History

A 1.5-year-old Thoroughbred colt was referred to the Louisiana State University Veterinary Teaching Hospital for evaluation of leukocytosis, persistently elevated liver enzymes, and weight loss. The colt was treated with several courses of antibiotics (oxytetracycline, enrofloxacin, and doxycycline; detailed treatment regimen including dosage not reported), which were only temporarily effective for the leukocytosis and did not improve the elevated liver enzymes.

Clinical and Gross Findings

Upon examination at Louisiana State University Veterinary Teaching Hospital, the colt had dull mentation, small stature, lean condition, tachycardia with a second-degree atrioventricular block, and mildly icteric mucous membranes. A CBC and serum biochemical analysis revealed hemoconcentration (PCV, 58%; reference range, 32% to 53%) and elevated serum AST (599 U/L; reference range, 0 to 350 U/L), serum GGT (251 U/L; reference range, 0 to 35 U/L), serum ALP activity (643 U/L; reference range, 0 to 250 U/L), serum bile acids (98 μmol/L; reference range, 0 to 20 μmol/L), and serum total bilirubin concentration (9.1 mg/dL; reference range, 0.0 to 2.0 mg/dL) but normal serum direct bilirubin (0.8 mg/dL; reference range, 0.1 to 1 mg/dL) and serum ammonia concentration (34 μmol/L; reference range, 0 to 90 μmol/L). An abdominal ultrasound showed a significantly enlarged liver with dilated bile ducts, mixed echogenicity of the hepatic parenchyma, and multifocal areas of hyperechoic tissue. The findings suggested hepatic fibrosis, hepatic abscesses, or neoplasia as possible differential diagnoses. Based on all findings, including the marked structural abnormalities of the liver noted on ultrasound and the severe elevation in bile acids, humane euthanasia was elected.

On postmortem examination, the liver was severely enlarged, weighing 21.25 kg, which was 6% of the body weight (reference value = approx 1.5% of body weight), and the parenchyma was replaced by variably sized multifocal to coalescing pale tan to yellow firm nodules throughout all liver lobes. Expanding the left liver lobe, there was a firm, irregularly shaped, multilobular mass measuring 45 X 35 X 35 cm that also extended to the left side of the right lobe; on cut section, the periphery of the mass was similar to that described above, and the center of the mass was hard, mottled yellow/brown to red with thick white fibrous connective tissue projecting into the mass, which also contained hard bony spicules (Figure 1). In the adjacent hepatic parenchyma, bile ducts had a thickened wall and dilated lumina, measuring up to 2 cm in diameter. The parietal surface of the liver was firmly attached to the diaphragm by multiple thick, fibrous adhesions.

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Photographs of the liver from a 1.5-year-old Thoroughbred colt that was evaluated because of a history of chronically elevated liver enzymes. A—The hepatic parenchyma is replaced by multifocal to coalescing pale tan to yellow firm nodules (arrows) throughout all liver lobes. The largest mass (asterisk), measuring 45 X 35 X 35 cm, is in the left liver lobe. B—On cut section, the masses are pale tan and multilobular, extending deep into the parenchyma (arrows). The center of the largest mass (asterisk) is hard and mottled yellow/brown to red with thick, white, fibrous connective tissue projecting into the mass; the mass also contains hard bony spicules.

Citation: Journal of the American Veterinary Medical Association 262, 11; 10.2460/javma.24.06.0422

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Histopathologic Findings

Histologic examination of the liver revealed a nonencapsulated, infiltrative, and multilobulated neoplasm infiltrating the hepatic parenchyma (Figure 2). This neoplasm was composed of polygonal cells arranged in packets, trabeculae, palisades, and pseudorosettes, separated by fine fibrovascular stroma. The neoplastic cells had indistinct cell borders, small amounts of eosinophilic to amphophilic granular cytoplasm, and basally located vesicular round to pleomorphic nuclei with prominent nucleoli. Anisocytosis and anisokaryosis were moderate. Mitotic count was 53 cells/2.37 mm² (equivalent to 10 field number[FN]22/400X fields or 10 hpf). The neoplasm had multifocal necrosis and hemorrhage. Blood vessels frequently contained clusters of neoplastic cells (tumor emboli). In sections representing the hard areas noted grossly, the neoplasm contained abundant immature bone matrix as well as well-differentiated mineralized trabecular bone and adipose tissue. The remaining hepatic parenchyma had mild multifocal lipid-type hepatocellular vacuolation, frequent bile plugs within bile canaliculi, moderate ductular reaction, and portal-to-portal bridging fibrosis. Relevant findings in other organs include infrequent Alzheimer type 2 astrocytes in the cerebral cortex.

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Photomicrograph of the liver from the colt described in Figure 1. A—Infiltrating the hepatic parenchyma (black asterisk) is an ill-defined and highly infiltrative neoplasm (white asterisk) arranged in packets and trabeculae. H&E stain; bar = 400 µm. B—The neoplastic cells have a small amount of eosinophilic to amphophilic granular cytoplasm and vesicular round to pleomorphic nuclei with prominent nucleoli. Frequent mitotic figures (arrows) are present. H&E stain; bar = 50 µm. C—Immature woven bone and mineralized bony trabeculae (arrows) are present within the neoplasm. H&E stain; bar = 200 µm. D—A blood vessel contains tumor emboli (arrow; vascular invasion). The remaining nonneoplastic hepatic parenchyma has frequent bile plugs (arrowheads; cholestasis). H&E stain; bar = 100 µm.

Citation: Journal of the American Veterinary Medical Association 262, 11; 10.2460/javma.24.06.0422

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Morphologic Diagnosis and Case Summary

Mixed epithelial-mesenchymal hepatoblastoma (HB) with liver failure in a colt.

Comments

The main clinical findings in this colt were persistently elevated liver enzymes and bile acids, icterus, and weight loss, indicating a hepatic disease. Hepatic disease is best detected by an increase in serum liver-derived enzymes. Among the liver enzymes tested in this case, elevation of GGT is considered specific for liver disease in horses and is associated with cholestasis.¹ Aspartate aminotransferase and ALP, even though not as specific, indicate hepatocellular injury and cholestasis, respectively. The elevation of liver enzymes in this case was attributed to progressive hepatocellular damage and cholestasis caused by the neoplasm. Other liver-specific enzymes not tested in this case include sorbitol dehydrogenase and glutamate dehydrogenase, and elevation of these enzymes reflect hepatocellular injury.¹ While elevated liver enzymes are often the first indicators of liver disease, they do not distinguish between different etiologies or inform specifically on liver function. Liver function tests include blood bile acid, conjugated (direct) and unconjugated (indirect) bilirubin, and ammonia measurements. In this case, the bile acid level was markedly elevated, indicating impaired liver function, which, with other findings including markedly abnormal appearance of the liver on ultrasound, suggested poor prognosis.

In our case, elevated liver enzymes had been noted for a 1-month duration, and the ultrasound revealed marked structural changes in the liver, indicating a chronic liver disease. Differential diagnoses for chronic liver diseases in horses include cholangiohepatitis; cholelithiasis; hepatic abscesses; primary and metastatic hepatic neoplasia; toxic hepatopathy including pyrrolizidine alkaloid toxicity, alsike clover poisoning, and mycotoxicosis; and amyloidosis.¹ The main antemortem differential diagnoses for this case were cholangiohepatitis, cholelithiasis, and neoplasia, with a definite diagnosis of neoplasia confirmed postmortem by gross and histopathologic examination. Antemortem diagnosis of hepatic neoplasms in horses can be challenging due to the often subtle and nonspecific clinical signs, nonspecific laboratory findings indicating chronic inflammation and/or hepatic disease,¹ and the advanced stage of the disease when horses present to the clinic. This was evident in our case, where the neoplasm was widespread throughout all liver lobes, accompanied by marked hepatic fibrosis and cholestasis. Additionally, the presence of Alzheimer type 2 astrocytes in the cerebrum, coupled with dull mentation, indicated hepatic encephalopathy.

Primary equine liver tumors are rare.² While cholangiocellular carcinoma is the most common neoplasm in older horses¹, primary hepatic tumors in young horses include HB, mixed hamartoma, mesenchymal hamartoma, and hepatocellular carcinoma.³ Most cases in young horses are classified as HB or hepatocellular carcinoma.² Hepatoblastoma is a rare malignant embryonic tumor of the liver³ and has been reported in stillborn fetuses, neonates, and juvenile horses < 4 years of age.^2,3 The causes of HB are largely unknown, but relation to genetic conditions such as abnormal gene imprinting in Beckwith-Wiedemann syndrome or mutated adenomatous polyposis coli tumor suppressor genes has been reported in humans.² The histological patterns reported in horses are pure epithelial type with embryonal and fetal components and mixed epithelial and mesenchymal type with or without teratoid components.⁴ A classification as teratoid is made when additional tissue types within the neoplasm are noted, including skeletal muscle and neural or neural crest elements such as ganglion cells or melanocytes.³ The histological pattern in the present case was a mixed epithelial and mesenchymal type with teratoid components based on the well-differentiated bone and adipose tissue identified within the neoplasm. While not performed in our case, immunohistochemistry can aid diagnosing HB. Even though no immunohistochemistry panel is distinctive for HB, α-fetoprotein is the most consistently expressed marker. Expression of pan-cytokeratin and vimentin is variable. HepPar-1, which is a marker for differentiated hepatocytes as well as neuron-specific enolase, chromogranin A, S100, and synaptophysin (which are neuroendocrine markers), is usually not expressed.^2,3

In humans, HB is most frequently diagnosed in fetuses, neonates, and young children.² The lung is the most common metastatic organ of HB,⁵ and brain and bone metastases have also been reported.⁵ In horses, metastases are observed in the liver, lungs, omentum, skin, brain, meninges, various bones, frontal sinuses, nasal septum, and tracheobronchial lymph node.³ However, in this case, no metastases were detected even though vascular invasion and tumor emboli were noted on histopathologic examination. In children, curing HB depends on the completeness of tumor excision.² Chemotherapy may be used to reduce the size of the tumor prior to surgery but, by itself, is not curative.² If complete resection is not possible, then liver transplantation may be considered.² Neither surgery nor chemotherapy has been attempted in equine hepatic tumors, and the prognosis of such tumors in horses therefore appears generally extremely poor.²

Although rare in young horses, HB should be included in the differential diagnoses for horses of young age presenting with weight loss and elevated liver values consistent with chronic liver disease. Due to the severity of the clinical signs, the difficulty of reaching an early diagnosis, and the limited response to medical treatment, the prognosis for horses with HB is generally poor.

Disclosures

The authors have nothing to disclose. No AI-assisted technologies were used in the generation of this manuscript.

Funding

The authors have nothing to disclose.