Pheochromocytoma: Current Approaches and Future Directions

Adler, Joel T.; Meyer‐Rochow, Goswin Y.; Chen, Herbert; Benn, Diana E.; Robinson, Bruce G.; Sippel, Rebecca S.; Sidhu, Stan

doi:10.1634/theoncologist.2008-0043

Cited by 182 publications

(209 citation statements)

References 158 publications

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“…Clinical behavior, including invasion of adjacent tissues and the presence of metastases at non-chromaffin sites, is the only currently accepted indication of malignant pheochromocytoma [5,6]. We found that the incidence of malignant pheochromocytomas among 152 patients with pheochromocytomas was 11.2%, in good agreement with the 8% to 12.5% previously reported [7][8][9][10][11].…”

Section: Discussionsupporting

confidence: 89%

Predictive Characteristics of Malignant Pheochromocytoma

Park¹,

Park²,

Song³

et al. 2009

Journal of Urology

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Purpose:The prognosis of patients with malignant pheochromocytoma is poor, but the predictive factors are not well understood. We aimed to identify the clinical characteristics predictive of malignancy after initial surgical removal in patients with pheochromocytoma. Materials and Methods:We retrospectively reviewed the records of 152 patients diagnosed with pheochromocytoma, including 5 (3.3%) with metastasis at the time of the initial surgical excision and 12 (7.9%) who developed metastasis during follow-up. To determine the factors predictive of malignancy, we compared clinical, radiographical, and urinary chemical findings between patients with benign and malignant disease. Mean follow-up was 41.5 months (range, 0.9-298 months) after surgery. Results: Malignant tumors were significantly larger than benign tumors (11.1±4.0 cm vs. 6.2±3.4 cm, p＜0.001), and postoperative persistence of arterial hypertension was more frequent after removal of malignant than benign tumors (p=0.001). Among the 147 patients without metastatic disease at diagnosis, those who developed metastasis had significantly lower concentrations of urinary catecholamine metabolites per unit of tumor, including vanillylmandelic acid (1.2 vs. 3.7 mg/day/cm, p=0.049), epinephrine (4.5 vs. 168.9 μg/day/cm, p=0.008), and norepinephrine (13.1 vs. 121.8 mg/day/cm, p ＜0.001). The overall 5-year metastasis-free survival rate was 84.4% and was significantly higher in patients with smaller tumors (≤5.5 vs. ＞5.5 cm; 90.6% vs. 81.2%, p=0.025) and higher 24-hour secretion of vanillylmandelic acid (＞2.1 vs. ≤2.1 mg/ day/cm; 94.9% vs. 70.9%, p=0.019). Conclusions: Large tumor size (＞5.5 cm) and minimally elevated 24-hour urinary vanillylmandelic acid (≤2.1 mg/day/cm) were significantly associated with a higher probability of a malignant pheochromocytoma portending a lower metastasis-free survival and mandating more rigorous follow-up after surgery.

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Section: Discussionsupporting

confidence: 89%

Predictive Characteristics of Malignant Pheochromocytoma

Park¹,

Park²,

Song³

et al. 2009

Journal of Urology

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“…1,2 Pheochromocytomas are rare catecholamine-secreting tumors occurring in approximately 1-20 per million people per year in the general population. 3,4 Severe complications including hypertensive crisis, stroke and myocardial infarction are associated with pheochromocytomas. Surgical removal is the treatment of choice.…”

mentioning

confidence: 99%

“…6 The histological analysis of pheochromocytomas is not reliable for the establishment of malignancy: according to the definition by the World Health Organization, malignancy of pheochromocytomas is based on the detection of metastases. 4 Ki-67 and S100 have been suggested as possible immunohistochemical markers of malignancy, but their reliability is a matter of debate. 7,8 Pheochromocytomas are unique among other tumors, because 25-30% of them arise due to germ-line mutations related to hereditary endocrine tumor syndromes.…”

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confidence: 99%

“…Furthermore, miRNA expression profiles of a metastatic pheochromocytoma and a pair of primary and recurrent tumors have also been studied. Our study has focused exclusively on adrenal pheochromocytomas, therefore SDH gene mutation-related hereditary paraganglioma syndromes predisposing patients to mostly extraadrenal pheochromocytomas 4 have not been included. Owing to the rarity of these neoplasms, the retrieval of sufficient quantities of fresh or immediately snapfrozen tumor samples is difficult.…”

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confidence: 99%

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MicroRNA expression profiling in benign (sporadic and hereditary) and recurring adrenal pheochromocytomas

et al. 2010

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MicroRNAs are involved in the pathogenesis of several tumors, however, there have been no data on microRNA expression in pheochromocytomas to date. The objective of our study was to perform microRNA expression profiling in sporadic and hereditary benign, and recurring adrenomedullary tumors. Furthermore, the applicability of formalin-fixed paraffin-embedded tissue samples for the analysis of microRNA expression in pheochromocytomas was examined. MicroRNA expression data of three matched frozen and formalin-fixed paraffin-embedded samples were correlated. A total of 21 formalin-fixed paraffin-embedded samples (sporadic benign, multiple endocrine neoplasia 2, von Hippel-Lindau disease, sporadic recurring) were subjected to microRNA expression profiling using microarrays. MicroRNAs with significant differences in expression were validated and sample sizes were extended including tumors from neurofibromatosis type 1 patients by real-time quantitative reverse-transcription PCR (n ¼ 33). MicroRNA target prediction was carried out by TargetScan and MicroCosm Targets. Pathway analysis of targets was performed by Ingenuity Pathway Analysis and DIANA mirPath. Furthermore, microRNA expression profiles of a malignant pheochromocytoma and a pair of primary and recurrent tumors were studied by TaqMan Human MicroRNA Cards. MicroRNA expression correlated well between frozen and formalin-fixed paraffinembedded samples (70-92%). Microarray analysis revealed 16 significantly differentially expressed microRNAs. Five of these were validated by real-time RT-PCR. miR-139-3p, miR-541 and miR-765 were significantly differentially expressed between sporadic benign and von Hippel-Lindau-related pheochromocytomas. Significantly higher expression of miR-885-5p and miR-1225-3p was found in multiple endocrine neoplasia type 2 and sporadic recurring pheochromocytomas, respectively. Pathway analysis revealed the possible involvement of Notch-and G-proteincoupled receptor signaling in tumor recurrence. MicroRNA expression profiles in the primary recurrent and recurring malignant comparisons have been similar. In conclusion, we have proved that formalin-fixed paraffinembedded samples can be used for the analysis of microRNA expression in pheochromocytomas. MicroRNA expression patterns differ between various sporadic, hereditary and recurring tumors and miR-1225-3p may be useful for identifying recurring pheochromocytomas.

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“…The hereditary forms often present as bilateral and multifocal neoplasms and at an earlier age than the sporadic forms. Susceptibility to develop either pheochromocytomas or paragangliomas was associated with germ mutations in some genes, for example in cases of type 2 multiple endocrine neoplasia (MEN2), type one neurofibromatosis (NF1), Von Hippel Lindau syndrome (VHL), Carney-Stratakis syndrome and genes encoding subunits B, C and D of the mitochondrial enzyme succinate dehydrogenase (SDH) 7,8 . It remains a controversial question as to whether it is necessary for all patients with pheochromocytomas/paragangliomas to be genetically tested.…”

Section: Discussionmentioning

confidence: 99%