Resection Margins in Pancreatic Cancer

Resection Margins in Pancreatic Cancer Caroline S. Verbeke, MD, PhD, FRCPath* KEYWORDS Pancreatic cancer Resection margin Pancreatoduodenectomy Pathology Survival KEY POINTS The rate of microscopic margin involvement (R1 rate) for pancreatic cancer varies between published studies from less than 20% to more than 80%. The pathology examination procedure and in particular the specimen grossing technique have a significant impact on the accuracy of margin assessment. Recent studies report a consistently higher R1 rate (70% or more) if a novel grossing technique based on axial specimen dissection and extensive tissue sampling is used. The lack of consensus regarding terminology, definition of microscopic margin involvement, and pathology examination jeopardizes the validity of clinical trials that include surgical resection as a treatment arm for pancreatic cancer. The prognostic significance of microscopic margin involvement in pancreatic cancer is currently unknown. INTRODUCTION In recent years, there has been an increasing interest in the margin status of surgical resection specimens for ductal adenocarcinoma of the pancreas, both in terms of pathologic assessment and clinical implications. Although the reasons for this continued attention are multiple, it was mainly triggered by the introduction of a novel pathology examination technique for pancreatoduodenectomy specimens, which resulted in a significantly higher microscopic margin involvement rate (R1 rate) than when traditional grossing techniques were used.1 In subsequent years the basic con- cepts of margin involvement in pancreatic cancer were critically reconsidered, as were the factors that influence the assessment of the margin status, and the implications of margin involvement regarding patient treatment and outcome. Although several Funding Sources, Conflict of Interest: Nothing to disclose. Division of Pathology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden * Clinical Pathology and Cytology, F42, Karolinska University Hospital, Huddinge, Stockholm SE-141 86, Sweden. E-mail address: [email protected] Surg Clin N Am 93 (2013) 647–662 http://dx.doi.org/10.1016/j.suc.2013.02.008 surgical.theclinics.com 0039-6109/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved. 648 Verbeke questions remain unanswered and controversies continue to exist, it has become clear that the current disconcerting variety in reported R1 rates is to a large extent accounted for by divergence of pathology practice. This situation obviously raises concern regarding the appropriateness of the individual patient’s management as well as the robustness of data from multicenter clinical trials.2 THE PROGNOSTIC SIGNIFICANCE OF MARGIN INVOLVEMENT Ductal adenocarcinoma of the pancreas, commonly denoted as pancreatic cancer, has a poor prognosis, which is mainly a result of late clinical presentation and the limited effect of chemotherapy. In only 15% to 20% of patients is the tumor amenable to surgical resection, which increases the 5-year survival rate from less than 5% to 7%-25%.3–5 Numerous studies have identified multiple prognostic predictors, including tumor grade, lymph node metastasis, and perineural invasion.6–10 The impact of microscopic margin involvement (R1) on overall and disease-free survival is not clear. The number of studies reporting a statistically significant prognostic impact of margin involve- ment6,7,11–13 is comparable with that of reports on the lack of such a correlation.4,14,15 However, the published R1 rates vary widely between studies, from less than 20% to more than 80% (Table 1), although patient-related and tumor-related characteristics are not significantly different, and all studies were undertaken in specialist pancreatic cancer centers, from which it can be presumed that surgery was performed according to current standards and preoperative patient selection followed comparable criteria. The considerable divergence in R1 rate is not reflected in a comparably large differ- ence in patient survival. The outcome of patients who underwent a complete resection Table 1 Comparison of the rate of microscopic margin involvement (R1) and median survival after surgical resection of ductal adenocarcinoma of the pancreas between studies using the axial slicing technique or another grossing technique Number of Median Median Reference (Year) Patients R1 Rate (%) Survival R0 Survival R1 Axial Slicing Technique Verbeke et al,1 2006 54 85 37 11 Esposito et al,16 2008 111 76 — — Menon et al,17 2009 27 82 >55 14 Campbell et al,18 2009 163 79 25 15 Jamieson et al,19 2010 1848 74 26 15 Other Technique Willet et al,20 1993 72 51 20 12 Millikan et al,21 1999 84 29 17 8 Benassai et al,22 2000 75 20 17 9 Sohn et al,6 2000 616 30 12 19 Neoptolemos et al,12 2001 111 19 17 11 Raut et al,15 2007 360 17 28 22 Westgaard et al,23 2008 40 45 16 11 Hsu et al,24 2010 509 44 19 11 Gnerlich et al,25 2012 285 34 22 16 Resection Margins in Pancreatic Cancer 649 (R0) seems to be better in series with a high R1 rate than in studies with lower rates (see Table 1). These observations are difficult to explain by possible differences in patient selection or treatment. However, on close scrutiny of the methods section of the studies, it seems that those reporting a high R1 rate (>70%) were based on a novel pathology examination method,1,16–19 whereas traditional methods had been used in studies with a lower R1 rate (17%–51%).6,12,15,20–25 In addition, the studies differ in the number and location of the margins that had been included in the investigations, as well as in the diagnostic criteria that had been applied for the reporting of microscopic margin involvement. These differences highlight the controversies that exist regarding almost every aspect of margin assessment in pancreatic surgical resection specimens and in particular in those after pancreatoduodenectomy. The nature, causes, and consequences of these controversies are outlined in the following sections. TERMINOLOGY A recent study critically reviewing free-text histopathology reports found that 28 different names were used to describe various margins of pancreatoduodenectomy specimens.26 This dissensus pertains only to the circumferential resection margins, whereas the terminology for the transection margins (of the stomach/proximal duodenum, distal duodenum, pancreatic neck and common bile duct) is universally accepted. Fig. 1 shows the circumferential surfaces as these are distinguished in several coun- tries and embedded in the national pathology guidelines of Sweden and the United Kingdom, for example.27,28 The terminology is simple and based on anatomic locali- zation or proximity to the superior mesenteric vessels. In particular, the surfaces facing the superior mesenteric artery (SMA) or vein (SMV) have been referred to by a variety Fig. 1. The circumferential margins in pancreatoduodenectomy specimens consist of the anterior and posterior surfaces, as well as the surfaces facing the SMV and SMA. Color-coded inking of the surfaces allows identification of the individual margins during microscopic examination. Inked in purple is the circumferential soft tissue margin of the extrapancreatic common bile duct. 650 Verbeke of terms, including retroperitoneal, uncinate, mesenteric, medial, and posterior. In some centers, the ‘SMA margin’ includes both the SMA-facing and SMV-facing surfaces, whereas in others the same term refers to the artery-facing margin only. The circumferential resection margin of the soft tissue sheath around the extrapancreatic common bile duct stump (sometimes referred to as the radial periductal margin) is usually not considered in studies on pancreatic cancer. However, it is of importance for distal bile duct cancer involving the extrapancreatic segment of the bile duct.29 The lack of international consensus on the terminology for the circumferential resection margins is closely linked to a divergence in opinion and practice regarding the pathology assessment of these surfaces in terms of specimen dissection and tissue sampling. GROSSING TECHNIQUES Worldwide, a variety of grossing techniques for pancreatoduodenectomy specimens are used. The 3 main approaches differ in the plane of dissection and whether or not the pancreatic and bile duct are opened longitudinally. Specimen dissection is pre- ceded by color-coded inking of the various surfaces of the pancreatoduodenectomy specimen, as shown in Fig. 1. Bivalving and Multivalving Technique For many decades, it has been traditional in pathology to open gastrointestinal cancer specimens longitudinally. Although this technique has now been abandoned in favor of cross sectioning of specimens from the tubular digestive tract, in some centers it continues being applied to pancreatoduodenectomy specimens. According to this technique, the main pancreatic duct and common bile duct are probed, and the specimen is sliced once or several times along the plane defined by both probes (Fig. 2). In this way, both ducts are exposed longitudinally in only 2 specimen slices facing the same dissection plane. This technique is challenging, not only when it comes to the insertion of probes into the narrow, distorted, or tumor-obstructed ducts but also regarding the subsequent slicing of the specimen along the probes. The resulting slices are large and require further dissection, which is usually performed by slicing in an additional, perpendicular plane,30 as shown in Fig.

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