Evaluating Pancreatic Factors using Preoperative Computed Tomography to Predict Pancreatic Fistula After Distal Pancreatectomy

DOI: https://doi.org/10.21203/rs.3.rs-1595395/v1

Abstract

Background

A postoperative pancreatic fistula (POPF) is a common and clinically relevant complication following distal pancreatectomy (DP). This study aimed to assess whether pancreatic factors, obtained with preoperative computed tomography (CT), may predict a clinical POPF after DP.

Methods

One hundred and ten patients were retrospectively assessed to determine the association between clinical POPF and clinicopathological data and imaging data from preoperative CT. Evaluations included the thickness of the pancreatic cut-line (TPC), main pancreatic duct (MPD) dilation, and pancreatic index (PI), which was calculated with the pancreas/spleen CT density ratio.

Results

Clinical POPF occurred in 22 (20%) patients. Univariate analysis showed that TPC and extrapancreatic malignancy were significantly associated with clinical POPF after DP; PI and MPD dilation were not. A 15.35-mm cutoff value for TPC was determined according to the receiver operating characteristic (ROC) curve. TPC ≥ 15.4 mm was identified as a significant independent risk factor of clinical POPF in multivariate analyses (odds ratio 28.41; P<0.001). In the subgroup of thick pancreatic cut-line, all four patients with dilated MPD developed clinical POPF; there was no statically significant difference compared with non-dilated MPD.

Conclusions

PI cannot predict the occurrence of clinical POPF after DP, for which TPC is a significant risk factor. When a thick pancreatic cut-line coexists with a dilated MPD, the clinical POPF rate may further increase.

Introduction

Postoperative pancreatic fistula (POPF) remains a clinically relevant and unresolved problem for patients undergoing distal pancreatectomy (DP). Until postoperative day 30, more than a third of patients develop a pancreatic fistula after DP and a quarter of patients develop severe complications.[1] Furthermore, POPF can cause fatal outcomes following hemorrhage or organ failure originating from severe infection (e.g. intra-abdominal abscess).[2]

Several studies have indicated that risk factors of POPF are divided into three categories: the patient’s clinicopathological characteristics,[36] surgical factors,[3, 4, 610] and the individual features of the pancreas.[1115] Among these parameters, surgical techniques are the most commonly reported and relevant. The safest type of closure technique to decrease the occurrence of POPF is still controversial. Three randomized controlled trials (RCTs) have compared the various techniques: hand-sewn vs. stapler,[1] duct-to-mucosa pancreaticogastrostomy vs. hand-sewn[16] and pancreaticojejunostomy vs. stapler.[17] However, none of the RCTs stated which closure technique is most effective in reducing the occurrence of POPF. Although the incidence of POPF has reduced over the past decade with the development of surgical techniques, approximately 20% of patients still develop clinical POPF after DP. Thus, we suspect that the high POPF rate after DP mainly originates from the pancreas itself, not from the type of closure technique. It is important to screen out high-risk patients with POPF based on their pancreatic factors before surgery.

Pancreatic factors such as pancreatic texture, which is a known risk factor of POPF after pancreatoduodenectomy (PD),[18, 19] is subjectively judged by the surgeon via palpation during surgery. Several studies have revealed that a lower pancreas/spleen density ratio (measured using CT scan), representing a soft pancreas, was related to a higher incidence of POPF after PD.[18, 20] Whether pancreatic texture plays as a significant role in POPF after DP compared with after PD remains controversial.[10] Few studies have reported the impact of pancreatic texture on POPF following DP based on preoperative objective evaluation.

In the present study, we aimed to evaluate the pancreatic factors, determined using preoperative CT scan, to predict the risk of developing clinical POPF after DP, and to detect high-risk patients.

Materials And Methods

Patient cohort

One hundred and thirteen patients who underwent DP at the First Affiliated Hospital of Fujian Medical University from January 2011 to January 2018 were retrospectively investigated in this present study. The indications for DP included primary pancreatic mass, invasion by extrapancreatic malignancies, and trauma. Three patients were excluded from this study: two patients who underwent pancreato-jejunostomy anastomosis because of exploration of the pancreatic duct and stone removal, and one patient who died on postoperative day 2 because of postoperative bleeding.

Surgical procedure

All surgeries were performed using a standardized procedure by the same surgical team. The pancreatic cut-line was classified as either “neck/body” (around the portal vein or the celiac axis) or ‘‘tail” (distal to the left of the celiac axis). Two closure techniques for the pancreatic stump were used. The first utilized a hand-sewn stump closure, which is when the pancreatic parenchyma was transected using an ultrasonic dissector and only the main pancreatic duct was cut off using a ten-blade scalpel, followed by ligation of the main pancreatic duct with non-absorbable sutures. After ligation of the main duct, the stump was closed using fish-mouth suturing with a single layer of non-absorbable interrupted sutures.

The second technique utilized stump closure with a stapler, which is when the pancreas was transected using an Echelon 60 stapling device (Ethicon Endo-surgery; Johnson & Johnson, Cincinnati, OH, USA) with either a white [compressible thickness to 1.0 mm] or blue [compressible thickness to 1.5 mm] cartridge. The pancreas was compressed directly with the Echelon. After the first compression, the pancreas was kept compressed for another 3 min, after which the stapler was fired. After firing, the pancreas was kept compressed for a further 2 min.[21] Prophylactic octreotide (0.1 mg subcutaneously thrice a day) was used in all patients after surgery until the third postoperative day. If POPF occurs, octreotide can be administered until recovery.

Clinical data collection and Imaging data from pre- and postoperative CT

To investigate the risk factors of POPF, we collected each patient’s clinicopathological characteristics, surgical features, and pancreatic features from our database of individual patient medical records. CT studies were performed with a Toshiba Aquilion one 320-detector row CT scanner (Toshiba Medical Systems, Otawara, Japan). Multiphasic CT scan was conducted before surgery as a routine preoperative assessment for the possibility of operative excision and for determining the surgical course. Based on the imaging data, we collected and calculated three pancreatic factors: the thickness of the pancreatic cut-line (TPC), pancreatic index (PI), and whether the main pancreatic duct (MPD) was dilated. The cut-line was estimated based on the comparison between pre- and postoperative MDCT images (Fig. 1a; Fig. 1b). The TPC was defined as the anterior-posterior diameter of the pancreas as measured on axial images of preoperative MDCT (Fig. 1a), The pancreatic parenchymal phase of dynamic MDCT was used to measure the pancreatic thickness to discriminate the pancreatic parenchyma from the surrounding tissues and vessels.[12] PI was the ratio between the CT density (Hounsfield unit; HU) of the pancreas (Fig. 1c) over that of the spleen (Fig. 1d) according to a description by Fukuda et al.[22] The spleen was selected as a reference because it does not contain fatty tissue and its CT density is not impervious to the body mass index (BMI). The MPD is generally regarded as abnormally dilated if the head is wider than 3 mm and the body or tail is wider than 2 mm.[23] Imaging data were collected and calculated by a single researcher (XQZ) who was blinded to the POPF result.

Definition of clinical POPF and Statistical analysis

A clinical POPF was defined using the 2016 update to the definition provided by the International Study Group (ISGPS) regarding the grading of POPF: a drain output of any measurable volume of fluid with amylase level greater than 3 times the upper institutional normal serum amylase level, associated with a clinically relevant development/condition related directly to the POPF.[2] Pancreatic fistulas were retrospectively graded according to the updated ISGPF grading system. All data were reported as the mean ± SD and/or median. Fisher’s exact test or Pearson χ2 test for categorical data and Mann-Whitney U test or t-test for continuous data were performed as appropriate. A multivariate analysis was carried out using a logistic regression model. The results of multivariate analysis were displayed as an odds ratio (OR) with 95% confidence intervals (CI). Data analyses were performed with the SPSS 24.0 software package (SPSS Inc., Chicago, Ill., USA), and P values below 0.05 were considered to be statistically significant. The optimal cutoff value of TPC was determined by performing receiver operating characteristic (ROC) curve analysis.

Results

Patient Characteristics

From January 2011 to January 2018, 110 patients underwent DP. Demographic and clinical characteristics of the patient population are summarized in Table 1. There were more females (N = 77; 60.9%) than males (N = 43; 39.1%). The mean patient age was 50 years (range 16–76 years). Diabetes mellitus was found in 19 (17.3%), while a history of acute pancreatitis was found in 6 (5.5%) patients. According to imaging data, the mean TPC was 14.4 mm (range 9.0–24.0 mm), the mean PI was 0.92 (range 0.43–1.47); a dilated MPD was found in 13 (11.8%) patients. Seventy (63.6%) patients underwent a laparoscopic procedure and 51 (46.4%) underwent DP with splenectomy. Additional organs (including the colon, kidney, liver, adrenal gland, and stomach) were resected in 29 (26.4%) patients. In 31.0% (N = 9) of the additional organs resected, two or more organs were affected. A stapler was utilized in 83 (75.5%) of the cases. The final pathology of resected specimens is summarized in Table 2. The most common pathologies were pancreatic adenocarcinoma (N = 26; 23.6%), mucinous cystadenoma (N = 15; 13.6%) and serous cystadenoma (N = 15; 13.6%). The overall complication rate was 45.5%, clinical POPF developed in 22 patients (20%), and two patients developed grade C pancreatic fistula with abdominal abscess and required re-operation necrosectomy.

Table 1

Patients’ demographics and clinical characteristics

Demographic and clinical characteristics (total = 110 patients)

Mean age (range)

50yrs(16-76yrs)

Gender (male)

43(39.1%)

Mean BMI (range)

21.9(16.4–27.4)

Diabetes mellitus

19(17.3%)

History of acute pancreatitis

6(5.5%)

Dilated MPD

13(11.8%)

Mean thickness of pancreatic cut-line(range)

14.6mm(9.0-24.0mm)

Mean PI (range)

0.92(0.43–1.47)

Laparoscopic procedure

70(63.6%)

Splenectomy

51(46.4%)

Additional organs resected

29(26.4%)

Stomach

11(10%)

Gallbladder

8(7.3%)

Colon

7(6.4%)

Adrenal

4(3.6%)

Hepatic lesion

7(6.4%)

Kidney

1(0.9%)

Small intestine

2(1.8%)

Pancreatic stump closure

 

Hand-sewn

27(24.5%)

Staple

83(75.5%)

Mean operative time (range)

172min(60-400min)

Mean blood loss(range)

289ml(30-1800ml)

Mean postoperative hospital stay(range)

13.5days(5-61days)

Clinical POPF

22(20%)

Grade B

20(18.2%)

Grade C

2(1.8%)

BMI body mass index, PI pancreatic index, POPF postoperative pancreatic fistula, MPD main pancreatic duct


Table 2

Final pathology of resected specimens

Pathology

No. of patients (%)

Pancreatic benign

70(63.6)

Mucinous cystadenoma

15(13.6)

Serous cystadenoma

15(13.6)

Neuroendocrine tumor

13(11.8)

Solid pseudopapillary neoplasm

13(11.8)

Pancreatic pseudocyst

8(7.3)

Trauma

2(1.8)

Microcystic adenoma

1(0.9)

Pancreatic tuberculosis

1(0.9)

Calcified nodule

1(0.9)

Accessory spleen

1(0.9)

Pancreatic malignancy

29(26.4)

Ductal adenocarcinoma

26(23.6)

Gelatinous carcinoma

1(0.9)

Mixedadenoendocrinecarcinoma

1(0.9)

Solid pseudopapillary carcinoma

1(0.9)

Extrapancreatic malignancy

11(10)

Gastric cancer

6(5.5)

Splenic lymphoma

2(1.8)

Retroperitoneal sarcoma

2(1.8)

Ovarian metastatic tumor

1(0.9)

 

Comparing the groups with or without clinical POPF

According to the occurrence of clinical POPF, all patients were divided into two groups. Univariate analyses between the two groups (clinical PF vs. non-clinical PF) revealed two significant differences: TPC (18.1 ± 2.8 vs. 13.7 ± 2.5 mm; P < 0.001) and extrapancreatic malignancy (5/22 vs. 6/88; P = 0.027). PI did not affect clinical POPF rate (0.9 ± 0.2 vs. 0.9 ± 0.2; P = 0.478), nor did the performance of dilated MPD failed (dilated 4/22 vs. no-dilated 9/88; P = 0.303) (Table 3). Patients were divided into two groups (thick ≥ 15.4 mm vs. thin < 15.4 mm) according to receiver operating characteristics (ROC) for TPC to predict clinical POPF, the area under the ROC curve was 0.895 (P < 0.001; Fig. 2). The ROC indicated that a TPC of more than 15.35 mm was the best cut-off value for the prediction of clinical POPF after DP. This cut-off value exhibited a specificity of 77%, sensitivity of 91%, positive predictive value of 50%, and negative predictive value of 97% for clinical POPF development. The multivariate analysis showed that TPC ≥ 15.4 mm (OR, 28.41; 95%CI, 7.10-113.78; P < 0.001) was the only significant independent risk factor for clinical POPF (Table 4). The thick (≥ 15.4 mm) pancreatic cut-line had more possibility to evolve the clinical POPF than the thin (< 15.4 mm) pancreatic cut-line (52.8% vs. 4.1%).

Table 3

Univariate analysis of preoperative risk factors for clinical POPF after DP

 

Clinical POPF

 

No

(N = 88)

Yes

(N = 22)

p value

Age

48.6 ± 17.0

53.9 ± 14.5

0.174

Gender, n(%)

   

0.846

Male

34(79.1)

9(20.9)

 

Female

54(80.6)

13(19.4)

 

BMI(kg/m2)

21.8 ± 2.8

22.5 ± 2.7

0.283

Diabetes mellitus, n(%)

   

0.900

Yes

15(78.9)

4(21.1)

 

No

73(80.2)

18(19.8)

 

History of acute pancreatitis, n(%)

   

0.210

Yes

6(100)

0(0)

 

No

82(78.8)

22(21.2)

 

Dilated MPD, n(%)

   

0.303

Yes

9(69.2)

4(30.8)

 

No

79(81.4)

18(18.6)

 

Thickness of pancreatic cut-line(mm)

13.7 ± 2.5

18.1 ± 2.8

< 0.0001

PI

0.9 ± 0.2

0.9 ± 0.2

0.478

Laparoscopic procedure, n(%)

   

0.324

Yes

58(82.9)

12(17.1)

 

No

30(75.0)

10(25.0)

 

Splenectomy, n(%)

   

0.254

Yes

44(84.6)

8(15.4)

 

No

44(75.9)

14(24.1)

 

Additional organs resected, n(%)

   

0.085

Yes

20(69.0)

9(31.0)

 

No

68(84.0)

13(16.0)

 

Pancreatic stump closure, n(%)

   

0.378

Hand-sewn

20(74.1)

7(25.9)

 

Staple

68(81.9)

15(18.1)

 

Operative time(min)

170.8 ± 62.1

175.7 ± 44.7

0.729

Blood loss(ml)

274.5 ± 300.5

345.5 ± 382.6

0.352

Pathology, n(%)

   

0.027

Pancreatic disease

82(82.8)

17(17.2)

 

Extrapancreatic malignancy

6(54.5)

5(45.5)

 
BMI body mass index, PI pancreatic index, POPF postoperative pancreatic fistula, DP distal pancreatectomy, MPD main pancreatic duct

 

Table 4

Multivariate logistic regression analysis of preoperative risk factors for clinical POPF after DP

Variable

Odds ratio

95%CI

p value

Thickness of pancreatic cut-line ≥ 15.4mm

28.41

(7.10-113.78)

< 0.001

Extrapancreatic malignancy

5.19

(0.87–31.08)

0.071

POPF postoperative pancreatic fistula, DP distal pancreatectomy

 

The relationship between combined pancreatic factors and clinical POPF

Even though PI was not a risk factor of clinical POPF, all patients were divided into two groups (soft ≤ 0.92 vs. hard > 0.92) based on the median PI. Therefore, all patients were split into four groups: thin + soft, thin + hard, thick + soft and thick + hard; their clinical POPF rates were 2.4% (1/40), 6.1% (2/33), 58.8% (10/17) and 47.4% (9/19). PI was unable to affect the clinical POPF whether it was in the thick group (P = 0.525) or in the thin group (P = 0.583).

According to TPC and MPD dilation, all patients were split into four groups: thin + non-dilated, thin + dilated, thick + non-dilated and thick + dilated, their clinical POPF rates were 4.6% (3/65), 0% (0/9), 46.9% (15/32) and 100% (4/4). Among the patients with the thick pancreatic cut-line, the subgroup of dilated MPD tended to develop clinical POPF in comparison with the subgroup of non-dilated MPD, but there was no significant difference (4/4 vs. 15/32, P = 0.106).

Discussion

Although the incidence of POPF has dropped over the past decade with the development of surgical techniques, the clinical POPF rate after DP is still high.[1] Pancreatic factors are considered to be important aspects of POPF after DP. Most studies assessed pancreatic factors by intraoperative subject judgement. Multiphasic CT is essential for the preoperative assessment before DP. Few studies have reported the prediction of POPF development after DP via preoperative CT evaluation of pancreatic factors. The results of the present study revealed that the occurrence of POPF after DP was not affected by any clinicopathological characteristics and surgical features other than pancreatic factors evaluated by CT imaging. Our study demonstrated that TPC was an independent predictor of clinical POPF following DP; however, PI and MPD dilation were not associated with clinical POPF. Furthermore, we found that patients with thick pancreatic cut-line and dilated MPD were more likely to develop a clinical POPF.

The controversy regarding pancreatic stump closure is hotly debated, with three recent RCTs on the topic. [1, 16, 17] None of the RCTs revealed which closure technique showed greater advantage over the other two. Our study found that clinical POPF did not differ between the stapler and hand-sewn closure (15/68 vs. 7/20; P = 0.378) groups. Thus, we suspected that the occurrence of the clinical POPF may not be solely dependent on the proper closure technique, but more on pancreatic factors.

There are three pancreatic factors that can be easily detected before surgery with a CT scan: TPC, pancreatic texture using PI, and MPD dilation. In 2011, Eguchi et al.[11] first showed that the thickness of pancreatic parenchyma in the remnants was an independent risk factor for PF after DP. Subsequently, Okano et al.[12] and Mendoza et al.[13] emphasized the role of pancreatic thickness in POPF after DP. Ecker et al.[4] tried to identify a clinical POPF risk score from 2026 patients following DP, and found that POPF occurrence cannot be reliably predicted, but pancreatic thickness was not included in their clinical POPF risk score. A thicker pancreatic cut-line means a larger-cut area[8] and more transected branches of the pancreatic duct. Thus, it is not surprising that a thicker cut-line is associated with a higher clinical POPF rate. In our study, all four patients with thick pancreatic cut-line and dilated MPD developed clinical POPF. A dilated MPD means that when MPD is obstructed, there is an increase in pressure on the transected branches of the pancreatic duct, which increases the possibility of POPF.[7] Therefore, when a thick pancreatic cut-line occurs along with a dilated MPD, clinical POPF is more likely to develop.

A major limitation of this widely used criterion (pancreatic texture) is intraoperative subjective assessment. It needs to be kept in mind that palpation-based determination is subjective and pancreatic texture was not accrued with palpation in laparoscopic cases. There are some objective preoperative evaluations introduced in published studies: CT,[18, 20, 22] MRI,[24] intraoperative ultrasound elastography,[25] and durometer[26]. Even though there is no research regarding which preoperative evaluation of pancreatic texture is the most accurate, preoperative CT is a reliable, critical, and convenient method. Several studies have revealed that a lower pancreas/spleen density ratio measured with CT scan represents a soft pancreas. [18, 20]

Pancreatic texture has long been considered an important factor in the occurrence and severity of POPF. Multiple studies about PD have identified that soft pancreatic texture poses a significantly higher risk of POPF than does hard pancreatic texture.[18, 19] Pancreatic texture in the upstream gland in a PD depends on the pathologic abnormality and is secondary to the MPD obstruction, while in the vast majority of cases, the abnormal area in DP has been resected so the remnant pancreas is mostly a soft, normal texture. Therefore, it is less probable that pancreatic texture plays the same significant role in PF after DP compared with PD.[10] A recent meta-analysis[14] showed that soft pancreatic texture (OR, 1.80; 95%CI, 1.08–3.02, P = 0.03) increased the risk of POPF in DP. Mendoza et al.[13] reported that although pancreatic texture alone was not a significant risk factor for PF, a soft thick pancreas may increase the likelihood of PF owing to the staplers used in laparoscopic DP. Our study failed to show that pancreatic texture evaluated with PI can affect the clinical POPF rate whether it is a thick or thin pancreatic cut-line. Further studies about combined pancreatic texture and thickness of the cut-line in different closure technique are needed.

Regarding thick pancreatic cut-lines, several studies reported that staple use can increase clinical POPF rate after DP.[12, 27] Kawai et al.[17] reported that pancreaticojejunostomy tended to be associated with a decreased incidence of clinical POPF in patients with a thick pancreas. Currently, no RCT or prospective study has verified which closure is suitable for a thick pancreas. Since staplers are the most commonly used surgical method in DP, determining how to improve staple use in a thick pancreas is very important. Prolonged peri-firing compression[21] can be helpful to reduce pancreatic tears, especially in a thick pancreas. It may be necessary to perform additional procedures to ensure better sealing of the pancreatic remnant when a stapler is used, such as additional running sutures or fibrin glue.

Furthermore, the selection of staple cartridge based on the thickness of pancreatic cut-line has drawn the attention of researchers. In 2013, Sugimoto et al.[8] first introduced a “compression index”, which was defined as the ratio between the height of staple cartridge over the thickness of pancreatic cut-line, and was also a risk factor for POPF. This finding indicated that a thicker pancreas should be transected using a greater height of staple cartridge; however, there is little research on the selection of cartridges in DP according to pancreatic thickness.

A systematic review[28] supported the strategy of selective drainage and early drain removal after pancreatic resection in low-risk patients, but mostly PD. Behrman et al.[29] found that drainage following DP was associated with a higher POPF rate and did not reduce intra-abdominal septic morbidity, nor the need for postoperative therapeutic intervention. There is only one study focused on the relationship between drainage and pancreatic thickness in DP. Chang et al.[30] reported that drainage following DP could be selectively indwelled in patients with a pancreatic thickness ≥ 17.3 mm. Data on this topic are currently limited. Definitive evidence regarding the necessity and indication for the use of drain in DP is needed, especially for a thick pancreas.

This study has several limitations. First, our data are limited by a small sample size and confounding variables, such as type of staple cartridge used. Second, as this was a retrospective study, subgroups were not randomly assigned, and the surgical decision varied depending on the surgery period. Finally, our study defined 15.35 mm as the cutoff value, but a true cutoff value still remains to be determined. Furthermore, the value of PI can be influenced by spleen lesions, such as splenic cyst, which may cause errors in the results. However, few studies have focused on the evaluation of pancreatic factors for POPF after DP using preoperative CT. Our findings may be helpful for evaluating the preoperative patients with CT scan, regarding risk stratification for POPF and postoperative management.

Conclusions

In conclusion, we found that evaluating pancreatic factors with a preoperative CT scan could be helpful for predicting the occurrence of clinical POPF after DP. The cutoff value of 15.35 mm for TPC has been determined and found to be helpful for risk stratification. Moreover, when a thick pancreatic cut-line coexists with a dilated MPD, the POPF rate may further increase. This method is simple and readily available in the preoperative period. Our findings may be valuable in preoperative risk assessment of POPF after DP and may help to plan the pre-, intra-, and postoperative patient management.

Abbreviations

POPF postoperative pancreatic fistula

DP distal pancreatectomy

CT computed tomography

TPC thickness of the pancreatic cut-line

MPD main pancreatic duct

PI pancreatic index

ROC receiver operating characteristic

RCTs randomized controlled trials

BMI body mass index

Declarations

Ethics approval and consent to participate The Institutional Review Board of the First Affiliated Hospital of Fujian Medical University approved this retrospective study and waived the requirement for written informed consent due to its retrospective nature.All methods in the study were carried out in accordance with the Helsinki guidelines and declaration.

Consent for publication Not applicable

Availability of data and materials The datasets analyzed in this study are available from the corresponding author on request.

Competing interests The authors declare that they have no competing interests

Funding Education Scientific Research Projects for Middle-aged Young Teachers from the Education Department Fujian Province(No.JAT200130)

Authors' contributions YPC contributions to the conception and design of the work; YHH contributions the acquisition, analysis, and interpretation of data and have drafted the work

Acknowledgements Not applicable

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