The mesopancreas is the primary site for R1 resection in pancreatic head cancer: relevance for clinical trials

Cancer of the pancreatic head is one of the most malignant gastrointestinal tumors. Surgery is still considered to be the only potentially curative approach if complete resection is possible [6, 20, 23]. However, surgical resection in patients with localized pancreatic cancer is still underused [14]. Retrospective analyses of data from patients treated in our department between 1996 and 2005 revealed a 5-year survival rate of 20% for R0 patients, which is in agreement with the literature, even though some authors deny the existence of 5-year survivors [4]. With respect to the classification of the pancreatic head resections evaluated retrospectively, the percentage of R1 resections (22.6%) also mirrors the literature [12, 15, 23, 27]. These data appear to indicate the possible misclassification of R1 resections as R0.

Local recurrence and disseminated cancer spread dramatically impair the prognosis of patients with pancreatic head cancer. This is supported by postmortem examinations reporting a local recurrence rate approaching 100% [5, 7, 19, 21, 24]. Luettges et al. [8, 13] already stated in 1999 that tumor recurrence is primarily due to incomplete removal at the site of resection rather than to metastatic disease. They pointed out that the retroperitoneal RM has an influence on patient survival. However, it was in 2006 when Verbeke et al. [22] first reported an incomplete resection rate of 85% using a standardized and intensified workup. For the 54 pancreatic head resections, a color code was implemented to distinguish between the anterior, posterior, and SMV groove surface. Similar results were published by Esposito et al. [2] who reported an R1 resection rate of 76% in 111 PDAC. As part of their protocol, they color-coded the anterior, posterior, medial margin, and groove surface of the SMV, respectively, whereas the retroperitoneal RM was not investigated separately. The importance of the retroperitoneal resection margin was confirmed by Westgaard et al. [25] who thoroughly worked up 114 periampullary adenocarcinomas by perpendicular sectioning. The overall R1 resection rate was 35%, whereas the retroperitoneal resection margin was involved in 80% of the specimens. However, it should be pointed out that all three studies classified the specimens according to the definition of The Royal College of Pathologists. Since there do not exist any general guidelines about the definition of R1 resection, we primarily applied the UICC criteria, i.e., a curative resection was defined as there being no microscopic evidence of residual tumor at the RM. We found an R1 resection rate of 50.8%, which demonstrates that a high rate of R1 resections is not only based on the definition of margin positivity as tumor clearance of ≤1 mm.

Our R1 rate (using RCP criteria) was comparable to those from Verbeke et al. [22] and Esposito et al. [2]. Therefore, we could confirm that the number of noncurative resections is considerably higher when a modified and intensified histopathological workup is applied. Interestingly, Westgaard et al. [25] only investigated the transection margins of the pancreas and reached R1 rate of 45% for PDAC and 59% for DBD. The anterior or posterior surfaces of the pancreas were not part of the workup.

We identified the mesopancreas as the primary site of positive RMs. In total, 66.6% of those cancers resected noncuratively displayed infiltration of this structure. As pointed out by other authors [8, 25] the retroperitoneal RM is of great interest with regard to curative resection. Interestingly, there is no exact definition of the retroperitoneal RM. Some consider the complete posterior surface of the pancreas as retroperitoneal margin, while others use the term to describe just the area of sharp dissection, similar to what we call mesopancreatic RM. Esposito et al. [2] defined medial and posterior soft tissue margins to acknowledge the importance of the region. This diversity of definitions impairs a meaningful comparison of RMs. Therefore, we introduced the term “mesopancreatic RM” to describe the dissection margin in the peripancreatic fatty tissue behind the pancreatic head and lateral to the mesenteric artery. It was chosen because of its anatomical origin and therapeutic implication. The tissue between the pancreatic parenchyma and the SMA consists of fatty tissue and contains blood and lymphatic vessels, as well as lymph nodes draining the pancreatic head and the uncinate. Additionally, nerve fibers are located in the mesopancreas innervating the pancreatic parenchyma. In this context, these structures should be defined as mesopancreas although the peritoneal attachment, which is a requisite to the existence of a “meso” [10], was lost during embryological development owing to duodenal rotation. The mesopancreas rises from the embryological mesentery attaching the pancreatic bud to the abdominal wall. This leads to the consequence that the mesopancreas must be resected and removed completely in its integrity down to the mesenteric artery. Based on the embryological development and according to our experience, the pancreatic tissue is not directly adjacent to the mesenteric artery but connected by a delicate meshwork of connective tissue rich in nerve fibers (mesenteric plexus). This layer should be separated close to the mesopancreas to prevent the complications of postoperative diarrhea.

As Verbeke and colleagues demonstrated [22], intensive embedding of resected tissue increases the rate of R1 resections. However, infiltration of the mesopancreas may have been misinterpreted in the past as a consequence of a cancer-induced fibrosis or disseminated cancer cells. Therefore, RMs in their integrity and numerous samples from the tumor with relation to the surfaces of the pancreas were embedded as part of this modified and standardized protocol.

It is widely accepted that only an R0 resection is considered as a curative approach and stratification for resection status is routinely performed in clinical trials such as in the CONKO-001 trial. Numerous trials failed to show significant differences in patients’ treatment which could possibly be due to the misinterpretation of the resection status based on the lack of a standardized workup [17]. In general, R1 resections rates of about 20% are reported [11, 16, 18, 27]. However, one can speculate that in these trials the low R1 resection rates are due to a conventional pathohistological workup. Being aware of the crucial importance of assessing the resection rate an intensified workup is obligatory in trials such as CONKO-005 and CONKO-006. Considering the mesopancreas as a structure guiding relevant vessels for lymphatic and blood drainage of the pancreatic head and the uncinate, it may be hypothesized that tumor cells drain into the lymphatic and blood vessels during manipulation of the pancreatic head (e.g., Kocher’s maneuver). As in the treatment of colorectal cancer, a no-touch technique would diminish this potential influence, resulting in the need to resect the mesopancreas along the superior mesenteric artery first.

Based on our data, we propose a standardized histopathological workup for pancreatic head cancer specimens, which may represent a more accurate assessment of curative and noncurative resection rates. As a consequence of this modified protocol, we demonstrate that the mesopancreas is a frequent site for positive resection margins, which has potential therapeutic implications and should be considered in clinical trials when stratifying patients into R0 and R1 resection classifications. Owing to morphological changes during formalin fixation, it is of upmost importance to color the mesopancreatic RM directly after surgical resection. We strongly believe that the complete and meticulous surgical resection of the mesopancreas as the structure to the right of the mesenteric artery must become the standard surgical approach in pancreatic head resection.