Pancreatic neck cancer has specific and oncologic characteristics regarding portal vein invasion and lymph node metastasis

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Pancreatic neck cancer has specific and oncologic characteristics regarding portal vein invasion and lymph node metastasis Seiko Hirono, MD, Manabu Kawai, MD, Ken-ichi Okada, MD, Motoki Miyazawa, MD, Atsushi Shimizu, MD, Yuji Kitahata, MD, Masaki Ueno, MD, and Hiroki Yamaue, MD, Wakayama, Japan

Background. Pancreatic cancer originating in the neck of the gland occurs in the small region surrounded by the common hepatic artery (CHA), gastroduodenal artery (GDA), and portal vein (PV). The specific clinicopathologic characteristics of pancreatic neck cancer remain unclear. Our aim was to identify specific biologic behaviors of pancreatic neck cancer for the improvement of treatment outcomes. Methods. This study was a retrospective cohort study with a comparative outcomes design. In 63 of 325 consecutive patients (19.4%) with pancreatic cancer who underwent operation, the tumor was located in the pancreatic neck. Clinicopathologic characteristics and prognostic factors specific to pancreatic neck cancer were analyzed by comparison with those of pancreatic head or body/tail cancers. Results. The rates of radiographic and pathologic PV and/or superior mesenteric vein (PV/SMV) invasion were greater in patients with pancreatic neck cancer (radiographic, 84%; pathologic, 37%) than those with pancreatic head and body/tail cancers (radiographic: 67% head, 25% body/tail; pathologic: 26% head, 6% body/tail). The most frequent lymph node (LN) metastases were found in the region along the CHA in pancreatic neck cancer, and the areas most likely to show a positive surgical margin were the dissected surface of the PV and the root of the GDA and/or CHA. For pancreatic neck cancer patients, 5 independent poor prognostic factors were found: pathologic PV/SMV invasion (P = .005), moderately or poorly differentiated tumors (P = .001), positive LN ratio of $0.1 (P < .001), distance from surgical margin of #1 mm (P = .018), and inability to complete the planned postoperative adjuvant therapy (P < .001). Conclusion. Pancreatic neck cancer showed specific clinicopathologic characteristics and prognostic factors after resection. (Surgery 2015;j:j-j.) From the Second Department of Surgery, Wakayama Medical University, School of Medicine, Wakayama, Japan

IN PANCREATIC CANCER, complete resection provides the only chance for cure or long-term survival. Unfortunately, only 15–20% of pancreatic cancer patients are candidates for curative resection at the time of initial diagnosis.1-3 Cancer located in the neck of the pancreas (pancreatic neck cancer) Disclosure of financial interests and potential conflicts of interest: We have no financial interests and potential conflicts of interest. Accepted for publication July 1, 2015. Reprint requests: Hiroki Yamaue, MD, Second Department of Surgery, Wakayama Medical University, School of Medicine, 811-1 Kimiidera, Wakayama, 641-8510, Japan. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2015.07.001

occurs in a small region at the boundary between the pancreatic head and body, anterior to the portal vein (PV), on the patient’s left side of the gastroduodenal artery (GDA), and caudal to the common hepatic artery (CHA; Fig 1, A).4-6 These anatomic characteristics may result in distinct clinicopathologic features of pancreatic neck cancer, compared with cancer located in the head of the pancreas (pancreatic head cancer) or in the body and/or tail of the pancreas (pancreatic body/tail cancer). There have been few reports, however, about pancreatic neck cancer, because these cases are classified commonly as pancreatic head or body cancer. Therefore, the specific biologic behaviors of pancreatic neck cancer, including favorable regions of lymph node (LN) metastases and prognostic factors, remain unclear. To determine the appropriate operative procedure, including SURGERY 1

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Fig 1. Location of carcinoma in the neck of the pancreas. A, The pancreatic neck is designated as segment of pancreas, approximately 2 cm long, anterior to the portal vein (PV), on the left side of the gastroduodenal artery (GDA), and below the common hepatic artery (CHA). B, Pancreatic neck cancer was defined as cancer of the pancreatic neck located between the left border of the PV and the GDA on CT findings.

the optimal LN dissection, and to evaluate the effect of neoadjuvant therapy for pancreatic neck cancer, we need to identify the clinically important distinguishing clinicopathologic characteristics. In this study, we reviewed 63 patients who underwent operation for pancreatic neck cancer. Our aim was to identify specific biologic behaviors, including likely LN metastatic regions and the prognostic factors, by comparing these cases with patients with pancreatic head or body/tail cancers to improve treatment outcomes for pancreatic neck cancer. METHODS Patients. From January 2000 to February 2014, 336 patients underwent pancreatic resection at Wakayama Medical University Hospital (WMUH) and were diagnosed with pancreatic ductal cancer pathologically. Clinicopathologic data and radiographic images were collected prospectively in the electronic medical record with data reviewed retrospectively. Eleven patients were excluded (pancreatic neck cancer, n = 1; pancreatic head cancer, n = 3; pancreatic body/tail cancer, n = 7), because the final pathologic diagnosis showed liver metastasis in 4 patients, gallbladder metastasis in 1 patient, and limited peritoneal dissemination in 6 patients. The remaining 325 patients were included in this analysis. This study followed the guidelines of our WMUH institutional review board. Preoperative radiographic findings and neoadjuvant therapy. Preoperative diagnosis and staging of pancreatic cancer were performed based on ultrasonography and the arterial and portal venous phases of their helical CT. Our criteria of operability for pancreatic cancer were the following: (1) no evidence of distant metastasis, (2) no more

than 1808 of abutment on the circumference of the superior mesenteric artery (SMA), (3) no abutment of aorta, (4) presence of reconstructive PV/ SMV invasion, and (5) no evidence of LN metastasis beyond the field of resection based on CT imaging at initial diagnosis. The pancreatic neck was defined as the segment of the pancreas 2 cm long between the left border of the PV and the GDA (Fig 1, A, B).4-6 The 325 patients were classified into 3 groups: 63 patients with pancreatic neck cancer, 150 patients with pancreatic head cancer, and 112 patients with pancreatic body/ tail cancer based on CT. Among 325 patients, 10 patients had tumor bridging the region of the pancreatic neck and were classified as follows: 5 were pancreatic neck cancers, 3 were pancreatic head cancers, and 2 were pancreatic body/tail cancers based on the dominant tumor location on CT. The radiographic findings of invasion of the PV and/or superior mesenteric vein (PV/SMV) were classified as type A (absent), type B (unilateral narrowing), type C (bilateral narrowing), or type D (stenosis or obstruction with collaterals), according to portal venous phase of the CT.7 From March 2010 onward, we performed neoadjuvant therapy only in patients with borderline resectable cancer defined as the tumor abutting #1808 of the circumference of the SMA and/or abutting the CHA and/or the celiac axis on CT, regardless of types of radiographic PV/SMV invasion. Two strategies of neoadjuvant treatment used were: (1) chemoradiation (external beam radiation with 50 Gy in 25 fractions with concurrent S-1, oral 5fluorouracil prodrug tegafur with oteracil and gimeracil with alternate-day administration) or (2) chemotherapy alone (concurrent S-1 with alternate-day administration and gemcitabine).8 The 40 patients with no evidence of progressive

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disease after neoadjuvant therapy underwent resection 3 weeks after the last dose of chemotherapy, whereas the 6 patients with progressive disease received continuous chemotherapy without resection. Operative techniques. For pancreatic neck cancer, we determined the appropriate operative procedures as follows. First, we chose a pyloruspreserving pancreatoduodenectomy (PD) or pylorus-resecting PD9 in case of radiographic evidence of the tumor abutting the distal GDA, and we chose a conventional PD if the tumor invaded to the duodenal bulb. The transection line of the pancreas was often performed at 2-5 cm to the left of the SMV during PD, including pylorus-preserving PD and pylorus-resecting PD. Second, we chose a distal pancreatectomy with en bloc celiac axis resection (DP-CAR)10,11 with tumor abutment of the CHA and/or the celiac axis, whereas we chose a subtotal left-side pancreatectomy often called extended distal pancreatectomy with the pancreas transected to the right of the SMV12 in the other cases. Two patients underwent total pancreatectomy; 1 had a concomitant endocrine tumor in the pancreatic tail, and the other had positive pancreatic surgical margins based on intraoperative pathologic assessment. All patients with pancreatic neck cancer underwent regional LN dissection, including removal of LNs in the hepatoduodenal ligament (#12), along the left gastric artery (#7), CHA (#8), celiac axis (#9), proximal splenic artery (#11p), and SMA (#14).13 To obtain a clear margin, a combined PV/SMV resection was performed if PV/SMV invasion was suspected intraoperatively. Intraoperative pathologic assessment of the proximal or distal pancreatic margin was performed using frozen sections. If the pancreatic margin was positive for malignant cells, further resection of the pancreas was performed to the maximum extent possible. Histopathologic diagnosis. Each tumor was classified as well, moderately, or poorly differentiated adenocarcinoma, according to the predominant pathologic grading of differentiation. Anterior serosal invasion, retropancreatic invasion, choledochal invasion, duodenal invasion, PV/SMV invasion, CHA or celiac axis invasion, extrapancreatic nerve plexus invasion, invasion of other organs, and LN metastasis were all examined pathologically. Surgical margins were considered macroscopically (R2) or microscopically positive (R1) if cancer was present at the transection lines or in the dissected peripancreatic soft tissue margins, whereas a negative margin (R0) was defined as no microscopic evidence of cancer cells

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along all margins. The distance from the surgical margin from the tumor cell (>1 or #1 mm) was also evaluated microscopically, as suggested by the Royal College of Pathologists.14 The final stage of pancreatic cancer was determined pathologically according to the TNM classification system of malignant tumors published by the International Union against Cancer (UICC), 7th edition.15 With regard to LN status, the total number of LNs examined and the number of metastatic LNs were counted. The LN ratio (LNR) was determined as the number of metastatic LNs divided by the total number of LNs examined. Follow-up. Patients were followed regularly in an outpatient clinic. CT was performed every 3 months during postoperative year 1 and every 6 months thereafter. All patients underwent adjuvant chemotherapy postoperatively, except for those patients with a poor condition (performance status of $2) or who refused chemotherapy. The regimens of postoperative adjuvant chemotherapy were (1) gemcitabine at 1000 mg/m2 on days 1, 8, and 15 for 6 cycles, (2) S-1 at a dose of 80 mg/m2 for the first 28 consecutive days followed by a 14day rest for 4 cycles, or (3) concurrent gemcitabine at 800 mg/m2 biweekly and S-1 at a dose of 80 mg/m2 for the first 7 consecutive days followed by a 7-day rest for 6 months. Overall survival was defined as the interval from the date of operation to death or the last follow-up date, and recurrencefree survival as the interval from the date of operation to first recurrence date. Statistical analysis. To identify characteristics and prognostic factors specific for pancreatic neck cancer, patient demographics, clinical and histopathologic factors, and preoperative and/or postoperative adjuvant therapy were compared with those of pancreatic head or body/tail cancer. Categorical variables were compared using the v2 test or Fisher’s test, as appropriate. Student’s t test was used for comparison of continuous variables. The overall survival and recurrence-free survival were estimated by the Kaplan–Meier method, and the log-rank test was used to examine the association of clinicopathologic variables with survivals. A multivariate analysis was performed using a Cox proportional hazards regression model in each group (pancreatic neck, head, or body/tail cancer group) separately, which included those variables with a P value of < .1 in a univariate analysis, in each group and surgical margin status, which was one of the most important prognostic factor in many previous reports.16-18 Statistical analyses were performed using SPSS 20.0 software (SPSS Inc, Chicago, IL).

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RESULTS Characteristics of pancreatic neck cancer compared with pancreatic head or body/tail cancers. The demographic and clinicopathologic data of the patients are summarized in Table I. The rate of biliary obstruction in pancreatic neck cancer (29%) was less than that in pancreatic head cancer (71%) and greater than in pancreatic body/tail cancer (2%). The tumor size of pancreatic neck cancer was smaller than other pancreatic cancers (median size: neck, 19.4 mm; head, 26.7 mm; body/tail, 32.0 mm; neck vs head, P < .001; neck vs body/tail, P < .001). On CT, patients with pancreatic neck cancer more often had tumor abutting the major arteries than those with pancreatic head cancer (neck, 52%; head, 37%; P = .042), although there was no difference between pancreatic neck cancer and body/tail cancer. Patients with pancreatic neck cancer also more frequently had radiographic evidence of PV/SMV invasion (types B, C, and D) than those with other pancreatic cancers (neck, 84%; head, 67%; body/tail, 25%; neck vs head, P = .012; neck vs body/tail, P < .001). Furthermore, radiographic assessments also revealed that the rates of abutment of >1808 of the circumference of the PV/SMV (types C and D) and stenosis or obstruction with collaterals of PV/SMV (type D) were significantly greater in pancreatic neck cancer than other pancreatic cancers (Table I). Among the 63 patients with pancreatic neck cancer, 51 (81%) underwent PD (conventional PD in 9, pylorus-preserving PD in 13, and pylorusresecting PD in 29), 10 (16%) underwent DP (subtotal left-side pancreatectomy in 6 and DPCAR in 4), and 2 patients (3%) underwent total pancreatectomy. Concomitant PV/SMV resection was performed most often in patients with pancreatic neck cancer (neck, 48%; head, 39%; body/tail, 20%; P < .001; Table I). According to pathologic findings, the rates of choledochal and duodenal invasion in pancreatic neck cancer were less than those in pancreatic head cancer and greater than in pancreatic body/ tail cancer (Table I). The rate of pathologic PV/ SMV invasion was the greatest in the patients with pancreatic neck cancer (neck, 37%; head, 26%; body/tail, 6%; P < .001). There were no differences in the rates of patients who received neoadjuvant therapy and postoperative adjuvant therapy between pancreatic neck cancer and other pancreatic cancers. Nevertheless, the rate of completion of the planned postoperative adjuvant therapy in pancreatic neck

Surgery j 2015

cancer patients was less than that in patients with pancreatic body/tail cancer, although the rate was similar between patients with pancreatic neck and head cancers (neck, 40%; head, 33%; body/tail, 56%; neck vs head, P = .326; neck vs body/tail, P = .035; Table I). The overall survival rate of the 63 patients with pancreatic neck cancer were 60% at 1 year, 20% at 3 years, and 15% at 5 years. There was no difference from head or body/tail cancers (median overall survival: neck, 16.6 months; head, 15.7 months; body/tail, 22.0 months; Fig 2, A). We also found no difference of recurrence-free survival between pancreatic neck and head or body/tail cancers (median recurrence-free survival: neck, 10.8 months; head, 10.5 months; body/tail, 12.0 months; Fig 2 B). LN metastases in patients with pancreatic neck cancer. Forty patients (64%) with pancreatic neck cancer had LN metastases; the mean number of evaluated LNs was 24.3 (range, 9–53), the mean number of metastatic LNs was 2.3 (range, 0–19), and the mean positive LNR was 0.09 (range, 0–0.59), and there was no significant differences between pancreatic neck cancer and other pancreatic cancers (Table II). Involved LNs were found frequently in the regions along the CHA (#8, 57%), around the pancreatic head (#13, #17, 19%), and along the SMA (#14, 11%) in pancreatic neck cancer. The rate of #8 LN metastasis in patients with pancreatic neck cancer was greater (neck vs head, P < .001; neck vs body/tail; P < .001). The rate of LN metastasis around the pancreatic head (#13, #17) was less than in the pancreatic head cancer (P < .001). There were no differences in the rates of #14 LN metastasis between pancreatic neck and other pancreatic cancers (Table II). The rate of LN metastases along the splenic artery (#11) in pancreatic neck cancer was less than in body/tail cancers (P < .001). PV/SMV invasion in pancreatic neck cancer patients. In patients with pancreatic neck cancer, the overall survival and recurrence-free survival of patients with pathologic PV/SMV invasion were significantly worse than those without invasion (overall survival, median survival, 9.6 vs 22.5 months; P < .001; Fig 3, A; recurrence-free survival, median survival, 6.4 vs 14.8 months; P < .001; Fig 3, B), but not in pancreatic head cancer (overall survival, P = .056; recurrence-free survival, P = .333) and pancreatic body/tail cancer (overall survival, P = .745; recurrence-free survival, P = .446). In pancreatic neck cancer patients, the rates of types C and D pathologic PV/SMV invasion were greater than those of type B (type B,

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Table I. Comparison of clinicopathologic characteristics between pancreatic neck cancer and pancreatic head or body/tail cancer Factors

Pancreatic neck (n = 63)

Median age, y (range) 72.5 (56–91) Sex, male/female 34/29 Median tumor size, mm (range) 19.4 (10.2–41.0) Biliary obstruction, n (%) 18 (29) Radiographic findings, n (%) Abutment of SMA, CHA, or 33 (52) celiac axis PV/SMV invasion type* Type A 10 (16) Type B 24 (38) Type C 22 (35) Type D 7 (11) Type A vs B, C, D 10 vs 53 Type A, B vs C, D 34 vs 29 Type A, B, C vs D 56 vs 7 Operative procedure PD 51 (81) Conventional PD 9 Pylorus-preserving PD 13 Pylorus-resecting PD 29 DP 10 (16) Conventional DP 0 Subtotal DP 6 DP-CAR 4 Total pancreatectomy 2 (3) Concomitant PV/SMV resection, 30 (48) n (%) Pathologic findings, n (%) Differentiation, well/ 21/35/7 moderate/poor Choledochal invasion 17 (27) Duodenal invasion 14 (22) Serosal invasion 27 (43) Retropancreatic tissue invasion 52 (83) PV/SMV invasion 23 (37) CHA or celiac artery invasion 4 (6) Extrapancreatic nerve plexus 16 (25) invasion Other organs invasion 0 (0) Surgical margin, n (%) R0 48 (76) R1 13 (21) R2 2 (3) Distance from surgical margin (mm) >1 45 (71) #1 18 (29) LN metastasis, n (%) 40 (64) Median positive LNRy 0.05 (0–0.59) UICC stage,z n (%) IA/IB 2 (3) IIA 20 (32) IIB 35 (56) III 4 (6) IV 2 (3)

Pancreatic head (n = 150)

Pancreatic body/tail (n = 112)

P neck vs head

P neck vs body/tail

69.0 (41–90) 77/73 26.7 (11.9–70.0) 107 (71)

69.0 (31–86) 71/41 32.0 (13.3–115.6) 2 (2)

.085 .725 <.001 <.001

.038 .222 <.001 <.001

.042

.384

.004

<.001

.012 .019 .004 <.001

<.001 <.001 .021 <.001

.263

<.001

.908

.849

(2) (2) (58) (88) (6) (7) (38)

.001 <.001 .191 .519 .123 .002 .498

<.001 <.001 .054 .280 <.001 .842 .103

2 (1)

15 (13)

.357 .086

.002 .132

121 (81) 29 (20) 0 (0)

83 (74) 29 (26) 0 (0) .761

.397

.080 .078 .011

.823 .896 .982

56 (37)

51 (46)

49 (33) 57 (38) 41 (27) 3 (2) 49 vs 101 106 vs 44 147 vs 3

84 13 12 3

149 (99) 22 29 98 0 (0) 0 0 0 1 (1) 59 (39)

53/83/14 79 98 79 129 39 0 45

(53) (65) (53) (86) (26) (0) (30)

104 46 113 .08

(69) (31) (75) (0–0.86)

3 34 105 0 8

(2) (23) (70) (0) (5)

(75) (12) (11) (3) 84 vs 28 97 vs 15 109 vs 3

0 (0) 0 0 0 108 (96) 68 4 36 4 (4) 22 (20)

33/67/12 2 2 65 99 7 8 42

73 39 73 0.06 4 35 63 8 2

(65) (35) (65) (0–0.42) (4) (31) (56) (7) (2)

(continued)

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Table I. (continued) Factors Neoadjuvant chemo(radiation) therapy Postoperative adjuvant therapy Completion of the planned postoperative adjuvant therapy, n (%) Recurrence, n (%)

Pancreatic neck (n = 63)

Pancreatic head (n = 150)

Pancreatic body/tail (n = 112)

P neck vs head

P neck vs body/tail

6 (10)

16 (11)

18 (16)

.802

.227

48 (76) 25 (40)

128 (85) 49 (33)

94 (84) 63 (56)

.108 .326

.209 .035

49 (78)

120 (80)

89 (80)

.715

.793

*The radiographic findings of PV/SMV were classified into type A (absent), type B (unilateral narrowing), type C (bilateral narrowing), and type D (stenosis or occlusion) based on CT imaging. yPositive LNR was determined as the number of metastatic LNs divided by total number of examined LNs. zThe pathologic stage was determined by the TNM classification system of malignant tumors published by the International Union against Cancer, 7th edition. CHA, Common hepatic artery; DP, distal pancreatectomy; DP-CAR, distal pancreatectomy with en-bloc celiac axis resection; LN, lymph nodes; LNR, lymph node ratio; PD, pancreatoduodenectomy; SMA, superior mesenteric artery; PV/SMV, portal vein and/or superior mesenteric vein.

Fig 2. There was no difference of overall survival (A) and recurrence-free survival (B) among the patients with pancreatic neck cancer, pancreatic head cancer, and pancreatic body and/or tail cancer, who underwent surgical resection (overall survival, P = .081; recurrence-free survival, P = .630).

20.8%; type C, 54.6%; type D, 85.7%; type B vs C, P = .018; type B vs D; P = .002); there was no difference between types C and D (P = .139). We found invasion into the tunica media and intima as well as tunica adventitia even for type B patients (Table III). The rates of pathologic PV/SMV invasion in each radiographic type were similar in pancreatic neck and head cancers; however, PV/ SMV stenosis was caused by inflammatory adhesion in 3 patients with pancreatic body/tail cancer who had radiographic type D invasion (Table III). Surgical resection margins of pancreatic neck cancer. Fifteen patients (24%) with pancreatic neck cancer had positive resection margins (R1, n = 13; R2, n = 2). The 2 patients with R2 margins occurred at the CHA during PD in 1 and the GDA in the other during DP-CAR; no further arterial resection was performed to preserve liver flow.

Two patients had a positive transected pancreatic margin on pathologic permanent assessment (R1), although they had negative margins on frozen section. Twelve patients had R1 margins at in the peripancreatic tissues, with areas of the R1 on the surface of the PV/SMV in 5 patients (8%), the nerve plexus along the root of the GDA and/or CHA in 5 patients (8%), and the nerve plexus along the celiac axis in 2 (3%). Thirty-three patients with pancreatic neck cancer had tumor abutment with the SMA, CHA, and/ or celiac axis on CT, and those who received neoadjuvant therapy (n = 6) tended to have an R0 more often than the 27 who underwent upfront surgery (100% vs 59.3%; P = .056). Prognostic factors for patients with pancreatic neck cancer. Univariate analysis revealed that tumor size >30 mm, types C and D PV/SMV invasion

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Table II. Anatomic localization of the LN involvement in pancreatic neck, head, and body/tail cancer Variable

Pancreatic neck (n = 63)

Pancreatic head (n = 150)

Pancreatic body/tail (n = 112)

P neck vs head

P neck vs body/tail

Evaluated LN number Mean ± SD 24.3 ± 10.6 26.5 ± 10.8 26.0 ± 13.3 .181 .382 Range (9–53) (8–64) (9–73) Metastatic LN Mean ± SD 2.3 ± 3.4 3.4 ± 4.4 2.4 ± 3.2 .070 .845 Range (0–19) (0–27) (0–23) Positive LNR Mean ± SD 0.09 ± 0.12 0.13 ± 0.14 0.09 ± 0.10 .086 .915 Range (0–0.59) (0–0.86) (0–0.42) Number of patients with LN metastasis in anatomic locations who underwent pancreatoduodenectomy, distal pancreatectomy, and total pancreatectomy, n (%) Right gastric artery (#5)* 0 (0) 0 (0) 0 (0) — — Right gastroepiploic artery (#6)* 3 (5) 3 (2) 0 (0) .266 .020 Left gastric artery (#7)* 0 (0) 2 (1) 0 (0) .357 — Common hepatic artery (#8)* 36 (57) 19 (13) 15 (13) <.001 <.001 Celiac axis (#9)* 2 (3) 1 (1) 4 (4) .156 .890 Splenic hilum (#10)* 0 (0) 0 (0) 3 (3) — .190 Splenic artery (#11) * 2 (3) 2 (1) 69 (62) .366 <.001 Hepatoduodenal ligament (#12)* 3 (5) 10 (7) 0 (0) .596 .020 Pancreatic head (#13,#17)* 12 (19) 106 (71) 1 (1) <.001 <.001 Superior mesenteric artery (#14)* 7 (11) 20 (13) 6 (5) .656 .164 Paraaortic region (#16)* 2 (3) 8 (5) 2 (2) .497 .555 Number of patients with LN metastasis in anatomic locations who underwent pancreatoduodenectomy or total pancreatectomy, n (%) n 53 150 4 Right gastric artery (#5)* 0 (0) 0 (0) 0 (0) — — Right gastroepiploic artery (#6)* 3 (6) 3 (2) 0 (0) .266 .625 Pancreatic head (#13,#17)* 12 (23) 106 (71) 1 (25) <.001 .914 Number of patients with LN metastasis in anatomic locations who underwent distal pancreatectomy and total pancreatectomy, n (%) n 12 1 112 Splenic hilum (#10)* 0 (0) 0 (0) 3 (3) — .566 Splenic artery (#11) * 1 (8) 0 (0) 69 (62) — <.001 *The region of LN based on Japanese general rules for the study of pancreatic cancer, the 6th edition. LN, Lymph nodes; SD, standard deviation.

based on radiographic assessment, and inability to complete the planned postoperative adjuvant therapy were associated with less overall survival in patients with pancreatic neck, head, or body/tail cancers (Table IV). On multivariate analysis, we found 5, independent risk factors (P # .018 each) of a lesser overall survival in the pancreatic neck cancer patients; pathologic PV/SMV invasion, moderately or poorly differentiated adenocarcinoma, LNR $ 0.1, distance of the surgical margin of #1 mm, and inability to complete the planned postoperative adjuvant therapy (Table V). There were 6 independent risk factors of a lesser overall survival in pancreatic head cancer (abnormal serum CEA level, type C and D radiographic PV/SMV invasion, pathologic retropancreatic tissue invasion, LNR $ 0.1, positive

surgical margin, and inability to complete the planned postoperative adjuvant therapy), and 4 factors in pancreatic body/tail cancer (pathologic serosal invasion, LNR $ 0.2, no administration of postoperative adjuvant therapy, and inability to complete the planned postoperative adjuvant therapy; Table V). On univariate analysis, we found 4 factors of a lesser recurrence-free survival in pancreatic neck, head, or body/tail cancer: radiographic abutment of the SMA, CHA, and/or celiac axis, LN metastasis, LNR $ 0.2, and inability to complete the planned postoperative adjuvant therapy (Table VI). On multivariate analysis, we found that LNR $ 0.2 and inability to complete the planned postoperative adjuvant therapy were independent risk factors of a lesser recurrence-free survival in pancreatic

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Fig 3. Overall (A) and recurrence-free (B) survival of pancreatic neck cancer patients with pathologic portal vein and/ or superior mesenteric vein (PV/SMV) invasion was significantly worse than those without pathologic PV/SMV invasion.

Table III. Relationship between type of radiographic PV/SMV invasion and pathologic PV/SMV invasion in pancreatic neck, head, and body/tail cancer Pancreatic neck (n = 63)

Characteristic All types Pathologic PV/SMV invasion, Tunica adventitia Tunica media Tunica intima Radiographic PV/SMV invasion n Pathologic PV/SMV invasion, Tunica adventitia Tunica media Tunica intima Radiographic PV/SMV invasion n Pathologic PV/SMV invasion, Tunica adventitia Tunica media Tunica intima Radiographic PV/SMV invasion n Pathologic PV/SMV invasion, Tunica adventitia Tunica media Tunica intima Radiographic PV/SMV invasion n Pathologic PV/SMV invasion, Tunica adventitia Tunica media Tunica intima

n (%)

23 12 2 9

(37) (19) (3) (14)

Pancreatic head (n = 150)

Pancreatic body/tail (n = 112)

P neck vs head

P neck vs body/tail

39 20 11 8

(26) (13) (7) (5)

7 4 0 3

(6) (4) (0) (3)

.123 .180

<.001 .837

type A n (%)

0 0 0 0

10 (0) (0) (0) (0)

1 1 0 0

49 (2) (2) (0) (0)

0 0 0 0

84 (0) (0) (0) (0)

.012 .649

<.001 —

5 3 1 1

24 (21) (13) (4) (4)

13 6 6 1

57 (23) (11) (11) (2)

3 2 0 1

13 (23) (15) (0) (8)

.990 .845

<.001 .874

12 8 1 3

22 (55) (36) (5) (14)

22 12 3 7

41 (54) (29) (7) (17)

4 2 0 2

12 (33) (17) (0) (17)

.268 .946

<.001 .236

6 1 0 5

7 (86) (14) (0) (71)

3 1 2 0

3 (100) (33) (67) (0)

0 0 0 0

3 (0) (0) (0) (0)

<.001 .490

<.001 .001

type B n (%)

type C n (%)

type D n (%)

PV/SMV, Portal vein and/or superior mesenteric vein.

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Table IV. Univariate overall survival analysis of prognostic factors of patients with pancreatic neck, head, and body/tail cancer who underwent surgical resection Pancreatic neck Factors

Median survival

Pancreatic head P

Sex Male 15.7 .524 Female 17.0 Biliary obstruction Yes 11.1 .384 No 16.6 Tumor size (mm) >30 6.6 <.001 #30 18.9 Serum CEA level Abnormal 11.1 .423 Normal 17.0 Serum CA19-9 level Abnormal 13.5 .071 Normal 29.5 Radiographic abutment of SMA, CHA, or celiac axis Abutment 13.5 .188 No abutment 21.0 Radiographic PV/SMV invasion* Type A 21.6 .642 Type B/C/D 16.1 Type A/B 21.6 .022 Type C/D 14.5 Type A/B/C 17.5 .001 Type D 8.6 Concomitant PV/SMV resection Yes 14.5 .411 No 21.3 Pathologic differentiation Well 25.6 .022 Moderate/poor 10.2 Pathologic choledochal invasion Yes 17.5 .944 No 16.1 Pathologic duodenal invasion Yes 10.2 .148 No 18.9 Pathologic serosal invasion Yes 14.8 .566 No 17.0 Pathologic retropancreatic tissue invasion Yes 13.5 .899 No 17.0 Pathologic PV/SMV invasion Yes 9.6 <.001 No 22.5 Pathologic extrapancreatic nerve plexus invasion Yes 9.1 .066 No 21.0 Pathologic invasion of other organs Yes — — No —

Median survival

Pancreatic body/tail P

Median survival

P

15.0 17.7

.341

19.4 23.5

.036

14.6 20.1

.029

4.5 22.0

.807

12.6 17.8

.013

13.8 23.8

.012

10.9 17.5

.004

19.4 22.0

.669

13.6 20.2

.045

18.7 33.5

.023

12.1 17.7

.045

15.6 25.7

.001

20.9 13.6 19.4 10.0 15.7 26.5

.001

23.4 11.9 23.4 8.1 22.0 11.9

.003

<.001 .837

.007 .184

13.3 19.4

.090

11.9 23.4

.013

20.1 15.0

.260

33.5 18.7

.032

13.3 20.1

<.001

4.5 22.0

.807

14.6 17.5

.124

4.8 22.0

.445

13.6 17.8

.278

15.9 30.8

.014

15.0 29.9

.011

21.5 22.0

.717

13.6 17.8

.056

9.6 22.0

.745

13.7 17.3

.084

15.6 24.1

.001

10.3 15.7

.718

15.6 22.1

.117 (continued)

ARTICLE IN PRESS 10 Hirono et al

Surgery j 2015

Table IV. (continued) Pancreatic neck Factors

Median survival

Pancreatic head P

Pancreatic body/tail P

Median survival

Surgical margin Positive 16.1 .106 13.2 Negative 16.6 16.6 Surgical margin length (mm) #1 15.7 .040 15.0 >1 18.9 16.6 LN metastasis Yes 13.7 .147 13.3 No 21.3 35.4 Positive LNRy $0.1 10.2 .001 11.6 <0.1 22.4 19.4 Positive LNRy $0.2 10.1 .075 11.6 <0.2 18.9 17.7 Postoperative adjuvant therapy Yes 17.5 .058 16.5 No 11.1 7.7 Inability to complete the planned postoperative adjuvant therapy No 34.4 <.001 42.7 Yes 9.9 11.9

Median survival

P

.393

12.5 23.4

.036

.536

12.5 24.1

.004

<.001

21.4 23.4

.160

<.001

15.6 23.4

.079

.001

15.6 23.4

.036

.345

23.5 6.7

<.001

<.001

36.5 10.5

<.001

*The radiographic findings of PV/SMV were classified into types A (absent), B (unilateral narrowing), C (bilateral narrowing), and D (stenosis or occlusion) based on CT imaging. yPositive LNR was determined as the number of metastatic LN divided by total number of examined LN. The following factors were not statistically significant (P > .2): age, pathologic CHA or celiac axis invasion, and neoadjuvant therapy. CA, Carbohydrate antigen; CEA, carcinoembryonic antigen; CHA, common hepatic artery; LN, lymph nodes; LNR, lymph node ratio; PV/SMV, portal vein and/or superior mesenteric vein; SMA, superior mesenteric artery.

Table V. Multivariate overall survival analysis of prognostic factors of patients with pancreatic neck, head, and body/tail cancer who underwent surgical resection Factor Pancreatic neck cancer Pathologic PV/SMV invasion Pathologic differentiation, moderate/poor Positive LNR $0.1* Distance from surgical margin #1 mm Inability to complete the planned postoperative adjuvant therapy Pancreatic head cancer Serum CEA level, abnormal Radiographic PV/SMV invasion,y type C/D Pathologic retropancreatic tissue invasion Positive LNR $0.1* Positive surgical margin Inability to complete the planned postoperative adjuvant therapy Pancreatic body/tail cancer Pathologic serosal invasion Positive LNR $0.2* No administration of postoperative adjuvant therapy Inability to complete the planned postoperative adjuvant therapy

P

Hazard ratio

95% CI

.005 .001 <.001 .018 <.001

3.86 4.18 5.35 6.62 7.04

1.49–9.99 1.91–9.09 2.47–11.59 1.39–31.25 2.71–18.29

.022 .001 .004 .011 .029 <.001

1.71 2.46 2.60 1.68 1.76 5.83

1.08–2.92 1.43–4.26 1.35–5.02 1.12–2.51 1.06–2.93 3.51–9.68

.004 .010 .019 <.001

2.31 2.37 2.55 4.37

1.30–4.09 1.24–4.55 1.16–5.59 2.45–7.79

*LNR was determined as the number of metastatic LN divided by total number of examined LN. yThe radiographic findings of PV/SMV were classified into types A (absent), B (unilateral narrowing), C (bilateral narrowing), and D (stenosis or occlusion) based on CT imaging. LN, Lymph nodes; LNR, lymph node ratio; ND, not determined by univariate analysis; PV/SMV, portal vein and/or superior mesenteric vein.

ARTICLE IN PRESS Hirono et al 11

Surgery Volume j, Number j

Table VI. Univariate recurrence-free survival analysis of prognostic factors of patients with pancreatic neck, head, and body/tail cancer who underwent surgical resection Pancreatic neck Factors

Median survival

Pancreatic head P

Sex Male 10.1 .973 Female 11.7 Tumor size (mm) >30 5.0 .094 #30 11.1 Serum CEA level Abnormal 10.8 .529 Normal 12.0 Serum CA19-9 level Abnormal 8.6 .097 Normal 17.3 Radiographic abutment of SMA, CHA, or celiac axis Abutment 6.6 .039 No abutment 14.8 Radiographic PV/SMV invasion* Type A 11.1 .477 Type B/C/D 10.8 Type A/B 17.3 .015 Type C/D 8.8 Type A/B/C 11.1 .023 Type D 5.0 Concomitant PV/SMV resection Yes 10.1 .218 No 13.4 Pathologic differentiation Well 18.2 .024 Moderate/poor 6.9 Pathologic choledochal invasion Yes 11.1 .637 No 10.8 Pathologic duodenal invasion Yes 6.5 .036 No 13.4 Pathologic serosal invasion Yes 10.1 .881 No 11.1 Pathologic retropancreatic tissue invasion Yes 11.7 .382 No 6.5 Pathologic PV/SMV invasion Yes 6.4 <.001 No 14.8 Pathologic CHA or celiac axis invasion Yes 4.6 .972 No 11.1 Pathologic extrapancreatic nerve plexus invasion Yes 6.6 .329 No 12.0 Positive surgical margin Positive 10.6 .175 Negative 11.1

Median survival

Pancreatic body/tail P

Median survival

P

10.2 10.5

.500

11.7 14.5

.114

6.6 13.6

.001

9.2 14.5

.018

6.2 12.3

.002

12.0 14.5

.150

9.2 13.8

.262

11.2 17.0

.049

7.3 12.7

.011

9.2 16.7

.007

13.9 9.2 12.7 6.4 10.2 15.3

.004

13.5 8.6 12.5 7.7 12.0 4.4

.036

.001 .864

.057 .508

8.6 12.5

.115

8.6 12.7

.061

13.9 8.7

.138

17.0 10.8

.043

9.8 13.9

.003

2.3 12.0

.254

9.5 13.7

.151

2.6 12.0

.208

7.4 11.9

.494

11.2 14.5

.076

9.8 31.2

.006

12.5 10.7

.564

8.6 11.3

.333

5.3 12.4

.446

—

13.3 11.9

.760

9.2 10.8

.205

10.7 16.6

.009

8.6 10.8

.657

9.2 13.5

.031

— —

(continued)

ARTICLE IN PRESS 12 Hirono et al

Surgery j 2015

Table VI. (continued) Pancreatic neck Factors

Median survival

Pancreatic head P

Median survival

Distance from surgical margin (mm) #1 10.6 .118 8.6 >1 11.1 10.8 LN metastasis Yes 8.8 .028 8.7 No 18.1 17.6 Positive LNRy $0.1 6.6 .001 7.2 <0.1 17.3 13.6 Positive LNRy $0.2 5.0 <.001 6.4 <0.2 12.0 12.6 Postoperative adjuvant therapy Yes 13.4 .732 10.5 No 10.6 10.0 Inability to complete the planned postoperative adjuvant therapy No 18.2 .001 23.8 Yes 6.9 7.2

Pancreatic body/tail P

Median survival

P

.651

9.2 14.5

.035

.001

11.8 14.5

.024

.001

9.6 13.7

.056

<.001

9.6 13.3

.015

.811

12.7 6.3

.100

<.001

18.0 6.4

<.001

*The radiographic findings of PV/SMV were classified into types A (absent), B (unilateral narrowing), C (bilateral narrowing), and D (stenosis or occlusion) based on CT imaging. yPositive LNR was determined as the number of metastatic LN divided by total number of examined LN. The following factors were not statistically significant (P $ .15): age, biliary obstruction, and neoadjuvant therapy. CA, Carbohydrate antigen; CEA, carcinoembryonic antigen; CHA, common hepatic artery; LN, lymph nodes; LNR, lymph node ratio; PV/SMV, portal vein and/or superior mesenteric vein; SMA, superior mesenteric artery.

neck, head, or body/tail cancers (Table VII). Furthermore, radiographic abutment of the SMA, CHA, and/or celiac axis, pathologic PV/SMV invasion, and moderately or poorly differentiated adenocarcinoma, LNR $ 0.2, and inability to complete the planned postoperative adjuvant therapy were independent risk factors (P # .042 each) of a lesser recurrence-free survival in pancreatic neck cancer (Table VII). DISCUSSION To identify the specific characteristics of pancreatic neck cancer, we compared the clinicopathologic features between patients with pancreatic neck cancer and those with cancers located in the pancreatic head or body/tail who underwent operative resection. This study showed that the tumor size was less, rates of radiographic PV/SMV invasion were greater, and LN metastases along the CHA (#8) were more frequent in pancreatic neck cancer patients. The reason that the size of pancreatic neck cancer was smaller than other pancreatic cancers might be (1) the anatomic area of pancreatic neck is small at the boundary between the pancreatic head and body, (2) invasion of major arteries is often found in the larger pancreatic neck cancers, and these tumors might be diagnosed as unresectable, locally advanced

cancer that is not be indicated for operative resection, which may cause inherent survival bias between pancreatic neck cancer and pancreatic head or body/tail cancers. Owing to its anatomic location, pancreatic neck cancer may readily invade the nerve plexus around major arteries, such as the CHA, the celiac axis, and/or the SMA, as well as the PV. Indeed, we found that the rates of radiographic abutment of the PV/SMV (types B, C, and D), abutment of >1808 of the circumference of the PV/SMV (types C and D), and stenosis or occlusion of the PV/ SMV (type D) on CT in pancreatic neck cancer patients were significantly greater than those in pancreatic head or body/tail cancers. In addition, the rate of the pathologic PV/SMV invasion was greatest in pancreatic neck cancer, as was the rate of radiographic abutment of major arteries on CT. With regard to radiographic abutment of major arteries, the rate of pancreatic neck cancer was greater than that of pancreatic head cancer, but there was no difference between the pancreatic neck and body/tail cancers. Potential reasons for this observation are that pancreatic body cancer invades frequently the nerve plexus around the celiac axis and/or CHA through nerve invasion along the splenic artery, and that is why the difference of the rate of radiographic abutment

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Surgery Volume j, Number j

Table VII. Multivariate recurrence-free survival analysis of prognostic factors of patients with pancreatic neck, head, and body/tail cancer who underwent operative resection Factor Pancreatic neck cancer Radiographic abutment of SMA, CHA, or celiac axis Pathologic PV/SMV invasion Pathologic differentiation, moderate/poor Positive LNR $0.2* Inability to complete the planned postoperative adjuvant therapy Pancreatic head cancer Serum CEA level, abnormal Pathologic retropancreatic tissue invasion Positive LNR $0.2* Inability to complete the planned postoperative adjuvant therapy Pancreatic body/tail cancer Pathologic serosal invasion Positive LNR $0.2* Inability to complete the planned postoperative adjuvant therapy

P

Hazard ratio

95% CI

.042 .018 .005 .002 <.001

2.22 2.93 2.70 5.34 4.67

1.03–4.80 1.20–7.16 1.36–5.35 1.81–15.75 2.05–10.62

.020 .010 .015 <.001

1.72 2.39 1.71 3.46

1.09–2.73 1.24–4.62 1.11–2.63 2.22–5.40

.008 .008 <.001

2.06 2.42 4.67

1.21–3.52 1.25–4.66 2.70–8.09

*LNR was determined as the number of metastatic LN divided by total number of examined LN. LN, Lymph nodes; LNR, lymph node ratio; ND, not determined by univariate analysis; PV/SMV, portal vein and/or superior mesenteric vein.

of major arteries was not significant between pancreatic neck and body/tail cancers. We found that the rates of radiographic PV/SMV invasion, duodenal invasion, and LN metastasis in pancreatic neck cancer was similar to those of cancer in the uncinate process of the pancreas head reported previously.19 Regarding the anatomic localization of the LN metastasis, LN metastasis along the CHA (#8) was found most frequently in pancreatic neck cancer, similar to the LN metastasis around pancreatic head (#13, 17) in pancreatic head cancer, and along the splenic artery (#11) in pancreatic body/tail cancer. Regarding operative procedures, we most often selected PD for the patients with pancreatic neck cancer, because it involved the GDA according to findings on preoperative CT. When we performed PD in pancreatic neck cancer patients, concomitant resection of the pancreatic body parenchyma was required frequently to achieve negative surgical margins, in addition to standard PD procedure, which was introduced previously as the ‘‘Whipple at the splenic artery; WATSA’’ by Strasberg et al.4 This procedure requires advanced operative techniques and operative time compared with the standard PD procedure.4 We also performed the DP-CAR procedure in patients whose tumor involved the plexus around the CHA and/or the celiac axis, and a subtotal, left-sided pancreatectomy in those without any involvement of the GDA, the CHA, nor the celiac axis. The rates of R0 resection with a distance from the surgical

margin of #1 mm and survival in the patients with pancreatic neck cancer who underwent these advanced operative procedures were similar to those in pancreatic head or body/tail cancer patients, although the radiographic rates of invasion of PV/SMV and arteries in pancreatic neck cancer were the greatest. Our results suggest that such aggressive operative procedures seem to provide survival benefit even to patients with advanced pancreatic neck cancer. In the present study, concomitant PV/SMV resection was required more frequently in pancreatic neck cancer than with the other pancreatic cancers. Definite intraoperative determination of whether the tumor invades the PV/SMVor just abuts the venous region secondary to an inflammatory response is quite difficult, and forcing a dissection at the surface of the PV might lead to a positive surgical margin, even if pathologic PV invasion is negative.20,21 Indeed, 5 patients with pancreatic neck cancer (8%), including 3 with type B radiographic PV/SMV invasions and 2 with type C radiographic invasions, had a positive surgical margin at the surface of the PV in our series, and we found that invasion of the tunica intima and media of PV/SMV were present even for type B patients. Recent reports showed that survival in patients with pancreatic cancer undergoing PV/SMV resection with no histopathologic evidence of PV/SMV invasion was greater than those without PV/SMV resection.20 Moreover, several studies have indicated that PV/ SMV resection during pancreatic resections was a

ARTICLE IN PRESS 14 Hirono et al

safe and feasible procedure that provides survival benefit to selected patients with pancreatic cancer.7,22-24 Indeed, we found no differences in survival between patients with pancreatic neck cancer with and without PV/SMV resection, although pathologic PV/SMV invasion was an independent risk factor of poor survival. Therefore, PV/SMV resection might be necessary for pancreatic neck cancer, especially with radiographic suggestion of PV/SMV invasion (types B, C, and D), to achieve a negative surgical margin, when the PV/SMV cannot be dissected easily from the tumor, although the benefit of this procedure remains controversial. In our study, pathologic PV/SMV invasion, moderately or poorly differentiated adenocarcinoma, a high LNR ($0.1), and the inability to complete the planned postoperative adjuvant therapy were found to be independent risk factors of less overall and recurrence-free survival, the distance from the surgical margin of #1 mm was a risk factor of poor overall survival, whereas radiographic abutment of SMA, CHA, or celiac axis proved to be a risk factor of poor recurrence-free survival in pancreatic neck cancer. As with other groups,16-18 we also found that a high LNR and the inability to complete the planned postoperative adjuvant therapy were also independent poor prognostic factors in pancreatic head and body/ tail cancers patients. The ESPAC-3 study showed that completion of the planned postoperative adjuvant therapy was the most important factor in prolonging the survival for patients with pancreatic cancer16; our study conferred this concept. In our study, however, the rate of completion of postoperative adjuvant therapy in pancreatic body/tail cancer patients was greater than that in pancreatic neck or head cancer, possibly because the operation for pancreatic neck cancer tended to be more extensive. Recent studies have shown that neoadjuvant therapy might lead to a decrease in the number of metastatic LN25-27 and the increase the rate of an R0 resection in comparison with upfront surgery in patients with locally advanced cancers.26-30 Neoadjuvant therapy might also prevent an unnecessary exploratory laparotomy in patients with rapidly progressive disease during the course of the neoadjuvant therapy.25,30,31 Indeed, in our study, all patients with pancreatic neck cancer that abutted major arteries who received neoadjuvant therapy (n = 6) had an R0 resection, in contrast, in the 27 patients who underwent upfront pancreatectomy, 1 potential reason R1/2 rates were high probably because they did not receive neoadjuvant therapy. Thus, neoadjuvant therapy seems to be an effective

Surgery j 2015

potential strategy for long-term survival for pancreatic neck cancer patients with poor prognostic risk factors, namely radiographic abutment of the PV/ SMV (types B, C, and D), radiographic abutment of major arteries, moderately or poorly differentiated adenocarcinoma on preoperative biopsy, suspected LN metastasis on preoperative imaging, and marked comorbidities that might limit the ability to tolerate postoperative adjuvant therapy, although recognition of some of these factors can be difficult preoperatively. With regard to regimens of neoadjuvant therapy, recent reports have shown promising outcomes of neoadjuvant therapy using FOLFIRINOX for borderline resectable pancreatic cancer.26,27 Further studies are needed to identify the optimal regimen of neoadjuvant therapy without increasing morbidity and allowing complete administration of postoperative adjuvant therapy. Our study has several limitations: its retrospective cohort design, the relatively small number of patients, and being a single institution study. These limitations call into question the potential for selection bias, particularly with respect to operative indications and adjuvant therapy; in addition, practice variations undoubtedly varied between the surgeons. The definition of the anatomic location of the pancreatic neck remains somewhat obscure, especially for the caudal extent as well as the extension to the GDA and CHA which is variable.32 In conclusion, this study identified specific clinicopathologic characteristics of patients with pancreatic neck cancer undergoing resection. R0 rates and overall and recurrence-free survival of the pancreatic neck cancer patients were similar to those with pancreatic head or body/tail cancers. In contrast, the high frequencies of abutment of the major arteries on CT and pathologic PV/SMV invasion were specific characteristics of pancreatic neck cancer. Likewise, #8 regional LN metastases were found more often than in pancreatic head or body/tail cancers. Independent predictors of worse overall survival for patients with pancreatic neck cancer included pathologic PV/SMV invasion, moderately or poorly differentiated adenocarcinoma, LNR $ 0.1, distance from the surgical margin of #1 mm, and the inability to complete the planned postoperative adjuvant therapy. Such patients might need true multimodality treatment strategies to prolong survival.

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