Author Affiliations: Division of Surgical Oncology, Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami-Miller School of Medicine, Miami, Florida, USA (Elabbasy F, Gadde R, Hanna MM, Sleeman D, Livingstone A and Yakoub D)

Corresponding Author: Danny Yakoub, MD, PhD, Division of Surgical Oncology, University of Miami-Miller School of Medicine, Jackson Memorial Hospital/Sylvester Comprehensive Cancer Center, 1120 NW 14th Street, CRB C232, Miami, Florida 33136, USA (Tel: +305-243-4902; Fax: +305-243-4907; Email: dyakoub@med.miami.edu)

 

© 2015, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(15)60399-X

Published online July 14, 2015.

 

 

Contributors: EF proposed the study. EF and GR performed research and wrote the first draft. EF, GR and HMM collected and analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. YD is the guarantor.

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.

 

 

BACKGROUND: Minimally invasive spleen-preserving distal pancreatectomy (SPDP) can be performed with either splenic vessel preservation (SVP) or resection [Warshaw procedure (WP)]. The aim of this study was to evaluate the postoperative clinical outcomes of patients undergoing both methods.

 

DATA SOURCES: Database search of PubMed, Embase, Scopus, Cochrane, and Google Scholar was performed (2000-2014); key bibliographies were reviewed. Qualified studies comparing patients undergoing SPDP with either SVP or WP, and assessing postoperative complications were included. Calculated pooled risk ratio (RR) with the corresponding 95% confidence interval (CI) by random effects methods were used in the meta-analyses.

 

RESULTS: The search yielded 215 studies, of which only 14 observational studies met our selection criteria. The studies included 943 patients in total; 652 (69%) underwent SVP and 291 (31%) underwent WP. Overall, there was a lower incidence of splenic infarction (RR=0.17; 95% CI: 0.09-0.33; P<0.001), gastric varices (RR=0.16; 95% CI: 0.05-0.51; P=0.002), and intra/postoperative splenectomy (RR=0.20; 95% CI: 0.08-0.49; P<0.001) in the SVP group. There was no difference in incidence of pancreatic fistula (WP vs SVP, 23.6% vs 22.9%; P=0.37), length of hospital stay, operative time or blood loss. There was moderate cross-study heterogeneity.

 

CONCLUSIONS: SVP is a safe, efficient and feasible technique that may be used to preserve the spleen. WP may be more suitable for large tumors close to the splenic hilum or those associated with splenomegaly. Randomized clinical trials are justified to examine the long-term benefits of SVP-SPDP.

 

(Hepatobiliary Pancreat Dis Int 2015;14:346-353)

 

KEY WORDS: splenic infarction; spleen-preserving distal pancreatectomy; splenic vessel preservation; Warshaw procedure; gastric varices

Over the last two decades, minimally invasive pancreatic resections especially in general and distal pancreatectomy, have become increasingly popular owing to the improvements in necessary surgical skills and equipment.^[1-8] Spleen preservation during laparoscopic distal pancreatectomy remains controversial owing to tediousness of techniques needed to do it.^[9-11] In patients with adenocarcinoma of the pancreas, distal pancreatectomy with splenectomy is recommended to assure that an adequate oncologic margins and lymph node clearance has been achieved.^[12-15] However, for patients with benign or low-grade malignant tumors in the body/tail of the pancreas, proponents of this technique argue that conservation of the spleen preserves immune function and eliminates the risk of overwhelming post-splenectomy infection and other complications related to the splenectomy procedure itself.^[16-20] Moreover, some authors reported that splenectomy has a negative influence on long-term survival along with an increased risk of lung and ovarian cancers.^[21-24]

 

Established surgical techniques to preserve the spleen include Warshaw procedure (WP) where the technique described includes ligation of splenic vessels with the preservation of the short gastric and left gastroepiploic vessels.^{[25, 26]} Another method, splenic vessel preservation (SVP), where sparing of the splenic vessels without ligation is performed, with meticulous ligation of small pancreatic branches, also known to some as Kimura procedure; this later technique is thought to provide better blood supply to the retained spleen.^{[27, 28]}

 

In recent years, as opposed to SVP, WP has gained favor of many surgeons, particularly in laparoscopic resections.^{[5, 29-31]} However, concern remains due to the higher incidence of splenic infarction and gastric varices with a theoretical risk of gastrointestinal bleeding during follow-up.^[31-33] The aim of this study was to review the literature with meta-analysis of pooled data to compare short- and long-term outcomes between WP and SVP.

 

 

A comprehensive online search of PubMed, Embase, Scopus, Google Scholar and the Cochrane database was performed for all published articles in the English language evaluating short- and long-term postoperative outcomes following spleen-preserving distal pancreatectomy (SPDP) with or without SVP between 2000 and 2014. The search was conducted using the following MeSH terms: "distal pancreatectomy", "spleen-preserving distal pancreatectomy", "left pancreatic resection", "Warshaw procedure", "Kimura procedure", "splenic vessel preservation", and "splenic vessel resection". The related-articles function was used to expand the search from each relevant study identified. All citations and abstracts identified were thoroughly reviewed. The latest search was performed on November 11, 2014. Bibliographies of retrieved papers were further screened for any additional eligible literature. The primary end-point for comparison was postoperative splenic infarction and gastric varices. Secondary end-points included operative outcomes and other complications as pancreatic fistula and the need for intra-/postoperative splenectomy. When an article reported more than one pancreatic procedure, data relating to SPDP only was included in the analysis.

 

All included studies used a minimally invasive approach for performing SVP and WP, which included: laparoscopic, hand-assisted, robotic assisted laparoscopic or totally robotic techniques. Depending on preoperative imaging or intraoperative circumstances, the surgeon opted for one or the other technique or converted to open procedure.

 

After the pancreas was dissected, the splenic vessels were mobilized with meticulous ligation of the pancreatic branches. Some of the included studies explained that the intention to treat was always SVP, but intraoperatively, decision to change from SVP to WP was taken due to several reasons including, a large sized tumor distorting or compressing the vessels or there was no possibility for dissection of the pancreas from the splenic vessels. Moreover, presence of intraoperative bleeding could lead to this decision.

 

To maintain blood supply to the spleen through the short gastric vessels after division of the greater omentum, care was taken not to divide the splenocolic and gastrosplenic ligament. An initial trial of temporarily clamping the splenic vessels for a couple of minutes while observing for any rapid change in splenic color was pursued. If the spleen remained viable, even with a dark red color, the clamp was then removed and the vessels ligated or transected; splenic vessels were managed apart from the splenic hilum to avoid damage to the splenic pedicle.

 

In order to be included in the analysis, studies had to: (i) Compare the outcome measures mentioned above between patients who had SVP-SPDP and WP-SPDP; (ii) Report on at least one of the outcomes of interest mentioned above. When the same institution reported two studies, we either included the one of better quality (larger sample size, the most recent publication), or both if the studies described different patient cohorts.

Studies were excluded from analysis if: (1) They were either non-comparative studies or case series; (2) The outcomes of interest were not reported for the two techniques; (3) There was significant overlap among authors, centers or patient cohorts evaluated.

 

Two reviewers (Elabbasy F and Gadde R) independently extracted the following data from each study: study characteristics (first author, year of publication, study design), population characteristics (number of patients included, demographics and histological tumor characteristics), and outcomes of interest as operative time, estimated blood loss, length of hospital stay, splenectomy rates, splenic infarction, pancreatic fistula, gastric varices.

 

Quality assessment of included studies was conducted using the 22-item checklist "strengthening the reporting of observational studies in epidemiology" (STROBE).^[34] This scoring system gives a quality score to studies based on various aspects of study design and reporting. The maximum score would be 34.

 

Follow-up included a thorough medical examination, routine blood tests, and a contrast-enhanced computed tomography (CT) scan or a magnetic resonance imaging at 3-month to one year from the index operation, in order to assess the presence of gastric varices and splenic perfusion together with other postoperative complications, if any. For SVP patients, the patency of splenic vessels was seen and followed up with contrast-enhanced CT scan, whereas in WP patients, perigastric collateral vessels were noted to be increasing throughout the follow-up.

 

Preoperative and postoperative CT images were compared in order to evaluate postoperative abdominal changes, splenic perfusion, and whether vessels were native or collaterals that developed after surgery. Splenic infarction was detected in both symptomatic and asymptomatic patients. Varices were defined as tortuous vascular structures larger than 3 or 5 mm in diameter and included submucosal or perigastric varices. Pancreatic fistula was defined as a concentration of drain amylase three to five times greater than the upper limit of normal in serum and a drainage of more than 30 mL at 5 days or longer after surgery and included all the different grades A, B and C (according to ISGPF classification).

 

Due to difficulty in analyzing the data about splenectomy, the meta-analysis collectively included both unplanned intraoperative and subsequent postoperative splenectomies. Intraoperative splenectomy was done in cases where splenic dissection and preservation was not possible or in some cases of intraoperative bleeding or tumor spread to the spleen requiring en-bloc splenectomy. Postoperative splenectomy was done in spleen related complications mainly major symptomatic splenic infarctions.

 

All statistical analyses were performed using STATA 13 (StataCorp LP, College Station, TX, USA) and Microsoft Excel 2013. For all dichotomous variables, we calculated the pooled risk ratio (RR) with the corresponding 95% confidence interval (CI) as the summary statistic. For continuous outcomes, we pooled the data using the weighted mean difference (WMD) with the corresponding 95% CI as the summary statistic; for all data reported as median and range, Hozo's method^[35] was used to estimate the mean and standard deviation. All P values <0.05 (two-tailed) were considered statistically significant. For the meta-analysis, both fixed and random effects models (weighted by the Mantel-Haenszel method)^[36] were used, and random effects model was selected in the presence of clinical or statistical heterogeneity. Clinical heterogeneity between studies was considered when differences were present in operative technique or definition of splenic infarction. Statistical heterogeneity across studies was quantified using the Chi-square test (or Cochran Q statistic) and I² statistic. The I² statistic was derived from the Q statistic ([Q-df/Q]×100), which provides a measure of the proportion of the overall variation attributable to heterogeneity between the studies. Homogeneity was considered absent if the Q statistic showed P<0.20 and the heterogeneity was considered significant when the I² statistic exceeded 50%. Subgroup analyses were relevant.

 

 

Our search yielded 215 publications. We excluded 160 studies at the title and abstract level, selected 55 studies for full-text review. Out of the 55 selected, 41 were excluded based on inclusion and exclusion criteria. Thus, we identified 14 retrospective cohort studies^{[2-5, 24, 31, 33, 37-43]} describing a total of 943 patients who underwent minimally invasive SPDP for inclusion in the meta-analysis (Fig. 1); 652 (69%) patients underwent the SVP and 291 (31%) patients underwent the WP.

 

Overall, most studies were of high quality, with a median STROBE score of 21 [interquartile range (IQR): 17-23]. All 14 studies were deficient in explaining how the study sample size was derived or how the missing patient data was handled; there was little use of a flow diagram to demonstrate study participants or discussion on the generalizability (external validity) of the study results. In all but one study,^[37] key study design elements were presented early in the paper; and except for in one study,^[41] key study results with reference to study objectives were discussed. Lastly, descriptions of eligibility criteria, sources and methods of study participant's selection, and methods of follow-up; explanation on handling of quantitative variables and grouping methods if any; and reasons for non-participation at each stage, were absent in all but four studies.^{[24, 37, 38, 42]}

 

Of the 14 included studies, 10 covered the period of 2010-2014 and 4 the period of 2004-2007 (Table 1). The median age was 50 years (IQR: 47-57) with an average male and female distribution of 26% and 74%, respectively. Pooled average median follow-up time was 29 months with a range of 1-139 months for SVP and 31 months with a range of 1-105 months for WP. There was no significant difference between the two groups regarding age, gender, tumor size, and histopathology (Table 1).

 

All 14 studies (943 patients) reported the postoperative incidence of splenic infarction (Table 2). SVP resulted in a lower incidence of splenic infarction (SVP vs WP, 6% vs 28%)(RR=0.17; 95% CI: 0.09-0.33; P<0.001); there was no significant heterogeneity between the studies (I²=29.3%; P=0.15) (Fig. 2). Overall a total of 120 splenic infarctions were recorded in all 14 studies. Forty-six of these complained of abdominal pain usually generalized but in some cases localized to the left upper quadrant. The remaining patients were asymptomatic and were detected in routine follow-up scans. Of these 46, nine patients' symptoms got worse and required splenectomy for splenic necrosis. The rest of these patients were treated conservatively until they became asymptomatic. Eight of these splenectomies were done in patients who underwent the WP.

 

Information about the incidence of gastric/perigastric varices was available for seven studies^{[5, 31, 38, 40-43]} describing 582 patients. Patients who had undergone the SVP had a decreased risk for postoperative gastric/perigastric varices (SVP vs WP, 2% vs 21%)(RR=0.16; 95% CI: 0.05-0.51; P=0.002) (Fig. 3). There was moderate heterogeneity among the included studies (I²=54.6%; P=0.04); this attributed mainly to one study with a RR=4.80 (95% CI: 0.21-112.18). Table 2 outlines the postoperative outcomes in the included studies.

 

Data regarding the rates of intra/postoperative splenectomy was assessable for all included studies. Overall, the rate of intra/postoperative splenectomy was significantly lower [0.6% (4/652)] with SVP than that with WP [7.9% (23/291)], (RR=0.20; 95% CI: 0.08-0.49; P<0.001) (Fig. 4); there was no heterogeneity among the included studies (I²=0%; P=0.50).

 

Data regarding operative time, estimated blood loss and length of hospital stay were reported in 12, 8, and 11 studies, respectively. Meta-analysis of the available data revealed no association between the two operative groups and operative time (P=0.67), operative blood loss (P=0.56), or length of hospital stay (P=0.84).

 

Nine studies^{[24, 31, 33, 37, 38, 40-43]} describing 649 patients reported on the incidence of postoperative pancreatic fistulas, and only 6 out of these articles used the ISGPF criteria for classification,^{[24, 31, 37, 38, 40, 43]} others were a subjective description of the complication. Fernández-Cruz et al^[33] defined pancreatic leaks as a drain amylase level (measured after the third postoperative day) more than three times the upper limit of the normal serum amylase level in the absence of clinical manifestations while a clinical leak was defined as a biochemical leak in the presence of clinical symptoms. There was no difference between the two procedures in terms of the incidence of postoperative pancreatic fistulae (SVP vs WP, 23% vs 24%)(RR=0.858; 95% CI: 0.614-1.198; P=0.37) (Table 2).

 

 

Minimally invasive distal pancreatectomy for benign and low grade malignancy tumor of the body and tail of the pancreas showed that there was a lower incidence of splenic infarction, less development of postoperative gastric varices, less need for splenectomy with SVP-SPDP as compared with ligation or resection of the splenic vessels during SPDP. There was no difference in operative time, blood loss, length of hospital stay or incidence of pancreatic fistula.

 

Comparative studies^{[23, 44-46]} showed that SPDP carries less risk of postoperative morbidity and development of some complications such as abscesses in the resection bed. This is in addition to other splenic infarction and/or splenectomy drawbacks as the lifetime risk of developing overwhelming post-splenectomy infection^[16-20] as well as a claimed elevated risk of some cancers.^{[21, 23, 24]} A meta-analysis was necessary to attain a sample size large enough to demonstrate statistical significance in this clinically relevant outcome of the surgical approaches. In our analysis, splenectomy was performed for intraoperative bleeding whereas it was done postoperatively mostly for splenic infarction and abscess. Our analysis showed that SVP had less chance of splenectomy than WP, thus preserving more spleens. In spite of the overall small number of clinically significant splenic infarctions, the analysis also showed that it was significantly higher in WP than in SVP. More studies are needed to elaborate the incidence of clinically relevant splenic infarctions in contrast to small non-consequential isolated pole infarctions. The method and timing of follow-up need to be standardized; in the articles reviewed in this meta-analysis, most studies used CT scans for diagnosis of infarction, whereas only one study^[40] assessed the spleen's postoperative function with a hematological screen for Howell-Jolly bodies.

 

Furthermore, in patients with an enlarged spleen who have undergone WP, relying on the collateral circulation for splenic perfusion has its own limitations, as collaterals have been found to be insufficient for maintaining the increased volume from an enlarged spleen. Lastly, the variability in number and size of the short gastric vessels compound matters further, as they can influence the incidence of postoperative splenic infarction.^[47]

 

The WP was classically favored as it is less technically challenging than SVP, as it does not need the tedious dissection of the small pancreatic branches of the splenic artery, which carries a higher risk of bleeding. Jain et al^[48] suggested that WP had significantly less operative time, estimated blood loss and length of hospital stay. Nonetheless, our analysis with more studies included, showed no statistically significant difference in any of these outcomes between the SVP and WP. This may be attributed to the development of more effective surgical techniques/devices as well as the advancement of the learning curve of minimally invasive surgeons. There might have been some surgeon bias (beyond technical skill, learning curve, etc.) about whether to perform a SVP versus WP based on the patient's individual tumor (e.g., location, type, and degree of inflammation). From another standpoint, differential rate of splenectomy is hard to be parsed out in a meta-analysis, therefore it seems harsh to allude that the higher rates of splenectomy observed during the WP makes it a worse technique. In other words, WP may have been simply used more during more technically challenging cases, subsequently leading to higher rates of splenectomy.

 

In the current analysis, SVP had the advantage of a lower incidence of perigastric varices as compared to WP. This may be explained by the increased backward pressure in the short gastric vessels after the ligation of the splenic vessels in WP. Although not common but these varices have the risk of upper gastrointestinal bleeding. Only one of the included studies in this meta-analysis, described one case of gastric varices bleeding, requiring intervention three years after SVP-SPDP.^[40] Larger studies with long-term follow-up are needed to evaluate this outcome more comprehensively. These risks are influenced by a number of factors including varices size, nodularity and location.^{[38, 49-52]}

 

Our analysis also showed that there was no significant difference in incidence of pancreatic fistulas (whenever reported) between both surgical procedures. This comes in agreement with other previously published studies.^[48]

 

In SVP-SPDP, potential advantages from maintaining splenic perfusion should be balanced against the risk of occlusion of the splenic artery and vein and the potential development of left-sided portal hypertension. Yoon et al^[53] reported rates of occlusion of the splenic vein in 77.3% and 50.1% of patients at the end of 1st and 6th month after laparoscopic SVP-SPDP, respectively. However, despite the compromised vessel patency, perfusion was well maintained in most patients. Additionally, early postoperative pancreatic fistula and intra-abdominal collections have been implicated as risk factors for the poor patency of the splenic vessels.^[53] Nonetheless, our analysis (8 studies) showed no difference in the development of postoperative pancreatic fistula between the two procedures, a possible indicator of vessel patency after SVP-SPDP. Lastly, in patients undergoing laparoscopic SVP-SPDP, the development of lateral thermal spread during division of the pancreatic branch vessels may contribute to subsequent stricture and vessel obliteration, which need further studies.^[54]

 

One limitation of our study is that all studies had a retrospective design, a problem commonly faced with surgical interventions in general. Another limitation is that some studies included in our study used an intention-to-treat analysis in contrast to others that caused some difficulty in grouping. Standardized randomized controlled trials need to be conducted to thoroughly compare SVP and WP to examine other contributing variables to the reported outcomes as differences in patient demographics and comorbidities, surgeon's experience and other factors.

 

In conclusion, for benign and low grade malignancy of the body and tail of the pancreas, SVP is a safe, efficient and feasible technique that may be pursued in a trial to preserve the spleen. Nonetheless, WP may be more suitable for large tumors close to the splenic hilum or those associated with splenomegaly. Well conducted randomized clinical trials with multi-institutional collaboration are justified to examine the short and long-term benefits of SVP-SPDP.

 

 

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