Significance of pathological positive superior mesenteric/portal venous invasion in pancreatic cancer

Mallika Tewari

Varanasi, India

Significance of pathological positive superior mesenteric/portal venous invasion in pancreatic cancer

Mallika Tewari

Varanasi, India

BACKGROUND: Pancreaticoduodenectomy with superior mesenteric/portal venous resection for pancreatic ductal adenocarcinoma (PDAC) is frequently performed with no added morbidity or mortality in case of tumor abutment to the superior mesenteric or portal vein so as to obtain a margin negative resection. True histopathological portal vein invasion is found only in a small subset of such patients. The aim of this review aimed to discuss the significance of histopathological venous invasion in PDAC.

DATA SOURCES: For this review available data was searched from PubMed and analyzed. No randomized trials have been published on this topic.

RESULTS: Existing data on prognostic factors in histopathological venous invasion by PDAC are limited and recent studies indicate worse survival in this subgroup of patients. In addition, venous invasion in PDAC has been associated with large tumors, involved lymph nodes, perineural invasion and R1 resection. The survival of patients with portal venous resection but without histologic venous invasion is reportedly better than those with histopathological venous invasion; though conflicting studies do exist on the subject. Some studies also relate the depth of venous invasion to prognosis after surgical resection of PDAC.

CONCLUSIONS: Frank/‘histopathological’ invasion of superior mesenteric/portal venous and R1 resection indicate a very poor survival. Such patients may be given the opportunity of benefit of neoadjuvant treatment.

(Hepatobiliary Pancreat Dis Int 2016;15:572-578)

pancreatic ductal adenocarcinoma;

superior mesenteric/portal venous invasion;

histologic venous invasion;

prognosis;

survival

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a very poor 5-year survival rate of ＜5%. Almost 80%-85% of patients present with unresectable/advanced PDAC and have a median survival of ＜6 months.[1,2]Over the years with improvement in the surgical techniques, perioperative care and multimodality approach, the operative mortality has dropped to less than 5% in high-volume centers, but the operative morbidity still remains close to 40%-50%.[3,4]In contrast to arterial resection, venous involvement of the superior mesenteric vern (SMV)/portal vein (PV) in PDAC is no longer considered a contraindication to surgery and venous resections are routinely performed in high-volume centers without added morbidity or mortality as compared to patients undergoing similar surgery without venous resection.[5,6]However, long-term survival following SMV/PV resection in PDAC remains uncertain. Few recent studies have reported that pathologic venous wall invasion is associated with poor survival in PDAC.[7,8]This finding will have strong implications on improved preoperative diagnosis and staging of venous invasion in PDAC and the utilization of neoadjuvant treatment protocols in this category of patients.

A PubMed search was made and the available data on the subject were analyzed and have been discussed in this review.

Applied anatomy

It is yet unclear if the poor survival of patients with

PDAC is due to early dissemination or to a delay in diagnosis. Compounded with it is the complex anatomy of the pancreas, it’s propensity for neuronal invasion often resulting in R1 resection and inherent chemoresistance.[9]

The pancreas is situated deep in the retroperitoneum. It is in close contact with major intraabdominal vessels such as the SMV/PV, superior mesenteric artery (SMA), common hepatic artery (CHA), hepatic artery (HA), gastroduodenal artery (GDA) and celiac trunk. It is wellknown that aberrations in the hepatic arterial anatomy are frequent and normal anatomy is observed in only 55% to 79% of patients.[10]The pancreaticoduodenal arterial arcades, veins, and nerves are situated on the fusion fascia of Treitz that also covers the pancreas, extrapancreatic nerve plexuses, SMA, and PV.[11]PDAC has a special tendency to invade neuronal plexus, and its prevalence may reach up to 100%.[12,13]Thus, surgical resection especially involving venous resection is a challenging operation and has high chances of having microscopic positive resection margins (R1) and hence an adverse prognosis.

Preoperative assessment of SMV/PV involvement

Tumor invasion of the SMV/PV by PDAC is common due to the anatomic proximity of the head of the pancreas and the veins. Many a times it is just tumor adhesion and not true venous invasion by PDAC due to tumor associated desmoplasia/inflammation/(radio)chemotherapyinduced fibrosis or fibrosis due to tumor regression that is difficult to differentiate by preoperative imaging.[14]Historically, major vessel involvement in PDAC has been a contraindication to resection as venous invasion was often a surprise finding on laparotomy and a high-risk resection performed by an unprepared surgical team had a low likelihood of yielding a complete R0 resection or long-term survival and was beset with complications.

Over the past two decades, improvements in crosssectional imaging and image reconstruction have allowed for more detailed preoperative planning and have contributed to accurate preoperative staging of PDAC. Undeniably, imaging of PDAC is hence of paramount importance to avoid unnecessary surgery in those with unresectable disease and, at the same time not to denying the opportunity for cure in patients with resectable PDAC. Various classification systems have been proposed to stage PDAC (based on imaging) as ‘resectable’, ‘borderline resectable’, and ‘unresectable’ depending upon various degrees of venous abutment, distortion or narrowing and encasement of the vessels (PV, SMV, SMA, CHA, GDA, etc) by PDAC amongst other criteria.[15-18]However, certain terminology used in these guidelines leave ambiguity as to which tumors should be considered resectable and which should be considered borderline resectable.

Efforts are now underway to develop imaging protocols and identify signs that reliably indicate possible venous invasion by PDAC. Pancreatic protocol contrastenhanced computed tomography (CECT) remains the best tool for assessing vascular involvement.[19]Tran Cao et al[19]retrospectively re-reviewed preoperative pancreatic protocol CECT images of 254 patients who underwent pancreaticoduodenectomy between 2004 and 2011 at the MD Anderson Cancer Center (MDACC). Ninetyeight (39.6%) patients had concomitant SMV-PV resection. The extent of tumor-vein circumferential interface (TVI) was defined as demonstrating no interface, ≤180° of vessel circumference, ＞180° of vessel circumference, or occlusion. SMV-PV resection was necessary in 89.5% of patients with TVI ＞180° or occlusion and 82.4% of these patients eventually had confirmed histologic SMV-PV invasion. TVI ≤180° was associated with favorable overall survival compared to a greater circumferential interface. Published studies[19,20]have categorized the relationship between the PDAC and the SMV/PV on the basis of the radiographic appearance of the vessel itself ranging from the simple to relatively complex methods using either CECT images or mesenteric angiograms. Tran Cao et al[19]categorized TVI using a simple and objective (rather than subjective) terms that characterized the radiographic interface between primary tumor and SMV-PV as observed on routine CECT images.

Another study by Nakao et al[20]proposed four different radiographic types of PV invasion for PDAC namely A (normal), B (unilateral narrowing), C (bilateral narrowing), or D (complete obstruction with collateral veins) assessed by portography or CECT. Pathological grades of PV wall invasion were classified as 0 (no invasion), 1 (tunica adventitia), 2 (tunica media), or 3 (tunica intima) and depth of invasion of the venous wall was related to survival. Radiographic classification of PV invasion correlated well with pathological PV wall invasion. Pathological PV wall invasion was observed in 0% of type A (n=111), 51% of type B (42/82), 74% of type C (72/97) and 93% of type D (63/68). Long-term survival (＞5 years) was observed in types A and B, and grades 0 and 1 subgroups.

Klauss et al[21]also previously reported an invasion score using 16-row spiral CECT in PDAC based on morphologic features, length of tumor contact, and circumferential involvement. Invasion of the surrounding vessels was assessed using an invasion score with a high sensitivity and specificity of 89% and 99%, respectively and also predicted resectability with a sensitivity of 94% and a specificity of 89%.

Almost 10% to 55% patients have non-dissociable tumor adherence with the PV/SMV axis requiring venous resection but do not have pathological venous invasion.[22,23]Recent studies focus not only on variables that help in categorizing pathological venous invasion preoperatively with considerable accuracy, but also try to correlate venous invasion with survival. One such multicenter study on 406 PDAC patients was recently published by Ramacciato et al;[24]wherein the authors reported that at multivariate analysis venous invasion on preoperative CECT was independently related to pathological venous invasion. Histological invasion of the resected vein was confirmed in 56.7% of specimens. Further, pathological venous invasion resulted in significantly lower 5-year survival, 20% at 5 years and median of 15.5 months versus 33.7% and 31.7 months, respectively in patients without pathological venous invasion.

Feasibility of venous resection in PDAC

Although randomized prospective studies are lacking, it has long been believed that venous resection in PDAC is technically feasible, safe and patients have similar outcomes compared to patients who undergo standard resection, with no differences in morbidity, mortality, lengths of stay and long-term survival.[5,6,25,26]In 2012, Zhou et al[27]performed a meta-analysis of 19 non-randomized studies including a total of 2247 patients. There was no difference in perioperative morbidity and mortality between patients with venous resection and those without venous resection. More recently, another metaanalysis by Yu et al[23]evaluating 22 retrospective studies including 2890 patients came to similar conclusions. There were, although, differences in median tumor size, R0 resection rate, lymph node metastases, and pancreatic fistula in the latter. However, conflicting reports[28-30]do exist suggesting increased overall morbidity and also mortality associated with vascular tumor involvement and reconstruction, such as two large-scale studies based on the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) and National Inpatient Sample. A recently published large multicenter retrospective study[31]from France involving 402 (29%) patients with and 997 without venous resection identified venous resection as a significant (P=0.0005) poor prognostic factor for long-term survival on multivariate analysis. There was, however, no significant difference in overall postoperative morbidity or mortality (P=0.16). Venous resection was associated with the larger tumors (P＜0.001), poorly differentiated tumors (P=0.004), higher number of positive lymph nodes (P=0.042), positive resection (R1) margins (P＜0.001). The authors did not comment on histopathological invasion of the SMV/PV and hence no inference can be drawn regarding true pathological venous invasion and prognosis.

As it is difficult to distinguish true neoplastic involvement from inflammatory adhesion both pre- and intraoperatively, pancreatectomy with venous resection is advisable whenever possible in high-volume centers by high-volume surgeons if a complete gross resection can be achieved.[32]If, however, preoperative imaging indicates the probability of frank venous invasion, one might consider preoperative neoadjuvant treatment protocols[7]although keeping in view the fact that PDAC is a relatively chemoresistant tumor and dramatic tumor regression is rarely seen. It is best to discuss management protocols for borderline resectable PDAC in a multidisciplinary meeting.

Depth of venous wall invasion by PDAC and prognosis

Some reports[33,34]suggest that the depth of invasion into the resected SMV/PV correlates with the prognosis and that involvement of tunica adventitia may not be major significance. Fukuda et al[34]reported that 3-year overall survival rate in their series was similar for patients with no PV invasion and those with superficial invasion into the tunica adventitia (40.0% vs 32.9%, respectively; P=0.85). Deeper PV wall invasion into the tunica media or the tunica intima was associated with a poorer 1-year survival similar to that of patients undergoing noncurative resection (21.5% vs 34.4%, respectively; P=0.53). Similar findings were reported by a large Japanese study[20]in which long-term survival (＞5 years) was observed in patients with either no invasion of PV or involvement up to tunica adventitia. Another study[26]reported a trend to worse prognosis with deeper PV wall invasion but without statistical significance. Han et al[35]found in their study that invasion into the tunica intima was a poor prognostic factor for survival even after margin-negative pancreaticoduodenectomy for PDAC.

Adverse tumor biology of PDAC with venous invasion

Available data regarding the role of tumor location versus biology of PDAC in venous invasion remain limited and controversial. Fuhrman et al[36]argued that SMV/PV invasion in PDAC is a function of tumor location rather than an indicator of aggressive tumor biology, because their data revealed that tumors invading the SMV/PV

confluence were not associated with histologic parameters indicative of a poor prognosis. Similarly, another study[37]supported the hypothesis that the presence of vascular tumor involvement of peripancreatic vessels by PDAC seems to be an indicator of unfavorable tumor topography, instead of being a sign of adverse tumor biology.

However, recent reports[8,38]suggest that adverse tumor biology is indeed associated with SMV/PV invasion and also influences survival in patients with PDAC. Wang et al[38]analyzed and reported their patient data of 122 consecutive patients with PDAC who underwent pancreaticoduodenectomy with [PD+VR; 64 (53%)] or without (PD-VR) venous resection between January 2004 and May 2012. Patients who underwent PD+VR had significantly greater American Society of Anesthesiologists (ASA) score, duration of operation, intraoperative blood loss and blood transfusion requirement compared with those in the PD-VR group. In addition, PD+VR group had significantly larger tumor size (P=0.009), higher rates of periuncinate neural invasion (P=0.008) and positive resection (R1) margin (P=0.004). The authors concluded that tumors requiring a venous resection are larger and biologically more aggressive.

In an MDACC series of 225 consecutive patients with stage II pancreatic adenocarcinoma who received neoadjuvant therapy and pancreaticoduodenectomy with or without SMV/PV resection, it was reported that histologic tumor involvement of the SMV/PV was associated with larger tumor size, increased intraoperative blood loss, higher rates of positive margin and local/distant recurrence.[8]Similarly, Okabayashi et al[7]also found pathologic portosplenomesenteric venous invasion to be significantly associated with larger tumor size, presence of lymphatic permeation, microvascular invasion, perineural invasion, retroperitoneal invasion, serosal invasion, lymph node metastases, and significantly fewer complete resections (R0) on univariate analysis.

Murakami et al[39]also reported data of 937 patients who underwent pancreaticoduodenectomy [435 (46.4%) had PV/SMV resection] from seven Japanese hospitals between 2001 and 2012 showed that patients who underwent PV/SMV resection had more advanced tumors with 71.5% having lymph node-positive disease. Similar observations were made by a recent multicenter French study.[31]Moreover, invasion of the PV by PDAC has also been found to be one of the risk factors for liver metastasis.[40,41]

Interestingly, aggressive tumor biology (like lymph node metastasis, high histologic grade, perineural invasion, higher pT stage, pancreatic invasion, and positive surgical margin) and inferior survival rates have even been found in patients with pathological PV invasion who had undergone pancreaticoduodenectomy with venous resection for distal cholangiocarcinoma. Miura et al[42]analyzed their data of 129 patients with distal cholangiocarcinoma (8 underwent venous resection) and reported that pancreatic invasion, pT, and pN were more advanced in the patients with PV invasion than in those without. Further, 3- and 5-year survival rates of patients with PV invasion were significantly poorer than those without: 17% and 0% vs 50% and 39%, respectively (P＜0.001). The authors however discuss the caveat that there is an anatomical difference between PDAC and distal cholangiocarcinoma and hence the two are not strictly comparable.

Venous invasion by PDAC, a harbinger of poor prognosis

Debate still surrounds the question if pathologic venous invasion by PDAC is related to poor overall survival after resection. Several reports[7,8,43]have published data showing equivalent survival between patients undergoing concomitant pancreaticoduodenectomy with venous resection with or without pathological SMV/PV invasion. Jeong et al[43]from Korea observed no significant difference in overall survival between patients with and without pathologic PV/SMV invasion (median 13 versus 16 months; P=0.663). Pathologic PV/SMV invasion was observed in only 30 (65.2%). The authors concluded that the prognosis of patients with pathologic PV/SMV invasion is not inferior to those without venous invasion and PV/SMV resection with reconstruction should be considered in PDAC with suspected PV-SMV invasion. Some studies, as discussed in the preceding paragraphs, report differences in survival with the depth of vein wall invasion by PDAC. It has been observed that venous invasion is usually associated with an increased chance of R1 resection and this could confound survival analysis when such group of patients is compared with those undergoing a R0 resection.

Okabayashi et al[7]retrospectively studied 160 patients with PDAC who underwent resection at their center between March 2005 and December 2012. Ninetyeight (61.3%) patients were pathologically negative for portosplenomesenteric venous invasion (PV-negative group) and 62 (38.7%) were positive (PV-positive group) after histopathological examination. The median overall survival was significantly longer in the PV-negative group compared with PV-positive group (48.0 vs 18.0 months, respectively; P＜0.001). The incidence of postoperative peritoneal dissemination was significantly higher in PV-positive group (P=0.033). Moreover, patients in

PV-negative group showed a significantly lower cumulative rate of pancreatic cancer recurrence in 2 years after pancreatic surgery versus PV-positive group (54.4% vs 89.4%, respectively; P＜0.001). Subgroup analyses of survival of patients in PV-positive group revealed a median overall survival of 18.0 months after pathologically complete resection for PDAC and 17.0 months after incurable surgical treatment (P=0.265). These results assume clinical significance as it suggests an ominous prognosis for patients with PDAC involving the portosplenomesenteric venous system even if the tumor is completely removed pathologically.

Another study[8]involving 225 stage II PDAC patients treated with neoadjuvant therapy and pancreaticoduodenectomy reported histopathologic tumor involvement of the SMV/PV as an independent predictor of both disease-free survival and overall survival on multivariate analysis. Notably, SMV/PV resection was performed in 85 patients and histologic tumor involvement of the resected SMV/PV was identified in 57 patients. Patients with histologic tumor involvement of the resected SMV/ PV had a significantly shorter disease-free survival and overall survival (9.2 and 27.6 months, respectively) compared to those without histologic tumor involvement of the resected SMV/PV including those who underwent pancreaticoduodenectomy alone (15.9 and 35.7 months, respectively; P=0.0001).[8]Han et al[35]also analyzed their data of patients who underwent margin-negative pancreaticoduodenectomy with SMV/PV resection for PDAC and found that those with histologically true invasion of the SMV/PV had poorer survival than those without (median 14 vs 9 months; P＜0.05).

One of the single largest retrospective studies was recently published by Lapshyn et al[44]wherein the authors tried to assess the prognostic factors after en-bloc portal venous resection with pancreaticoduodenectomy for PDAC with long-term follow-up. Review of records of 86 patients that underwent en-bloc portal venous resection with pancreaticoduodenectomy for PDAC from 2001 to 2012 revealed that histopathological portal venous invasion was seen in 39 resection specimens and adhesion without infiltration in 47. Baseline demographic and standard histopathological parameters were comparable between patients with or without portal venous invasion; although, venous invasion was associated with microscopic hemangiosis (P=0.001) and positive margin (R1) status (46% vs 15%, P=0.001). Of 25 patients with margin-positive resections (R1), 11 had positive margin at the portal vein segment, all of who had histopathological portal vein invasion (P＜0.001 for association). Median survival was significantly inferior (P=0.042) in patients with portal venous invasion compared to those without (14 vs 25 months, respectively). Portal venous invasion and lymph node ratio were independent predictors of survival after resection.

Conclusions

The data from high-volume centers seem to suggest that SMV/PV resection and reconstruction is certainly feasible with acceptable and comparable short-term outcomes in terms of operative morbidity and mortality. Studies specifically looking in to the pathological ‘true’invasion of the SMV/PV are scarce and those available report survival data on a low number of patients. Frank invasion of SMV/PV and R1 resection indicate a very poor survival. Such patients may be given the opportunity of benefit of neoadjuvant treatment. Clearly effort should be directed to develop imaging tools and to identify biomarkers that enable categorizing patients with poor prognosis preoperatively. High-volume experienced surgeons may undertake vascular resections in PDAC if R0 resection can be obtained.

Contributors: TM proposed the study, collected and analyzed the data, and wrote the article.

Funding: None.

Ethical approval: Not needed.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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Received July 16, 2016

Accepted after revision October 7, 2016

Author Affiliations: Hepato Pancreatico Biliary and Gastrointestinal Division, Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi - 221005 U.P., India (Tewari M)

Mallika Tewari, MS, MRCSEd, M.Ch. (Surgical Oncology), Hepato Pancreatico Biliary and Gastrointestinal Division, Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi - 221005 U.P., India (Tel: +91-9415600250; Fax: +91-542-2367568; Email: drmtewari@gmail.com)

? 2016, Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872(16)60156-X

Published online November 8, 2016.