 2 mm, and a negative margin greater than 1.5 mm was a protective factor for the long-term prognosis of patients29. A clinical trial showed a 37.6% R1 resection rate, based on a resection margin more than 1 mm, after neoadjuvant chemotherapy in patients with borderline resectable pancreatic cancer7. Although, according to the NCCN guidelines, the standard of resection margin is greater than 1 mm, the distance greater than 2 mm as the standard of positive resection margin can effectively evaluate the prognosis of patients. Due to the high rate of early local recurrence around the resection margin and the discrepancy between pathological assessment and poor clinical outcomes, microscopic margin involvement is often underestimated30. Therefore, 2.5 mm was adopted as the criteria to evaluate the resection margin in our center while the R1 resection rate reached 42.0% in our cohort. Under this criteria, R1 resection is an independent risk factor for overall survival. This more stringent evaluation criteria cannot only reflect the biological characteristics of pancreatic cancer itself, but also prompt clinicians to carry out subsequent treatment to reduce the impact of R1 resection on the prognosis of patients.
This study systematically introduces the diagnostic indicators of EPNI, the prognostic value of iPNI, and the guiding significance of iPNI in selecting a resection range for pancreatic cancer. The limitation of this study is that it is a single-center, retrospective, and cohort study. This conclusion needs to be further verified by multicenter-controlled trials.
Ethical approval
This study was approved by the Ethics Committee of Tianjin Medical University Cancer Institute and Hospital (bc2023010).
Sources of funding
This work was supported by the National Key Research and Development Program of China(2021YFA1201100), the National Natural Science Foundation of China (grants 82072657).
Author contribution
X.G.: the main designer and executor of the study and responsible for the overall design of the study. The writing of the manuscript and the revision of the manuscript. Y.S.: the principal investigator of the study and is responsible for the collection of data in the database. P.X.: one of the researchers involved in the collection of data from the database. W.Z.: one of the study researchers involved in the follow-up of case data. H.W.: one of the study researchers involved in the patient’s surgical procedures. Y.Z.: one of the study researchers involved in the patient’s surgical procedures. C.H.: one of the study designers involved in the overall design of the study. J.H.: one of the study designers, involved in the design and implementation of the surgical protocol. S.G.: the primary designer of the study, the surgical protocol.
Conflicts of interest disclosure
The authors have no conflicts of interests.
Research registration unique identifying number (UIN)
Name of the registry: Clinicaltrials.gov.
Unique Identifying number or registration ID: Panc-2023129.
Hyperlink to your specific registration (must be publicly accessible and will be checked): https://clinicaltrials.gov/ct2/show/NCT05723978
Guarantor
Song Gao.
Data availability statement
The dataset used and analyzed in this study were obtained from the corresponding authors upon reasonable request.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Supplementary Material
Acknowledgements
None.
Footnotes
X.G. and Y.S. authors contributed equally to this work.
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Supplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal’s website, www.lww.com/international-journal-of-surgery.
Published online 16 May 2023
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References
- 1. Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA Cancer J Clin 2022;72:7–33. [DOI] [PubMed] [Google Scholar]
- 2. Jang JY, Kang MJ, Heo JS, 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;259:656–664. [DOI] [PubMed] [Google Scholar]
- 3. Jang JY, Kang JS, Han Y, et al. Long-term outcomes and recurrence patterns of standard versus extended pancreatectomy for pancreatic head cancer: a multicenter prospective randomized controlled study. J Hepato-Biliary-Pancr Sci 2017;24:426–433. [DOI] [PubMed] [Google Scholar]
- 4. Nimura Y, Nagino M, Takao S, et al. Standard versus extended lymphadenectomy in radical pancreatoduodenectomy for ductal adenocarcinoma of the head of the pancreas: long-term results of a Japanese multicenter randomized controlled trial. J Hepato-Biliary-Pancr Sci 2012;19:230–241. [DOI] [PubMed] [Google Scholar]
- 5. Pedrazzoli S, DiCarlo V, Dionigi R, et al. Standard versus extended lymphadenectomy associated with pancreatoduodenectomy in the surgical treatment of adenocarcinoma of the head of the pancreas: a multicenter, prospective, randomized study. Lymphadenectomy study group. Ann Surg 1998;228:508–517. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Kim RY, Christians KK, Aldakkak M, et al. Total neoadjuvant therapy for operable pancreatic cancer. Ann Surg Oncol 2021;28:2246–2256. [DOI] [PubMed] [Google Scholar]
- 7. Yamaguchi J, Yokoyama Y, Fujii T, et al. Results of a Phase II Study on the Use of Neoadjuvant Chemotherapy (FOLFIRINOX or GEM/nab-PTX) for Borderline-resectable Pancreatic Cancer (NUPAT-01). Ann Surg 2022;275:1043–1049. [DOI] [PubMed] [Google Scholar]
- 8. Kang MJ, Jang JY, Kim SW. Surgical resection of pancreatic head cancer: what is the optimal extent of surgery? Cancer Lett 2016;382:259–265. [DOI] [PubMed] [Google Scholar]
- 9. Qian L, Xie J, Xu Z, et al. The necessity of dissection of no. 14 lymph nodes to patients with pancreatic ductal adenocarcinoma based on the embryonic development of the head of the pancreas. Front Oncol 2020;10:1343. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Jurcak NR, Rucki AA, Muth S, et al. Axon guidance molecules promote perineural invasion and metastasis of orthotopic pancreatic tumors in mice. Gastroenterology 2019;157:838–50.e6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Yang YH, Liu JB, Gui Y, et al. Relationship between autophagy and perineural invasion, clinicopathological features, and prognosis in pancreatic cancer. World J Gastroenterol 2017;23:7232–7241. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Guo X, Gao S, Yu J, et al. The imaging features of extrapancreatic perineural invasion (EPNI) in pancreatic Cancer：a comparative retrospective study. Pancreatol 2021;21:1516–1523. [DOI] [PubMed] [Google Scholar]
- 13. Tempero MA, Malafa MP, Al-Hawary M, et al. Pancreatic adenocarcinoma, Version 2.2021, NCCN clinical practice guidelines in oncology. J Nat Comp Cancer Net 2021;19:439–57. [DOI] [PubMed] [Google Scholar]
- 14. Amin MB, Greene FL, Edge SB, et al. The eighth edition AJCC cancer staging manual: continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin 2017;67:93–99. [DOI] [PubMed] [Google Scholar]
- 15. Del Chiaro M, Segersvärd R, Rangelova E, et al. Cattell-Braasch Maneuver combined with artery-first approach for superior mesenteric-portal vein resection during pancreatectomy. J Gastrointest Surg 2015;19:2264–2268. [DOI] [PubMed] [Google Scholar]
- 16. Chatterjee D, Katz MH, Rashid A, et al. Perineural and intraneural invasion in posttherapy pancreaticoduodenectomy specimens predicts poor prognosis in patients with pancreatic ductal adenocarcinoma. Am J Surg Pathol 2012;36:409–417. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Agha R, Abdall-Razak A, Crossley E, et al. STROCSS 2019 guideline: strengthening the reporting of cohort studies in surgery. Int J Surg 2019;72:156–165. [DOI] [PubMed] [Google Scholar]
- 18. Li D, Yang M, Liang M, et al. c-Met-targeted near-infrared fluorescent probe for real-time depiction and dissection of perineural invasion and lymph node metastasis lesions in pancreatic ductal adenocarcinoma xenograft models. Biomat Sci 2021;9:6737–6752. [DOI] [PubMed] [Google Scholar]
- 19. Lu M, Xiu DR, Guo LM, et al. Extrapancreatic neuropathy correlates with early liver metastasis in pancreatic head adenocarcinoma. Onco Targets Ther 2019;12:11083–11095. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Inoue Y, Saiura A, Yoshioka R, et al. Pancreatoduodenectomy with systematic mesopancreas dissection using a supracolic anterior artery-first approach. Ann Surg 2015;262:1092–1101. [DOI] [PubMed] [Google Scholar]
- 21. Hackert T, Strobel O, Michalski CW, et al. The TRIANGLE operation - radical surgery after neoadjuvant treatment for advanced pancreatic cancer: a single arm observational study. HPB 2017;19:1001–1007. [DOI] [PubMed] [Google Scholar]
- 22. Nagakawa Y, Yi SQ, Takishita C, et al. Precise anatomical resection based on structures of nerve and fibrous tissue around the superior mesenteric artery for mesopancreas dissection in pancreaticoduodenectomy for pancreatic cancer. J Hepato-Biliary-Pancr Sci 2020;27:342–351. [DOI] [PubMed] [Google Scholar]
- 23. Farnell MB, Pearson RK, Sarr MG, et al. A prospective randomized trial comparing standard pancreatoduodenectomy with pancreatoduodenectomy with extended lymphadenectomy in resectable pancreatic head adenocarcinoma. Surgery 2005;138:618–628; discussion 28-30. [DOI] [PubMed] [Google Scholar]
- 24. Groot VP, Rezaee N, Wu W, et al. Patterns, timing, and predictors of recurrence following pancreatectomy for pancreatic ductal adenocarcinoma. Ann Surg 2018;267:936–945. [DOI] [PubMed] [Google Scholar]
- 25. Morales-Oyarvide V, Rubinson DA, Dunne RF, et al. Lymph node metastases in resected pancreatic ductal adenocarcinoma: predictors of disease recurrence and survival. Br J Cancer 2017;117:1874–1882. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Joliat GR, Allemann P, Labgaa I, et al. Prognostic value of positive histological margins in patients with pancreatic head ductal adenocarcinoma and lymph node involvement: an international multicentric study. HPB 2021;23:379–386. [DOI] [PubMed] [Google Scholar]
- 27. Tol JA, Gouma DJ, Bassi C, 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. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Kaltenmeier C, Nassour I, Hoehn RS, et al. Impact of resection margin status in patients with pancreatic cancer: a national cohort study. J Gastrointest Surg 2021;25:2307–2316. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Chang DK, Johns AL, Merrett ND, et al. Margin clearance and outcome in resected pancreatic cancer. J Clin Oncol 2009;27:2855–2862. [DOI] [PubMed] [Google Scholar]
- 30. Verbeke CS. Resection margins and R1 rates in pancreatic cancer--are we there yet? Histopathology 2008;52:787–796. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The dataset used and analyzed in this study were obtained from the corresponding authors upon reasonable request.