Pathology in Practice

Stephanie E. Howell Capital Veterinary Specialists, Jacksonville, FL 32257.

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Steven Neihaus Capital Veterinary Specialists, Jacksonville, FL 32257.

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Sunil More Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 30602.

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William F. Craft Department of Comparative, and Population Medicine, College of Veterinary Medicine, University of Florida, Gainesville, FL 30602.

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History

A 1.5-year-old 28.0-kg (61.6-lb) sexually intact male Labrador Retriever was presented because of weight loss, vomiting, and diarrhea of approximately 5 months' duration. The dog had been managed for inflammatory bowel disease for 5 months after gastrointestinal endoscopy had revealed a bile-stained esophagus, stomach, and duodenum. Histologic examination of endoscopic biopsy specimens revealed mild, diffuse, chronic-active lymphoplasmacytic and eosinophilic enteritis and colitis.

Clinical and Gross Findings

On examination, the dog was thin (body condition score, 3/9), and its sclera and mucous membranes were icteric. A serum biochemical profile revealed severely high alanine aminotransferase (ALT) activity (1,500 U/L; reference interval, 12 to 118 U/L), alkaline phosphatase (ALP) activity (> 2,000 U/L; reference interval, 23 to 212 U/L), γ-glutamyltransferase activity, and cholesterol concentration and slightly low amylase activity.

A focal lesion of mixed echogenicity in the left medial liver lobe was detected ultrasonographically; examination of a fine-needle aspirate specimen of the lesion revealed hepatocellular vacuolar degeneration with mild hepatocellular necrosis and reactive fibroplasia. A recheck serum biochemical profile performed 8 days after presentation revealed low ALT activity (< 10 U/L) with continued high ALP activity (> 2,000 U/L), γ-glutamyltransferase activity, and cholesterol concentration, along with high total bilirubin concentration and low BUN concentration.

Exploratory laparotomy revealed extensive biliary changes. The dog's poor clinical status was discussed with the owners, and euthanasia (by IV injection of pentobarbital sodium and phenytoin sodiuma during anesthesia and surgery) was elected. The gallbladder and dissected biliary tree were placed in neutral-buffered 10% formalin for histologic examination (Figure 1). The biliary duct walls of the biliary tree were markedly thickened with partial to nearly complete occlusion of the duct lumina. The gallbladder wall was light tan and markedly and diffusely thickened, and the gallbladder contents were pale yellow and gelatinous.

Figure 1
Figure 1

Photographs of the gallbladder (A) and dissected biliary tree (B) from a 1.5-year-old Labrador Retriever that was evaluated because of weight loss, vomiting, and diarrhea of approximately 5 months' duration. Notice that the gallbladder mucosa is severely thickened and contains pale yellow gelatinous material. The biliary tree is severely distended, and the lumen is obstructed with mineralized debris. In each panel, bar = 3 cm.

Citation: Journal of the American Veterinary Medical Association 258, 5; 10.2460/javma.258.5.467

Histopathologic and Immunohistochemical Findings

The histopathologic and immunohistochemical findings within representative sections of the gallbladder wall and biliary tree were similar. The lamina propria and tunica muscularis of the lobar, cystic, and common bile ducts as well as the gallbladder wall were infiltrated and markedly thickened by a poorly demarcated mass of low to moderate cellularity. The mass was composed of neoplastic nerve cell bodies (ganglion cells) and nerve fibers within a fibrous stroma (Figure 2). The ganglion cells were large and oval to polygonal and were single or formed small aggregates within the stroma. The ganglion cells had abundant eosinophilic cytoplasm with Nissl substance and distinct cellular borders (Figure 3). The large, single vesicular nucleus of each ganglion cell was irregularly round to oval and had a large, prominent nucleolus. There was mild anisocytosis and anisokaryosis, and 3 mitoses/10 hpf (400× [2.37 mm2]) were observed. Multifocally, the lamina propria glands were entrapped in the dense stroma. The mucosal epithelium also formed papillary projections lined by hyperplastic biliary epithelial cells that extended into the lumina. The lumina were markedly narrowed as a result of the combination of thickening of the lamina propria and the papillary projections. There were low to moderate numbers of lymphocytes, plasma cells, and macrophages and very few neutrophils within the lamina propria of the lobar, cystic, and common bile ducts.

Figure 2
Figure 2

Photomicrograph of a section of the wall of the common bile duct from the dog in Figure 1. The duct wall is markedly thickened by neoplastic nerve cell bodies (ganglion cells) that are surrounded by streams of nerve fibers and fascicles within a fibrous stroma. The hyperplastic ductal epithelial cells line papillary projections that extend into the duct lumen. H&E stain; bar = 200 mm.

Citation: Journal of the American Veterinary Medical Association 258, 5; 10.2460/javma.258.5.467

Figure 3
Figure 3

Photomicrograph of another section of the wall of the common bile duct. Large neoplastic nerve cell bodies (ganglion cells) and nerve fibers are present within a fibrous stroma. The neoplastic nerve cell bodies are large and oval to polygonal and have abundant eosinophilic cytoplasm with Nissl substance. H&E stain; bar = 50 mm.

Citation: Journal of the American Veterinary Medical Association 258, 5; 10.2460/javma.258.5.467

Within the gallbladder lumen, there was proteinaceous, inspissated matter mixed with mucinous material, sloughed epithelial cells, low numbers of neutrophils, karyorrhectic debris, and basophilic mineralized material. The lamina propria was moderately expanded with edema and moderate numbers of lymphocytes and plasma cells mixed with few neutrophils. The gallbladder glands were expanded by small to moderate amounts of mucinous secretory material that often contain mineralized matter. There was moderate to marked edema present diffusely throughout the gallbladder walls, and the lymphatic vessels were diffusely ectatic. The tunica muscularis was moderately thickened and expanded with haphazardly arranged fibroblasts, edema, and fibrin. The tunica adventitia was expanded by scattered hemorrhage and necrotic cellular debris. There were small sections of liver attached to the gallbladder wall; in those sections, the portal areas were markedly expanded by fibrosis with marked bile duct proliferation (ductal reaction). The portal fibrosis surrounded and isolated small hepatic lobules (nodular regeneration). Low to moderate numbers of lymphocytes and plasma cells and variable numbers of neutrophils were present in the portal areas. Multifocal hepatocellular necrosis and hemorrhage were evident within the attached liver tissue.

Immunohistochemical analysis of gallbladder sections was performed, and the neoplastic nerve fibers had strong cytoplasmic immunoreactivity for glial fibrillary acid protein (Figure 4) and vimentin and weak cytoplasmic immunoreactivity for neurofilament proteins. The cells lacked immunoreactivity for smooth muscle actin and KIT protein (CD117), which ruled out leiomyosarcoma and gastrointestinal stromal tumor, respectively. The ganglion cells had strong immunoreactivity for vimentin. Interestingly, the ganglion cells lacked immunoreactivity for synaptophysin and neurofilament protein; this finding has been previously reported for ganglioneuromas. The prominent component of ganglion cells was not consistent with a diagnosis of malignant nerve sheath tumor. The interpretation was that the combination of histomorphologic and immunohistochemical findings was more supportive of a diagnosis of a ganglioneuroma than a diagnosis of a nonangiogenic nonlymphogenic intestinal mesenchymal tumor (or nongastrointestinal stromal tumor), versus a non–smooth muscle, nonlymphogenic intestinal mesenchymal tumor.1

Figure 4
Figure 4

Photomicrograph of a section of the gallbladder wall. The neoplastic nerve cell bodies (neurons) have strong cytoplasmic immunoreactivity for glial fibrillary acidic protein. Anti-glial fibrillary acidic protein antibody reaction; bar = 20 mm.

Citation: Journal of the American Veterinary Medical Association 258, 5; 10.2460/javma.258.5.467

Morphologic Diagnosis and Case Summary

Morphologic diagnosis and case summary: ganglioneuroma of the biliary tree and gallbladder in a young dog with moderate, chronic, diffuse, lymphoplasmacytic, and neutrophilic cholecystitis associated with diffuse mucosal hyperplasia and hyperplastic submucosal glands that contained mucinous material.

Comments

Ganglioneuromas are rare tumors of peripheral nervous tissue that contain mixtures of ganglion cells, Schwann cells, and nerve fibers. In the case described in the present report, the anatomic location for the development of this type of tumor was uncommon. To the authors' knowledge, there are only 2 other reported cases of ganglioneuroma with hepatobiliary involvement in dogs.2,3 Ganglioneuromas develop more commonly in the adrenal gland medulla and gastrointestinal tract.4,5,6 In one of the previously published case reports,3 a ganglioneuroma was present in the dog's common bile duct, perihepatic tissues, and duodenum with infiltration into the major duodenal papilla (papilla of Vater).

In the dog of the present report, the lamina propria and tunica muscularis were the primary targets of multifocal infiltration by the mass, which caused partial to complete occlusion of the lobar, cystic, and common bile ducts with resultant extrahepatic biliary obstruction. The tumor was isolated to the hepatobiliary system, without known duodenal involvement3 or pancreatic infiltration,2 as has been previously reported; however, intestinal segments were not submitted for histologic examination because of their grossly normal appearance at the time of surgery.

In the case described in the present report, historically high serum ALT activity was the primary biochemical abnormality prior to the development of abnormalities in ALP and γ-glutamyltransferase activities and cholesterol concentration concurrent with worsening clinical signs. These variables became more abnormal prior to surgery followed by a precipitous decrease in ALT activity (< 10 U/L) and BUN concentration. These changes could have been the result of initial hepatocellular necrosis followed by severe liver dysfunction. Extrahepatic biliary duct obstruction as a result of luminal narrowing caused by neoplastic infiltration could precipitate such severe increases in the ALT and ALP activities and cholesterol concentration. Additionally, the dog had cholecystitis with cystic mucosal and epithelial hyperplasia consistent with mucocele development.

A congenital abnormality in the development of neuroectodermal cells is a theory for the origin of ganglioneuromas.5 In previous reports2,3 of ganglioneuroma involving the hepatobiliary tissue in dogs, the diagnosis was made at a young age; the dog of the present report was 1.5 years old. Similarly, in another report2 of a 7-month-old dog with a hepatopancreatic ganglioneuroma, the authors discussed lack of involvement of the gastrointestinal tract, positing that infiltration of the tumor into intestinal tissues may have occurred had that dog's clinical condition not declined so quickly. The case described in the present report progressed in a similar manner, with euthanasia elected on the basis of surgical findings and the dog's poor clinical condition; it was not determined whether infiltration of the tumor into adjacent gastrointestinal structures had occurred.

The case described in the present report represented a rare neoplastic development, and the fact that the ganglioneuroma was confined to hepatobiliary tissues distinguished it from previous case reports involving dogs. Evidently, the origin and infiltration pathways of localized ganglioneuromas are not fully understood, and although uncommon, ganglioneuroma should be included in the differential diagnosis list for extrahepatic biliary obstruction in young dogs.

Footnotes

a.

Euthasol, Virbac, Westlake, Tex.

References

  • 1.

    Munday JS, Löhr CV, Kiupel M. In: Meuten DL, ed. Tumors in domestic animals. 5th ed. Ames, Iowa: John Wiley & Sons Inc, 2017;579584.

    • Search Google Scholar
    • Export Citation
  • 2.

    Zafra R, Bautista MJ, Perez J, et al. Hepatopancreatic ganglioneuroma in a young dog: a case report. Vet Med (Praha) 2011;56:9396.

  • 3.

    van den Ingh TSGAM, Rothuizen J. Ganglioneuroma of Vater's papilla and extrahepatic cholestasis in a dog. Vet Pathol 1984;21:254256.

  • 4.

    Fairley RA, McEntee MF. Colorectal ganglioneuromatosis in a young female dog (Lhasa Apso). Vet Pathol 1990;27:206207.

  • 5.

    Reimer ME, Leib MS, Reimer MS, et al. Rectal ganglioneuroma in a dog. J Am Anim Hosp Assoc 1999;35:107110.

  • 6.

    Ribas JL, Kwapien RP, Pope ER. Immunochemistry and ultra-structure of intestinal ganglioneuroma in a dog. Vet Pathol 1990;27:376379.

  • Figure 1

    Photographs of the gallbladder (A) and dissected biliary tree (B) from a 1.5-year-old Labrador Retriever that was evaluated because of weight loss, vomiting, and diarrhea of approximately 5 months' duration. Notice that the gallbladder mucosa is severely thickened and contains pale yellow gelatinous material. The biliary tree is severely distended, and the lumen is obstructed with mineralized debris. In each panel, bar = 3 cm.

  • Figure 2

    Photomicrograph of a section of the wall of the common bile duct from the dog in Figure 1. The duct wall is markedly thickened by neoplastic nerve cell bodies (ganglion cells) that are surrounded by streams of nerve fibers and fascicles within a fibrous stroma. The hyperplastic ductal epithelial cells line papillary projections that extend into the duct lumen. H&E stain; bar = 200 mm.

  • Figure 3

    Photomicrograph of another section of the wall of the common bile duct. Large neoplastic nerve cell bodies (ganglion cells) and nerve fibers are present within a fibrous stroma. The neoplastic nerve cell bodies are large and oval to polygonal and have abundant eosinophilic cytoplasm with Nissl substance. H&E stain; bar = 50 mm.

  • Figure 4

    Photomicrograph of a section of the gallbladder wall. The neoplastic nerve cell bodies (neurons) have strong cytoplasmic immunoreactivity for glial fibrillary acidic protein. Anti-glial fibrillary acidic protein antibody reaction; bar = 20 mm.

  • 1.

    Munday JS, Löhr CV, Kiupel M. In: Meuten DL, ed. Tumors in domestic animals. 5th ed. Ames, Iowa: John Wiley & Sons Inc, 2017;579584.

    • Search Google Scholar
    • Export Citation
  • 2.

    Zafra R, Bautista MJ, Perez J, et al. Hepatopancreatic ganglioneuroma in a young dog: a case report. Vet Med (Praha) 2011;56:9396.

  • 3.

    van den Ingh TSGAM, Rothuizen J. Ganglioneuroma of Vater's papilla and extrahepatic cholestasis in a dog. Vet Pathol 1984;21:254256.

  • 4.

    Fairley RA, McEntee MF. Colorectal ganglioneuromatosis in a young female dog (Lhasa Apso). Vet Pathol 1990;27:206207.

  • 5.

    Reimer ME, Leib MS, Reimer MS, et al. Rectal ganglioneuroma in a dog. J Am Anim Hosp Assoc 1999;35:107110.

  • 6.

    Ribas JL, Kwapien RP, Pope ER. Immunochemistry and ultra-structure of intestinal ganglioneuroma in a dog. Vet Pathol 1990;27:376379.

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