Granular cell tumor is an uncommon, largely benign neoplasm that most likely originates from a Schwann-like mesenchymal cell. Malignant transformation has been described, but is quite rare. Granular cell tumors are usually found in the subcutaneous tissue of the chest and upper extremities, tongue, and gastrointestinal tract.1 When granular cell tumors develop in these externally or endoscopically accessible locations, histologic diagnosis is easily established based upon typical morphologic and staining characteristics after tissue biopsy or excision. In a structure such as the bile duct, accessibility is more difficult and, therefore, it delays diagnosis. Furthermore, the tumor mimics more common biliary stricturing conditions clinically and radiologically, and more readily causes obstruction, resulting in compromised hepatic function. Thus far, 76 cases of bile duct granular cell tumor have been reported in the English literature.
We present the case of a 16-year-old African-American female with a granular cell tumor in the extrahepatic bile duct that was initially suspected to be a choledochal cyst based upon clinical findings. The lesion led to significant liver failure requiring orthotopic liver transplant. In this case report, we also examine other reported cases of biliary granular cell tumor in terms of patient age, gender, race, presenting symptoms, and the precise locations of the tumor within the extrahepatic biliary system.
Case Report
A 16-year-old, Jehovah's witness, African-American female presented with a 4-month history of increasing right upper quadrant abdominal pain, jaundice, fatigue, ascites, and hepatomegaly. The patient had an elevated total bilirubin level of 6.4 mg/dL (normal, 0.2–1.3 mg/dL), an elevated direct bilirubin level of 5.2 mg/dL (normal, 0–0.4 mg/ dL), an elevated alkaline phosphatase level of 580 U/L (normal, 30–125 U/L), an elevated gamma-glutamyl transpeptidase level of 1,171 U/L (normal, 14–51 U/L), an elevated serum glutamic oxaloacetic transaminase level of 173 U/L (normal, 3–44 U/L), and an elevated serum glutamic pyruvic transaminase level of 52 U/L (normal, 0–40 U/L). This profile was consistent with obstructive jaundice. The patient also had an elevated international normalized ratio of 1.86 and an elevated prothrombin time of 40 sec (normal, 23–33 sec). Initial work-up for possible causes of hepatomegaly and jaundice revealed a negative viral and autoimmune profile with the exception of a positive cytomegalovirus immunoglobulin (Ig)G antibody, Epstein-Barr virus IgG antibody, and varicella IgG antibody indicating past exposure. Ceruloplasmin and alpha-fetoprotein were within normal limits.
Abdominal ultrasound showed fusiform dilatation of the common bile duct with right and left intrahepatic ductal dilatation. Computed tomography scan showed a markedly enlarged liver and spleen with massive intra- and extrahepatic biliary dilatation (Figure 1). This pattern was radiologically suggestive of a choledochal cyst type IV.
Figure 1.
Postcontrast computed tomography scan showing massive intra- and extrahepatic biliary dilatation. The common bile duct (CBD) is displayed centrally.
At the time of presentation, the patient opted not to undergo a liver biopsy due to her anemia, coagulopathy, and religious beliefs preventing the use of blood products. Despite efforts to correct her anemia and nutritional issues, her symptoms and liver functions worsened significantly over the subsequent 8 months. Therefore, an orthotopic liver transplant was performed.
Pathologic Findings
The explanted liver examined in the pathology laboratory was a 2,750-g, 28-cm × 24-cm × 9.8-cm liver with an attached 7.0-cm × 4.0-cm × 0.3-cm gallbladder (Figure 2). The surface of the liver was cholestatic, finely fibrotic, and nonbosselated. Serial sectioning of the liver showed diffuse cholestasis, fine fibrosis, and visibly enlarged portal areas with markedly dilated ducts. The distal common bile duct was concentrically thickened by a 1.5-cm × 1-cm × 1-cm tan yellow mass resulting in an extremely narrow lumen (Figure 3). The proximal bile duct was significantly dilated, corresponding to the dilated common bile duct seen on abdominal ultrasound and computed tomography scan.
Figure 2.
Gross photograph of the explanted liver showing fine fibrosis and cholestasis without any bosselations.
Figure 3.
Gross photograph showing the concentrically thickened common bile duct with an extremely narrow lumen (center of the photograph).
Upon microscopic examination, the mass from the distal bile duct showed a transmural diffuse neoplastic infiltrate (Figure 4). The infiltrate was composed of sheets and clusters of large, ovoid-to-round cells separated by thin fibrous connective tissue septa. The cells had abundant granular eosinophilic cytoplasm and small uniform hyperchromatic nuclei. There was minimal pleomorphism without any mitotic activity or necrosis. Morphologically, these findings were characteristic of granular cell tumor.
Figure 4.
Microphotograph of the bile duct showing monomorphic tumor cell infiltrate in the submucosa and the lamina propria of the mucosa (hematoxylin and eosin stain).
Microscopic examination of the liver showed characteristic changes of a secondary biliary cirrhosis with extensive bridging fibrosis extending from portal tract to portal tract, cholestasis, and cholangiolar proliferation (Figure 5).
Figure 5.
Microphotograph of the liver showing extensive bridging fibrosis, cholangiolar proliferation, and cholestasis (hematoxylin and eosin stain).
Ancillary Studies
Unsurprisingly, the tumor was positive for periodic acid-Schiff stain pretreated by diastase digestion. The tumor cells were strongly positive for S-100 immunohistochemical stain (Figure 6). Electron microscopy revealed the presence of numerous intracytoplasmic lysosomes filled with lipid material, including microtubules thought to be related to myelin.2,3 These ancillary studies confirmed the morphologic diagnosis of granular cell tumor.
Figure 6.
Microphotograph of the S-100 immunohistochemical stain positivity of the tumor cells.
Discussion
Granular cell tumor was first described in the oral cavity by Abrikosoff in 1926.4 Abrikosoff initially called the lesion “granular cell myoblastoma” due to the belief that it originated from striated muscle.4 The lesion was then noted to develop adjacent to peripheral nerves and, therefore, termed “granular cell neuroma.”5 Later on, electron microscopy demonstrated that the lesion may actually be of Schwannian origin due to lysosomes containing myelin-like tubules and cytoplasmic processes surrounded by layers of basal lamina reminiscent of Schwann cells.3 Immunohistochemistry revealed that the tumor was positive for S-100 and neuron-specific enolase and negative for desmin and smooth muscle actin, supporting the possibility of Schwannian origin.6Until the exact origin is identified, the tumor is best described as a granular cell tumor.
Typically, granular cell tumors present as solitary, yellow-tan, painless nodules less than 3 cm in their greatest dimension. They can develop at any age but are more prevalent among people in their 40s and 50s. There is also a slight female and African-American predominance.1Granular cell tumors most commonly develop in the dermis and subcutaneous tissue of the chest and upper extremities. After the skin and subcutis, the next most common site is the tongue, accounting for approximately 40% of cases.1 These lesions are relatively rare in the gastrointestinal tract, accounting for 5–9% of reported cases.1Within the gastrointestinal tract, they are primarily found within the esophagus, followed by the colon, stomach, small intestine, and anal canal.7 Less than 1% have been reported to develop within the biliary tree.
The first biliary case was described by Coggins in 1952 during the autopsy of a patient with alleged Laennec's cirrhosis.8 Since then, there have been 76 reported cases within the literature, which indicates the rarity of the disease in this location (Table 1).1 Despite its rarity, granular cell tumor is the most common benign nonepithelial tumor of the extrahepatic biliary tract occurring more commonly in the bile duct than the gallbladder.9Within the biliary tree, 63% of the cases have occurred in black women, at a median age of 32 years (range, 14–91 years).1 Typically, most patients (95%) have presented with abdominal pain and/or jaundice (Table 2). Only 2 cases were found incidentally at autopsy or during an exploratory laparotomy while resecting colorectal cancer. Many patients were clinically suspected of having cholangiocarcinoma prior to surgery and, therefore, underwent extensive procedures such as a Whipple procedure. Other presentations included suspected metastatic melanoma, primary sclerosing cholangitis, and biliary strictures. Due to the rarity of the disease, patients are usually misdiagnosed with another entity such as a choledochal cyst, based upon similar characteristic radiologic findings of intra- and/or extrahepatic dilatation. However, many conditions obstructing this narrow lumen structure can create the clinical picture of a choledochal cyst. The differential diagnosis of such obstructive lesions includes cholangiocarcinoma, primary sclerosing cholangitis, biliary stricture, polyps, papillomas, adenomas, choledochal cysts, and, infrequently, granular cell tumors.1
Table 1.
Reported Cases of Biliary Granular Cell Tumors
| Reference | Age (years) | Gender | Race | Symptoms | Location |
|---|---|---|---|---|---|
| This case report* | 16 | F | B | Jaundice/pain | CBD |
| Zaidi (J Coll Physicians Surg Pak. 2007;17:572-573.) | 39 | F | – | Jaundice | CBD |
| Lochan (Surg Today. 2006;36:934-936.) | 51 | F | – | Jaundice | CHD |
| Tonsi (Minerva Chir. 2006;61:247-255.) | 26 | M | B | Jaundice/pain | CBD |
| Hoda (Acta Cytol. 2005;49:199-203.) | 24 | F | B | Jaundice | CBD |
| 38 | F | B | Jaundice | CHD | |
| Altavilla (Ultrastruct Pathol. 2004;28:171-176.) | 39 | M | W | Jaundice | CBD |
| Heuer (Z Gastroenterol. 2004;42:323-325.) | 26 | F | – | Jaundice | CBD |
| Reynolds (J Ped Surg. 2000;35:652-654.) | 14 | F | B | Fatigue | CBD |
| Karakozis (Surgery. 2000;128:113-115.) | 32 | F | B | Pain | CD |
| 40 | F | B | Pain | CBD | |
| 63 | F | B | Pain | CBD | |
| Te Boekhorst (Dig Surg. 2000;17:299-303.) | 37 | M | W | Jaundice/pain | CHD/HD |
| 43 | F | W | Fatigue/cholestasis | CHD/HD | |
| Ogawa (J Jpn Surg Assoc. 1999;60:183-187.) | 83 | F | A | Incidental finding | CD |
| Fairchild (Transplantation. 1999;68:315-317.)* | 34 | F | – | Jaundice | CHD |
| Dusoleil (Gastroenterol Clin Biol. 1999;23:993-994.) | 35 | M | W | Jaundice | CBD |
| Aubert (Gastroenterol Clin Biol. 1999;23:1090-1093.) | 22 | F | W | Jaundice | CBD |
| 38 | F | W | Jaundice | CBD | |
| Butler (Am Surg. 1998;64:1033-1036.) | 31 | F | B | Jaundice | CBD/CHD/CD |
| Ferri Romero (Rev Esp Enferm Dig. 1994;85:217-219.) | 44 | M | W | – | CD |
| MacKenzie (Med Pediatr Oncol. 1994;23:50-56.) | 33 | F | B | Jaundice/pain | CBD/CHD/CD |
| 53 | F | B | Jaundice/pain | CBD | |
| Foulner (Clin Radiol. 1994;49:503-504.) | 38 | F | W | Pain | CD |
| Yang (South Med J. 1993;86:478-479.) | 32 | F | B | Jaundice | CHD |
| Yazdanpanah (Gastroenterol Clin Biol. 1993;17:607.) | 33 | M | W | – | CBD |
| Lewis (HPB Surg. 1993;6:311-317.) | 27 | F | W | Jaundice/pain | CHD |
| Mulhollan (Am J Surg Pathol. 1992;16:204-206.) | 35 | F | B | – | CHD |
| LaFreniere (J Surg Oncol. 1991;46:60-66.) | 32 | F | B | Pain | CHD/CD |
| Eisen (Am J Surg Pathol. 1991;15:460-465.) | 24 | F | B | Jaundice | CBD |
| 24 | M | W | Jaundice | CBD | |
| Sanchez (Am Surg. 1991;57:446-450.) | 29 | F | B | Jaundice | CHD |
| Timberlake (Mil Med. 1988;153:98-99.) | 44 | F | W | Pain | CD |
| Butterly (Surgery. 1988;103:328-334.) | 26 | F | W | Pain | CHD |
| 37 | F | B | Jaundice | CHD | |
| Hobbiss (J R Coll Surg Edinb. 1987;32:117-118.) | 31 | F | B | Pain | CD |
| Cheslyn-Curtis (Postgrad Med J. 1986;62:96-103.) | 38 | F | W | Pain | CHD/CD |
| Kienzle (Dtsch Med Wochenschr. 1986; 111:197.) | 33 | F | – | Pain | CBD |
| Yamaguchi (Acta Pathol Jpn. 1985;35:687-691.) | 58 | M | A | Pain | GB |
| Yamashina (Am J Gastroenterol. 1984;79:701-703.) | 37 | F | A | Pain | CD |
| Barber (J R Coll Surg Edinb. 1984;29:56-57.) | 38 | F | – | Pain | CD |
| Chandrasoma (Cancer. 1984;53:2178-2182.) | 43 | F | B | Jaundice | CBD |
| Orenstein (Am J Surg. 1984;147:827-831.) | 31 | M | B | Pain | CD |
| 91 | F | B | Jaundice | CBD | |
| Balart (Am J Gastroenterol. 1983;78:297-300.) | 56 | F | B | Jaundice/pain | CBD |
| Aisner (Arch Pathol Lab Med. 1982;106:470-471.) | 41 | F | B | Pain | GB/CD/CBD |
| Penalba (Ann Chir. 1982;36:723-726.) | 22 | F | B | Jaundice | CBD |
| Dewar (Gut. 1981;22:70-76.) | 28 | F | W | Jaundice | CBD |
| Manstein (Dig Dis Sci. 1981;26:938-942.) | 31 | F | B | Jaundice | CBD |
| Mauro (J Can Assoc Radiol. 1981;32:254-256.) | 38 | F | B | Jaundice | CHD/CD |
| Bocquet (Arch Anat Cytol Pathol. 1980;28:360-364.) | 21 | F | B | Jaundice | CBD |
| Jain (Am J Gastroenterol. 1979;71:401-407.) | 46 | F | B | Pain | CBD |
| Assor (Am J Surg. 1979;137:673-675.) | 31 | F | B | Pain | CD |
| 33 | F | B | Jaundice | CBD | |
| 37 | F | B | Pain | CBD | |
| Farris (Arch Pathol Lab Med. 1979; 103:510-512.) | 23 | F | B | Jaundice/pain | CD |
| 31 | F | B | Pain | CBD | |
| Zvargulis (Am J Dis Child. 1978;132:68-70.) | 11 | M | B | Jaundice | CBD |
| Raia (AMB. 1978;24:379-380.) | 30 | M | W | Jaundice | CBD |
| Ishii (Am J Gastroenterol. 1977;68:38-44.) | 39 | F | A | Pain | CBD |
| Savage (Postgrad Med J. 1977;53:574-577.) | 30 | F | W | Jaundice | CBD |
| Reul (Am J Surg. 1975;129:583-587.) | 39 | F | B | Pain | CD |
| Kittredge (Am J Radiol. 1975;125:35-46.) | 41 | F | B | Jaundice/pain | CHD/CD |
| Dursi (Rev Surg. 1975;32:305-310.) | 30 | F | B | Jaundice | CBD |
| Whisnant (Am J Dig Dis. 1974;19:471-476.) | 15 | M | B | Jaundice | CBD |
| LiVolsi (Arch Pathol. 1973;95:13-17.) | 30 | F | B | Jaundice | HD |
| 40 | F | W | Pain | CD | |
| Abt (Mt Sinai J Med. 1971;38:457-461.) | 44 | F | B | Pain | CD |
| Christiansen (Arch Pathol. 1970;90:423-432.) | 34 | F | W | Pain | CD |
| Whitmore (Am J Dig Dis. 1969;14:516-520.) | 37 | F | B | Jaundice | CBD |
| 61 | F | B | Autopsy | CBD | |
| McKay (Can J Surg. 1968;11:44-51.) | 34 | F | – | Pain | CD |
| Goldman (JAMA. 1967;200:1185-1186.) | 14 | F | B | Pain | CD |
| Serpe (Am J Dig Dis. 1960;5:824-826.) | 34 | F | B | Pain | CD |
| Duncan (Ann Surg. 1957;145:271-274.) | 30 | F | B | Jaundice | CBD |
| Fialho (Rev Bras Med. 1952;9:616-618.) | 21 | F | B | Pain | CD |
| Coggins (Arch Pathol. 1952;54:398-402.) | 25 | F | B | Jaundice | CBD |
- A=
Asian
- B=
black
- CBD=
common bile duct
- CD=
cystic duct
- CHD=
common hepatic duct
- F=
female
- GB=
gallbladder
- HD=
hepatic duct
- M=
male
- W=
white
Transplanted cases.
Table 2.
Reported Cases of Biliary Granular Cell Tumors Summarized by Age, Gender, Race, Clinical Symptoms, and Location
| Number of cases | Percent | ||
|---|---|---|---|
| Age (years) | <20 | 5 | 6.5% |
| 20–29 | 15 | 19.5% | |
| 30–39 | 39 | 50.6% | |
| 40–49 | 10 | 13.0% | |
| ≥50 | 8 | 10.4% | |
| Gender | Male | 12 | 15.6% |
| Female | 65 | 84.4% | |
| Race | Black | 47 | 61.0% |
| White | 19 | 24.7% | |
| Asian | 4 | 5.2% | |
| Unknown | 7 | 9.1% | |
| Clinical symptoms | Jaundice | 33 | 42.8% |
| Jaundice and pain | 9 | 11.7% | |
| Pain | 28 | 36.4% | |
| Fatigue | 2 | 2.6% | |
| Incidental | 2 | 2.6% | |
| Unknown/not listed | 3 | 3.9% | |
| Location | CBD | 38 | 49.4% |
| CD | 19 | 24.6% | |
| CHD | 9 | 11.7% | |
| HD | 1 | 1.3% | |
| GB | 1 | 1.3% | |
| Multiple sites | 9 | 11.7% | |
- CBD=
common bile duct
- CD=
cystic duct
- CHD=
common hepatic duct
- GB=
gallbladder
- HD=
hepatic duct
Microscopically, these tumors are composed of polygonal cells with granular eosinophilic cytoplasm and small vesicular nuclei.1 These granules within the cytoplasm react to periodic-acid Schiff and S-100 staining. They appear as clusters or sheets and infiltrate diffusely within the surrounding tissue separated by thin fibroconnective tissue septa. Typically, mitoses are rare, with no necrosis present. Reactive atypia of the overlying epithelium and metaplastic pyloric glands may occur, mimicking carcinoma.9 Malignant granular cell tumors are quite rare but have been described within the subcutis and dermis showing rapid growth, a size greater than 4 cm, necrosis, pleomorphism, infiltrative edges (rather than pushing borders), and increased mitotic index.10-12 Thus far, no malignant biliary granular cell tumors have been described.1 Two cases have shown local recurrence but were likely secondary to incomplete removal.13,14
Within the biliary tree, these lesions can cause obstruction by concentric narrowing of the bile duct. As with all causes of biliary obstruction, over time, the long-term effect will be secondary biliary cirrhosis, if left untreated.15 Rarely, the secondary biliary cirrhosis may cause liver failure requiring transplantation, as in our patient. In the literature, only 1 other case of transplantation has been described of a granular cell tumor of the bile duct causing severe secondary biliary cirrhosis with liver failure due to a lack of suspicion and correct diagnosis in a timely manner.15
Typically, the accepted treatment for granular cell tumors in this location is surgical excision with tumor-free margins followed by hepaticojejunostomy.1 Treatment with percutaneous or endoscopic stents is only used for temporary decompression.1 If complete excision is obtained, the patient typically has good tumor-free long-term survival, as with our patient 21 months postsurgery. However, these patients do require long-term follow-up care for possible local recurrence and the potential for severe secondary effects requiring transplantation.15
Summary
Granular cell tumors of the biliary tree are rare benign lesions typically occurring in young African-American women initially presenting with abdominal pain and jaundice. The lesions are often clinically misdiagnosed as a more common disorder such as choledochal cyst, but physicians should be aware that the lesions may be granular cell tumors. Timely intervention with limited local excision in such cases may prevent secondary long-term damage to liver function and the need for transplantation.
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