Functional paragangliomas presenting as primary liver tumors.

Paragangliomas are rare neuroendocrine tumors derived from the extra-adrenal paraganglia. They can present anywhere along the sympathetic paraganglia chains from the neck to the pelvis, but they occur most often intra-abdominally in the periaortic region and the organ of Zuckerkandl. They also have been reported in other unusual sites, such as the gallbladder, the biliary ductal system, and the urinary bladder. (1-3) There are a handful of reports of either eccentric right adrenal neoplasms or paragangliomas mimicking primary liver tumors, usually in segments 7 or 8. (4,5)

While patients may present with signs and symptoms of catecholamine excess or vague abdominal discomfort, some tumors will be detected incidentally on radiographic examination. Patients may demonstrate no classic symptomatology and may be normotensive, without signs of catecholamine excess. Paragangliomas lack the enzyme phenylethanolamine N-methyltransferase (PNMT), which converts norepinephrine to epinephrine. CT scan will show a hypervascular lesion, MRI will show a lesion with high intensity on T2 weighted imaging, and 123I MIBG will usually show intense uptake. The differential diagnosis of a lesion in the pericaval area and hepatic segments 7 or 8 should include the possibility of a neuroendocrine tumor that is either adrenal or extra-adrenal in origin, along with other primary hepatic neoplasms or metastases.

Paragangliomas and other neuroendocrine tumors are hypervascular and, therefore, have hyperintense signals on T2-weighted MR-images. However, hepatocellular carcinoma also can exhibit increased signal when it is marked by high levels of vascular endothelial cell growth factor (VEGF). (6) Tumors with rapid growth and central necrosis also frequently exhibit intense T2 weighted signals. Another entity with high signal intensity on T2-weighted images is focal eosinophillic infiltration of the liver, which can be found in patients with malignancy, parasite infestation, allergy, and hypereosinophilic syndrome. These focal hepatic lesions are often confused with metastasis in patients with malignancy. (7) Exophytic pheochromocytoma invaginating into the liver is extremely rare. In 1997, Takayasu (Ueda et al (5)) described a 5-cm exophytic pheochromocytoma extending into the posterior area of the liver. Interestingly, the blood supply to this lesion was derived from the hepatic artery, and the venous drainage was into the portal system. Hence, the patient had no systemic elevation of catecholamines because hepatocytes metabolized the catecholamines. One postulate for the genesis of this lesion was an adrenal rest. (5) Up to 9.9% of people, based on autopsy studies, may develop adrenal hepatic fusion in the course of their life as a result of loss of the fibrous tissue between the liver parenchyma and the cranial portion of the right adrenal gland. (8)

The cytology of fine needle biopsy (FNB) material from paragangliomas or pheochromocytomas is usually insufficient for a clear diagnosis. The pathologic diagnosis depends on adequate histologic examination showing polygonal cells with finely granular eosinophilic cytoplasm and oval nuclei arranged in fibrous bundles and nests, called "Zellballen," immunohistochemistry, or in situ hybridization. Neuroendocrine markers, such as chromogranin A, neuron-specific enolase (NSE), synaptophysin, and insulin growth factor II (IGF II) are specific to pheochromocytomas and paragangliomas, and are not present in hepatocellular tumors. S-100 protein is present in the sustentacular cells of the neuroendocrine tumors. (9)

Given the low return of percutaneous preoperative biopsy (FNB or core biopsy) and the potential for a life-threatening crisis if the lesion is a pheochromocytoma or paraganglioma, we strongly discourage such evaluation. The differential diagnosis of lesions in this location is broad and always should include a neuroendocrine tumor. Biochemical evaluation should include a 24-hour urine collection for norepinephrine, epinephrine, metanephrines, normetanephrines, dopamine, and VMA, or plasma metanephrines and normetanephrines, which is expensive, but more sensitive, especially in patients who may harbor occult diagnoses of familial syndromes, such as multiple endocrine neoplasia Type 2, Von Hippel Lindau or familial paragangliomas. Preoperative imaging should be maximized to include MRI and MIBG, as well as possible evaluation of arterial supply to the lesion and venous drainage with MR-angiography. Standard contrast angiography is contraindicated because of the risk of dye-induced hypertensive crisis. Finally, if there is suspicion that the lesion is a paraganglioma or pheochromocytoma, preoperative [alpha]-blockade should be instituted at least seven days before surgery, with careful intraoperative surveillance of intravascular volume and blood pressure. This should be instituted even if there is only a strong suspicion of a catecholamine-producing tumor, as the [alpha]-1 selective blockers are generally well tolerated.

References

1. Freschi M, Sassi I. Paraganglioma of the gallbladder. Pathologica 1990;82:459-463.

2. Juraschek F, Engloff H, Buemi A, et al. Paraganglioma of the urinary bladder. Urology 1983;22:659-663.

3. Sarma D, Rogriguez F, Hoffmann E. Paraganglioma of the hepatic duct. South Med J 1980;73:1677-1678.

4. Corti B, Derrico A, Pierangeli F, et al. Primary paraganglioma strictly confined to the liver and mimicking hepatocellular carcinoma. Am J Surg Pathol 2002;26:945-949.

5. Ueda J, Takayasu K, Muramatsu Y, et al. Pheochromocytoma growing exophytically from the right adrenal gland and invaginating into the liver. Jpn J Clin Oncol 1997;27:346-349.

6. Kanematsu M, Semelka R, Osada S, et al. MRI and expression of vascular endothelial growth factor in hepatocellular nodules in cirrhosis and hepatocellular carcinomas. Top Magn Reson Imaging 2005;16:67-75.

7. Sun J, Kim J, Won J, et al. MR findings in eosinophillic infiltration of the liver. Comput Assist Tomogr 2005;29:191-194.

8. Honma K. Adreno-hepatic fusion: an autopsy study. Zenlralbl Pathol 1991;137:117-122.

9. Yeo H, Roman S. Pheochromocytoma and functional paraganglioma. Curr Opin Oncol 2005;17:13-18.

Sanziana A. Roman, MD, FACS, and Julie Ann Sosa, MA, MD, FACS

Department of Surgery, Yale University School of Medicine, New Haven, CT.

Reprint requests to Sanziana A. Roman, MD, FACS, Department of Surgery, Yale University School of Medicine, New Haven, CT. Email: [e-mail]