Total pancreatectomy with Langerhans islets autotransplantation for pancreatico-pleural fistula 2 years after pancreatoduodenectomy for chronic pancreatitis

Overview

Introduction: Pancreaticopleural fistula (PPF) represents a rare complication of chronic pancreatitis. The treatment is complex including pleural drainage, decompression of main pancreatic duct by endoscopic retrograde cholangiopancreatography, pancreas rest with parenteral or enteral nutrition via naso-jejunal feeding tube and somato­statin analogues application. Surgery is indicated when the conservative or endoscopic treat­ment is not successful. In selected cases, total pancreatectomy may be consid­ered. ­After these procedures, unstable diabetes mellitus may be a problem. In this case report, the authors present an alternative way to resolve pancreatico-pleural fistula in patients with a history of pancreatic resection.

Case report: A 49-year-old man underwent pancreatoduodenectomy with pancreato-gastrostomy for chronic pancreatitis in 2018. Two years after the procedure, he had severe dyspnea, with X-ray showing left-sided fluidothorax. Pleuracentesis confirmed high amylase activity in pleural effusion. A CT scan was performed and a diag­nosis of pancreaticopleural fistula was made. Due to the failure of conservative treatment, the residual pancreas was resected. The islets of Langerhans from the resected pancreatic tissue were isolated and transplanted back into the patient’s liver via the portal vein. The postoperative course was uneventful. Two year after the procedure, the patient was asymptomatic without pleural effusion recurrence and no need of insulin replacement therapy.

Conclusion: Total pancreatectomy with islet autotransplantation may be an appropri­ate method of treatment for recurrent pancreaticopleural fistula in situations where less radical procedures are not possible.

Keywords:

fistula – chronic pancreatitis – autotransplantation – Langerhans islet

Introduction

The introduction of total pancreatectomy into the spectrum of surgical procedures performed for chronic pancreatitis in the 1960s brought a major clinical problem, which was unstable diabetes mellitus [1]. The idea of transplantation of pancreatic islets isolated from the patient’s own pancreas provided a solution. These are injected into the portal vein after resection, carried by the venous stream to the liver where they settle and stabilize glycaemia by their own endocrine hormone production. Despite the initial failures of experiments performed on dogs, mainly due to frequent thromboses of the portal vein, a safe technique has been developed. After resection, the pancreas is washed with a stabilizing solution and transported on ice to the laboratory. Here, it is first digested with collagenase. Subsequently, exocrine and endocrine cells are released in a Ricordi chamber. Finally, during centrifugation, the pancreatic islets are accumulated due to their similar mass density in a single layer, from which they are subsequently aspirated and prepared for application in suspension [2,3]. The first autotransplantation of pancreatic islets following total pancreatectomy was performed in 1980 [4]. In the Czech Republic, the program of transplantation of pancreatic islets was introduced in 2005 at Institute for Clinical and Experimental Medicine (IKEM) Prague [5]. The first autotransplantation was performed at the same site in 2014 [6]. In the following case report, the authors describe the possibility of using this method in the treatment of pancreatico-pleural fistula.

Case report

A 49-year-old man underwent uncomplicated pancreaticoduodenectomy for recurrent acutely exacerbating chronic pancreatitis of toxonutritive etiology at the Department of Surgery of University Hospital Brno in 2018. He was subsequently followed up in the surgical outpatient clinic and in the gastroenterology department. Two years after pancreatic resection, there was a gradual progression of chronic inflammation in the pancreatic remnant and the development of a left-sided fluidothorax with exertional dyspnea. Thoracentesis demonstrated high (more than 400 μkat/L) amylase activity in the pleural effusion. Abdominal CT demonstrated progressive calcifying pancreatitis with cystic dilatation of the pancreatic duct system (Fig. 1).

Due to the pancreatico-gastro anastomosis performed during the primary pancreatectomy, an endoscopic solution with dilation and stenting of the Wirsung duct was considered. However, due to the long interval since the primary procedure and the completely healed orifice of the Wirsung duct into the stomach wall, this was not pos­sible. After the introduction of antisecretory therapy with somatostatin in a therapeutic dose of 6 mg per 24 hours in a continuous infusion, the waste into the chest drain was minimized and the chest drain was subsequently extracted. Within 2 months, there was a recurrence of the left-sided effusion with an amylase activity of 300 μkat/L. The current CT scan shows calcification in the course of the pancreatico-pleural fistula (Fig. 2).

Due to the failure of conservative treatment, a decision was made at a multidisciplinary indication seminar to complete a total pancreatectomy. This carries the risk of unstable diabetes mellitus. One option to prevent this complication is allogeneic or autologous transplantation of pancreatic islets. Given the sufficient endocrine capacity of the pancreatic remnant confirmed by the oral glucose tolerance test (OGTT), which demonstrated a threefold increase in the level of C-peptide after an oral glucose load, the possibility of pancreatic islet autotransplantation was con­sulted in cooperation with the Clinic of Diabetology at IKEM Prague. The resection procedure (completion of total pancreatectomy) was performed at the Department of Surgery, University Hospital Brno, in the morning hours of March 8, 2021. Immediately after its removal from the patient’s body, the pancreatic tissue was washed with a stabilizing solution (custodiol; Fig. 3) and sent in a bag with ice to IKEM Prague. Here,  the pancreatic islets were isolated from the pancreatic tissue and sent back to University Hospital Brno in the form of a suspension on the same day. Afterwards, they were infused into the portal vein during relaparotomy in the evening.

The postoperative course was uncomplicated. Glycaemia was corrected with small doses of parenterally administered insulin. The concentration of C-peptide, which reflects autologous insulin secretion, was already 715 pmol/L on the ninth postoperative day, which indicated good “attachment” of beta cells of the islets in the liver. The patient was discharged to home care on the tenth postoperative day. He was subsequently monitored by the surgical and diabetes outpatient clinics. Based on a satisfactory glycemic profile, the diabetologist completely discontinued insulin therapy 2 months after the procedure. The autotransplantation was successful. Two years after the procedure, he did not need insulin. However, he divorced and, unfortunately, after the divorce, he started drinking again. This was followed by the development of liver insufficiency, subsequent liver cirrhosis, portal hypertension and bleeding from the stomach area, which two years after the autotransplantation necessitated reoperation and suturing of the source of venous bleeding in the area of ​​the pyloro-jejunal anastomosis.

Discussion

Pancreatico-pleural fistula (PPF) is a rare complication of chronic pancreatitis affecting less than 1% of patients with this disease [7]. The cause of PPF formation is pressure in­crease in the pancreatic duct system due to obstruction, most commonly at the pancreatic head. Pancreatic fluid accumulates, forming collections (pseudocysts), which rupture and leak through the path of least resistance, most often into the mediastinum and pleural cavity. In most cases, it affects patients with alcoholic form of chronic pancreatitis [8]. Trauma is a less common cause. The initial symptom is usually shortness of breath accompanied by cough and abdominal pain [9]. After the chest X-ray and transabdominal ultrasound, an abdominal computed tomography (CT) is indicated as the gold standard in the diagnosis of PPF today [10]. Magnetic resonance cholangiopancreaticography (MRCP) is a suitable alternative in cases where the CT find­ings are inconclusive [11]. A diagnosis is confirmed by the analysis of pleural fluid following thoracocentesis, which reveals an extremely elevated pleural fluid amylase level (normal < 150 IU/L), lipase, and high albumin content ­(> 3 g/dL) [12]. There are no randomized studies indicating the most appropriate treatment for PPF [13]. The initial conservative approach generally includes pleural drainage, antisecretory therapy with somatostatin analogs, and “pancreas rest” consisting of restricting oral intake, which is  replaced by parenteral or, better, enteral nutrition administered via a naso-jejunostomy tube. The success of such treatment ranges between 30–60% [14]. Wronski et al. considered that the management should be based on the anatomy of pancreatic duct seen on imaging studies. In cases of Wirsung duct stenosis localized in the pancreatic head, the first-choice therapeutic method is the placement of a stent via endoscopic retrograde cholangiopancreatography (ERCP). ERCP also allows for the bridging of a defect in the case of traumatic rupture of the main pancreatic duct [15]. In the context of the above, we initially considered the possibility of endoscopic decompression of the Wirsung duct for our patient as well. Due to the long interval since the primary surgery, the target of pancreas was completely fibrously healed, which made the endoscopic procedure impossible, leading us to think about a surgical solution. According to the literature, surgical aproach in PPF is indicated when conservative and endoscopic treatment fails or is not possible [16]. Drainage procedures are preferred. In the case of dilation of the majority of Wirsung duct, pancreatic-jejunostomy according to Partington and Rochelle or Izbicki procedures can be indicated. In the situation of a pseudo-tumor located in the pancreatic head, longitudinal drainage of the pancreatic duct may be supplemented with a partial resection of the pancreatic head, known as Frey’s procedure [17–20]. In exceptional cases of dominant inflammation mass in the area of the pancreatic tail, resection of the pancreatic tail can be performed, supplemented with longitudinal incision of the Wirsung duct and pancreatic jejunostomy on an excluded loop of the jejunum (Peustow procedure) [21]. Given the findings on CT, we also considered this type of procedure for our patient. Due to concerns about severe inflammatory changes after pancreatogastrostomy in the lesser sac, anticipating difficult reconstruction phase, we finally decided for total pancreatectomy completion. We considered how to protect the patient from unstable diabetes mellitus after total pancreatectomy. Given the absence of diabetes mellitus, it was possible to expect sufficient endocrine capacity of the pancreatic remnant. This was confirmed by an OGTT, and total pancreatectomy with autotransplantation of the Langerhans islets was performed in collaboration with IKEM Prague.

Conclusion

This case report shows that total pancreatectomy with islet autotransplantation may be an appropriate method of treat­ment for recurrent pancreaticopleural fistula in a situation where less radical procedures are not possible.

Acknowledgement

The National Institute for Research of Metabolic and Cardiovascular Diseases (Programme EXCELES, ID Project No. LX22NPO5104) –⁠ Funded by the European Union –⁠ Next Generation EU. Supported by MH CZ-DRO (“Institute for Clinical and Experimental Medicine –⁠ IKEM, IN 00023001”).

Conflict of interests

The authors declare that they have no conflict of interest related to the creation of this article, and that this article has not been published in any other journal with access to congress abstracts.