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Hypertension Unit (L.A., A.S., P.-F.P.) and Departments of Genetics (A.-P.G.-R.), Visceral Surgery (F.Z.), and Clinical Epidemiology (G.C.), Hôpital Européen Georges Pompidou, 75908 Paris, France
Address all correspondence and requests for reprints to: Dr. Pierre-François Plouin, Hypertension Unit, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75908 Paris Cedex 15, France. E-mail: pierre-francois.plouin{at}egp.ap-hop-paris.fr.
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Abstract |
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Introduction |
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Biochemical tests, specifically the determination of metanephrines in urine or plasma, and imaging techniques, including computed tomography and [123I]metaiodobenzylguanidine ([123I]MIBG) scintigraphy, have become increasingly accurate and more widely available over the last decades (1, 2). We investigated whether these improvements are associated with a reduction in the time taken to diagnose the disease and with a reduction in the size of the tumor at diagnosis. PHEO/PGL can occur in either the left or the right adrenal and in extraadrenal chromaffin tissue (11, 12, 13). We investigated whether there was a difference between patients in whom the disease subsequently recurred and those who were disease-free at their last follow-up. The factors considered were the year of diagnosis, the presence or absence of signs and symptoms or a family history of PHEO/PGL (11, 12, 13), and the site (left adrenal, right adrenal, or extraadrenal) and the size of the tumor.
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Subjects and Methods |
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PHEO/PGL was diagnosed in 263 patients referred to our unit between October 1975 and June 2003. To avoid a referral bias that would lead to the overrepresentation of malignant or recurring tumors, we excluded 54 patients who were referred either for an incomplete resection or for a recurrence after a first PHEO/PGL operation performed elsewhere. Because we wanted to study postoperative survival, we also excluded three patients who did not undergo tumor resection and 14 who were referred from abroad and who could not be followed up. Thus, 192 patients were included.
Initial assessment and follow-up
The procedures used for PHEO/PGL diagnosis and management were consistent with institutional guidelines and have been described previously (4, 5, 6, 14, 15). Patients gave informed written consent to participate in the study. Clinical data and the results of biochemical and imaging tests were collected prospectively using a standardized, computerized form. Urinary excretion of total metanephrines (metanephrine plus normetanephrines) and plasma catecholamine concentrations were determined since 1975, using liquid chromatography with electrochemical detection since 1982. In the late 1970s, angiography was used to locate the tumors. Subsequently, computed tomography and [123I]MIBG scintigraphy were introduced in 1979 and 1983, respectively. Magnetic resonance imaging has been used instead of computed tomography since 1985 in some patients, mostly children and pregnant women. Seventeen patients in the first quartile underwent MIBG scintigraphy, and 33 underwent computed tomography. All nonpregnant adult patients in subsequent quartiles underwent computed tomography and [123I]MIBG scintigraphy (see below for definition of quartiles of date of operation).
Familial disease was diagnosed on the basis of family history or of phenotypic evidence of multiple endocrine neoplasia type 2 (MEN2; including the determination of plasma calcitonin concentration before and after pentagastrin infusion), von Hippel-Lindau disease (VHL; including retinal examination), neurofibromatosis 1 (NF1), or hereditary PGL. Tumors were excised by either open or laparoscopic surgery. In cases of PHEO, the adjacent adrenal tissue was also removed along with any other possible tumors or lymph node or visceral metastases. To screen for tumor persistence or recurrence, we determined total metanephrine concentrations 15 d and 6 months after the operation and every other year thereafter. [123I]MIBG scintigraphy was performed whenever patients excreted high concentrations of total metanephrines.
Clinical, tumoral, and follow-up criteria
Most patients with PHEO/PGL showed adrenergic symptoms. In contrast, adrenal incidentalomas were discovered fortuitously in 29 patients during diagnostic testing for symptoms or clinical conditions not related to adrenal disease. Permanent hypertension was diagnosed in patients taking antihypertensive drugs and in patients who did not display any paroxysmal symptoms, but whose blood pressure was 140/90 mm Hg or more. Resistant hypertension was diagnosed in patients with blood pressures of 140/90 mm Hg or more despite triple antihypertensive treatment (16). We excluded patients with familial disease and those with refractory hypertension from the incidentaloma category, because screening for PHEO is conducted in these cases even if the patient displays no suggestive symptoms (1, 2, 3, 4, 16). Diabetes was diagnosed when the results of two plasma glucose assays were above 1.26 g/liter (7 mmol/liter) (17). Tumors were scored as malignant if there was histological evidence of tumor cells invading nonchromaffin organs or if computed tomography or MIBG scintigraphy detected distant metastases (5, 18, 19). Tumors were considered persistent when biochemical and/or imaging tests revealed postoperative evidence of disease. Recurrence was defined as the reappearance of the disease after eradication of the tumor had been confirmed by negative biochemical and imaging tests (5, 20). A malignant recurrence was defined according to the malignancy criteria described above. Other recurrences were deemed benign. In familial diseases that predispose to PHEO and PGL, tumor recurrence may be associated with new tumors as well as with true recurrence of a previous tumor (21). Particularly in cases with retroperitoneal nodules, new tumors, true recurrence, and lymph node metastasis can coexist. As we wanted to assess the risk of recurrence for a given patient and not for a given tumor, new tumors were not analyzed separately from true recurrences.
Data analysis
We sorted patients by date of first operation. We then divided them into four quartiles, each containing the same number of patients, i.e. 48 patients. The features displayed at presentation were compared between patients sorted into quartiles of date of operation; between patients with adrenergic symptoms and those with incidentalomas; among patients with left-sided adrenal, right-sided adrenal, and extraadrenal tumors; and between patients with recurrence and those without. Features associated with recurrence were entered into a logistic regression model to determine which factors were independently associated with the probability of recurrence. Values indicate the number of patients (percentage), the probabilities [95% confidence intervals], the median [interquartile range] or the mean ± SD, as appropriate.
Differences between means were assessed using the unpaired t test or the Mann-Whitney U test for two means or an ANOVA or the Kruskal-Wallis test for more than two means, as appropriate. The 
2 test or Fisher’s exact test was used to compare qualitative variables. The presence of a trend through the four time periods was assessed using the 2 test for trends for qualitative variables or using either ANOVA or a nonparametric method, as appropriate, for quantitative variables. To assess whether PHEO occurred more frequently on the right side than on the left side, we compared the actual proportion to the proportion expected under the null hypothesis, i.e. 50/50. Tumor-free survival probabilities were estimated using the Kaplan-Meier method. StatView (SAS Institute, Inc., Cary, NC) and Stata (Stata Corp., College Station, TX) statistical software were used for the statistical analysis. P < 0.05 was considered significant.
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Results |
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Patient characteristics at presentation by quartiles of date of operation are shown in Table 1
. There were no significant differences among the four quartiles concerning age; sex distribution; the proportions of patients with adrenergic symptoms or with permanent or resistant hypertension; the proportions of patients with extraadrenal, bilateral, or malignant tumors; or the proportions of patients with sporadic or familial disease. Of the 34 patients with familial disease, 10 had MEN2, 11 had VHL, 11 had NF1, and two had hereditary PGL. Symptoms were reported by 88.4% of all patients. Patients in recent quartiles tended to report symptoms for shorter duration than those in earlier quartiles. Hypertension was observed in 89.1% of all patients. Patients in recent quartiles had had hypertension for shorter durations than those in earlier quartiles. Tumors from patients in recent quartiles secreted less adrenaline, were smaller, and weighed less than those from earlier quartiles.
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Features at presentation and tumor site
Tumor site distribution differed between patients with familial disease and those without. Bilateral adrenal tumors, PGL, left adrenal tumors, and right adrenal tumors were found in eight, three, seven, and 16 of the patients with familial disease, and in one, 22, 48, and 87 of the patients with sporadic tumors (P < 0.001, by 2 test), respectively. Twenty-five patients had PGL in the Zuckerkandl body (n = 9), the renal hilum (n = 8), the mediastinum (n = 7), or the bladder (n = 1). Given the small number of patients with PGL, differences in initial characteristics between patients with PGL and those with adrenal PHEO did not reach statistical significance. One hundred and fifty-eight patients had single adrenal tumors, 103 in the right side and 55 in the left side. This is significantly different from the expected number (n = 79) on each side under the null hypothesis (P = 0.001, by 2 test; 1 df). Patients with right-sided tumors more frequently presented as incidentalomas than those with left-sided tumors (21.4% and 9.1%, respectively; P = 0.051). Compared with patients with left-sided tumors, patients with right-sided tumors excreted larger amounts of total metanephrines [2.9 (interquartile range, 1.8, 5.2) and 5.4 (interquartile range, 2.4, 9.8) mg/d; 16.0 (interquartile range, 9.7, 28.1) and 29.5 (interquartile range, 13.0, 53.5) µmol/d, respectively; P = 0.008] and had larger [40 (interquartile range, 30–55) and 50 (interquartile range, 37–70) mm, respectively; P = 0.016] and heavier [29 (interquartile range, 19–65) and 54 (interquartile range, 27–100) g, respectively; P = 0.026] tumors. The plasma catecholamine concentration did not differ between the two groups. Total metanephrine excretion, but not plasma catecholamine concentration, was correlated with tumor weight and diameter in patients with adrenal tumors.
Perioperative outcome
Fourteen patients (7.3%) had malignant tumors at first operation (Table 1
). Three of these patients had secreting PGL, and 11 had PHEO. Total metanephrine excretion, plasma catecholamine concentration, tumor diameter, and tumor weight were all significantly higher in malignant than benign tumors. Five patients died during the 30 d after surgery. One patient, with 90-mm left adrenal PHEO and lymph node metastasis, had normal total metanephrine excretion postoperatively, and neither computed tomographic scan nor [123I]MIBG scintigraphy showed evidence of persistent tumor. Therefore, 176 patients were at risk of recurrence (Fig. 1) and were followed postoperatively for 9.1 yr (interquartile range, 5.5, 15.3), a total of 1792 patient-years.
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Five patients moved during follow-up and could not be traced. Their urinary total metanephrine excretion was normal at their last follow-up, conducted between 83 and 210 months after their operations. All other patients were followed-up to the present or to death. Twelve patients died of nontumor-related conditions. The cause of death for two elderly (82- and 91-yr-old) patients was unknown. For these patients, the probability of recurrence was calculated using data up to their last follow-up or at the time of death. Twenty-nine patients suffered recurrence (Fig. 1): 19 patients with sporadic disease (malignant in 13 cases) and 10 with familial disease (malignant in one patient with VHL and one with NF1). Recurrences arose in the right adrenal in seven patients, in the left adrenal in six and at extraadrenal sites in two; 15 patients had distant metastases. Overall, the 5- and 10-yr probabilities of recurrence in the 176 patients at risk were 0.065 (95% confidence interval, 0.026, 0.104) and 0.161 (95% confidence interval, 0.092, 0.230), respectively.
Features at presentation and recurrence
Univariate comparisons between patients with and without recurrence are shown in Table 2. Patients with recurrences had their first operation performed earlier (P < 0.001), because a longer follow-up is associated with a higher probability of being diagnosed with a recurrence. The 5-yr probability of recurrence did not differ significantly between patients in quartiles 1 [0.025 (95% confidence interval, 0.001, 0.074)], 2 [0.133 (95% confidence interval, 0.033, 0.233)], and 3 [0.044 (95% confidence interval, 0.001, 0.105)], however, and most patients in quartile 4 were followed for less than 5 yr. Patients with recurrence tended to be younger and have significantly larger and heavier tumors at first operation than those with no recurrence. Patients with recurrence were also more likely than those with no recurrence to have familial disease and bilateral, right adrenal, or extraadrenal tumors. The 5-yr probabilities of recurrence were 0.150 (95% confidence interval, 0.013, 0.297) in patients with a familial disease and 0.047 (95% confidence interval, 0.001, 0.084) in those with sporadic PHEO/PGL (P = 0.034).
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Discussion |
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Presentation
Among the 171 patients with PHEO or PGL and sustained hypertension, the duration of the hypertension was shorter in patients diagnosed more recently. At first operation, patients diagnosed more recently had smaller tumors (diameter and weight) than patients diagnosed in previous decades. This suggests that PHEO/PGL were diagnosed earlier in more recent cases. Earlier diagnosis probably reflects improvements in the availability and accuracy of diagnostic tests for catecholamine-secreting tumors. Biochemical diagnosis using urinary or plasma metanephrines coupled to modern imaging, i.e. computed tomography, magnetic resonance imaging, [123I]MIBG scintigraphy, can now detect tumors smaller than 20 mm (1, 2, 8). The number of tumors presenting as incidentalomas increased over the study period as a result of the increased availability of imaging facilities.
Tumor site
More of the PHEO were in the right than in the left adrenal gland. We searched the literature for studies that reported tumor sites in at least 50 patients with PHEO (when several studies originated from the same center, we only considered the most recent publication). In 12 studies involving a total of 1239 patients with PHEO (11, 12, 13, 22, 23, 24, 25, 26, 27, 28, 29, 30), there were 561 single right-sided adrenal tumors and 396 left adrenal tumors, i.e. right-sided tumors were 42% more common than left-sided tumors. This distribution is significantly different that expected (479 left and 479 right) according to the null hypothesis (P < 0.001, by 2 test; 1 df). A referral bias favoring the diagnosis of right-sided PHEO is unlikely, because right-sided tumors present more frequently than left-sided tumors as incidentalomas. We found no reports of developmental or anatomical asymmetry that could account for a higher prevalence of PHEO on the right side. On the contrary, the left adrenal gland is usually heavier than the right adrenal gland in normal human fetuses (31), newborns (32), and adults (33). This difference is due to the weight of the adrenal cortex, rather than that of the medulla (34).
Recurrences
We next estimated the risk of recurrence of PHEO/PGL according to the patients’ characteristics at presentation. The 10-yr probability of recurrence was fairly high (0.161), confirming that patients with PHEO or PGL should be followed-up indefinitely (5, 35, 36, 37, 38). Patients with recurrences had their first operation performed earlier, were younger, had larger tumors, and were more likely to have familial disease and/or bilateral, extraadrenal, or right-sided tumors than patients with no recurrence. The date of the first operation is a confounding factor, because patients with a longer follow-up have a higher probability of being diagnosed with a recurrence. This was confirmed by the absence of a difference in tumor-free survival between patients undergoing operations during the first, second or third quartiles of the study period. Univariate analysis suggested that recurrence was associated with younger age, but this association was not confirmed by multivariate analysis. This may be because patients with familial disease in whom tumors frequently recur tended to be young at diagnosis. As for many other tumors (39), PHEO/PGL size is related to the risk of recurrence (5, 40, 41). The presence of a familial disease and tumor site and size at first operation were independent predictors of recurrence.
The tumor site at first operation was also independently associated with the risk of recurrence. Patients with extraadrenal tumors (i.e. PGL) and with right adrenal PHEO were 11.2-fold (95% confidence interval, 2.2–57.0) and 3.1-fold (95% confidence interval, 0.7–13.7) more likely, respectively, to have a recurrence than patients with left adrenal PHEO. Some (28, 40, 41), but not all (29, 42), previous reports mention more frequent aggressive phenotypes, initially malignant, persistent, or recurrent disease, in cases of PGL than adrenal PHEO. Benign PGL display an immature secretion pattern with low concentrations of neuropeptide Y and adrenaline; this pattern is also found in malignant PHEO (5, 43, 44, 45). Overproduction of angiogenic factors, including hypoxia-inducible factors and vascular endothelial growth factor, has been reported in malignant PHEO as well as in benign PGL with subsequent malignant recurrence (46). The high risk of recurrence in cases of PGL may also reflect genotypic differences. Apparently sporadic tumors, particularly PGL, may be hereditary tumors associated with mutations in genes encoding succinate dehydrogenase subunits B, C, and D (3, 4, 47). We also found that the risk of recurrence was higher in right-sided than in left-sided adrenal tumors. Right-sided tumors were larger than left-sided tumors. Tumor diameter and weight were higher in cases with recurrence than in cases without. The difference in tumor size was not the sole explanation for the difference in recurrence rate, however, because tumor side predicted the risk of recurrence independently of tumor diameter. Future studies should compare germline DNA and tumoral expression of oncogenes, growth factors, and enzymes in patients with adrenal and extraadrenal tumors, left and right PHEO, and PHEO with and without recurrence.
Genetic diseases
Mutations activating a protooncogene (RET in MEN2) (48) or a loss of tumor suppressor gene (VHL in VHL, SDHs in hereditary PGL, and NF1 in NF1) (49, 50) all affect the patient’s chromaffin tissue. Consequently, patients with familial PHEO or PGL are at high risk of bilateral or extraadrenal tumors and of recurrence (1, 2, 3, 4, 5). A weakness of our study is the characterization of PHEO or PGL as familial or sporadic only on the basis of family history and phenotypic evidence. We currently screen all patients with PHEO and PGL for germline mutations in RET, VHL, and SDH, but these mutations were described many years after our cohort was initiated; by the time genotypic testing became feasible, many patients were not available or were not willing to give consent for such screening.
The clinical implications of recent studies (3, 4, 47) are that all patients with catecholamine-secreting tumors should be offered genetic screening for familial diseases. Our study also suggests that clinical and biochemical follow-up should continue indefinitely, probably on a yearly basis for patients with familial, extraadrenal, and right adrenal tumors, and every 2 yr for patients with left adrenal tumors.
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Footnotes |
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First Published Online January 11, 2005
Abbreviations: MEN2, Multiple endocrine neoplasia type 2; MIBG, metaiodobenzylguanidine; NF1, neurofibromatosis 1; PGL, paraganglioma; PHEO, pheochromocytoma; VHL, von Hippel-Lindau disease.
Received July 19, 2004.
Accepted January 5, 2005.
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