Research ArticleClinical Studies

Significance of Histopathological Evaluation of Pancreatic Fibrosis to Predict Postoperative Course After Pancreatic Surgery

KAORI TANAKA, HIROYUKI TOMITA, SHINJI OSADA, HARUO WATANABE, HISASHI IMAI, YOSHIYUKI SASAKI, SATOSHI GOSHIMA, HIROSHI KONDO, MASAYUKI KANEMATSU, AKIRA HARA and KAZUHIRO YOSHIDA
Anticancer Research March 2015, 35 (3) 1749-1756;

Abstract

Background/Aim: Pancreatic stellate cells (PSC) play a critical role in pancreatic fibrosis and the apparent diffusion coefficient (ADC) value based on the diffusion-weighted image (DWI) from magnetic resonance imaging (MRI) may be a predictor of tissue fibrosis. This study aimed to evaluate the pancreas texture from both histopathological and radiological viewpoints and to investigate the effect of pancreas texture on occurrence of postoperative pancreatic fistula (PF). Patients and Methods: We divided 40 patients into soft-pancreas group and hard-pancreas group, according to the histopathological evaluation of pancreatic fibrosis. We compared ADC values and occurrences of PF between the two groups. Results: Histopathological measurement lengths of interlobular and intralobular fibrosis increased significantly with the progression of fibrosis grade and PSC stage, while PSC stage correlated significantly with fibrosis grade (r=0.868, p<0.001). PF was detected in 14 out of 40 patients, including grade A in 7 patients and grade B/C in 7 patients, but there were no operative deaths. Pancreas texture (soft/hard), determined based on the combination of fibrosis grade and PSC stage, was 16/10 (no PF) and 14/0 (grade A/B/C PF) and the difference in the incidence was significant (p=0.022). Though ADC value was significantly lower in the hard-compared to the soft-pancreas group (1.48±0.42 vs. 1.73±0.27×10−3 mm2/sec; p=0.033), there was no significant difference in ADC value between no PF versus grade A/B/C PF group. Conclusion: Histopathological evaluation of pancreas texture correlated negatively with ADC values and is critical to predict the occurrence of PF.

After pancreatic surgery, despite an overall <5% decrease in the mortality rate, the morbidity rate remains still high for 30% to 50% of patients affected (1-3). As one cause of morbidity from pancreatic surgery, the occurrence of pancreatic fistula (PF) is a critical trigger of potentially life threatening complications, such as intra-abdominal abscess and hemorrhage and is also associated with markedly prolonged hospitalization. Risk factors for PF depend upon i) general patient factors, including age, sex, jaundice and nutrition; ii) disease-related factors, including pancreatic duct size, pancreatic texture and pathology; and iii) procedure-related factors, including blood loss, operative time and anastomotic method (4). Among these risk factors, the most important might be the texture of the remnant pancreas. Indeed, the occurrence of PF rises to nearly 20% in cases of soft pancreatic texture, despite an occurrence rate of 5% in cases of hard pancreatic tissue (5). However, the judgment of pancreatic texture itself has been based on the surgeon's observation and there still exists no objective method of assessing pancreatic texture (6).

The pancreatic stellate cell (PSC) has been well studied and found to produce desmoplasia in the progress of chronic pancreatitis or pancreatic ductal oncology (7). PSCs transform from the quiescent phase to the activated form and the myofibroblast-like phenotype is described to lead to the fibrosis seen in chronic pancreatitis or pancreatic cancer (8) suggesting that PSCs play a critical role in pancreatic fibrosis and cancer progression. The apparent diffusion coefficient (ADC) value based on the diffusion-weighted image (DWI) from magnetic resonance imaging (MRI) has been focused on as a preoperative imaging method for prediction of tissue fibrosis. According to DWI studies, water diffusion, which quantifies the combined effects of capillary perfusion and diffusion, was developed to calculate the ADC value and has been used to indicate hepatic fibrosis in liver cirrhosis (9). To apply the concept to pancreas disease, recent studies showed the ADC value to be higher in cancer tissues (10, 11), as well as in patients with large tumor size, positive lymph node metastases and invasion to the portal vein or extrapancreatic nerve plexus (12). We previously reported that the ADC value was valuable for evaluating pancreatic fibrosis as a preoperative observation (13). Therefore, the goal of the present study was to investigate these novel methods for evaluating pancreatic texture and predicting the post-surgical course.

View this table:
Table I.

Fibrosis grade and pancreatic stellate cell (PSC) stage.

View this table:
Table II.

Postoperative factors evaluated by pancreas texture.

View this table:
Table III.

Postoperative factors evaluated by pancreas fibrosis.

View this table:
Table IV.

Fibrosis parameters according to pancreatic fistula (Grade A/B/C) occurrence in all patients (n=40).

Patients and Methods

Patients and clinical evaluation. Among the patients who underwent surgical treatment at the Department of Surgical Oncology, Gifu University Hospital between 2004 and 2011, 40 patients (22 men and 18 women with a mean age of 67±11 years (range, 22-79 years)) underwent surgery of the pancreas. In this study, we added 11 new patients to our previous data (13) and totally analyzed 40 patients. Cancer in the pancreas (n=27), bile duct (n=1), gallbladder (n=1) and ampulla of Vater (n=1) was present in 30 of the 40 patients. The other 10 patients were diagnosed with intraductal papillary mucinous neoplasm (n=4) and mucinous cystic neoplasm (n=1). Pancreatoduodenectomy (PD) and distal pancreatectomy (DP) were performed in 19 and 21 patients, respectively, according to the disease site. All patients were operated and followed by the same team of surgeons who specialized in hepatobiliary and pancreatic surgery. The surgical procedure for reconstruction after PD was performed by the separate loop method as described previously (14). After DP, the main pancreatic duct was ligated twice.

View this table:
Table V.

Fibrosis parameters according to pancreatic fistula occurrence in the patients after pancreatoduodenectomy (n=19).

Patient condition was evaluated by body-mass index (BMI) and laboratory data, including glycosylated hemoglobin (HbA1c) preoperatively and amylase level of drainage fluid (D-Amy), serum amylase level (S-Amy) or inflammatory change as indicated by C-reactive protein (CRP) and white blood cell (WBC) count on days 1, 3 and 5 after surgery. The diagnosis and classification of PF was suspected based on the guidelines of the International Study Group on Pancreatic Fistula (ISGPF) (2).

Calculation of ADC from diffusion-weighted MRI. MRI was performed with a 3.0-T superconducting system (Intera Achieva Quasar Dual; Philips Medical Systems, Best, The Netherlands) with a six-channel torso array coil. The MR imaging protocol consisted of the following imaging sequences: breath-hold two-dimensional dual-echo axial T1-weighted fast field-echo imaging (repetition time msec/echo time msec, 292/2.3 (in phase) and 292/1.1 (opposed phase)); respiratory-triggered two-dimensional fat-suppressed axial T2-weighted turbo spin-echo imaging (1,600/80 (effective)); free-breathing two-dimensional axial diffusion-weighted imaging with a single-shot echo-planar sequence (4583 (effective)/46 (effective); parallel imaging factor, three; b factors, 0 and 500 sec/mm2; isotropic motion-probing gradient pulses along three orthogonal oblique directions; field of view, 38×30 cm; image matrix, 112×90 with 256×256 reconstruction; section thickness, 8 mm with a 0-mm intersection gap; (acquisition time for 30 sections, 23 minutes 17 seconds)). The ADC value was reconstructed for each pixel using b factors of 0 and 500 sec/mm2. ADC values were determined by manually placed regions of interests (ROIs). ROIs with areas of approximately 50-150 mm2 were drawn in the same location as the surgical specimen, i.e., the location of the surgical resection margin, with great care to exclude the dilated pancreatic duct, normal intrapancreatic vasculature and cystic lesions. The final ADC was calculated from the average of several ROIs. The details of the calculation method for ADC have been described previously (15, 16).

Histopathological and immunochemical staining. The pancreatic texture was evaluated histopathologically from the specimen at the cut surface of the resected pancreas. Paraffin-embedded tissues were cut into 4-μm-thick serial sections and deparaffinized. These sections were stained with hematoxylin and eosin and Azan stains for collagen fibers. For immunohistochemistry, the sections were placed in citrate buffer (10 mmol-1, pH 6.0) and then in an autoclave chamber at 121°C for 1 min to retrieve the antigen. The sections were rinsed and blocked in 10% H2O2 solution with methanol for 10 min and incubated with monoclonal mouse anti-human actin smooth muscle clone 1A4 (Dako, Glostrup, Denmark) at 1:100 dilution overnight at 4°C. They were then rinsed in PBS and incubated for 30 min with a secondary antibody labeled with streptavidin-biotin-peroxidase for mouse monoclonal antibody (LSAB2 System-HRP; Dako). The bound complex was visualized using diaminobenzidine liquid chromogen (SIGMA, Saint Louis, MO, USA) and counterstained with hematoxylin.

To evaluate pancreatic fibrosis, the following three kinds of histopathological fibrosis parameters were adopted: histopathological measurement length (HML) of the fibrosis, fibrosis grade evaluated by change in the fibrotic structure and PSC stage evaluated by the intensity of PSC activity. The HML from actual measurement of interlobular and intralobular collagen fibers was calculated using the average length of 10 points of view. In the Azan-stained specimens, fibrosis grade was evaluated using the following four-stage scoring system adopted by Wellner et al. (6): normal pancreas parenchyma and no fibrotic changes (grade 0), mild fibrosis with thickening of periductal fibrosis (grade 1), moderate fibrosis with marked sclerosis of interlobular septa or intralobular sclerosis with no evidence of architectural changes (grade 2) and severe fibrosis with detection of architectural destruction or acinar cell atrophy (grade 3) (Figure 1).

To indicate the PSC stage, the immunohistological evaluation of PSC activity was performed using the following four-stage scoring system: no staining except in the periductal tissue (stage 0), weak positive staining that is irregular or sometimes patchy (stage 1), weak positive staining that is always homogenous or diffuse (stage 2) and strong positive staining that is always homogenous and diffuse (stage 3) (Figure 2).

Based on a previous report (6), patients with grade 3 fibrosis or stage 3 PSC activity were assigned to the hard-pancreas group, whereas patients with grade 2 or less fibrosis and stage 2 or less PSC activity were assigned to the soft-pancreas group. Histological evaluation was performed with the support of two experienced pathologists (H.T. and K.T.).

Figure 1.
Figure 1.

Histopathological evaluation of pancreatic fibrosis according to fibrosis grade. Fibrosis grade was evaluated in Azan-stained specimens with a four-grade scoring system as described in the Patients and Methods section: grade 0 (a), grade 1 (b), grade 2 (c) and grade 3 (d). Scale bar indicates 300 μm.

Statistical analysis. Continuous data are presented as the mean±standard deviation. A non-parametric Mann-Whitney U test, Spearman's rank correlation test, Chi square test, ANOVA and the Kruskal-Wallis test were used according to the circumstances. A p value of <0.050 was considered to be statistically significant. Statistical analysis was performed using the MedCalc software, Ver. 12.4.0 (MedCalc Software, Ostend, Belgium).

Results

Significance of fibrosis grade and PSC stage evaluated by HML or ADC value. To confirm the significance of fibrosis grade and PSC stage, HML of fibrosis by using Azan staining and ADC value were compared. Both HMLs of interlobular and intralobular fibrosis increased significantly with the progression of fibrosis grade and PSC stage, as shown in Figure 3. Especially, HMLs in specimens with fibrosis grade 3 and PSC stage 3 were clearly higher than HMLs for the other values. A significant correlation (r=0.868, p<0.001) was detected between fibrosis grade and the PSC stage (Table I) indicating that the presence of both PSC stage 3 and fibrosis grade 3 was a means to detect hard pancreas in the present study. The ADC value was also compared to fibrosis grade and PSC stage (Figure 4). A decrease in the ADC value was found to correlate with the progression of fibrosis grade and PSC stage but the difference was not statistically significant. The ADC value itself was significantly lower in hard pancreas determined according to fibrosis grade and PSC stage than in soft pancreas (1.48±0.42 vs. 1.73±0.27×10−3 mm2/sec; p=0.033).

Figure 2.
Figure 2.

Immunohistological evaluation of pancreatic stellate cell (PSC) activity according to PSC stage. PSC activity was evaluated by the expression of alpha-smooth muscle actin with a four-stage scoring system as described in the Patients and Methods section: stage 0 (a), stage 1 (b), stage 2 (c) and stage 3 (d). Scale bar indicates 300 μm.

Clinical application of histopathological findings and ADC value. There was no significant difference in patient profiles with regard to softness versus hardness of the pancreas in terms of age (65.7±11.7 vs. 69.5±6.6 years), BMI (23.5±2.9 vs. 21.9±2.0 kg/m2) or sex (data not shown). Although preoperative blood analysis data, such as HbA1c or albumin, were not significantly different according to pancreas texture, S-Amy was found to be significantly higher in the hard versus soft pancreas group (116.9±38.6 vs. 88.9±49.9 IU/l; p=0.032). The postoperative course was also compared according to pancreas texture (Table II). D-Amy (3826.3±7148.4 vs. 299.1±217.7 IU/l, p=0.005 on POD 1; 2966.2±8413.9 vs. 40.6±58.0 IU/l, p=0.005 on POD 3-4) and WBC (11015.0±3010.4 vs. 8580.0±2779.2/mm3, p=0.039 on POD 1; 9548.3±3335.9 vs. 6578.0±2306.8/mm3, p=0.010 on POD 3-4) were detected to be significantly higher in the soft-pancreas group. Postoperative factors were also studied according to the pathological findings and ADC value (Table III). D-Amy on POD 1 decreased with progression of fibrosis grade, PSC stage and interlobular and intralobular fibrosis but not with ADC value. D-Amy level on POD 3-4 and WBC on POD 1 decreased with progression of fibrosis grade and intralobular fibrosis but not with PSC stage, interlobular fibrosis and ADC value. WBC on POD 3-5 was found to be affected by all factors.

To estimate the influence of pancreatic fibrosis on the incidence of PF, fibrotic parameters and ADC value were evaluated. Based on the ISGPF criteria, PF was detected in 14 out of 40 patients, including grade A in 7 patients and grade B/C in 7 patients; however, there were no operative deaths. Fibrosis grade and PSC stage, but not interlobular/intralobular fibrosis and ADC value, were critical to predict the occurrence of PF. Also, pancreas texture determined on the basis of combination of fibrosis grade and PSC was well-reflected in the prediction of PF (Table IV). With regard to differences in the two operation types, in the patients undergoing PD (n=19), the present parameters, except for ADC value, were found to predict the occurrence of PF well (Table V). Among these factors, fibrosis grade, PSC stage and HML of intralobular fibrosis were more critical for detection of serious PF-induced complications. In contrast, in patients undergoing DP, none of the parameters were found to have a significant role in postoperative PF (data not shown).

Figure 3.
Figure 3.

Evaluation for pancreatic fibrosis according to histopathological measurement length (HML). The HMLs of interlobular (a, c) and intralobular (b, d) fibrosis were compared according to fibrosis grade (a, b) and PSC stage (c, d). Both factors were shown to increase as fibrosis grade and PSC stage advanced. *p<0.050, as determined by the Kruskal-Wallis test.

Discussion

In the past, pancreatic fibrosis was evaluated basically with two methods. One was the fibrosis grading system, based on the degree of interlobular/intralobular fibrosis, the presence of architectural destruction or acinar cell atrophy (17, 18) and the other was fibrosis ratio, which is the calculation of the percentage of stained collagen in pancreas tissue made by an image analysis program (12, 19). As a novel concept to evaluate pancreatic fibrosis, the present study proposed the HML of fibrosis as the measurement of collagen width in interlobular and intralobular fibrosis. The HML of fibrosis was found to relate to the already estimated “fibrosis grade” (6) indicating the ability of the present method to evaluate the advancement of fibrosis. Furthermore, PSC stage was also important because it correlated with both fibrosis grade and HML and was useful to demonstrate tissue texture in combination with fibrosis grade.

Figure 4.
Figure 4.

Evaluation for pancreatic fibrosis according to apparent diffusion coefficient (ADC) value. ADC values were compared according to fibrosis grade (a) and PSC stage (b). The value was found to decrease as fibrosis grade and PSC stage advanced but the difference was not statistically significant. The ADC value was lower in hard than in soft pancreas (c). *p<0.050, as determined by the non-parametric Mann-Whitney U test.

The ADC value has been found to negatively correlate with liver fibrosis (9, 10) and several reports show a critical relation with the cancerous pancreatic site. However, to our knowledge, the present study was the first step in demonstrating the application of the ADC value to non-cancerous pancreatic tissue. As a similar inspection method for MRI, the time-signal intensity curve (TIC) was also shown to correlate with fibrosis in non-cancerous areas (1, 19). Although TIC was found to be useful to predict the degree of pancreas fibrosis, the use of the ADC could be safer even for patients with renal disease or contrast allergy (20), from a point that administration of contrast medium is not required.

There are still a few reports focusing on the relation between objective pancreatic texture and postoperative outcome. In these reports, postoperative complications were detected more frequently in patients with a soft pancreas, which was evaluated by postoperative pathological findings according to whether the main pancreatic duct obstruction induced fibrotic pancreatitis (21). Another concept for the evaluation of PF in the soft pancreas was based on intra/interlobular fibrosis, dilatation of pancreas duct and the presence of inflammatory cells (17). In the present study, pancreas texture evaluated with a combination of fibrosis grade and PSC activity was found to be useful for the prediction of postoperative D-Amy and leukocyte count. A higher D-Amy or leukocyte count on POD 3 was found to be significant for the prediction of relevant pancreas-related infectious complications (22, 23). Lower interlobular fibrosis grade is a critical factor for PF (24) and PSC activity was also shown to be significant not only as a single factor but also in combination with fibrosis grade to evaluate pancreas texture objectively.

In summary, the present study showed the ADC value could be a predictor of pancreas texture but not useful in predicting the occurrence of PF. The preoperative ADC value could help us to identify pancreas texture, thus facilitating the simulation of operation. However, for the prediction of PF, histological evaluation of pancreas texture of excised specimen is required.

Acknowledgements

The Authors would like to thank Kyoko Takahashi and Ayako Suga for their valuable technical assistance and all members of the Department of Tumor Pathology for helpful comments and discussion. Hiroyuki Tomita is supported by the Pancreas Research Foundation of Japan.

Footnotes

  • ↵* These Authors contributed equally to this study.

  • Disclosure

    Non of the Authors have any conflicts of interest and there are no financial disclosures and no specific funding.

  • Received November 4, 2014.
  • Revision received December 8, 2014.
  • Accepted December 11, 2014.

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Significance of Histopathological Evaluation of Pancreatic Fibrosis to Predict Postoperative Course After Pancreatic Surgery
KAORI TANAKA, HIROYUKI TOMITA, SHINJI OSADA, HARUO WATANABE, HISASHI IMAI, YOSHIYUKI SASAKI, SATOSHI GOSHIMA, HIROSHI KONDO, MASAYUKI KANEMATSU, AKIRA HARA, KAZUHIRO YOSHIDA
Anticancer Research Mar 2015, 35 (3) 1749-1756;
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