|Year : 2014 | Volume
| Issue : 3 | Page : 131-139
Influence of standardized histopathological workup on reporting of the resection margin status in pancreatic head cancer
Ahmed M El-Gendi1, Saba El-Gendi2
1 Department of Surgery, Faculty of Medicine, Alexandria University, Alexandria, Egypt
2 Department of Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
|Date of Submission||20-Feb-2014|
|Date of Acceptance||23-Mar-2014|
|Date of Web Publication||29-Sep-2014|
Ahmed M El-Gendi
Department of Surgery, Faculty of Medicine, University of Alexandria, El Sultan Hussein Street, El-Azarita, Khartom Square, Alexandria 21131
Source of Support: None, Conflict of Interest: None
Resection margin (RM) status in pancreatic head adenocarcinoma is assessed histologically, but pathological examination is not standardized. Our aim was to determine the influence of the 'standardized histopathological workup' of pancreaticoduodenectomy specimens on the reporting of the RM status using a 'surgical quality protocol'.
Patients and methods
Starting October 2009, 42 patients underwent pancreaticoduodenectomy using the 'surgical quality protocol' for pancreatic ductal adenocarcinoma and were examined using 'standardized histopathological workup'. We prospectively evaluated and validated its results for 50 months. We evaluated different sites of R1 at 0 and 1 mm resections according to the color code and determined the most frequent site of incomplete tumor resection.
Patients included 14 women and 28 men. Their age ranged from 46 to 74 years, with a median of 60 years. Changing to 'standardized histopathological workup' from traditional pathological examination procedures resulted in an increase in the R1 rate from 14.3 to 64.3% in this prospective series. Fifteen percent of R1 resections showed multifocal margin involvement (i.e. more than one margin involved in a single specimen) for the 0 mm in contrast to 33% for the 1.0 mm margin. The uncinate margin represents the most frequent site with residual tumor mass by far (42% at 0 mm and 43% at 1 mm), followed by the posterior margin. When R1 resection was defined by a positive margin of 0 mm, 48% of the present patients achieved R1 resection. In contrast to when R1 resection was defined by the presence of tumor cells within 1.0 mm, 64% of the present patients achieved R1 resection.
Standardization of the histopathological examination of pancreaticoduodenectomy specimens influences the reporting of RM status. The RM involvement is significantly more frequent than commonly reported. Complete and meticulous surgical resection of the uncinate process en bloc with all the peripancreatic tissues between the artery and the pancreatic parenchyma must become the standard surgical approach in pancreatic head resection as it is the most frequent site for residual tumor by far.
Keywords: histopathological workup, pancreatic cancer, R1 resection, resection margin, uncinate margin
|How to cite this article:|
El-Gendi AM, El-Gendi S. Influence of standardized histopathological workup on reporting of the resection margin status in pancreatic head cancer. Egypt J Surg 2014;33:131-9
|How to cite this URL:|
El-Gendi AM, El-Gendi S. Influence of standardized histopathological workup on reporting of the resection margin status in pancreatic head cancer. Egypt J Surg [serial online] 2014 [cited 2018 Dec 14];33:131-9. Available from: http://www.ejs.eg.net/text.asp?2014/33/3/131/141894
| Introduction|| |
Surgical resection with negative resection margins (RMs) (R0) remains the only potentially curative treatment for pancreatic ductal adenocarcinoma (PDAC). Because of its late presentation, aggressive tumor biology, and lack of early specific biological markers, only 10-15% of cases are resectable .
RM involvement (R1) is generally believed to be, among others (tumor size, degree of differentiation, nodal affection), a critical prognostic indicator to survival in those patients [2-6] and was reported to be an independent predictor of poor long-term survival in several studies [7-23]. However, even patients with tumor-free margins (R0 resection) frequently experience local recurrence and distant metastases. Consequently, more radical approaches have been evaluated, as described by Fortner . Even though there was an initial indication of some survival benefit, follow-up studies have failed to confirm these promising results . This raised the question as to whether such a discrepancy is caused, other than through incomplete lymphadenectomy and perineural invasion, by a misclassification of R1 resections as R0 resections . Quoted R1 resection rates can vary significantly between individual specialist centers (14-85%) [5, 6, 20, 27, 28], and it is not known to what extent these differences reflect different pathological practices.
Because RM involvement is generally believed to be determined by the quality of surgery, a low R1 rate is often considered an indicator of high-quality surgery. Recent studies, however, have brought the pathologist as a second player into the field, on the basis of the growing awareness that standardization and meticulousness of the pathological examination have a significant impact on the accuracy of the reported RM status [20, 27, 28]. The R1 rate is therefore a performance measure not only for the surgeon but possibly also for the reporting pathologist.
The aim of this study was to determine the influence of the 'standardized histopathological workup' of pancreaticoduodenectomy (PD) specimens on the reporting of the RM status using a 'surgical quality protocol' to test prospectively the hypothesis that current histopathological reports underestimate the proportion of R1 pancreatic head resections.
Toward this goal, we first implemented color coding of the RMs and the organ surfaces. Second, we carefully re-evaluated the different sites of R1 resections according to the color code and found the most frequent site of incomplete tumor resection.
| Patients and methods|| |
To fulfill our aim and test our hypothesis, we first investigated our rates of curative resections by retrospectively identifying all patients who had undergone pancreatic head resection, either through pylorus-preserving pancreaticoduodenectomy (PPPD) or the Kausch-Whipple procedure because of malignant diseases (PDAC), in the Department of Surgery, Alexandria University, between 2004 and 2009. During this period, all the specimens were examined by the same experienced team of pathologists using conventional histopathological workup, where longitudinal opening of the main pancreatic duct and common bile duct was the preferred dissection method (mainly bivalve slicing). The following margins were examined: common bile duct margin, the proximal duodenal (gastric) margin, jejunal RM, pancreatic neck transaction margin, and the anterior and posterior surface. When present, vascular, lymphatic, and perineural invasion were reported. Histological classification [tumor type, grade of malignancy, pathological tumor-node-metastasis (TNM)] was carried out according to the current World Health Organization and Union for International Cancer Control (UICC) criteria . According to the UICC criteria, the operation was considered potentially curative (R0) if the RMs and organ surfaces were free of tumor cells, whereas histopathologically verified tumor cell infiltration was defined as R1 resection. In cases of macroscopically visible tumor tissue, the resection was classified as R2.
Starting October 2009, we introduced the 'standardized histopathological workup' [27, 30, 31] to examine all PD specimens. We prospectively evaluated and validated its results for 50 months till December 2013. During this period, 54 consecutive patients with pancreatic head tumors underwent PD and provided an informed consent to their inclusion in the study before surgery. Forty-two out of the 54 patients with true macroscopic margin-free PDAC who underwent PD entered the present study, whereas 12 patients were excluded after surgery because of findings of macroscopic residual tumor (R2 resection), non adherence to the 'surgical quality protocol', and nonductal adenocarcinoma.
Standardized 'quality protocol' for pancreaticoduodenectomy
All of our studied patients received pancreatic head resection with curative intent. All resection procedures were performed by the same experienced surgical team. After a bilateral subcostal incision, assessment of resectability was performed by an examination of the abdominal cavity to exclude any contraindications for resection mainly liver metastases or peritoneal carcinomatosis. The duodenum was kocherized with the dissection plane developed. With extension of the Kocher maneuver, an adequate exposure of the aortocaval area was obtained. The superior mesenteric vein (SMV) was then identified as it passes anterior to the third part of the duodenum by ligating and dividing all the tributaries to the head of the pancreas. A plane is developed anterior to the SMV and portal vein by remaining in the periadventitial layer of the vein. All portal vein tributaries are ligated and divided individually until the portal vein is completely free from the pancreatic head.
The dissection of the retroperitoneal margin was performed by extending the excision of the perivascular neural plexus around the superior mesenteric artery (SMA). This was done by approaching the SMA after retracting the SMV with an eyelid ophthalmic retractor. A part of the inferior medial boundary of the uncinate process was defined by identifying the SMV and the partially exposed SMA and this plane was developed. This plane was extended posteriorly by dissecting the right meridian neural plexuses of the SMA. From there, the SMA was identified and the perivascular plexus on the lateral side was dissected laterally right up to the vessel, and all the tissues between the artery and the pancreatic parenchyma were resected [Figure 1]. The SMA was not dissected from the medial side and the perivascular neural plexus on the medial side was preserved to avoid postoperative diarrhea. The dissection was then extended superiorly along the SMA toward its origin. It was then possible to place the left hand just anterior to the inferior vena cava (IVC) and aorta and retract the uncinate process to the right of the patient, allowing the peripancreatic tissue around the uncinate process to be resected en bloc. The dissection of SMA continues along the plane of the adventitia up to the junction of the third and fourth parts of the duodenum. Standard lymphadenectomy plus resection of lymph nodes to the right of the celiac trunk, hepatic artery, and hepatoduodenal ligament were carried out in all patients . After resection of the specimen, the posterior and retroperitoneal margin was grossly inspected for its integrity.
|Figure 1:Operative pictures after resection of the pancreatic head showing the portal vein (PV) and superior mesenteric artery (SMA) after excision of the perivascular neural plexus on its lateral surface.|
Click here to view
Standardized protocol for pathological examination
All surfaces and RMs of the pancreatic head resection specimen were stained according to a well-established five-color code [Figure 2]: the anterior (ventral) surface was painted yellow, the posterior (dorsal) surface green, the groove of the SMV blue, the pancreatic transection margin red, and the uncinate margin silver. Considerable emphasis was placed on clarifying the status of the RMs. Besides examining the status of RMs in the conventional technique, special attention was directed toward examining the circumferential resection margins (CRM) of the specimen including the anterior, posterior, and medial surfaces (SMV groove), with dedicated study of the status of the retroperitoneal uncinate margin. Isolated tumor involvement of the anterior surface of the pancreatic specimen was not considered an R1 resection in our patient cohort. No cases were classified as R1 exclusively on the basis of perineural invasion at a RM. Similarly, nodal involvement at a RM did not constitute an R1 classification in the absence of direct tumor involvement.
|Figure 2: All surfaces and resection margins of the pancreatic head resection specimen were stained according a well-established fi ve-color code: the anterior (ventral) surface was painted yellow, the posterior (dorsal) surface green, the groove of the superior mesenteric vein (SMV) blue, the pancreatic transection margin red, and the uncinate margin silver.|
Click here to view
The uncinate process margin that extends along the proximal 3-4 cm of the SMA was identified immediately following resection [Figure 3] as it was very difficult for the pathologist to identify, especially after formalin fixation, if it has not already been inked by the surgeon while the other parts were being colored after formalin fixation for 24-36 h. All staining procedures were performed by the operating surgeon or by a surgeon present during the procedure. The specimen was serially sliced (0.5-1-cm slices) in a single axial plane, that is, perpendicular to the longitudinal axis of the duodenum [20, 27, 28], according to the guidelines of the Royal College of Pathologists and the Leeds Pathology Protocol [27,30-32]. Therefore, large slices were obtained (median number 12), allowing the precise study of each colored margin at 0 and 1 mm. R1 resection rates were calculated twice: one with 'R1 resection' defined by a positive margin of 0 mm [33-35] and the other with 'R1 resection' defined by the presence of tumor cells within 1.0 mm [30,36]. Margin involvement (R1) was defined for the 0-mm margin if tumor cells were present at the inked margin; R1 was also defined for 1 mm margin width if tumor cells were present within the margin, independent of the mode of tumor spread. The pathological protocol also included the maximal transverse diameter of the tumor, the TNM classification, the grade of differentiation, the presence or absence of perineural, lymphatic, and/or vascular spread, and the number of lymph nodes retrieved from the specimen, enabling the calculation of the lymph node ratio. Several samples were taken from the tumor in relation to the anterior and posterior surface.
|Figure 3: Pancreaticoduodenectomy fresh specimen showing the uncinate margin (silver), superior mesenteric vein superior mesenteric vein groove, and pancreatic neck transaction margin.|
Click here to view
| Results|| |
To compare the rates of curative and noncurative resections in our department with the published data, we retrospectively identified 78 patients with malignant pancreatic head tumors (PDAC), excluding cases of distal bile duct cancer and ampullary carcinoma, who had undergone either PPPD or a Kausch - Whipple procedure over 5 years' duration. In 61 of these 78 (78%) patients, the operation could be considered potentially curative (R0), whereas the RMs in 17 cancer specimens was infiltrated (R1 = 22%). The most common site of infiltration was at the pancreatic neck transaction margin, followed by the posterior margin. The uncinate process margin was not assessed as a separate margin [Table 1].
Starting October 2009, we introduced the 'standardized histopathological workup' and applied it prospectively until December 2013. During this 50-month period, 42 consecutively resected pancreatic head specimens (PDAC) were processed according to this protocol. The patient population included 14 women and 28 men. Their age ranged from 46 to 74 years, with a median of 60 years. Eighteen patients underwent a Kausch-Whipple procedure, whereas the remaining 24 patients were treated by PPPD. None of our cases required partial or complete resection of the SMV. Clinicopathological data for the entire cohort showed that 81% were classified as T3 tumors (T1: 7%, T2: 12%). Sixty percent of the tumors were moderately differentiated (grade 1: 25%, grade 2: 58%, grade 3: 17%). None of our patients died within 30 days after surgery.
All 42 pancreatic head resections were invasive ductal adenocarcinoma on the final histopathological assessment after excluding those of distal bile duct cancer and ampullary adenocarcinoma. Applying our old conventional protocol for histopathological assessment, 36 cancers were curatively resected (R0 = 86%), whereas six (14%) cases turned out to be R1 resections. These six cases were classified as R1 on the basis of infiltration of the pancreatic neck margin. Applying the standardized histopathological workup and R1 resection at 0 mm, an additional set of 12 specimens had to be considered as R1 resections, resulting in a total percentage of 48% of noncurative operations (R1), reducing the rate of R0 resection to 52%. This is in contrast to when applying the 1 mm margin rule for R1 resection, a set of 21 specimens had to be considered R1 resections, resulting in a total percentage of 64% of noncurative operations (R1), reducing the rate of R0 resection to 36% [Table 1].
[Table 2] and [Table 3] show the breakdown of RM involvement at 0 and 1.0 mm according to the number of involved margins per specimen and the distribution of margin involvement. Our results showed that 15% of R1 resections indicated multifocal margin involvement (i.e. more than one margin involved in a single specimen) for the 0 mm in contrast to 33% for the 1.0 mm margin. The posterior and medial margins were the most commonly involved margin locations at 0 and 1 mm. Out of the total 20 cases of R1 resection at 0 mm, 17/20 R1 resections showed tumor infiltration at a single site (eight uncinate, six neck, three posterior surface), two patients had tumor infiltration in two stained areas and in one patient tumor infiltration was found in three stained areas.
Out of the total 27 cases of R1 resection at 1 mm, 18/27 R1 resections showed tumor infiltration at a single site (nine uncinate, six neck, three posterior surface), three patients had tumor infiltration in two stained areas, and in six patients, tumor infiltration was found in three stained areas. Interestingly, the uncinate margin was the most common site of infiltration in 10 and 18 of these R1 specimens at 0 and 1 mm, respectively. Uncinate margin infiltration was either alone (n = 8 at 0 mm and n = 9 at 1 mm) or in combination with the posterior surface and SMV groove (n=1 at 0 mm and n = 3 at 1 mm), in combination with the posterior surface (n = 1 at 0 mm and n=3 at 1 mm), or in combination with the posterior and anterior surface (n = 0 at 0 mm and n = 3). In all, the uncinate margin was determined to be the most frequent site with residual tumor mass by far (n = 10, 42% at 0 mm) and (n = 18, 43% at 1 mm). Invasion of the uncinate margin was present in 42% of specimens at the 0-mm margin and 43% at the 1.0-mm margin.
|Table 2 Breakdown of resection margin involvement according to the number of involved margins per specimen and the distribution of margin involvement|
Click here to view
|Table 3 R1 resection rate for each margin increment (0 and 1.0 mm) and the proportion of patients with at least one, two, or three positive margins|
Click here to view
In summary, if R1 resection is defined by a positive margin of 0 mm [33-35], 48% of the present patients achieved R1 resection. If R1 resection is defined by the presence of tumor cells within 1.0 mm [30,36], 64% of the present patients achieved R1 resection. Pancreatic neck transaction invasion resulted in an additional percentage of R1 resections for any definition of R1 on the inked margins. Thus, the rate of R1 resections was 48% when R1 was defined according to the 0-mm rule and 64% when R1 was defined according to the 1.00-mm rule (ratio: 2.2).
| Discussion|| |
RM status is an important prognostic factor in pancreatic cancer [2, 37, 38]. Although it is assessed histopathologically, there is currently no internationally recognized standard protocol for pathological examination and reporting of pancreatic head specimens, nor a universally accepted definition of CRM positivity. Meaningful comparison of R1 rates between individual centers is further complicated by the lack of standardized terminology for margins, which may explain the wide variation in published R1 rates. Increasing evidence exists to suggest that the standard of histopathological processing and reporting has a significant impact on R1 resection rates [20, 27, 28]. The hypothesis that R1 resections are commonly under-reported is also supported by the observation that 60-80% of cases with resected pancreatic cancer develop local recurrence [39-41], a finding that seems to be inconsistent with quoted R1 resection rates of less than 20%.
The Leeds  and Heidelberg  groups were the first to show that the standardization of histopathological study resulted in a significant increase in R1 resection rates, without requiring any change in surgical technique (respectively, from 53 to 85%  and 14 to 76% ). Thus, a high rate of R1 resection in PDAC is clearly a marker of high-quality pathology and depends, first, on the number of peripancreatic soft tissue RMs examined, second, on the number of blocks analyzed [30,31], and third, on the minimum clearance in millimeters used to define microscopic margin involvement (R1).
In a study published recently by Campbell et al. , tumor involvement within 1.0 mm of, but not directly reaching, one or more RMs represented 45% of the 79% of RMs identified as positive. In the most recent series, comparisons of R1 rates performed using the UICC criteria (R1: 0 mm definition), which are commonly used in North America [5, 33, 34], and those achieved using the UK Royal College of Pathologists criteria (R1: 1.0 mm definition)  show ratios ranging from 1.3 to 1.8 [28,44-46]. The ratio was 2.2 in the present study. Katz et al.  reported a ratio of 5.5 (4-22%) in a study in which only the superior mesenteric artery margin (SMAm) was assessed and in which 76% of patients had received preoperative radiochemotherapy; this study also showed that preoperative CT overestimated the SMAm in 73% of patients. Hartwig et al.  reported a maximum ratio of 8.4 in a study comparing the 0 mm definition with the revised 'R1=1.0 mm' definition (4.8-40.5%).
In our study, retrospective analyses of data from patients treated in our department between 2004 and 2009 with respect to the classification of the pancreatic head resections using the traditional dissection technique showed that the percentage of R1 resections was 21.7%, which is in agreement with the literature [8, 11, 48, 49]. Shifting from traditional pathological examination procedures (mainly bivalving) to serial slicing of the specimen in a single axial plane, that is, perpendicular to the longitudinal axis of the duodenum as advocated in recent studies  resulted in an increase in the R1 rate from 14.3 to 64.3% in the prospective series. This is in agreement with a publication of the Heidelberg group  [Table 4]. The data also provide further evidence to indicate that robust pathological practice is a more important determinant of R1 classification in pancreatic cancer than operative expertise.
|Table 4 Resection margin status and R1 rates in our study compared with some published literature|
Click here to view
Longitudinal opening of the main pancreatic duct and common bile duct has traditionally been the preferred dissection method. This technique is of limited value for the assessment of the RMs, tumor origin, and tumor extension. Opening of the ducts disrupts the specimen surface along two tracks that run across the entire head of pancreas. This interferes with accurate evaluation of the CRM. As the common bile duct traverses the pancreatic head posteriorly, it is usually opened through the posterior surface, hence disrupting that part of the CRM that is frequently involved [27,51-54].
The axial slicing technique adopted in this study does not prescribe longitudinal opening of the pancreatic or bile duct; hence, the entire surface (or CRM) of the pancreatic head remains intact. Axial slicing is easy to perform, independent of the location and nature of the pathology encountered. A large number of slices are produced - usually between 10 and 13 - allowing extensive views of the lesion and its relation to the entire CRM and key anatomical structures . Interestingly, axial slicing was the standardized dissection technique used in the recent studies that reported an unusually high R1 rate of over 75% [20, 27, 28]. The frequent identification of margin involvement reported in these studies is at least partially explained by the fact that all parts of the CRM can be inspected in each specimen slice obtained with this technique. This seems to indicate that the dissection and sampling technique has a significant impact on the assessment of the margin status in PD specimens.
Malignant pancreatic tumors often invade the retroperitoneal peripancreatic tissues. The retroperitoneal peripancreatic tissue surrounds the first 3-4 cm of the SMA origin behind the SMV [52, 55, 56]. Gockel et al.  have defined this anatomical structure as 'mesopancreas' similar to the mesorectum. Therefore, PD with curative intent should include complete clearance of the peripancreatic retroperitoneal tissue, which represents the most tedious step of PD, with an increased risk of intraoperative bleeding. The importance of the retroperitoneal RM was confirmed by Westgaard et al. .
When analyzing the distribution of margin involvement in R1 resections for pancreatic cancer and despite the current lack of consensus in terminology to denote the different CRMs, the finding that the uncinate margin represents the most frequently involved margin (42% at 0 mm and 43% at 1 mm), followed by the posterior margin is also consistent with the existing literature [20, 27, 28, 58]. This was followed by the SMV groove CRM and anterior pancreatic surface. This pattern of CRM involvement is in line with Japanese studies [10,59]. Involvement of the pancreatic transection margin was observed in six cases of R1 specimens in the present study, a low rate that may be explained by the impact of intraoperative frozen-section examination of that margin.
The 'uncinate margin' is confusing as it is mainly used synonymously with the medial CRM, but occasionally refers to a true transection margin, produced by the surgeon when dividing the uncinate process as close to the SMA as possible [60,61]. With current standardized surgical procedures, however, the uncinate process remains intact and dissection of the SMA is performed in the soft tissue plane, which corresponds to the medial CRM of the specimen. Owing to morphological changes during formalin fixation, it is of utmost importance to color the uncinate RM directly after surgical resection. If the uncinate margin is not assessed separately, a positive margin here can be misinterpreted as a positive margin in the posterior or SMV groove CRM. We strongly believe that the complete and meticulous surgical resection of the uncinate margin as the structure to the right of the mesenteric artery must become the standard surgical approach in pancreatic head resection.
Although microscopic margin involvement is staged as 'R1' irrespective of which parts of the CRM are involved, detailed CRM mapping is important. It provides feedback both to the surgical and to the radiological teams, to enable improved preoperative assessment of resectability, identification of areas at risk of incomplete resection, and improved surgical technique. Further studies are needed to correlate the data from margin mapping and involvement to show the significance of involvement of each individual CRM in terms of survival and recurrence pattern.
| Conclusion|| |
Standardization of the histopathological examination of PD specimens influences the reporting of RM status and represents a more accurate assessment of curative and noncurative resection rates. Our study seems to indicate that RM involvement is significantly more frequent than reported commonly and the rates obviously depend on the definitions of microscopic invasion used. The uncinate margin is a frequent site for positive RMs, which has potential therapeutic implications. Owing to morphological changes during formalin fixation, it is of utmost importance to color uncinate RM directly after surgical resection. We strongly believe that the complete and meticulous surgical resection of the uncinate process en bloc with all the peripancreatic tissues between the artery and the pancreatic parenchyma must become the standard surgical approach in pancreatic head resection. Meanwhile, the standardization of histological examination is not only necessary to provide accurate prognostic information, but may represent a significant step forward in the design of future randomized controlled trials and the optimization of adjuvant treatment strategies.
| Acknowledgements|| |
| References|| |
|1.||Alexakis N, Halloran C, Raraty M, Ghaneh P, Sutton R. Neoptolemos JP Current standards of surgery for pancreatic cancer. Br J Surg. 2004; 91:1410-1427. |
|2.||Benassai G, Mastrorilli M, Quarto G, Cappiello A, Giani U, Forestieri P, et al. Factors influencing survival after resection for ductal adenocarcinoma of the head of the pancreas. J Surg Oncol. 2000; 73:212-218. |
|3.||Han SS, Jang JY, Kim SW, Kim WH, Lee KU, Park YH. Analysis of long-term survivors after surgical resection for pancreatic cancer. Pancreas. 2006; 32:271-275. |
|4.||Moon HJ, An JY, Heo JS, Choi SH, Joh JW, Kim YI. Predicting survival after surgical resection for pancreatic ductal adenocarcinoma. Pancreas. 2006; 32:37-43. |
|5.||Raut CP, Tseng JF, Sun CC, Wang H, Wolff RA, Crane CH, et al. Impact of resection status on pattern of failure and survival after pancreaticoduodenectomy for pancreatic adenocarcinoma. Ann Surg. 2007; 246:52-60. |
|6.||Winter JM, Cameron JL, Campbell KA, Arnold MA, Chang DC, Coleman J, et al. 1423 pancreaticoduodenectomies for pancreatic cancer: a single-institution experience. J Gastrointest Surg 2006; 10:1199-1210; discussion 1210-1211. |
|7.||Neoptolemos JP, Stocken DD, Dunn JA, Almond J, Beger HG, Pederzoli P, et al. Influence of resection margins on survival for patients with pancreatic cancer treated by adjuvant chemoradiation and/or chemotherapy in the ESPAC-1 randomized controlled trial. Ann Surg. 2001; 234:758-768. |
|8.||Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007; 297:267-277. |
|9.||Sohn TA, Yeo CJ, Cameron JL, Koniaris L, Kaushal S, Abrams RA, et al. Resected adenocarcinoma of the pancreas - 616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg 2000; 4:567-579. |
|10.||Pingpank JF, Hoffman JP, Ross EA, Cooper HS, Meropol NJ, Freedman G, et al. Effect of preoperative chemoradiotherapy on surgical margin status of resected adenocarcinoma of the head of the pancreas. J Gastrointest Surg 2001; 5:121-130. |
|11.||Wagner M, Redaelli C, Lietz M, Seiler CA, Friess H, Buchler MW. Curative resection is the single most important factor determining outcome in patients with pancreatic adenocarcinoma. Br J Surg. 2004; 91:586-594. |
|12.||Kuhlmann KF, de Castro SM, Wesseling JG, ten Kate FJ, Offerhaus GJ, Busch OR, et al. Surgical treatment of pancreatic adenocarcinoma; actual survival and prognostic factors in 343 patients. Eur J Cancer 2004; 40:549-558. |
|13.||Howard TJ, Krug JE, Yu J, Zyromski NJ, Schmidt CM, Jacobson LE, et al. A margin-negative R0 resection accomplished with minimal postoperative complications is the surgeon's contribution to long-term survival in pancreatic cancer. J Gastrointest Surg 2006; 10:1338-1345; discussion 1345-1346. |
|14.||Westgaard A, Tafjord S, Farstad IN, Cvancarova M, Eide TJ, Mathisen O, et al. Resectable adenocarcinomas in the pancreatic head: the retroperitoneal resection margin is an independent prognostic factor. BMC cancer. 2008; 8:5. |
|15.||Van den Broeck A, Sergeant G, Ectors N, Van Steenbergen W, Aerts R, Topal B Patterns of recurrence after curative resection of pancreatic ductal adenocarcinoma. Eur J Surg Oncol 2009; 35:600-604. |
|16.||Fatima J, Schnelldorfer T, Barton J, Wood CM, Wiste HJ, Smyrk TC, et al. Pancreatoduodenectomy for ductal adenocarcinoma: implications of positive margin on survival. Arch Surg 2010; 145:167-172. |
|17.||Hartwig W, Hackert T, Hinz U, Gluth A, Bergmann F, Strobel O, et al. Pancreatic cancer surgery in the new millennium: better prediction of outcome. Ann Surg. 2011; 254:311-319. |
|18.||Ferrone CR, Pieretti-Vanmarcke R, Bloom JP, Zheng H, Szymonifka J, Wargo JA, et al. Pancreatic ductal adenocarcinoma: long-term survival does not equal cure. Surgery. 2012; 152(Suppl 1):S43-S49. |
|19.||Bilimoria KY, Talamonti MS, Sener SF, Bilimoria MM, Stewart AK, Winchester DP, et al. Effect of hospital volume on margin status after pancreaticoduodenectomy for cancer. J Am Coll Surg 2008; 207:510-519. |
|20.||Menon KV, Gomez D, Smith AM, Anthoney A, Verbeke CS. Impact of margin status on survival following pancreatoduodenectomy for cancer: the Leeds Pathology Protocol (LEEPP). HPB (Oxford). 2009; 11:18-24. |
|21.||Jamieson NB, Denley SM, Logue J, MacKenzie DJ, Foulis AK, Dickson EJ, et al. A prospective comparison of the prognostic value of tumor- and patient-related factors in patients undergoing potentially curative surgery for pancreatic ductal adenocarcinoma. Ann Surg Oncol 2011; 18:2318-2328. |
|22.||Rau BM, Moritz K, Schuschan S, Alsfasser G, Prall F, Klar E. R1 resection in pancreatic cancer has significant impact on long-term outcome in standardized pathology modified for routine use. Surgery. 2012; 152:S103-S111. |
|23.||Gnerlich JL, Luka SR, Deshpande AD, Dubray BJ, Weir JS, Carpenter DH, et al. Microscopic margins and patterns of treatment failure in resected pancreatic adenocarcinoma. Arch Surg 2012; 147:753-760. |
|24.||Fortner JG. Regional resection of cancer of the pancreas: a new surgical approach. Surgery. 1973; 73:307-320. |
|25.||Michalski CW, Kleeff J, Wente MN, Diener MK, Buchler MW, Friess H. Systematic review and meta-analysis of standard and extended lymphadenectomy in pancreaticoduodenectomy for pancreatic cancer. Br J Surg. 2007; 94:265-273. |
|26.||Buchler MW, Kleeff J, Friess H. Surgical treatment of pancreatic cancer. J Am Coll Surg 2007; 205(Suppl):S81-S86. |
|27.||Verbeke CS, Leitch D, Menon KV, McMahon MJ, Guillou PJ, Anthoney A. Redefining the R1 resection in pancreatic cancer. Br J Surg. 2006; 93:1232-1237. |
|28.||Esposito I, Kleeff J, Bergmann F, Reiser C, Herpel E, Friess H, et al. Most pancreatic cancer resections are R1 resections. Ann Surg Oncol. 2008; 15:1651-1660. |
|29.||Wittekind C, Klimpfinger M, Sobin LM. UICC: TNM Atlas. Illustrierter Leitfaden zur TNM/pTNM-Klassifikation maligner Tumoren. Berlin, Heidelberg, New York: Springer 2005. |
|30.||Campbell FBM, Foulis AJ. Minimum dataset for histopathological reporting of pancreatic, ampulla of vater and bile duct carcinoma. London: Royal College of Pathologists; 2002. |
|31.||Verbeke CS. Resection margins and R1 rates in pancreatic cancer - are we there yet?. Histopathology. 2008; 52:787-796. |
|32.||Verbeke CS, Menon KV. Redefining resection margin status in pancreatic cancer. HPB (Oxford). 2009; 11:282-289. |
|33.||Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC Cancer Staging Manual. 7th ed. New York: Springer 2010. |
|34.||Sobin L, Gaspodarowicz M, Wittekind C. TNM classification of malignant tumors. 7th ed. New York: Wiley Blackwell 2009. |
|35.||Hruban RH, Pitman MB, Klimstra DS. Tumors of the pancreas. Atlas of tumor pathology. Washington: Armed Forces Institute of Pathology 2007. |
|36.||Konstantinidis IT, Warshaw AL, Allen JN, Blaszkowsky LS, Castillo CF, Deshpande V, et al. Pancreatic ductal adenocarcinoma: is there a survival difference for R1 resections versus locally advanced unresectable tumors? What is a 'true' R0 resection?. Ann Surg. 2012; 257:731-736. |
|37.||Yeo CJ, Cameron JL, Lillemoe KD, Sohn TA, Campbell KA, Sauter PK, et al. Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma, part 2: randomized controlled trial evaluating survival, morbidity, and mortality. Ann Surg. 2002; 236:355-366; discussion 366-368. |
|38.||Geer RJ, Brennan MF. Prognostic indicators for survival after resection of pancreatic adenocarcinoma. Am J Surg 1993; 165:68-72; discussion 73. |
|39.||Kayahara M, Nagakawa T, Ueno K, Ohta T, Takeda T, Miyazaki I. An evaluation of radical resection for pancreatic cancer based on the mode of recurrence as determined by autopsy and diagnostic imaging. Cancer1993; 72:2118-2123. |
|40.||Westerdahl J, Andren-Sandberg A, Ihse I. Recurrence of exocrine pancreatic cancer - local or hepatic? Hepatogastroenterology. 1993; 40:384-387. |
|41.||Sperti C, Pasquali C, Piccoli A, Pedrazzoli S. Recurrence after resection for ductal adenocarcinoma of the pancreas. World J Surg. 1997; 21:195-200. |
|42.||Verbeke CS, Gladhaug IP Authors' reply: resection margin involvement and tumour origin in pancreatic head cancer (Br J Surg 2012; 99: 1036-1049). Br J Surg. 2012; 100:299. |
|43.||Verbeke CS, Gladhaug IP. Resection margin involvement and tumour origin in pancreatic head cancer. Br J Surg. 2012; 99:1036-1049. |
|44.||Campbell F, Smith RA, Whelan P, Sutton R, Raraty M, Neoptolemos JP, et al. Classification of R1 resections for pancreatic cancer: the prognostic relevance of tumour involvement within 1 mm of a resection margin. Histopathology. 2009; 55:277-283. |
|45.||Gaedcke J, Gunawan B, Grade M, Szoke R, Liersch T, Becker H, et al. The mesopancreas is the primary site for R1 resection in pancreatic head cancer: relevance for clinical trials. Langenbecks Arch Surg 2010; 395:451-458. |
|46.||Jamieson NB, Foulis AK, Oien KA, Going JJ, Glen P, Dickson EJ, et al. Positive mobilization margins alone do not influence survival following pancreatico-duodenectomy for pancreatic ductal adenocarcinoma. Ann Surg 2010; 251:1003-1010. |
|47.||Katz MH, Wang H, Balachandran A, Bhosale P, Crane CH, Wang X, et al. Effect of neoadjuvant chemoradiation and surgical technique on recurrence of localized pancreatic cancer. J Gastrointest Surg 2012; 16:68-78; discussion 79. |
|48.||Richter A, Niedergethmann M, Sturm JW, Lorenz D, Post S, Trede M. Long-term results of partial pancreaticoduodenectomy for ductal adenocarcinoma of the pancreatic head: 25-year experience. World J Surg. 2003; 27:324-329. |
|49.||Yeo CJ, Cameron JL, Sohn TA, Lillemoe KD, Pitt HA, Talamini MA, et al. Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: pathology, complications, and outcomes. Ann Surg1997; 226:248-257; discussion 257-260. |
|50.||Nishimura Y, Hosotani R, Shibamoto Y, Kokubo M, Kanamori S, Sasai K, et al. External and intraoperative radiotherapy for resectable and unresectable pancreatic cancer: analysis of survival rates and complications. Int J Radiat Oncol Biol Phys 1997; 39:39-49. |
|51.||Compton CC, Henson DE. Protocol for the examination of specimens removed from patients with carcinoma of the exocrine pancreas: a basis for checklists. Cancer Committee, College of American Pathologists. Arch Pathol Lab Med. 1997; 121:1129-1136. |
|52.||Luttges J, Vogel I, Menke M, Henne-Bruns D, Kremer B, Kloppel G. The retroperitoneal resection margin and vessel involvement are important factors determining survival after pancreaticoduodenectomy for ductal adenocarcinoma of the head of the pancreas. Virchows Arch 1998; 433:237-242. |
|53.||Chatelain D, Flejou JF. Pancreatectomy for adenocarcinoma: prognostic factors, recommendations for pathological reports. Ann Pathol. 2002; 22:422-431. |
|54.||Luttges J, Zamboni G, Kloppel G. Recommendation for the examination of pancreaticoduodenectomy specimens removed from patients with carcinoma of the exocrine pancreas. A proposal for a standardized pathological staging of pancreaticoduodenectomy specimens including a checklist. Dig Surg. 1999; 16:291-296. |
|55.||Riall TS, Cameron JL, Lillemoe KD, Campbell KA, Sauter PK, Coleman J, et al. Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma - part 3: update on 5-year survival. J Gastrointest Surg 2005; 9:1191-1204; discussion 1204-1206. |
|56.||Noto M, Miwa K, Kitagawa H, Kayahara M, Takamura H, Shimizu K, et al. Pancreas head carcinoma: frequency of invasion to soft tissue adherent to the superior mesenteric artery. Am J Surg Pathol. 2005; 29:1056-1061. |
|57.||Gockel I, Domeyer M, Wolloscheck T, Konerding MA, Junginger T. Resection of the mesopancreas (RMP): a new surgical classification of a known anatomical space. World J Surg Oncol. 2007;5:44. |
|58.||Nagakawa T, Nagamori M, Futakami F, Tsukioka Y, Kayahara M, Ohta T, et al. Results of extensive surgery for pancreatic carcinoma. Cancer. 1996; 77:640-645. |
|59.||Tsuchiya R, Noda T, Harada N, Miyamoto T, Tomioka T, Yamamoto K, et al. Collective review of small carcinomas of the pancreas. Ann Surg. 1986; 203:77-81. |
|60.||Khalifa MA. Intraoperative assessment of the Whipple resection specimen. J Clin Pathol. 2007; 60:975-980. |
|61.||Khalifa MA, Maksymov V, Rowsell CH, Hanna S. A novel approach to the intraoperative assessment of the uncinate margin of the pancreaticoduodenectomy specimen. HPB (Oxford) 2007; 9:146-149. |
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]