Multifocal granular cell tumour of the biliary tree

Abstract

Fewer than 90 cases of granular cell tumour (GCT) of the biliary tract have been reported, including only five cases of multiple GCTs. We present the unusual case of a 40-year-old woman with multifocal GCTs affecting the intrahepatic biliary tree, which were initially suspected to be hepatic multiple metastases from a malignancy of unknown origin. The surgical specimen consisted of a hepatic segment in which five whitish nodular lesions were observed. On microscopic examination, nodular lesions were found in the portal tracts; these were composed of large polygonal cells with abundant highly granular cytoplasm. The nuclei were small and centrally located. The tumour cells tested diffusely positive for CD68-PGM1, S100 protein and α-inhibin, so a diagnosis of multifocal GCT of the biliary tree was made. Three years later, the patient is still alive and a MRI has shown no changes.

Background

Granular cell tumour (GCT) of the biliary tree is infrequent, with the first case reported in 1952.¹ Since then, fewer than 90 cases of biliary tract GCT have been reported. These have usually been solitary masses, clinically confused with cholangiocarcinoma. Only five cases of multiple GCTs of the biliary system have been reported. We present the unusual case of a 40-year-old woman with a benign multifocal GCT of the intrahepatic biliary tree, which was initially suspected to be hepatic multiple metastases from a malignancy of unknown origin. The tumour was as an incidental finding in the course of imaging explorations motivated by an episode of acute appendicitis.

Case presentation

A 40-year-old woman without personal antecedents went to the emergency service having suffered the colic abdominal pain for 12 hours. A physical examination revealed the pain in the right iliac fosse with an unclear Blumberg’s sign, while abdominal ultrasonography showed no consistent signs of appendicular inflammation. Given this scenario, CT was carried out, followed by abdominal positron emission tomography-CT, revealing multiple hypodense space-occupying lesions of the liver. Although the hepatic parenchyma presented a metabolically homogeneous capture, the hypodense lesions were regarded as potential metastases from an unknown primary tumour (figure 1A). Blood analysis showed normal values of alkaline phosphatase, α-glutamyltransferase, aminotransferases and tumour markers including carcinoembryonic antigen, cancer antigen 19-9, cancer antigen 125 and α-fetoprotein. Initially, fine-needle aspiration cytology was performed on one hepatic lesion. Both the direct smears and H&E staining from the cell block sections showed very few normal hepatocytes, with there being insufficient material for diagnosis. The multidisciplinary liver tumour board of the hospital decided to carry out exploratory laparoscopy. In the course of the laparoscopic exploration, a hepatic segmentectomy was carried out and sent to the pathology department as an intraoperative biopsy.

Figure 1.

(A) CT revealing multiple hypodense space-occupying lesions of the liver, suspicious of being metastases from an unknown primary tumour. (B) Macro-micro vision of two sections of the hepatic surgical specimen, showing some whitish nodular lesions; original magnification. (C) Small portal tract with some large polygonal cells with abundant highly granular cytoplasm, consistent with GCT (×200). (D) Large focus of GCT surrounding a portal tract (original magnification ×200). GCT, granular cell tumour.

Grossly, the surgical specimen consisted of a hepatic segment measuring with a maximum diameter of 4.6 cm. After making serial cuts, five whitish nodular lesions were observed, measuring up to 6 mm in maximum diameter. On microscopic examination, all the nodular lesions were composed of large polygonal cells with abundant highly granular cytoplasm. The smallest nodular lesions were located in the portal tracts (figure 1B,C). The nuclei were small, dark, uniform and centrally located (figure 1D). Fewer than two mitoses per 10 high-powered fields were observed. The tumour cells tested diffusely positive for CD68-PGM1, S100 protein and α-inhibin (figure 2A,B). Immunostaining of Ki-67 was clearly <10% of the tumour cells (figure 2C). Immunostaining for glypican-3 and CD34 was negative (figure 2D,E). Based on the histological criteria of malignancy of GCT reported by Nasser et al,² a diagnosis of benign multifocal GCT of the biliary tract was made. Five months later, magnetic resonance cholangiopancreatography (MRCP) showed both the intrahepatic and extrahepatic bile ducts to have normal morphology and signals, without any evidence of lithiasis or any obstructing mass (figure 2F).

Figure 2.

(A) and (B) The tumour cells showing diffusely positive immunostaining for S100 protein and α-inhibin (original magnification, ×400 and ×100, respectively). (C) Ki-67 immunostaining, clearly <10% in tumour cells (original magnification ×400). (D) and (E) Immunostaining for glypican-3 and CD34 was negative (original magnification, ×100). (F) MRCP showing intrahepatic and extrahepatic bile ducts with both normal morphology and signal, without any evidence of lithiasis or obstruction. MRCP, magnetic resonance cholangiopancreatography.

Treatment

Given that this was a benign multifocal tumour, and impossible to remove the multidisciplinary liver tumour board of the hospital rejected surgical intervention and proposed follow-up monitoring, initially consisting of half-yearly checks and later annual revisions.

Outcome and follow-up

Subsequent to the histological diagnosis, it was decided to conduct half-yearly controls involving MRI. Now, 3 years later, the patient is still alive and the MRIs have shown no change in her condition.

Discussion

The first case of GCT tumour was reported by Abrikossoff in the skeletal muscle of the tongue.³ There has been considerable speculation about the origin of GCT based on histological and immunohistochemical findings. The cell type was initially thought to be the myoblast, hence the initial name of myoblastoma. Some years later, based on histological and histochemical studies, a neural origin was suggested by Bangle.⁴ More recently, electron microscopy has demonstrated that these lesions may actually be of Schwannian origin.⁵ Tumour cells test positivity for S100 protein and neuron-specific enolase, which are normally expressed in Schwann cells.⁶ GCT has been reported at any age, but it is most prevalent in people in their 50s and 60s, with a slight predominance in women and those of African-American origin. These tumours are typically solitary and take the form of painless nodules that are <3 cm in diameter. GCT has been found in almost every part of the body. The subcutaneous tissue of the chest and arms, and the head and neck regions are the sites most commonly affected, accounting for 45%–65% of cases.⁷

Microscopic analysis has revealed that GCTs are composed of a solid and diffuse population of large polygonal cells with a highly granular cytoplasm. These seem to infiltrate the surrounding tissues in the form of sheets of granular cells separated by fibroconnective tissue septa. In the cytoplasm, it is possible to observe some larger granules together with many small regular granules, all of which are strongly reactive to Periodic Acid-Schiff. Immunohistochemically, the tumour cells may be strongly immunolabelled with anti-S100, neuron-specific enolase, vimentin or other antibodies against Schwann cell-related antigens, like α-inhibin. The mitotic rate is usually very low and there are no signs of necrosis. GCT of the biliary tract is very rare, with the first case having been described by Coggins, during an autopsy on a patient with cirrhosis.¹ Since then, 82 cases of biliary tract GCT have been reported in the literature published in English. More than half of the reported cases (about 52%) of biliary tract GCTs have been observed in black women with a median age of 32 years (range, 14 to 91 years old). The most frequent sites are the common bile duct (58% of cases), common hepatic duct (23%), cystic duct (14%) and gallbladder (2.3% of cases).⁸ GCT of the biliary tract is more prevalent in slightly younger people and in women (female to male ratio, 5.3:1). In the literature reviewed, most of those affected had complained of jaundice (44.4%), abdominal pain (34.6%) or both (11.1%). There have also been some incidental findings during laparotomies or autopsies.

Many patients with GCT of the biliary tree are clinically and radiologically suspected of having cholangiocarcinoma prior to surgery. They, therefore, tend to be subjected to extensive interventions such as Whipple’s procedure. Other patients present as biliary strictures or primary sclerosing cholangitis. GCTs can usually be cured by a surgical excision leaving tumour-free margins, followed by hepaticojejunostomy. The vast majority of GCTs are benign tumours; malignant forms represent fewer than 2% of this kind of tumours. If completed excision is achieved, the patient usually has good prospects for long-term, disease-free survival. A long-term follow-up may be required to control any possible local recurrence. To date, however, there have been no reports of malignant biliary tract GCT.

Multifocal GCT of the biliary tree is even rarer than solitary biliary GCT, with only five cases having previously been reported.^{9 10} These cases mostly consisted of combinations of three GCTs affecting the cystic duct, common bile duct, gallbladder and even the head of the pancreas. In these previous reports, the patient was subjected to a cholecystectomy and an isolated resection of the distal and proximal common bile duct. To the best of our knowledge, the case that we report here is the first involving multiple, and almost countless numbers of, GCTs scattered throughout the liver. Provided that GCTs do not originate from epithelial cells but rather from schwannian tissue, we think that the multiple GCTs observed in our patient did not originate in the biliary ductal epithelia but probably came from neural tissue associated with the biliary tracts. We are of this opinion because the smallest foci of granular cells that we found in the liver in the case that we report here were located in intrahepatic portal triads, as shown in figure 1C. Our patient did not present any symptoms associated with persistent biliary stricture because she did not have any mass obstructing the extrahepatic bile duct; this was shown by MRCP performed 5 months after the biopsy (figure 2F). In the current case, the initial diagnosis suggested the possibility of metastases from an unknown primary tumour stemming from an incidental finding in the course of imaging explorations motivated by an episode of acute appendicitis. Given the benign nature of the tumours and the impossibility of surgical resection, the multidisciplinary liver tumour board of the hospital rejected the option of surgical intervention and instead proposed monitoring the case via half-yearly follow-ups.

In summary, GCTs of the biliary tree, which usually present symptoms of biliary obstruction symptoms like abdominal pain and jaundice, may also present as multiple space-occupying lesions of the liver. GCT should, therefore, be included in differential diagnoses of liver metastases from unknown primary tumours. Given that GCTs are usually benign neoplasms, expectant surveillance could be recommended in such clinical situations, depending on the liver function.

Learning points.

• Granular cell tumour (GCT) of the biliary tree is infrequent.

• GCT usually appears as a solitary mass and can be clinically confused with cholangiocarcinoma.

• GCT of the biliary tree may be observed as multiple intrahepatic lesions that resemble metastases from an unknown primary tumour.