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(Hypertension. 1997;29:1133-1139.)
© 1997 American Heart Association, Inc.

Articles

Tumor Recurrence and Hypertension Persistence After Successful Pheochromocytoma Operation

Pierre-François Plouin; Gilles Chatellier; Isabelle Fofol; ; Pierre Corvol

From the Hypertension Department (P.-F.P, P.C.) and Department of Medical Informatics (G.C., I.F.), Hôpital Broussais, Paris, France.

	Abstract

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Abstract Pheochromocytoma is a catecholamine-secreting tumor and a rare cause of hypertension that is usually curable. However, pheochromocytoma may recur as a benign or malignant tumor, and hypertension may persist after successful surgical intervention. The frequency of and risk indicators for tumor recurrence and hypertension persistence after successful surgical intervention have not been adequately studied. We determined tumoral and blood pressure outcome in 129 patients followed-up from initial pheochromocytoma resection to death or to 1994 (796 patient-years). We assessed several candidate indicators for their predictive value for the risk of tumor recurrence or hypertension persistence. Recurrence was defined as the reappearance of disease after normalization of biochemical tests. Pheochromocytoma caused death or persistent or recurrent disease in 28 patients. Of the 114 with benign tumors at initial operation, pheochromocytoma recurred as a benign or malignant tumor 17 to 194 months after initial operation in 16 cases. Kaplan-Meier estimates of pheochromocytoma-free survival were 92% and 80% at 5 and 10 years, respectively. In the 98 living patients without recurrence, Kaplan-Meier estimates of hypertension-free survival were 74% and 45% at 5 and 10 years. In the Cox model, familial pheochromocytoma and a low ratio of plasma epinephrine to total catecholamines were independently associated with recurrence. Familial hypertension and age were similarly associated with hypertension persistence. After surgery for pheochromocytoma, patients should be followed-up indefinitely, especially those with familial tumors or a low epinephrine secretion. Pheochromocytoma should not unreservedly be considered a surgically remediable cause of hypertension.

Key Words: catecholamines • Hippel–Lindau disease • metanephrine • multiple endocrine neoplasia type 2a • multiple endocrine neoplasia type 2b • neurofibromatosis 1 • pheochromocytoma • recurrence

	Introduction

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Pheochromocytoma is a catecholamine-secreting neoplasm of chromaffin tissue.^{1 2} It is a life-threatening condition because catecholamine secretion is unpredictable, resulting in hypertension, arrhythmias, and/or hyperglycemia and because the tumor is malignant in 3% to 13% of cases.^{1 2 3 4 5 6 7} Tumor resection is indicated to normalize blood pressure and prevent subsequent tumor growth. Long-term postoperative outcome has been good in some series, with survival rates similar to the survival rate of the normal population.³ Other reports underline the risk of tumor recurrence,^{4 5 6 7} with estimates of recurrence frequency of between 6% and 23%. There are several plausible explanations for the wide range in estimated frequencies of malignancy and recurrence. They include biases in referral and follow-up, the poor sensitivity of criteria establishing that a pheochromocytoma is malignant,^{8 9} and ambiguities in distinguishing tumor progression from tumor recurrence.¹⁰

We report long-term tumoral and blood pressure outcome in a series of 129 patients with pheochromocytoma who were clinically and biochemically followed-up from the initial operation to death or December 1994, totaling 796 patient-years of follow-up. Malignancy was defined as the presence of lymph node or distant metastases. Recurrence was defined as the reappearance of disease after complete pheochromocytoma eradication. To detect risk indicators for recurrence, we analyzed clinical, biological, and tumoral features of patients who suffered recurrence. Blood pressure outcome was analyzed in live patients without recurrence.

	Methods

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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.

	Results

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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).

View this table: [in this window] [in a new window]   Table 1. Preoperative Features: Association With Benign/Malignant Status

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).

View this table: [in this window] [in a new window]   Table 2. Initial Characteristics and Follow-up in Patients With Malignant Tumor and/or Recurrence

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).

View larger version (42K): [in this window] [in a new window]   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).

View larger version (31K): [in this window] [in a new window]   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).

View this table: [in this window] [in a new window]   Table 3. Predictors of Pheochromocytoma-Free Survival in 114 Patients at Risk of Recurrence

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).

	Discussion

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The results of this long-term cohort study show that periodic clinical and biochemical follow-up is necessary after surgical intervention for pheochromocytoma. Although patients initially referred for a recurrence were excluded from the study, 11 of 129 patients included had lymph node or distant metastases at first operation. As expected, the survival rate was much lower for these patients than those without initial evidence of malignancy. However, of the 114 patients with normal test results after initial operation, 16 subsequently suffered benign or malignant recurrence. The 10-year estimate of pheochromocytoma-free survival in patients at risk of recurrence was 80%, and that of hypertension-free survival in those without recurrence, 45%. Schematically, of 10 patients with pheochromocytoma, 1 had a malignant tumor at first operation; of 10 with benign pheochromocytoma, 2 had a recurrence; of 2 without recurrence, 1 was hypertensive at most recent follow-up.

Previous cohort studies report long-term outcome for 51 to 96 patients surviving initial operation for pheochromocytoma and give recurrence frequency estimates of 6% to 23%.^{3 4 5 6 7} There are several possible explanations for this fourfold range. All cohort studies, including this one, originate from referral centers; thus, the most obvious explanation is referral bias. In our study, we tried to limit this by excluding patients referred for a recurrence or from abroad. Follow-up bias may also overestimate recurrence frequency because patients with recurring pheochromocytoma are more likely than healthy patients to present for follow-up examination in specialized units. Follow-up was exhaustive in only one of the previous studies, involving 64 patients, among whom the recurrence rate was 6%.³ The recurrence rate depends on the definition of patients at risk. Patients with malignant tumor at first operation usually have a persistent disease (partial response) rather than recurrence (normalization, then disease reappearance).¹⁰ Postoperative and follow-up diagnostic tests are therefore required to distinguish between disease persistence and recurrence, especially in asymptomatic patients. Previous studies did not make this distinction. We did not distinguish between benign or malignant recurrence because there were too few patients for subgroup analysis. In addition, the current definition of malignancy based on lymph node or distant invasion is specific but lacks sensitivity because small or distant metastases may go long undetected. The strengths of this study include the large number of patients, complete follow-up of all patients, follow-up tests including periodic urinary metanephrine assessment, definition of patients at risk on the basis of negative postoperative biochemical and, when necessary, scintigraphic tests, and definition of recurrence on the basis of positive follow-up biochemical tests.

It would be valuable to physicians managing patients with pheochromocytoma to be able to base follow-up methods and periodicity on validated prognostic indicators. In cross-sectional studies, young age of onset,²² male sex,^{8 23} extra-adrenal and large pheochromocytoma,^{8 9 22 23} aneuploid or tetraploid tumoral DNA pattern,²² and reversion to a primitive secretion pattern (high proportion of the epinephrine precursors dopamine and norepinephrine,^{24 25} high normetanephrine excretion,⁸ low epinephrine and neuropeptide Y secretions²⁵ ) have been associated with malignancy. However, previous studies did not assess whether these variables are associated with subsequent benign or malignant recurrence. A better prognosis has been reported for patients with sustained hypertension than for those with paroxysmal hypertension, but the authors thought the association to be fortuitous.³ In the present analysis, variables associated with malignant status at initial operation (Table 1) and/or with prognosis in previous studies^{3 8 9 22 23 24 25} were considered as candidate prognostic indicators for recurrence. We found no relationship between the risk of subsequent recurrence and age, sex, blood pressure status at diagnosis, plasma catecholamines, or urinary metanephrines. Recurrence was more frequent in patients with large (>50 mm) and bilateral or extra-adrenal tumors, but the associations were not significant in multivariate analysis if the ratio of epinephrine to epinephrine plus norepinephrine and the presence of a familial disease were considered.

The ratio of epinephrine to epinephrine plus norepinephrine, an index of tumor differentiation, was significantly associated with malignancy at diagnosis, and in patients without evidence of malignancy at diagnosis, it was an independent predictor of subsequent recurrence. Genetic diseases that predispose to pheochromocytoma are logical candidates for recurrence predictors because a mutation activating a proto-oncogene (MEN 2²⁶ ) or loss of tumor-suppressor genes (von Hippel–Lindau disease²⁷ and neurofibromatosis 1²⁸ ) affect all the patient's chromaffin tissue. Previous cohort studies did not identify any relationship between familial syndromes and recurrence, probably because they included too few patients with such syndromes.^{3 4 5 6 7} In our cohort, unifactorial analysis and the Cox model showed that familial pheochromocytoma was consistently and independently associated with a high risk of subsequent recurrence. In familial pheochromocytomas and more specifically in MEN 2, the disease is diffuse at the cellular level and affects both adrenals as well as extra-adrenal chromaffin tissue even if unilateral and adrenal at the time of clinical presentation. Subsequent contralateral or ectopic pheochromocytomas therefore represent another localization of the underlying disease rather than a true recurrence of the initial tumor. Prophylactic bilateral total adrenalectomy has been advocated for patients with MEN 2. Close follow-up with elective surgery seems preferable, however,²⁹ because not all patients with MEN 2 and pheochromocytoma develop bilateral tumors even during long-term follow-up (see References 29 and 30^{29 30} and the present data), whereas bilateral adrenalectomy cannot prevent the subsequent occurrence of extra-adrenal tumors.³⁰

Pheochromocytoma is considered to be a curable cause of hypertension since the early report of Mayo.³¹ In the long term, however, a substantial proportion of our patients without recurrence (one in four at 5 years, and one half at 10 years) had a blood pressure of 140/90 mm Hg or more and/or were taking antihypertensive agents. Blood pressure status at latest follow-up was predicted by nonspecific indicators such as age and family history of hypertension and were in good concordance with blood pressure status in the year after initial operation. Individuals with renal artery stenosis or primary aldosteronism lose the ability, with increasing age, to reverse the structural vascular changes associated with secondary hypertension.^{32 33} This also applied to our patients operated on for a pheochromocytoma. The presence of an underlying predisposition to essential hypertension, as suggested by a family history of hypertension, was another nonspecific predictor of high blood pressure after etiologic treatment.

Blood pressure and catecholamines should be followed-up indefinitely in patients operated on for pheochromocytoma, and pheochromocytoma should not unreservedly be considered a surgically remediable cause of hypertension. The high rate of recurrence associated with familial syndromes (relative risk, 13.2; 95% confidence interval, 2.1 to 84.8) or a low ratio of epinephrine to epinephrine plus norepinephrine (relative risk, 4.0; 95% confidence interval, 1.1 to 14.9) underlines the usefulness of screening for a genetic disorder using phenotypic^{18 19} or genotypic^{34 35} methods and of determining plasma catecholamines in all patients with pheochromocytoma. Although the remote benefits of early screening and intervention for tumor recurrence are not known,³⁶ the present data have practical implications concerning the frequency of follow-up after initial operation. The recurrence time course in Fig 2 suggests that a biennial follow-up might be adequate in low-risk patients, whereas annual follow-up should be preferred in those with familial, large, extra-adrenal, or bilateral tumors or with a low epinephrine secretion. In addition to biochemical screening for pheochromocytoma recurrence, patients with MEN 2A or 2B should be screened annually for medullary thyroid cancer using the pentagastrin stimulation test and those with von Hippel–Lindau disease for renal cell cancer using renal ultrasound or computed tomographic scanning.^{34 35} Finally, blood pressure should be determined during the first year after pheochromocytoma resection, and patients with high postoperative blood pressure should be followed-up and managed as if they had essential hypertension.

	Acknowledgments

 
This study was supported in part by Institut National de la Santé et de la Recherche Médicale (INSERM) grant 493015 for the COMETE Network. We thank Dr Joël Ménard for insightful comments on the manuscript.

	Footnotes

 
Reprint requests to P.-F. Plouin, Hôpital Broussais, 96 rue Didot, 75674 Paris Cedex 14, France.

Received August 9, 1996; first decision October 10, 1996; accepted October 29, 1996.

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