De novo malignancy sporadically occurs in patients who undergo liver transplantation (LT). Its incidence ranges from 4% to 16%, depending on the length of follow-up, age distribution of the recipients, and type of immunosuppressive regimens [1,2]. We previously reported a single-center incidence of solid organ de novo malignancy after LT of 2.3% in a mean follow-up period of 42 months [1]. The relative risk of overall de novo malignancy following LT was significantly higher than that of the Korean general population. Although the prevalence of de novo malignancy after LT is not negligibly low, its incidence is still sporadic, especially for malignancies uncommon in the general population.

Repeated major abdominal surgery long after living donor liver transplantation (LDLT) is often demanding because of heavy adhesion around the hepatoduodenal ligament and risk of vascular injuries. Pancreaticoduodenectomy (PD) following LDLT has been rarely reported [3,4]. PD after LDLT using duct-to-duct anastomosis has not been reported yet in the literature. We herein present a case of a patient who underwent PD for de novo ampulla of Vater cancer at 15 years after LDLT using duct-to-duct anastomosis. This study was approved the Institutional Review Board of Asan Medical Center (2021-0839) and informed consent was obtained.

A 59-year-old male patient was admitted to our institution for hepatitis B virus-associated liver cirrhosis. The patient was suffering from massive ascites (Fig. 1A), and the model for end-stage liver disease score was 22. Because there was a low chance for deceased donor liver transplantation, he underwent LDLT using a modified right liver graft (Fig. 1B). The donor was his 28-year-old son. The right liver graft weighed 540 g, making a graft-to-recipient weight ratio of 0.81. The graft middle hepatic vein branches were reconstructed using a cryopreserved iliac vein allograft conduit. The right liver graft had two bile duct openings, so double duct-to-duct anastomoses were performed using the orifices of the recipient’s right and left hepatic ducts (Fig. 1C). A 1 cm-sized hepatocellular carcinoma (HCC) was incidentally identified at the explant liver (Fig. 1D). The patient recovered uneventfully from the LDLT operation and was discharged at 21 days from our institution. The patient was followed up regularly every 3 to 4 months at his hometown university hospital.

Figure 1. Peritransplant findings. (A) Pretransplant computed tomography shows liver cirrhosis with ascites. (B) Computed tomography taken 4 days after living donor liver transplantation using a modified right liver graft shows the usual posttransplant findings. (C) Direct tubogram taken at posttransplant 7 days through the external biliary drainage tube shows good patency of the two duct-to-duct anastomoses. (D) The explant liver shows advanced liver cirrhosis.

At 15 years after LDLT, elevation of liver enzyme levels led to performance of abdomen computed tomography, in which a mass inducing distal bile duct obstruction was identified at the ampulla of Vater (Fig. 2A). The patient was referred to our institution for further evaluation. Magnetic resonance cholangiopancreatography showed marked dilatation of the common bile duct (CBD) with good patency of the double duct-to-duct anastomoses (Fig. 2B). Endoscopic retrograde cholangiopancreatography was performed for biliary drainage and tumor biopsy (Fig. 2C). The endoscopic biopsy showed a tubulovillous adenoma with high grade dysplasia, suggesting the possibility of well-differentiated adenocarcinoma. The blood flow to the proximal bile duct appeared to be normal on dynamic liver computed tomography, so we presumed that the proximal part of the recipient’s own bile duct could be left safely due to the presence of retrograde arterial blood supply.

Figure 2. Preoperative findings and gross photographs of the tumor. (A) Initial computed tomography shows obstructing mass at the ampulla of Vater (arrow). (B) Magnetic resonance cholangiopancreatography shows dilatation of the common bile duct and the pancreatic duct with good patency of the double duct-to-duct anastomoses. (C) Endoscopic retrograde cholangiopancreatography shows a tubulovillous adenoma at the ampulla of Vater. (D) The surgical specimen shows a 2 cm-sized adenocarcinoma at the ampulla of Vater.

At one week after biliary decompression with endoscopic nasobiliary drainage, when the patient was 74 years of age, we performed PD. The hepatic hilum was meticulously dissected to prevent damage to the reconstructed graft right hepatic artery. The dilated CBD was transected at the midway and dissection continued toward the site of the previous duct-to-duct anastomoses with direct visualization of the bile duct lumen (Figs. 3A–C). At 1 cm away from the previous biliary anastomosis site, the recipient CBD was transected again. We identified active arterial back bleeding from the proximal bile duct stump, indicating good development of arterial collaterals to the interposed remnant proximal bile duct (Fig. 3D).

Figure 3. Intraoperative photographs of bile duct transection. (A, B) The common bile duct (CBD) is markedly dilated. (C) The dilated CBD was transected at the midway to observe the intraluminal status. (D) The proximal CBD (arrow) is transected at 1 cm away from the previous biliary anastomosis site.

The remaining surgical procedures were similar to the standard procedures of PD, with additional application of extended pancreatic transection and pylorus-resecting surgery. The main portal vein was dissected without dissection of the previous anastomosis site. The gastroduodenal artery was transected and securely ligated. The pancreatic neck was transected with tie-ligation of both stumps, and the pancreatic head with uncinate process and the proximal jejunum were resected. Thereafter, the proximal part of the pancreatic body was dissected and transected again at the level of the celiac axis. This extended pancreatic transection removed 3 cm more of the pancreatic body than in the conventional pancreatic transection (Fig. 4).

Figure 4. Intraoperative photographs of biliary reconstruction. (A) The anterior wall of the remnant proximal bile duct opening is anchored with multiple double-arm 5-0 Prolenes. (B) The posterior wall of the remnant proximal bile duct opening is repaired with running sutures. Arrows indicate two graft duct openings. (C, D) Pancreaticojejunostomy and choledochojejunostomy are completed, leaving a redundant intervening jejunal loop for insertion of an omental tissue flap.

The surgical technique for end-to-side duct-to-mucosa pancreaticojejunostomy (PJ) was as follows. Running sutures were made at the dorsal edge of the pancreatic stump with 5-0 Prolene. Multiple interrupted sutures with 6-0 Prolene were done for duct-to-mucosa anastomosis. A small size-matched silastic tube of 10 cm in length was inserted into the remnant pancreatic duct and then transfixed it with a 6-0 absorbable monofilament. The ventral edge of the pancreatic stump was repaired with interrupted 6-0 Prolene sutures. Choledochojejunostomy was performed to the remnant recipient CBD by means of running sutures of the posterior wall and interrupted sutures of the anterior wall using 5-0 Prolene (Fig. 5).

Figure 5. Intraoperative photographs after pancreaticoduodenectomy with extended pancreatic transection. Arrow and arrow head indicate the opening of the remnant proximal bile duct and the celiac axis, respectively.

The blood supply to the remnant first portion of the duodenum did not appear to be optimal because of the dissection of the adhesions, so the distal part of the gastric antrum was additionally resected. As a result, pylorus-resecting PD was performed. Braun anastomosis of side-to-side jejunojejunostomy was performed. An omental graft patch was attached around the PJ site, and then the evacuated space of the uncinate process was filled with the mobilized omental tissue flap. Three closed suction-type cigarette drains and two pigtail drains were inserted around the PJ site to cope with potential PJ leak (Fig. 6A).

Figure 6. Postoperative imaging study findings. (A) Simple abdomen X-ray shows insertion of multiple abdominal drains. (B) Computed tomography taken at postoperative 8 days shows the usual postoperative findings. (C, D) Computed tomography taken at 2 months shows the usual postoperative findings following pancreaticoduodenectomy. Arrows indicate an internal pancreatic stent tube.

The surgical specimen showed a 2×1.5×1 cm-sized moderately differentiated adenocarcinoma arising from a tubular adenoma of the intestinal subtype at the ampulla of Vater (Fig. 2D). The tumor involved the mucosa and submucosa of the duodenal wall with no involvement of the resection margins. There was lymphovascular invasion, but perineural invasion was not identified. No metastasis was present in 9 lymph nodes. There was low grade biliary intraepithelial neoplasia at the CBD and cystic duct. The extent of the tumor was pT1bN0M0 according to the 8th edition of American Joint Committee on Cancer staging, thus being regarded it as stage IB.

This patient recovered uneventfully from the surgery without any significant surgical complication and was discharged from our institution at 25 days after the PD operation (Fig. 6B). Adjuvant chemotherapy was not performed. The patient has been doing well for 3 months after PD without any evidence of tumor recurrence or de novo diabetes mellitus (Fig. 6C, D). The postoperative follow-up surveillance protocol for the patient is the same as that for the usual non-transplant patients who had undergone PD for ampulla of Vater cancer.

The patient had been administered mycophenolate mofetil (MMF) monotherapy for more than 10 years primarily because of calcineurin inhibitor-associated nephrotoxicity before PD. After PD, immunosuppression was stopped for postoperative 5 days and a reduced-dose MMF was administered for the next 2 weeks with a target mycophenolic acid concentration at 2 μg/mL. Thereafter, the immunosuppressant was switched to everolimus, with a target concentration of 2 ng/mL.

The incidence of de novo malignancy after LT has been gradually increasing in Korea because many LT recipients have been living longer and their ages have also been increased along with long-term administration of immunosuppression. Many kinds of de novo malignancy can occur in LT recipients just as in the general population. Thus, it is highly recommended surveilling the LT recipients for life by means of regular health and cancer screening [1,5,6].

The incidence of ampulla of Vater cancer in the general population is very low [7]. Accordingly, its incidence is also very low in the LT recipients. There is only one case report of PD for ampulla of Vater cancer performed at 2 years after LDLT in the literature [3]. Our patient is the first case of de novo ampulla of Vater cancer in more than 5,000 adult LT recipients who have survived more than 1 year in our LT experience [8]. The nature of ampulla of Vater cancer inducing early biliary obstruction led to early diagnosis of the tumor in our patient [7].

Performance of PD after LDLT has two theoretical hurdles. The first is heavy adhesion around the hepatoduodenal ligament and its dissection can carry risk of vascular injury, especially the hepatic artery. The second is biliary reconstruction. If a whole liver graft is implanted, biliary reconstruction does not matter because it can be done with complete removal of the recipient CBD [9]. In contrast, if LDLT using duct-to-duct anastomosis is performed, it is not feasible to remove the recipient CBD completely because the graft liver had no extrahepatic bile duct stump. Thus, some proximal part of the recipient CBD should be left for biliary reconstruction, in which the recipient bile duct segment is interposed between the graft bile duct and jejunal bowel loop. We had worried about the blood supply of this interposed portion before PD. During PD, we found that there was retrograde arterial blood flow to the recipient CBD from the graft side, as shown in the bidirectional arterial blood flow in the usual blood supply to the normal CBD. Such good blood supply enabled us to perform the CJ successfully. If a patient has suffered from biliary stricture, retrograde blood supply should be prudently assessed because such a biliary stricture might be associated with impaired blood supply to the proximal CBD stump. On the other hand, if hepaticojejunostomy is done for biliary reconstruction in LDLT, it is reasonable to preserve the pre-existing hepaticojejunostomy [4]. PJ should be performed using a new Roux-en-Y jejunal limb, as shown in redo PD after segmental bile duct resection [10].

Since our patient had to restart immunosuppression during the early postoperative recovery phase, it was essential to prevent infection-prone surgical complications. We have adopted three techniques to reduce the risk of PJ leak-associated complications. The first is extended pancreatic transection to facilitate secure PJ at the celiac axis level. The second is an omental flap graft to wrap the PJ site and the gastroduodenal artery stump. The third is insertion of multiple abdominal drains in combination with closed-suction cigarette drains and pigtail catheters. Based on our experience, we think that application of these three techniques is effective to prevent and cope with PJ leak [11].

Performing PD in our patient provided a unique opportunity to observe the long-term intraluminal status of duct-to-duct anastomosis. The anastomotic site was remodeled as with a choledochal cyst with hypoplastic intrahepatic ducts. Considering that the intrahepatic ducts were not dilated, there were no biliary complications leading to anastomotic stricture. Transection of the proximal CBD also provided important information that retrograde arterial blood supply to the proximal CBD can be regained after duct-to-duct anastomosis. Our experience suggests that if the duct-to-duct anastomosis appears normal, an interposition of a short proximal CBD segment may be permissible for CJ with an acceptably low risk of stump ischemia. To the best of our knowledge, our present patient is the world-first case of successful PD after LDLT using duct-to-duct anastomosis in the literature.

For patients with de novo malignancy, the primary immunosuppressant has often been switched from a calcineurin inhibitor to a mammalian target of rapamycin (mTOR) inhibitor [12]. MMF is known to have no detrimental effect on the clinical course of de novo malignancy, so it can be used if the patient cannot tolerate an mTOR inhibitor or if risk of tumor recurrence is low [13,14]. The tumor of our patient was stage IB, so there is a considerably risk of tumor recurrence [7]. With an expectation of anti-tumor effect from the mTOR inhibitor, we have switched from MMF monotherapy to everolimus monotherapy. Because the patient had adapted well to MMF monotherapy for a long time, we think that he would tolerate everolimus monotherapy well again.

We have reported that LT recipients who have been diagnosed with HCC have a higher risk of de novo extrahepatic malignancy than those without HCC, thus suggesting that LT recipients who have had pretransplant HCC should undergo follow-up surveillance for extrahepatic malignancy more strictly [15].

In conclusion, our experience with the present case suggests that PD can be eligibly performed after LDLT using duct-to-duct anastomosis if there is no evidence of pre-existing biliary complication.

There was no funding related to this study.

The authors have no conflict of interest to disclose.

Conceptualization: SH. Data curation: BGN, SMK, GY. Methodology: All. Visualization: SH. Writing - original draft: BGN, SH. Writing - review & editing: All.