Case Reports

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Patient 1 is a 27-year-old man in whom the incidental discovery of retinal angiomatosis in 1989 led to the diagnosis of von Hippel-Lindau disease when further imaging studies showed a right renal mass and cerebellar hemangioblastoma. Eight months after resection of a right renal carcinoma, a follow-up computed tomographic scan revealed a new left renal mass and a 2-cm left adrenal nodule. He was normotensive and did not have headache, palpitations, or diaphoresis, which are typical of pheochromocytoma. Results of urine metanephrine and catecholamine evaluations and of plasma catecholamine studies were negative for pheochromocytoma, as were results of an I¹³¹ metaiodobenzylguanidine adrenal scan. During enucleation of a left renal carcinoma, a left adrenalectomy was done without any surgical complications. Histologic examination showed a 0.5-cm pheochromocytoma.

Patient 2 is a 24-year-old man who was seen in 1992 for initial evaluation because of a family history of pheochromocytoma. He did not have hypertension or symptoms of pheochromocytoma. However, his urine metanephrine and catecholamine levels were elevated. His basal plasma catecholamine levels were elevated and not suppressed after he received clonidine. An abdominal computed tomographic scan showed a left adrenal nodule, whereas an I¹³¹ metaiodobenzylguanidine scan showed uptake in both adrenal nodules, indicating bilateral pheochromocytoma [4]. Ophthalmologic evaluation identified retinal angiomas, establishing the diagnosis of von Hippel-Lindau disease. Histologic examination, after uncomplicated adrenalectomies, confirmed bilateral pheochromocytoma.

Patient 3 is a 38-year-old woman who had classic signs and symptoms of pheochromocytoma at 24 years of age. An 8-cm left pheochromocytoma was resected. Von Hippel-Lindau disease was diagnosed in 1981 when retinal angiomas were found. During the next 11 years, she was completely asymptomatic and normotensive. In 1992, an abdominal computed tomographic scan showed bilateral renal masses and a 1.5-cm right adrenal nodule. A preoperative evaluation showed that her blood pressure level was normal and she had no symptoms of pheochromocytoma. Results of 24-hour urine studies and basal plasma catecholamine levels were normal. Results of an I (¹³¹) metaiodobenzylguanidine adrenal scan were negative. She had enucleation of a renal cell carcinoma from the left kidney without perioperative hemodynamic instability. Hypertension (blood pressure, 140/100 mm Hg) developed 5 months later and she complained of headaches. A magnetic resonance imaging scan showed the right adrenal nodule to be hyperintense on T₂-weighted imaging, suggestive of pheochromocytoma. Results of repeated 24-hour urine studies were again normal. Basal plasma catecholamine levels and a clonidine suppression test were nondiagnostic. A glucagon stimulation test supported the diagnosis of pheochromocytoma. A repeated I (¹³¹) metaiodobenzylguanidine scan showed right adrenal uptake. Right adrenalectomy was done without any perioperative complications. Pathologic evaluation of the adrenal nodule confirmed a 1-cm pheochromocytoma.

Patient 4 is a 41-year-old woman who had left adrenalectomy at 29 years of age for pheochromocytoma. Twelve years later, von Hippel-Lindau disease was diagnosed by ophthalmologic evaluation. She had no clinical evidence of pheochromocytoma since the previous resection. A computed tomographic scan revealed a 1.5-cm right adrenal nodule that was bright on T (₂-weighted) magnetic resonance imaging, yet results of I¹³¹ metaiodobenzylguanidine scanning were negative. Results of evaluation, including glucagon-stimulation testing, were negative for pheochromocytoma. We continue to observe this patient for possible subclinical pheochromocytoma.

The clinical characteristics of all four patients are summarized in Table 1.

Discussion

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Pheochromocytoma is often more difficult to diagnose in familial syndromes. Grossman and colleagues [5] observed that basal plasma norepinephrine levels are misleading in familial pheochromocytoma. Glucagon-stimulation testing is also less sensitive in familial pheochromocytoma. Siqueira-Filho and associates [6] described four patients with multiple endocrine neoplasia syndrome type II and pheochromocytoma but who had negative results on glucagon-stimulation tests. Shapiro and colleagues [4] showed that sensitivity of I¹³¹ metaiodobenzylguanidine adrenal scanning is reduced in patients with familial pheochromocytoma. Patients with familial syndromes are less likely to have symptoms or sustained hypertension than are those with sporadic pheochromocytoma [7]. This may be a result of identification of other clinical features of the familial disorder, which leads to much earlier evaluation and diagnosis of pheochromocytoma. None of the patients with von Hippel-Lindau disease who we described had clinical features of pheochromocytoma when the adrenal nodule was first identified. These cases show that pheochromocytoma may be difficult to diagnose even when a high index of suspicion exists.

Patients with von Hippel-Lindau disease should have an annual evaluation that includes a detailed history, blood pressure measurement, and a screening 24-hour urine test for metanephrines and catecholamines. Resection is indicated if any of these results suggest pheochromocytoma and imaging studies identify an adrenal nodule. If no clinical evidence of pheochromocytoma exists yet an adrenal nodule is revealed on imaging studies, plasma catecholamine levels should be measured [8], and glucagon-stimulation and other imaging studies should be ordered. If the suspicion for pheochromocytoma is high based on this evaluation or if ipsilateral renal resection is planned, then the risk for induced adrenal insufficiency by adrenal resection should be weighed against the possibility that the nodule may later require resection. Discovery of an adrenal nodule in a patient with von Hippel-Lindau disease who has a history of contralateral pheochromocytoma strongly suggests pheochromocytoma, given the frequent occurrence of bilateral nodules in cases of familial disease.

Retaining a high index of suspicion for pheochromocytoma in familial syndromes may yield a diagnosis at its earliest clinical stage.

The opinions and assertions contained herein are those of the authors and are not to be construed as official or as reflecting the views of the Navy Department or the Naval Service at large.