Epidemiology, risk factors, diagnosis, and treatment of intra-abdominal traumatic neuromas - a narrative review

Traumatic neuroma (TN) is not a true neoplasm but an abnormal proliferation of injured nerves with scar tissues resulting from trauma, surgery, bleeding, or ischemia [1]. It may occur anywhere but is most common in the lower extremities, followed by the head and neck [2]. The first TN was reported by Odier in 1811 with veterans suffering from disabling pain in their amputated limbs [3, 4]. TN in the digestive system is rare and mostly occurs in the biliary tree after cholecystectomy or liver transplantation, known as traumatic biliary neuroma (TBN), because of the abundant nerve supply to the gallbladder, cystic duct, and hepatic ducts [5]. The first case involving the digestive system was described in 1928 by Husseinoff [6]. Most intra-abdominal TNs are asymptomatic [7, 8]. Some TBNs in cystic duct after cholecystectomy may cause biliary-type pain and result in post cholecystectomy syndrome [9, 10]. Only a few patients develop acute cholangitis or fatal graft dysfunction due to obstruction by a neuroma, presenting with jaundice [11‐15]. Other sites reported including celiac trunk, ampulla of Vater, pancreas, inferior mesenteric artery stump and rectal wall, etc. [2, 7, 8, 16, 17]. Although TN is a benign lesion, it is sometimes difficult to differentiate it from a malignant tumor, and some patients receive aggressive treatment. In this review, we collected a total of 93 cases of intra-abdominal TNs reported in the past 30 years in the literature and those diagnosed in our medical center in the past 20 years and determined the clinical and pathological characteristics and diagnostic and therapeutic approaches for intra-abdominal traumatic neuroma.

Owing to the lack of effective methods for preoperative diagnosis and the large proportion of asymptomatic patients, the incidence of TN may be underestimated [9]. Only a few European studies have reported the incidence of TBN after cholecystectomy or liver transplantation; the rest of the TNs in the abdomen are sporadic cases [2, 8, 17, 18].

One study reported that TBN was found in approximately 10% post cholecystectomy patients during autopsy [19]. Another postmortem study suggested that remarkable nerve proliferation in the remnant cystic duct was observed in almost 40% post cholecystectomy patients, 28% of whom had TBN [20]. In this review, we collected 32 cases of TBN after cholecystectomy (Table 1), including 4 patients who underwent laparoscopic cholecystectomy and 4 patients who underwent common bile duct exploration. The ratio of men to women was nearly 3:1 (23 males, 8 females and 1 unknown). The incidence is higher in males than females, which is in contrast to the fact that women develop cholecystolithiasis more often than men [21]. The incidence of TBN increases with age, nearly 70% patients are > 60 years of age. The median age at diagnosis was 64 years (range:39–81 years). The interval between cholecystectomy and the diagnosis varied from 2 months to 56 years. The median interval between the open cholecystectomy and TBN was 17 years. Over 65% patients diagnosed above 10 years after open cholecystectomy, which is consistent with another study’s result that the median time from surgery to diagnosis is more than 12 years in the subgroup of patients who underwent open cholecystectomy [12]. Compared with open cholecystectomy, rare cases have been reported after laparoscopic cholecystectomy. On the one hand, patients who receive open cholecystectomy usually suffer from severe cholecystitis or other complications, which may increase the difficulty of the surgery and risk of damaging bile ducts, nerves and arteries. However, given the long time from TBN formation to symptom onset, it is premature to conclude that the incidence of TBN after laparoscopic cholecystectomy is lower than that after open cholecystectomy.

Nine patients from our center were included in this study (8 males and 1 female). Patients who undergo cholecystectomy in our hospital receive regular follow-up, and the maximum follow-up time for asymptomatic patients is 10 years. Among these nine patients, five had TN during follow-up. Four patients showed no changes during the follow-up period, but were found to have TN after more than 10 years of follow-up and were treated again in our hospital. The patients ranged in age from 51 to 75 years, with a minimum onset time of 4 months and a maximum of 21 years after surgery. Seven patients had previously undergone open cholecystectomy, one had previously undergone laparoscopic cholecystectomy, and one had previously undergone resection of a congenital choledochal cyst. Abdominal pain was the main clinical manifestation in six patients, 2 patients, abdominal pain in two patients, and abnormal liver function in one patient.(Table 1).

Biliary stenosis is one of a common complication of liver transplantation (LT), with an incidence of 5% ~ 28% after deceased-donor transplant and 28% ~ 37% after living-donor transplant [22, 23]. A study from France reported that symptomatic and histologically proven TBN accounted for 9.6% of anastomotic biliary stenosis [24], which is similar to the study from Croatia on TBN, representing 6.1% of liver re-transplantation [15]. As for the incidence of TBN after LT, the results vary from 0.6 to 9.2% in different studies (Table 2) [9, 15, 25, 26]. When it comes to the symptomatic TBN, the incidence is even lower from 0.5% ~ 2.8% [9, 25]. There are totally 56 cases in this review (Table 2). Similar to TBN after cholecystectomy, the incidence was much higher in male than female with a ratio at 4 of 1. The interval between the diagnosis of TBN and first transplantation ranged from 1 to 239 months. Although the time span is quite long, more than 50% TBN diagnosed within one year of the first transplantation. The median time to diagnosis of TBN varies from 6 to 69 months [15, 24, 25]. There is discrepancy in the median time from surgery to diagnosis after liver transplantation of different studies, but it’s notably shorter than neuromas diagnosed after cholecystectomy [9, 15]. Among the 30 patients with certain types of biliary reconstruction, only one underwent hepaticojejunostomy and the rest underwent duct-to-duct anastomosis.

TN also occurres after other abdominal surgeries, including gastrectomy, polypectomy and, rectal cancer surgery(Table 3) [2, 7, 8, 27]. One patient did not have a history of surgery, but suffered from blunt abdominal trauma [18].

Normally, the continuity between the two ends of a severed nerve is re-established by the orderly growth of axons from the proximal to the distal stump through tubes of proliferative Schwann cells. When the nerve ends are far apart or missing stumps, which prevent the reestablishment of neural continuity, hyperplastic proliferation of axons mixing with Schwann cells in a fibrocollagenous stroma develops into TN at the proximal end of the injured nerve [26]. The mechanism of this dysregulating growth pattern still remains unclear, athough a few studies have reported increasing levels of fibroblast growth factor and its receptor in TN [19, 28]. Targeting the pathophysiology of TN, He et al. found that chondroitin sulfate proteoglycans (CSPGs) can inhibit the formation of TN by blocking irregular axon regeneration in the proximal nerve stump. Kryger et al. found that trkA-IgG (an inhibitor of nerve growth factor) can reduce the information of TN in a rat model, but further research is still needed [29, 30].

Surgery is the primary risk factor for TN. Surgical manipulations, including excessive exploration, thermocoagulation, and vascular ligation, which may damage the surrounding nerves or arteries, can increase the risk of TN [1]. As many sympathetic and parasympathetic nerves are located outside the wall of the bile ducts, most TBN are extraluminal. However, if the common duct or hepatic duct is damaged during a careless or difficult surgery, intraluminal proliferation of nerves associated with an inflammatory scar can occur [31, 32], which may cause bile duct obstruction at the early stage after surgery. Three patients (two with laparoscopic cholecystectomy and one with open cholecystectomy) had bile duct injury during cholecystectomy and were diagnosed with TBN within 3 months, which was significantly different from the long interval time of cholecystectomy. With progress in laparoscopic techniques, laparoscopic cholecystectomy has been applied to a wider range of patients. When performing difficult laparoscopic cholecystectomy for acute cholecystitis, bailout procedures could be helpful in preventing bile duct injury, which theoretically decreases the incidence of TBN [33].

The situation is much more complicated with regard to TBN after LT. The origin of TBN after transplantation is still controversial, with some suggesting that it arises from the recipient bile ducts because most TBNs reported after LT occurred in patients who had duct-to-duct biliary reconstructions and less frequently occurred after bilioenteric reconstruction, since nerve regeneration originated from the proximal nerve ending [5, 24]. Others considered that it may arise from the recipient, or from the donors’ nervous tissue, on account of the small bifurcating nerve trunks seen in the perihilar intrahepatic septa during histological examinations of allografts with hilar neuromas, which indicates the survival of donors’ innervation [9, 26].

A few studies found that the number of nerve fibers decreased immediately after severing of the main hilar trunks; then, it increased due to proliferation and reinnervation in the post-transplant period [34, 35]. This result is consistent with the fact that the incidence of TBN is much higher in patients more than 3 months after transplantation [9]. Immunosuppressors may play an important role in accelerating nerve proliferation and reinnervation. Tacrolimus was found that could improve neurologic recovery and enhance axon regeneration by its neurotrophic and immunosuppressive actions after peripheral nerve injures [36], what’s more, the another common immunosuppressor, cyclosporine, was also found that had a promotion in axon growth of the recipient proximal nerve endings into nerve allografts in rats [37]. Therefore, immunosuppressants may be risk factors for TBN.

Besides surgical manipulations and immunosuppressants, infections, foreign bodies, trauma, ischemia, and scarring may also contribute to the formation of TBN [18, 38]. The continuity of the nerve can also be inhibited by granulation and fibrous tissue arising from the surrounding blood vessels and adjacent soft tissues [26]. There are also a few neuromas in the bile duct without any history of surgery or trauma; it might be postulated that bile or cholesterol are the inciting stimuli for fibrous and neural proliferation [31, 38].

There are several classification methods that are based on various factors. Nerve continuity is the most commonly used method. End-bulb neuroma (EBN), also known as terminal neuroma or stump neuroma, is a bulbous enlargement from the end of a completely disrupted nerve. Neuroma-in-continuity (NIC), also called spindle neuroma, results from partial nerve transection [39‐43], and is divided into two pathological types: spindle neuromas with intact perineurium or lateral neuromas that occur after partial disruption of the perineurium and after nerve repairs [44]. This is similar to the results of Colina et al. that if the perineurial continuity of injured axons is preserved, encapsulated neuroma occurs macroscopically as small white-gray nodules macroscopically [9, 10] If the continuity of the perineurium is interrupted, branching axons would invade the mesenchyme, resulting in uneven thickening of duct walls [9]. Herrera et al. classified TBN into two types according to its pathological characteristics and location: type I originates from and is located in the main biliary tract wall, while type II originates from the surrounding tissues next to the main biliary tract [25]. They suggested that this type of classification is useful for treatment decision making.

A flow chart of the diagnostic and management options for TN is shown in Fig. 4. The management of TNs should differ according to their location and symptoms. Regular follow-up is recommended [58, 67]. Regarding patients who only developed abdominal pain without biliary obstruction, Topazian et al. reported that patients experienced temporary relief of pain after injection of bupivacaine and triamcinolone under EUS-guided, but the security and effectiveness still need further confirmation [73]. Surgery is not recommended because pain can recur after resection of TBNs [73‐75].

Surgery and interventional management are the most common treatments for patients with biliary obstructions. Several authors suggested that surgery was optimal choice for symptomatic patients of TBN [15, 16, 24]. Among all cases reviewed in this article, resection of the lesion with hepaticojejunostomy was the most common surgical procedure, accounting for 47.1%. Resection followed by duct-to-duct anastomosis occurred in the second place, accounting for approximately 20% patients. Navez et al. considered hepaticojejunostomy to be the best type of biliary reconstruction, based on the fact that the incidence of TBN was higher in patients who underwent duct-to-duct anastomosis during the first liver transplantation, and as a result, it seemed more likely for TBN to recur after duct-to-duct anastomosis [24]. None of the patients who underwent duct-to-duct anastomosis experienced recurrence during the follow-up. The best method for biliary reconstruction requires further study and more precise evidence. Some patients underwent much more aggressive surgeries, including periportal lymphadenectomy, pancreaticoduodenectomy, and hemihepatectomy, owing to difficulties in distinguishing them from biliary malignancies [1, 16, 28, 76]. Frozen section examination during surgery is useful for confirming diagnoses to avoid unnecessary extensive resections [5, 7, 77]. In addition, almost 20% of patients with TBNs after liver transplantation receive retransplantation for reasons of liver failure or rejection [15, 25].

Interventional management consists of two parts. One is preoperative drainage to relieve jaundice, including endoscopic drainage and percutaneous transhepatic drainage under ultrasound or radiologic guidance. The second part aimed to solve the stricture of the bile ducts, including balloon dilatation and stent placement. However, the effects of the interventional treatments did not improve. Multiple cases reported failure of biliary stenting or balloon dilatation for relieving biliary obstruction in the long term [12, 15, 24‐26, 28, 78]. Fibrotic nature and poor compressibility may account for these unsuccessful outcomes. In addition, repetitive invasive interventions may accelerate the formation, resulting in an early biliary structure [78]. As for TN located in the gastrointestinal tract, a few authors considered that it was effective to achieve en bloc resection by endoscopic mucosal resection [8, 69].

Although TN is a benign lesion, it is sometimes difficult to differentiate it from a malignant tumor. TN lacks the typical clinical characteristics. Therefore, it is necessary to make a comprehensive judgment based on the patient’s medical history, clinical manifestations, and imaging findings. If necessary, needle biopsy can be performed to confirm the diagnosis. Conservative treatment is recommended for patients with TN without biliary obstruction. If biliary obstruction occurs, surgical or interventional treatment is necessary.