Tumor Recurrence and Hypertension Persistence After Successful Pheochromocytoma Operation

Study Population

Between March 1975 and March 1994, a pheochromocytoma was identified in 154 patients referred to our department. To limit referral bias, we excluded 10 patients with malignant pheochromocytoma who were referred for recurrence. Since we aimed to analyze postoperative long-term outcome, we excluded 1 patient who was not operated and 14 patients referred from abroad. All 129 eligible patients were followed-up from initial operation to death or December 1994.

Initial Assessment

The procedures used for pheochromocytoma diagnosis and treatment were in accordance with institutional guidelines and have been described previously.^{11 12 13 14 15} Urinary excretion of vanillylmandelic acid was determined in the late 1970s with a colorimetric assay¹¹ ; this test was subsequently replaced by assaying total urinary metanephrines by liquid chromatography with electrochemical detection^{11 12 13 16} (22 patients). Plasma epinephrine and norepinephrine concentrations were routinely determined after 1980 (106 patients) with a radioenzymatic assay¹¹ or liquid chromatography with electrochemical detection,¹² as were plasma neuropeptide Y levels, with an immunoradiometric assay,¹⁷ after 1985 (71 patients). The upper normal limits were 3.08 μmol/d for metanephrines, 1.44 and 2.63 nmol/L for epinephrine and norepinephrine, respectively, and 7.5 pmol/L for neuropeptide Y.^{11 12 13 17}

Arteriography was used for preoperative tumor location in the late 1970s; thereafter, computed tomographic scan and metaiodobenzylguanidine scintigraphy were used. Family history and phenotypic evidence of multiple endocrine neoplasia type 2 (MEN 2), von Hippel–Lindau disease, or neurofibromatosis 1^{18 19} were analyzed to identify any underlying genetic disease involving pheochromocytoma. In cases with intra-abdominal pheochromocytomas, patients were operated on using a midline incision to explore both adrenals, the organ of Zuckerkandl, the urinary bladder, and the periaortic and pericaval lymphatic chains. Tumor extirpation involved the adjacent adrenal (in cases of adrenal pheochromocytoma) and/or any other possible tumors, lymph nodes, or visceral metastases.¹⁴ The procedure used in thoracic pheochromocytomas has been described previously.¹⁵

Postoperative Follow-up

Urinary metanephrines were measured 15 days and 6 months after operation. Patients were examined 1 year after operation and then biennially; metanephrines were determined at similar intervals. Scintigraphy was performed postoperatively or during follow-up in patients with high metanephrine excretion. All living patients were contacted by mail or phone between May and December 1994 and agreed to have their blood pressure measured and urinary metanephrine levels determined.

Clinical, Tumoral, and Follow-up Criteria

Sustained hypertension was diagnosed in patients with a blood pressure of 140/90 mm Hg or more in the absence of paroxysmal symptoms and in those taking antihypertensive drugs. Paroxysmal hypertension was defined as a history of documented rises in blood pressure with normal blood pressure at entry without treatment. Other patients were considered normotensive. Hyperglycemia was defined as two plasma glucose assays scoring higher than 7.8 mmol/L.²⁰ Pheochromocytoma diagnosis and tumor site and size were confirmed at surgery. Malignancy was defined by histological evidence of tumor cells at sites where chromaffin tissue is not normally present and/or by evidence of distant metastases documented by computed scan or scintigraphy.^{8 9} Recurrence was defined as the reappearance of disease (documented at reintervention or by combined biochemical and imaging tests) after complete tumor eradication (documented by negative biochemical and imaging tests).¹⁰ A malignant recurrence was defined according to the malignancy criteria described above, other recurrences being deemed benign. Note, however, that this definition of benign recurrences lacks specificity because small or distant metastases may go long undetected. This definition also applies to the occurrence of new tumors affecting the contralateral adrenal or ectopic chromaffin tissue in patients with familial pheochromocytomas. In the latter case, recurrence is another manifestation of a permanent underlying disease. Time to recurrence in months was counted between initial operation and documentation of recurrence. Partial response to treatment was defined as a 50% or greater reduction in tumor load and metanephrine excretion.¹⁰

Data Analysis

Differences between means were tested with unpaired Student’s t test or, in the case of non-normal distribution, the Mann-Whitney test. Fisher’s exact test was used for the comparison of qualitative variables. For survival and, in patients normalized after initial operation, for pheochromocytoma-free survival, we considered the following prognostic indicators: sex; age; body mass index; the presence of sustained hypertension, hyperglycemia, or an underlying genetic disease; urinary metanephrine excretion; plasma catecholamines; and the ratio of epinephrine to epinephrine plus norepinephrine (an index of tumor differentiation) as well as tumor site and size. Survival and pheochromocytoma-free survival probabilities were estimated with the Kaplan-Meier method. Cox’s proportional hazards regression models were used to identify the factors independently predicting prognosis.²¹ For Cox analysis, continuous variables were dichotomized using values above and below median. A value of P<.05 was considered significant.

Features at Presentation

Patient characteristics are summarized in Table 1⇓. The patients were 13 to 80 years old; 6 were 20 years old or younger (1 with MEN 2A and a single adrenal tumor). The ratio of males to females was 0.96. Pheochromocytoma was associated with a genetic disease in 25 patients: 10 had MEN 2A and 1 had MEN 2B; 8 patients had neurofibromatosis 1, and 6 had von Hippel–Lindau disease. Hypertension was sustained in 98 patients, paroxysmal in 15, and not detected in 16. Thirty-five patients were hyperglycemic. Pheochromocytoma was in the right adrenal in 73 patients and in the left in 37. It was bilateral in 5 patients and extra-adrenal in 14 (in the Zuckerkandl body, n=5; pericardium, n=3; renal hilum, n=3; mediastinum, n=2; and prostate, n=1). Patients with adrenal and extra-adrenal tumors had similar urinary metanephrine excretions and plasma epinephrine concentrations. Mean plasma norepinephrine levels were higher (56.6±69.1 [SD] versus 27.0±39.9 nmol/L, P=.03), and plasma neuropeptide Y levels (2.4±7.3 versus 22.4±58.1 pmol/L, P=.03) and the ratio of epinephrine to epinephrine plus norepinephrine (4.6±7.2% versus 16.5±18.5%, P=.02) were lower in patients with extra-adrenal than in those with adrenal tumors. Mean ages were similar in patients with a ratio of epinephrine to epinephrine plus norepinephrine below median (40.7±14.7 years) and in those with a ratio above median (43.7±14.9 years).

Eleven patients, including 2 with extra-adrenal tumors, had a malignant pheochromocytoma at first operation (Tables 1⇑ and 2⇓). Malignant tumors were more frequent in males than females (P=.02). Plasma norepinephrine levels and urinary metanephrine excretions were higher, the ratio of epinephrine to epinephrine plus norepinephrine was lower, and the tumor was larger in patients with malignant pheochromocytoma than in those with benign tumors (Table 1⇑).

Survival

Three patients died in the 28 days after operation, and another 10 subsequently died of the consequences of pheochromocytoma (Fig 1⇓ and Table 2⇑). Death was caused by metastases in 9 patients: 7 with initially malignant tumors died 2 to 24 months after operation; 2 with an initially benign tumors suffered malignant recurrence 38 and 91 months after initial operation and died 69 and 202 months after initial operation, respectively. Recurrence was associated with a 10-fold increase in metanephrine excretion in patient 18; she refused reintervention and died suddenly 91 months after initial operation. Three patients who exhibited normal metanephrine excretion at follow-up died from stroke, myocardial infarction, or colonic cancer. The 5-year survival probability for patients with malignant tumor at first operation was 22.7% (SE 13.6%) versus 96.8% (SE 1.9%) for those with benign tumor (P<.0001 by the log rank test).

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Figure 1.

Overall patient outcome. Recurrence is defined as reappearance of disease after normalization of imaging and biochemical tests. Partial response to surgery is a 50% or more reduction of tumor load and metanephrine excretion, no change being a less than 50% reduction.¹⁰

Pheochromocytoma-Free Survival

Metanephrine excretion normalized in 117 patients surviving initial operation, including 116 with benign tumor and 1 with malignant tumor (patient 7 in Table 2⇑). Excluding the 3 patients who died for reasons unrelated to pheochromocytoma (see above), 114 patients with postoperative normalization were therefore at risk of recurrence. Of these, 16 exhibited benign or malignant recurrences 17 to 194 months after initial operation (Fig 1⇑). For the 9 patients with malignant recurrence, the time to recurrence was between 20 and 163 months, and for the 7 with benign recurrence, 17 and 194 months (P=.13 by Mann-Whitney U test). Patients with malignant or benign recurrences did not differ significantly in terms of preoperative characteristics. Therefore, 98 patients were alive and pheochromocytoma-free by the end of 1994 (Fig 1⇑). Kaplan-Meier estimates of pheochromocytoma-free survival in patients at risk were 92% (SE 3%) at 5 years and 80% (SE 6%) at 10 years.

As assessed by univariate analysis, pheochromocytoma-free survival was not linked to sex, age, body mass index, the presence of sustained hypertension or hyperglycemia, plasma epinephrine or norepinephrine levels, or urinary metanephrine excretion. The Kaplan-Meier estimate of pheochromocytoma-free survival was shorter in patients with a genetic disease (P=.01 by the log rank test), bilateral or extra-adrenal tumors (P=.02), and larger than median (50 mm) tumor diameter (P=.05) (Fig 2⇓). Pheochromocytoma-free survival tended to be shorter in patients with a lower-than-median (8.4%) ratio of epinephrine to epinephrine plus norepinephrine (P=.14) (Fig 2⇓).

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Figure 2.

Pheochromocytoma-free survival. Kaplan-Meier estimates of pheochromocytoma-free survival in 114 patients at risk of recurrence according to the presence or absence of familial disease, tumor site and diameter, and the ratio of epinephrine to epinephrine plus norepinephrine (E/E+NE).

In the Cox model, the presence of a familial disease (relative risk, 13.2; 95% confidence interval, 2.1 to 84.8) and a lower-than-median ratio of epinephrine to epinephrine plus norepinephrine (relative risk, 4.0; 95% confidence interval, 1.1 to 14.9) were independently associated with subsequent recurrence, whereas the presence of bilateral or extra-adrenal tumors (relative risk, 4.2; 95% confidence interval, 0.8 to 22.8) and tumor diameter (relative risk, 1.2; 95% confidence interval, 0.3 to 5.0) were not significantly associated with recurrence (Table 3⇓).

Hypertension-Free Survival

Of 98 patients alive without recurrence, 70 were hypertensive at diagnosis and 50 at most recent follow-up. Kaplan-Meier estimates of hypertension-free survival in the 98 patients without recurrence were 74% (SE 5%) at 5 years and 45% (SE 6%) at 10 years. In the Cox model, hypertension-free survival was significantly associated with age (relative risk per year of age, 1.03; 95% confidence interval, 1.01 to 1.05) and a family history of hypertension (relative risk, 1.96; 95% confidence interval, 1.10 to 3.50). It was not associated with sex or the presence of sustained hypertension at diagnosis.

Blood pressure and any antihypertensive treatment were documented during the year after initial operation in 88 of the living 98 patients without recurrence. The presence or absence of hypertension at the 1-year follow-up was a good predictor of final blood pressure status. Of the 46 patients who were hypertensive at last follow-up, 30 were already hypertensive after 1 year (sensitivity of 1-year blood pressure status for predicting final status: 0.65), whereas of the 42 patients who were eventually normotensive, 38 were normotensive after 1 year (specificity, 0.90).