EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Traumatic neuromas of the biliary tract have occasionally been reported to cause strictures at the cystic duct stump as a late complication of cholecystectomy with common bile duct exploration. The incidence of symptomatic traumatic biliary neuroma appears to be low after orthotopic liver transplant, as only 25 patients have been described previously in the English-language literature. Traumatic (amputation) neuroma is a reactive proliferation of pericholangial nerve fibers induced by injury, but it is not a true neoplasm. The diagnosis of traumatic neuroma is possible only by histopathologic examination; the diagnostic finding is a mass of hyperplastic nerve bundles. We report a patient with a traumatic neuroma causing an early biliary stricture with intrahepatic extension after an orthotopic liver transplant. The lesion failed to respond to repeated endoscopic stenting and eventually required hepaticojejunostomy. A biopsy of the liver graft, performed in the 13th month after transplant, showed chronic ductopenic rejection.

Key words : Amputation neuroma, Chronic ductopenic rejection, Pericholangial nerve fibers, Repeated endoscopic stenting

Biliary strictures are among the major complications following orthotopic liver transplant (OLT), with a reported incidence of 5% to 28% after deceased-donor transplant and 28% to 37% after living-donor transplant. They are commonly seen as a late complication, occurring approximately 5 to 8 months after OLT.^1,2 Although traumatic neuromas of the biliary tract have been well described after cholecystectomy,³ it is unusual for a traumatic neuroma to cause a stricture of the biliary tract after OLT. This rarity may pose difficulties with diagnosis and prognostication. We report a patient with a traumatic neuroma causing an early biliary stricture and acute cholangitis with mild acute cellular rejection. Within several months of the transplant, the patient experienced chronic ductopenic allograft rejection.

A 17-year-old girl underwent OLT for autoimmune hepatitis that progressed to cirrhosis; the donor was her uncle. She underwent duct-to-duct biliary reconstruction during the transplant procedure. On postoperative day 15, she underwent revision of the biliary anastomosis for anastomotic leakage, and on postoperative day 17, she underwent plastic biliary stenting. Repeated endoscopic stenting and nasobiliary drainage procedures were performed for biliary anastomotic leakage. The liver graft was biopsied several times for persistent elevated transaminase and bilirubin levels. The biopsies showed conspicuous hepatocanalicular cholestasis and acute cholangitis, with mild acute cellular rejection. A biliary stricture at the level of the anastomosis was detected by percutaneous transhepatic cholangiography 3 months after the transplant (Figure 1). Nearly total anastomotic obstruction was corrected by resecting the bile duct stricture and performing a Roux-en-Y hepaticojejunostomy 7 months after the transplant. Gross examination of the distal choledochotomy section revealed thickening of the wall throughout the full length (1.6 cm), with intrahepatic extension. Histopathologic examination revealed nerve-like nodular structures, nearly 4 mm in diameter, penetrating deep into the wall of the biliary tract (Figure 2). There was a haphazard proliferation of pericholangial nerve fibers in the fibromuscular layer of the bile duct. Infiltrating nerve fibers were seen up to the peribiliary glands and were associated with findings of acute cholangitis (Figure 3). Abundant nerve fascicles, mainly composed of Schwann cells that stained positive on immunohistochemistry for S 100 protein (Figure 3), intermingled occasionally with the collagen bundles. The pathologic diagnosis was traumatic neuroma of the bile duct.

The patient received standard immunosuppressive therapy with prednisolone, tacrolimus, and mycophenolate mofetil. With each episode of acute graft rejection, she received intravenous methylprednisolone, 2 × 200 mg for 7 consecutive days. The patient remained well, without signs of stricture recurrence, until the third month after the hepaticojejunostomy when her liver-graft function began to steadily deteriorate, to the point where she required listing for retransplant. Her most recent biopsy, performed 13 months after OLT, showed chronic ductopenic rejection.

Only 2 case series of symptomatic traumatic biliary neuroma (TBN) after OLT have been reported. In the first, the authors described 15 patients with TBN in a series of 428 OLT patients; the incidence of symptomatic and histologically proven TBN was 3.5%.⁴ The other series described 5 patients with TBN out of 52 patients who developed an anastomotic biliary stricture after OLT. All 5 patients with TBN had a duct-to-duct biliary reconstruction during OLT and subsequent repeated surgical procedures. Of a cohort of 1030 consecutive patients who underwent OLT, the incidence of symptomatic TBN was 0.5%, representing 9.6% of the anastomotic biliary strictures observed.⁵ Another study revealed 26 cases of hilar TBN in 93 hepatectomy specimens (27.9%) obtained between 3 and 26 months after OLT, although only a single patient (1.3%) was symptomatic. The authors found that the incidence of neuroma is higher in specimens resected more than 3 months posttransplant.⁶ In our patient, a symptomatic biliary stricture developed at the level of the anastomosis in the first 3 months after transplant. We believe that she developed an early biliary structure because of repetitive invasive interventions and episodes of acute cholecystitis that triggered recurrent episodes of acute rejection. Her liver graft developed chronic ductopenic rejection only 13 months after OLT. There is only a single reported patient with a course similar to ours. This patient’s liver graft developed chronic rejection 45 months after resection of the TBN with hepaticojejunostomy. The patient underwent retransplant 63 months after the original procedure.⁴

The clinical and imaging features of TBN are usually nonspecific; the only valid diagnostic modality is histologic analysis. Because of the move toward conservative treatment of late biliary strictures, many patients are no longer treated surgically, and a true assessment of the incidence of TBN is impossible.⁵ Owing to the possibility of progression to chronic rejection and the lack of specific imaging features for a preoperative diagnosis of TBN, physicians must be mindful of the possibility of TBN when facing an unexplained anastomotic biliary stricture after OLT.

A TBN consists of a benign exaggerated proliferation of nerve bundles caused by inappropriate regeneration after nerve transection. It has been hypothesized that division of the common bile duct may trigger such inappropriate regeneration because of its large amount of surrounding innervation, thus causing the development of TBN. The use of calcineurin inhibitors is a possible pathophysiologic factor in TBN formation. Tacrolimus, in particular, may play a role in TBN development. Some studies have suggested that it acts as a neuroprotective agent and improves neurologic recovery after peripheral nerve and spinal cord injuries through its immunosuppressive and neurotrophic actions. It has a powerful effect on promoting axon regeneration.⁷ However, there is so far no evidence showing a relation between neuroma development and treatment with calcineurin inhibitors. It may be worthwhile to explore whether expansion of anticalcineurin immunosuppressive regimens has an effect on the incidence of TBN.

Traumatic neuroma should be considered in the differential diagnosis of an early or late unexplained anastomotic biliary stricture after OLT, particularly when the structure occurs in the setting of early postoperative complications of the biliary anastomosis. If TBN causing biliary stricture is not promptly diagnosed and treated, it may trigger recurrent episodes of acute cholangitis, with acute rejection attacks resulting in chronic ductopenic allograft rejection within months.

Volume: 15 Issue: 1 February 2017 - Supplement - 1

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