Topic Highlight Open Access
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 28, 2016; 22(28): 6424-6433
Published online Jul 28, 2016. doi: 10.3748/wjg.v22.i28.6424
Re-evaluation of classical prognostic factors in resectable ductal adenocarcinoma of the pancreas
Daniel Åkerberg, Daniel Ansari, Roland Andersson, Department of Surgery, Clinical Sciences Lund, Lund University, and Skåne University Hospital, SE-221 85 Lund, Sweden
Author contributions: Åkerberg D and Ansari D conducted the literature search and drafted the manuscript; Andersson R conceived the study; all authors were involved in manuscript writing and read and approved the final manuscript.
Conflict-of-interest statement: No potential conflicts of interest. No financial support.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Roland Andersson, MD, PhD, Department of Surgery, Clinical Sciences Lund, Lund University, and Skåne University Hospital, SE-221 85 Lund, Sweden. roland.andersson@med.lu.se
Telephone: +46-46-172359
Received: March 24, 2016
Peer-review started: March 25, 2016
First decision: May 12, 2016
Revised: May 24, 2016
Accepted: June 15, 2016
Article in press: June 15, 2016
Published online: July 28, 2016

Abstract

Pancreatic ductal adenocarcinoma carries a poor prognosis with annual deaths almost matching the reported incidence rates. Surgical resection offers the only potential cure. Yet, even among patients that undergo tumor resection, recurrence rates are high and long-term survival is scarce. Various tumor-related factors have been identified as predictors of survival after potentially curative resection. These factors include tumor size, lymph node disease, tumor grade, vascular invasion, perineural invasion and surgical resection margin. This article will re-evaluate the importance of these factors based on recent publications on the topic, with potential implications for treatment and outcome in patients with pancreatic cancer.

Key Words: Pancreatic cancer, Survival, Prognostic factors

Core tip: Many studies have investigated morphological indicators of survival in patients with resectable pancreatic cancer. This article scrutinizes the recent literature related to these classical prognostic factors and examines whether these factors still are able to influence patients’ outcomes in the era of multimodal treatment.



INTRODUCTION

Pancreatic cancer has a devastatingly poor prognosis. The overall survival remains unchanged over a wide period of time with at a 5-year survival of 5%-10%[1]. Furthermore, according to recent data, the incidence of pancreatic cancer is increasing[2-4]. Pancreatic ductal adenocarcinoma constitutes the most common histopathological subtype of pancreatic cancer originating from the ductal cells of the exocrine pancreas. Surgery remains the only cure for pancreatic cancer, but long-term survival is uncommon despite the addition of oncological treatments.

Over the years, several important prognostic factors for resectable pancreatic cancer have been identified. Among these prognostic factors are tumor size, presence or absence of lymph node metastases (loco-regional and/or distant), vascular tumor involvement (e.g., portal vein, mesenteric vein and/or artery), perineural tumor growth and resection margin status (from tumor to resection line)[5-9].

Many studies have been conducted to elucidate the relative importance of these prognostic factors in terms of recurrence-free survival and long-term cure. Despite this information, limited progress has been made regarding survival aspects. Pancreatic surgery is associated with high morbidity and potentially also immune suppression. Therefore, it is of vital importance to accurately determine which patients that really derive benefit from surgery in order to avoid unnecessary surgical intervention, as well as facilitate treatment planning and guide neo- and adjuvant treatments. The aim of this review was to re-investigate classical morphological prognostic factors in resectable pancreatic cancer by summarizing the recent literature on the topic published since the year 2000.

TUMOR SIZE

Tumor size is a morphological variable that can be determined preoperatively and as such as carries much important information for treatment planning. Being part of the current TNM staging system of pancreatic cancer, tumor size is the only discriminant between T1 and T2 tumors (cut-off 2 cm). However, the size at which point a pancreatic tumor becomes associated with aggressive features remains undetermined. This is why most studies that have evaluated the effects of tumor size on survival have not used uniform definitions (Table 1). In general, larger tumors > 2-3 cm have worse prognosis compared to smaller tumors. Tumor size has also been linked to other adverse prognostic factors. For example, tumors with a diameter above 2 cm have been found to have an increased risk of lymph node metastases[10].

Table 1 Tumor size and survival for resectable pancreatic cancer.
Ref.YearnTumor size, cut-offMedian OSStatistical modelHR (95%CI)P value
Matsumoto et al[38]2015968≥ 3 cmNRMultivariable1.72 (1.16-2.56)0.006
Jeong et al[39]2015276 ≤ 2.5 cm13 moMultivariable1.65 (1.17–2.32)0.004
> 2.5 cm25 mo
Hur et al[17]201518338In situ120 moMultivariable1
≤ 1.0 cm27 mo3.09 (2.35-4.07)< 0.001
1.1-2.0 cm17 mo4.35 (3.42-5.53)< 0.001
> 2.0 cm11 mo5.69 (4.49-7.21)< 0.001
Yamamoto et al[40]2015195 ≤ 2 cm29 mo (mean)Multivariable0.40 (0.17-0.83)0.012
Elberm et al[41]20151070< 2 cm19 moMultivariable0.63 (0.50-0.78)< 0.001
Liu et al[31]2015411> 2 cmNRUnivariable1.46 (1.14-1.88)0.003
Okada et al[42]2014200≥ 3 cmNRMultivariable3.26 (1.52–7.00)0.002
Dusch et al[21]2014415< 3 cm16 moUnivariable-< 0.03
Shin et al[15]2014537 ≤ 3 cm22 moMultivariable1.4 (1.13-1.73)0.002
> 3 cm14 mo
Kooby et al[37]20141399Continuous20 moMultivariable1.12 (1.06-1.18)< 0.001
Petermann et al[10]2013114 ≤ 2 cm35 moMultivariable0.52 (0.25–1.05)0.071
2.1–3.4 cm16 mo
3.5–4.5 cm20 mo
> 4.5 cm8 mo
Jamieson et al[43]2013217 ≤ 3 cm23 moMultivariable1.28 (0.93–1.76)0.13
> 3 cm16 mo
Franko et al[14]20137135 ≤ 1 cmN0/N1: 38/18 moMultivariable1
1.1–2 cmN0/N1: 26/19 mo1.18 (0.94-1.48)0.152
> 2 cmN0/N1: 19/14 mo1.67 (1.34-2.07)< 0.001
Lad et al[44]2013382Continuous16 moMultivariable1.23 (1.07–1.41)0.003
Sugiura et al[45]2013208≥ 3 cmNRUnivariableNR0.014
Hong et al[18]2012209< 3 cm20 moUnivariableNR0.06
≥ 3 cm15 mo
Bhatti et al[46]201084 ≤ 2 cm34 moUnivariableNR0.017
> 2 cm, invasion-27 mo
> 2 cm, invasion+11 mo
Yamada et al[47]2009335> 4 cmNRMultivariable2.69 (1.30-5.56)< 0.05
Ueda et al[48]2009140< 3 cm22 moMultivariable1.85 (1.14-3.10)0.013
≥ 3 cm11 mo
Kaneoka et al[49]200984< 2 cmNRMultivariable1
2–4 cm20 mo1.7 (1.0–3.1)0.031
> 4 cm11 mo2.3 (1.3–4.5)0.003
Campbell et al[50]2009163Continuous14 moMultivariable1.02 (1.00-1.03)0.049
Doi et al[51]2007133 ≤ 4 cm45% dead within 1 yrUnivariable1.55 (1.06–2.24)0.02
> 4 cm67% dead within 1 yr
Zacharias et al[52]200781 ≤ 3 cm28 moMultivariable1.9 (1.1–3.1)0.018
> 3 cm14 mo
Pawlik et al[6]2007905≥ 2 cm17 moMultivariable1.24 (1.01-0.51)0.04
Moon et al[53]200694< 3 cm25 moMultivariable0.46 (0.27-0.78)0.004
Cleary et al[20]2004123Continuous14 moUnivariable1.2 (1.0–1.4)0.01
Ahmad et al[54]2001125< 2 cm16 moUnivariable1
2-4 cm1.05 (0.58-1.89)0.87
> 4 cm1.15 (0.61-2.15)0.66
Sohn et al[55]2000616< 3 cm21 moMultivariable0.72 (0.57-0.90)0.004
≥ 3 cm14 mo
Meyer et al[56]2000113 ≤ 2 cm28 moMultivariable2.27< 0.006
> 2 cm13 mo

Tumor size may also affect the rates of margin positivity following pancreatic surgery. It has been found that larger tumors increase the risk of tumor deposits being harbored in the resection line[11]. Larger tumors generally have a greater malignant potential, increasing the risk of tumor involvement of peripancreatic structures[12,13].

However, although most studies indicate impaired survival for larger tumors, a small tumor diameter does not exclude poor prognosis[14,15]. Interestingly, it has been found that tumors with a diameter less than 1 cm may also be associated with malignant potential and rapid disease progression[16,17]. Histopathological data obtained from analysis of “early” pancreatic cancer show that small tumor may display the same microvascular invasiveness pattern (i.e., a poor prognostic factor) as larger tumors[18,19].

This, somewhat, unclear relationship between tumor size and prognosis may reflect different tumor biology and invasiveness, independent of tumor size[20], regulating outcome.

LYMPH NODE STATUS

Dissemination into the lymphatic system is a major route for pancreatic cancer metastasis. Lymph node status has been demonstrated to be one of the most potent predictors of survival. Several recent studies (Table 2) have proposed that the ratio of metastatic to examined lymph nodes (LNR) may be more powerful predictors of survival than the mere dichotomization into positive or negative lymph nodes. LNR also seems to have negative impact on the long-term survival (≥ 60 mo)[21]. Poor prognosis has been observed with an LNR over 0.3-0.4.

Table 2 Prognostic relevance of lymph node ratio.
Ref.YearnCut-offDetection rate (%)Median OS with highest LNR (mo)Survival modelHR (95%CI)P value
Fouquet et al[34]20141660.276 (46)NRMultivariable2.38 (1.4-4.0)0.001
Dusch et al[21]2014415Continuous0.10 (0-0.81)1NRMultivariable1.73 (NR)0.002
Valsangkar et al[57]2013149070.34038 (27)NRMultivariable2.27 (1.67-3.08)< 0.001
Lewis et al[58]20134240.383 (20)16Multivariable1.97 (NR)< 0.001
Robinson et al[59]20121310.1570 (53)NRMultivariable4.14 (NR)< 0.010
La Torre et al[60]20111010.230 (30)13Multivariable4.88 (1.07-22.2)0.008
Bhatti et al[46]2010840.326 (31)6Multivariable2.7 (1.6–4.4)0.010
Riediger et al[61]20091820.332 (18)NRMultivariable2.2 (1.4-3.6)< 0.001
Slidell et al[22]200838680.4602 (16)10Multivariable1.82 (1.59-2.07)< 0.001
Pawlik et al[6]20079050.4154 (17)12Multivariable2.55 (1.75-2.70)0.001

There is a wide time span in terms of median survival between studies evaluating the impact of lymph node status on survival after resection for pancreatic cancer. Patients with N0 tumors displayed a superior median survival of up to 40 mo and patients with LNR > 0.3 displayed a median survival of 6 mo at the lowest. The wide range in median survival may reflect different biology in those tumors that spread to lymph nodes and those that do not. It may also be speculated that there is a biological difference in the tumor invasiveness both regarding loco-regional and distant lymph node metastases. In general, lymph node metastases can be correlated to increasing tumor size but not in all of the cases.

It is recommended to sample at least 12 lymph nodes for histopathological diagnosis and staging[22]. Standard lymphadenectomy for pancreatic head tumors include resection of lymph node stations 5, 6, 8a, 12b1, 12b2, 12c, 13a, 13b, 14a, 14b, 17a and 17b, while tumors of the body and tail of the pancreas require removal of stations 10, 11, and 18. Extended lymphadenectomy during Whipple’s procedure include resection of lymph nodes along the left side of the superior mesenteric artery and around the celiac trunk, splenic artery or left gastric artery. There is no convincing evidence that extensive lymph node resection in conjunction to pancreatic surgery increases the overall survival and is therefore not recommended[23].

Lymph node status may also be defined based on the location of the lymph nodes involved. Several studies describe lymph node involvement as N1 (metastases in loco-regional lymph nodes) or N2-3 (metastases in distant lymph nodes). A few studies evaluated para-aortic lymph denoted as N3. There is a clear survival difference between local or distant lymph nodes metastases (e.g., para-aortic lymph node metastases). Most studies, but not all, report that para-aortic lymph node involvement is associated with a poor prognosis, being an independent factor of adverse outcome (Table 3). Frozen-section examination of para-aortic nodes accurately detects distant lymphatic involvement reliably and should be routinely performed[24]. The presence of metastases is considered a contraindication to proceed with pancreatic resection.

Table 3 Para-aortic lymph node involvement and survival.
Ref.YearnDetection rate (%)Median OS with PALN (mo)Survival modelHR (95%CI)P value
Sho et al[62]2015882102 (12)17Multivariable1.15 (0.87-1.50)0.335
Schwarz et al[24]201411117 (15)16UnivariableNR0.038
Kanda et al[63]201142949 (11)8UnivariableNR0.006
Murakami et al[64]201010318 (17)12Multivariable1.84 (0.28-1.07)0.078
Doi et al[51]200713319 (14)5Multivariable2.90 (1.60-5.02)0.001
Shimada et al[65]200613329 (22)13UnivariableNR< 0.001
TUMOR GRADE

The WHO classification of tumor grade in pancreatic cancer is based on the original proposal of Klöppel et al[25] and takes into consideration mucin production, glandular differentiation, mitotic activity and nuclear atypia. Several studies have shown that tumor grade is an important prognostic indicator after resection of pancreatic cancer[26-28]. Wasif et al[29] analyzed 8082 patients with resected pancreatic cancer. This study found that high tumor grade had a larger impact on survival than both tumor size and lymph node metastases, both of which are part of the current TNM staging system. This observation lead the authors to conclude that the inclusion of tumor grade into the TNM staging for pancreatic cancer would improve prognostic stratification and better reflect the aggressive prognosis of poorly differentiated tumors.

VASCULAR INVASION AND PORTO-MESENTERIC VEIN RESECTION

Pancreatic tumors may occlude peripancreatic vascular structures, either partly or totally, and in the latter case are categorized as unresectable. The extent of vessel wall involvement, i.e., involvement of tunica adventitia, media or intima, has been correlated with outcome[30]. Invasion of major retroperitoneal blood vessels has been found to be an independent predictor of poor survival[11,30,31]. Vascular resections should be performed if it is possible to obtain R0 resections, which is supported by previous histopathological data[32]. In the situation with positive para-aortic lymph nodes, however, venous and arterial tumor involvement may not be a prognostic factor for survival. It has been speculated that para-aortic lymph node involvement might be a stronger prognostic factor than vascular involvement.

Portal vein and superior mesenteric vein invasion often occurs due to the anatomic location of the tumor. Venous invasion was for a long time considered a contraindication to surgery. Today, vascular resection has become more common. Most studies indicate that vascular resection has similar survival rates as standard resection (Table 4), but it should be performed in carefully selected cases, given the slightly increased perioperative mortality rate and some reports that indicate worse survival, likely due to more advanced disease. Arterial resection during pancreatic resection is associated with poor short- and long-term outcome and is not recommended outside of clinical trials[33].

Table 4 Porto-mesenteric vein resection and survival.
Ref.YearnVR rate (%)Median OS without VR/with VR (mo)Survival modelHR (95%CI)P value
Jeong et al[39]201527646 (17)16/12Multivariable1.15 (0.78–1.71)0.474
Murakami et al[66]2015937435 (46)26/19Multivariable1.16 (0.89-1.53)0.268
Wang et al[67]201412264 (53)31/18MultivariableNRNS
Kelly et al[68]201349270 (14)19/12Multivariable1.14 (0.83-1.57)0.410
Gong et al[69]2013566119 (21)20/13UnivariableNR< 0.050
Castleberry et al[70]20123582281 (8)Increased 30-d postoperative mortality, 2.9% vs 5.7%Multivariable2.1 (1.22-3.73)0.008
Chakravarty et al[71]20108712 (14)10/9MultivariableNR0.591
Ouaissi et al[72]201014959 (40)19/18MultivariableDFS: 0.43 (0.22-0.82)0.011
Kaneoka et al[49]20098442 (50)26/12MultivariableNRNS
Kurosaki et al[73]20087735 (45)20/20UnivariableNR0.330
Fukuda et al[30]200712137 (31)NRUnivariableNR0.550
Carrère et al[74]200613345 (34)19/15UnivariableNR0.690
Shimada et al[75]200614986 (58)35/14Multivariable2.25 (1.09–3.62)NR
Tseng et al[76]2004291110 (38)27/23Multivariable1.13 (0.79-1.63)0.500
Poon et al[77]20045012 (24)21/20UnivariableNR0.769
Nakagohri et al[78]20038133 (41)10/15UnivariableNRNS
Bachellier et al[79]20018731 (36)12/12UnivariableNR0.480
PERINEURAL INVASION

Perineural invasion (PNI) is a common way of pancreatic tumor growth. Several studies have revealed that PNI in specimens from patients who underwent surgical resection was associated with worse survival (Table 5). Data also indicate that perineural involvement is a predictor for early cancer recurrence[34]. The lack of perineural involvement may be a good prognostic marker of disease free survival[35]. However, various criteria for the diagnosis of PNI have been used, and the frequency of PNI in pancreatic cancer varies widely among the previous reports, between 30%-96%. According to a recent study the severity of PNI can be correlated with survival[36]. This study demonstrated that the number of PNIs was a potent predictor of survival in patients with resectable pancreatic cancer.

Table 5 Prognostic role of perineural invasion.
Ref.YearnDetection rate (%)Median OS with PNI (mo)Survival modelHR (95%CI)P value
Kondo et al[36]2015209197 (94)15MultivariableNo of PNIs:< 0.001
< 14: 1
14-40: 1.96 (1.01-3.93)
> 40: 5.81 (3.17-11.35)
Fouquet et al[34]2014166133 (81)NRMultivariable2.77 (1.40-5.26)0.001
Chatterjee et al[80]2012212123 (58)29Multivariable1.70 (1.18-2.45)0.005
Takahashi et al[81]201211056 (51)NRMultivariable2.48 (1.11-5.52)0.026
Sahin et al[82]2012544473 (87)29Multivariable1.60 (1.08-2.36)0.019
Robinson et al[59]2012134128 (96)NRMultivariable5.52 (NR)< 0.050
Kanda et al[63]2011429148 (34)NRMultivariable1.72 (1.15-2.58)< 0.001
Shimada et al[35]2011153146 (94)7 (DFS)Multivariable2.19 (1.36-3.52)0.001
Murakami et al[64]201010331 (30)NRMultivariable1.93 (1.03–3.62)0.041
Kazanjan et al[83]2008182112 (62)20Multivariable2.66 (1.74-4.06)< 0.001
RESECTION MARGINS

The R classification for pancreatic cancer entails estimation of the radicality of resection. R0 denotes complete microscopic tumor removal. R1 indicates microscopic residual tumor, while R2 indicates macroscopic residual tumor. The influence of margin status on outcomes in pancreatic cancer remains controversial (Table 6). This is largely due to lack of standardization of margin definitions and reporting. Most studies show a worsened prognosis of R1 compared to R0 resection.

Table 6 Radicality of resection and survival.
Ref.YearnR1 definitionR1 rate (%)Median OSSurvival modelHR (95% CI)P value
R0/R1 (mo)
Kooby et al[37]201413991 mmR0 (86)21Multivariable10.009
R1→R0 (5)121.55 (1.11-2.16)0.004
R1 (9)141.46 (1.13-1.90)
Konstantinidis et al[84]20135541 mm157 (28)35/14UnivariableNR< 0.001
Kimbrough et al[85]20132830 mm76 (27)22/15MultivariableNRNS
Gnerlich et al[86]20122851 mm97 (34)22/16UnivariableNR0.010
Jamieson et al[11]20101481 mm110 (74)27/15Multivariable1.76 (1.15–2.28)0.009
Van den Broeck et al[87]20091441 mm48 (33)24/12UnivariableNR< 0.001
Chang et al[88]20093650 mm131 (36)20/13Multivariable1.48 (1.15–1.89)0.002
Campbell et al[50]20091631 mm128 (79)25/13Multivariable1.44 (0.90-2.32)0.132
Westgaard et al[89]2008401 mm18 (45)16/11UnivariableNR0.300
Esposito et al[90]20081111 mm84 (76)NRUnivariableNR0.370
Raut et al[91]20073600 mm61 (17)28/22MultivariableNRNS
Verbeke et al[92]2006261 mm22 (85)37/11MultivariableNR0.790
Howard et al[93]20062260 mm68 (30)NRMultivariable1.39 (1.02-1.90)0.030

The poor prognosis in R1 resections is underscored by the observation that once tumor cell deposits have reached beyond the resected pancreatic surface area, it is difficult to improve survival by trying to convert R1 to R0 resections. Data show that the overall survival of turning R1 to R0 resections is still not convincingly high and once a positive intraoperative resection margin is discovered on frozen section it is doubtful whether the conversion to R0 resection is a “true R0” since the overall survival is not changed[37].

The definition of margin clearance is still under debate. However, nowadays most studies now use a margin clearance over 1 mm to define R1 resection.

CONCLUSION

Despite technical advances in the field of pancreatic surgery, the long-term prognosis of pancreatic cancer still remains dismal. This article updates the role of established prognostic factors after curatively intended surgery for pancreatic cancer.

Tumor size is a prognostic factor, with survival decreasing in parallel to increased tumor size. However, small tumors (< 2 cm) may still metastasize and be associated with a poor outcome.

Lymph node involvement is associated with poor survival. A LNR of > 0.3 is a strong prognostic determinant. Para-aortic node sampling with frozen-section examination detects distant lymphatic involvement reliably and should be performed routinely. Metastatic deposits in para-aortic lymph nodes indicate distant disease, and should be considered a contraindication for surgical resection.

Tumor grade may be as powerful a prognostic factor as tumor size and lymph node status.

Invasion of major retroperitoneal blood vessels predicts poor outcome. The extent of vessel wall involvement is correlated with survival. Patients undergoing portal vein resection for pancreatic cancer have a similar long-term prognosis to patients undergoing standard resection.

PNI is present in most pancreatic tumors. The severity of PNI is a novel prognostic factor.

Tumor cells in the resection margin increase the risk of early deaths. A margin clearance over 1 mm should be achieved. However, additional resection to achieve a negative neck margin after positive frozen section is not recommended due to lack of survival advantage.

Footnotes

Manuscript Source: Invited manuscript

Specialty Type: Gastroenterology and Hepatology

Country of Origin: Sweden

Peer-Review Report Classification

Grade A (Excellent): 0

Grade B (Very good): B, B, B

Grade C (Good): 0

Grade D (Fair): 0

Grade E (Poor): 0

P- Reviewer: Kleeff J, Yang F, Zhang ZM S- Editor: Ma YJ L- Editor: A E- Editor: Ma S

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