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Departments of General, Visceral, and Vascular Surgery (A.M., M.B., P.N.T., H.D.) and Pathology (H.-J.H.), Martin Luther University Halle-Wittenberg, D-06097 Halle (Saale), Germany; and Department of Endocrinology and Metabolic Diseases (H.L.), Otto von Guericke University, D-39120 Magdeburg, Germany
Address all correspondence and requests for reprints to: Andreas Machens, M.D., Department of General, Visceral, and Vascular Surgery, Martin Luther University Halle-Wittenberg, Ernst-Grube-Straße 40, D-06097 Halle (Saale), Germany. E-mail: gensurg{at}medizin.uni-halle.de.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Objective: The objective of this study was to delineate the codon-specific, age-related development of multiple endocrine neoplasia type 2-associated pheochromocytoma.
Design: We describe a cohort study with a mean observation period of 26.9 yr.
Setting: The study took place in a tertiary referral center at a university hospital.
Patients: Included in this study were 206 consecutive carriers (74 index, 132 nonindex) operated on at this institution who harbored point mutations in the RET (rearranged during transfection) protooncogene.
Intervention: The intervention was adrenalectomy for clinically confirmed pheochromocytoma.
Main Outcome Measure: The main outcome measure was time to histopathological diagnosis of pheochromocytoma.
Results: Pheochromocytomas developed in 28% (five of 18) of carriers with mutations in codon 918, 29% (20 of 68) of carriers with mutations in codon 634, 14% (three of 21) of carriers with mutations in codon 618, 13% (two of 16) of carriers with mutations in codon 620, and 13% (two of 16) of carriers with mutations in codon 791. Earliest age of manifestation for each genotype was 22, 18, 29, 22, and 39 yr. Contralateral pheochromocytomas developed after 4 yr (one carrier each had a mutation in codon 618 or 620) and 5.2 yr (six carriers had mutations in codon 634). No pheochromocytomas were identified in carriers of mutations in codons 609 (n = 2), 611 (n = 8), 630 (n = 2), 768 (n = 8), 790 (n = 22), 804 (n = 18), and 891 (n = 7).
Conclusions: Based on these and published preliminary data, annual screening for pheochromocytoma may be warranted from age 10 yr in carriers of RET mutations in codons 918, 634, and 630, and from age 20 yr in the remainder.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Recent data indicate a codon-specific, age-related progression from C cell hyperplasia to medullary thyroid carcinoma, the most common tumor associated with the MEN type 2 syndrome (5, 13, 14). Owing to the comparative rarity of pheochromocytoma among RET gene carriers, much less information has become available on the age-related development of this condition within the MEN type 2 setting. The codon-specific, familial rates of concomitant adrenal involvement (13) and the closer association between pheochromocytoma and the codon 634 RET genotype relative to codon 609, 611, 618, and 634 RET genotypes (15, 16, 17) support the notion of a codon-specific, age-related development of pheochromocytoma in RET gene carriers.
Genetic information can be harnessed to define the optimal timing of prophylactic thyroidectomy before RET gene carriers develop medullary thyroid carcinomas (5, 13, 14). Likewise, information on RET genotype may also help improve the effectiveness of screening for pheochromocytoma. This screening should be intensified during the time frame in which pheochromocytomas commonly develop. In the absence of more detailed information, routine screening is often implemented on genetic evidence of RET germline mutations, irrespective of the carrier’s age and at variable follow-up intervals. This institutional study was set up to characterize the codon-specific, age-related development of pheochromocytoma as a foundation for a cost-effective practice of evidence-based medicine.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Between November 1994 and September 2004, a total of 206 consecutive RET gene carriers underwent at this institution thyroidectomy for C cell hyperplasia or medullary thyroid carcinoma, subtotal or total adrenalectomy for pheochromocytoma, or both procedures. All surgical interventions represented standard practice of care. Before surgery was undertaken, informed consent was obtained from all patients or their legal guardians. All surgical specimens were examined histopathologically. For 167 of the 206 RET gene carriers, details on age-related progression to medullary thyroid carcinoma have been published previously (14). With only two exceptions, primary thyroidectomy or thyroid reoperation were carried out at this institution, which serves as a tertiary surgical center with referrals of RET carriers from all over Germany. To minimize any impact that selective referral of RET carriers to our institution potentially might have had, all pertinent information on the RET carriers was gleaned from the referring and other institutions. Half of the 32 RET carriers underwent primary adrenalectomy for pheochromocytoma at our hospital, whereas the other half were operated on at outside hospitals. Contralateral adrenalectomy for subsequent adrenal recurrence was performed elsewhere on six of eight RET carriers. Screening for pheochromocytoma was based on determination of plasma, 24-h urinary fractionated catecholamines, metanephrines, or all three. Suspected pheochromocytomas were localized through adrenal ultrasonography, computerized tomography, magnetic resonance imaging, 131I-metaiodobenzylguanidine scanning, or any combination of these imaging modalities.
Genetic testing
Before undergoing genetic testing, all patients or their legal guardians, respectively, had given informed consent in accordance with institutional guidelines and national regulations that have their origin in the Declaration of Helsinki. For the identification of germline mutations in the RET protooncogene, genomic DNA was purified from peripheral blood leukocytes using standard techniques. Genomic DNA was amplified by the PCR with the use of oligonucleotide primers for exons 10, 11, 13, 14, 15, and 16. Single-strand conformation polymorphism analysis and direct sequencing were performed according to national laboratory regulations for RET analysis.
Statistical analysis
To ensure unbiased time-to-event estimates, all analyses were stratified by RET genotype and risk category, respectively. Genomic information and patient age at first histopathological diagnosis were related to thyroid (medullary thyroid carcinoma) and adrenal medullary histopathology (pheochromocytoma) to explore the codon-specific, age-related development of pheochromocytoma. Time to diagnosis of either tumor was calculated for each RET genotype (or RET risk category) using the Kaplan-Meier method and evaluated with the log-rank test (18).
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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There were 74 index and 132 nonindex RET gene carriers. Three RET risk categories were devised based on the 1999 consensus statement (5), with minor adaptations to accommodate recent literature (8, 12, 19) (Table 1
): during the mean observation period of 15.8, 24.7, and 33.3 yr since birth, respectively, pheochromocytomas had developed in 28% of RET carriers in the highest-risk category (mutations in codon 918), in 21% of RET carriers in the high-risk category (mutations in codons 634, 630, 609, 611, 618, 620), and 3% of RET carriers in the least high-risk category (mutations in codon 768, 790, 791, 804, 891). There were no extraadrenal pheochromocytomas. Pheochromocytomas developed in 28% of carriers with mutations in codon 918, 29% of carriers with mutations in codon 634, 14% of carriers with mutations in codon 618, 13% of carriers with mutations in codon 620, and 13% of carriers with mutations in codon 791. Among the 32 RET gene carriers with pheochromocytoma, only a single patient (3%), a 54-yr-old carrier of a mutation in codon 634 reported elsewhere (20), harbored a malignant pheochromocytoma with liver metastases. No pheochromocytomas were identified in carriers of mutations in codons 609, 611, 630, 768, 790, 804, and 891. The temporal relationship between pheochromocytoma and medullary thyroid carcinoma varied according to RET risk category: Whereas pheochromocytomas occurred only synchronously or metachronously in the highest-risk category, they emerged equally often in the high-risk category before, together with, or after medullary thyroid carcinoma. In the least-high category, conversely, pheochromocytomas exclusively preceded medullary thyroid carcinoma. In the entire RET population, medullary thyroid cancers were found four times more often (135 to 32) than pheochromocytomas.
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Time to diagnosis of pheochromocytoma (Table 2, upper panel) differed significantly according to RET risk category with means of 26.4 (highest risk), 34.9 (high risk), and 46.5 yr (least high risk). A similar, although less blunted, pattern was seen when time to diagnosis of medullary thyroid carcinoma was stratified by RET risk category: 14.3 (highest risk), 30.1 (high risk), and 51.6 yr (least high risk). On average, medullary thyroid carcinomas preceded pheochromocytomas by 12.1 (highest risk) and 4.8 yr (high risk), respectively, but lagged behind by 5.1 yr in the least-high risk category.
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Mean increments from one RET risk category to another were calculated separately for either tumor (Table 2
, lower panel). For each increment in RET risk category, pheochromocytoma to medullary thyroid carcinoma ratios were calculated: all three ratios approximated 54%. This finding suggests that chromaffin adrenal medullary cells may have 54% of the susceptibility to RET activation that have thyroidal C cells.
Time to contralateral pheochromocytoma after unilateral adrenalectomy
On primary adrenalectomy, bilateral pheochromocytomas were noted in two of 18 carriers (11%) of mutations in codon 918, six of 68 carriers (9%) of mutations in codon 634, and one of 21 carriers (5%) of codon 618 mutations (Table 3). Contralateral pheochromocytomas developed in six of 62 carriers (10%) of codon 634 mutations at a mean interval of 5.2 yr after unilateral adrenalectomy and 4 yr each after primary adrenalectomy in one of 21 carriers (5%) of mutations in codon 618 and one of 16 carriers (6%) carriers with mutations in codon 620 (Table 3).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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DNA-based timing of screening for pheochromocytoma
In a worst-case scenario, routine surveillance should be implemented before the earliest manifestation of pheochromocytoma (youngest patient age ever reported), taking the individual RET genotype into account. Table 4 summarizes our preliminary institutional experience and the international literature: Considering the present and limited body of clinical evidence (6, 9, 10, 13, 21, 22, 23, 24, 25, 26, 27) along with in vitro data from cell transfection experiments (28, 29), it may be warranted to initiate screening for pheochromocytoma at age 10 yr in carriers of mutations in codons 918, 634, and possibly 630 and age 20 yr in the remainder (Table 4). As more clinical information is forthcoming, further modifications of this scheme are likely to be needed, especially with regard to carriers of RET genotypes that do not involve mutations in codons 918 or 634. The 1999 consensus statement proposes the age of thyroidectomy (5–7 yr) or an age of 15 yr as the starting point for annual determination of urine metanephrines with imaging every 3–5 yr, regardless of RET genotype (5). Alternatively, if the lower bound of the 95% confidence interval of our preliminary data were used (Table 2, upper panel), biochemical surveillance would have to commence in the highest RET risk category (mutations in codon 918) with age 20 yr and in the high and least high RET risk category (mutations in codons 618, 620, 634, 791) with age 30 yr. This alternative approach does not seem viable, considering the current paucity of observations for most RET genotypes and a recent account of malignant pheochromocytoma in a 21-yr-old carrier of the codon 634 RET germline mutation (30). The individual RET genotypes within a single RET risk category share a broadly comparative transforming activity during in vitro transfection experiments (Table 4) and a similar mechanism of RET activation (3): alteration of the intracellular substrate recognition pocket of the catalytic core (highest-risk category), extracellular ligand-independent dimerization and cross-phosphorylation (high-risk category), and interference with intracellular ATP binding (least-high category).
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In a MEN type 2b transfection mouse model mimicking the high RET risk group (mutation in codon 918), pheochromocytomas developed through chromaffin cell hyperplasia of the adrenal medulla (31). In keeping with this notion, two 5- and 8-yr-old MEN type 2b carriers who underwent bilateral adrenalectomy for an elevated urinary vanillylmandelic acid to creatinine ratio on initial screening displayed adrenal medullary hyperplasia but not yet pheochromocytomas (32). Pheochromocytomas may occur by a second hit that causes a dominant effect on the mutant RET allele, through loss of the normal wild-type RET or through amplification of mutant RET by trisomy 10 (33). Alternative somatic mutations involve deletion of the von Hippel-Lindau gene (34) or allelic loss at chromosome 1p (35). Owing to the unpredictability of the timing of somatic hits required for malignant progression, there may be some risk of earlier progression to pheochromocytoma beyond that delineated by our preliminary data.
Conclusion
Correct ascertainment of a RET gene carrier’s lifelong risk of developing pheochromocytomas is critically dependent on the total length of follow-up. The mean follow-up since birth of our RET gene carriers (Table 1), 64% of whom were nonindex patients, would have to be extended by an additional 10–13 yr to reach the mean time span required to develop pheochromocytomas (Table 2, upper panel). For carriers of the codon 634 genotype, this is likely to raise our pheochromocytoma rate of 29% to the published rates of 50–57% (5, 36). Ideally, screening for pheochromocytoma should be implemented at an interval that is related to the genetically encoded risk. Further research is needed to clarify whether the proposed annual screening intervals (5) can be extended to 2-yr intervals without compromising safety in carriers of RET genotypes that entail a lesser degree of RET activation. This is even more important as cortical-sparing adrenalectomy in RET gene carriers is increasingly gaining favor over bilateral adrenalectomy (37, 38). Minimizing the risk of Addisonian crisis, these surgical procedures leave behind adrenal medullary remnants. In RET gene carriers, adrenal remnants require lifelong monitoring, as do virgin contralateral adrenal glands, because of their capability of giving rise to additional pheochromocytomas in 10% of carriers (38).
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Footnotes |
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Abbreviations: MEN, Multiple endocrine neoplasia; RET, rearranged during transfection.
Received January 12, 2005.
Accepted April 6, 2005.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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