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PubMed2006

Gene expression profiling of rat pheochromocytoma.

Sporadic and syndrome-associated human pheochromocytomas exhibit a spectrum of common and distinctive phenotypic markers. Animal models may contribute to understanding of common denominators leading to development and progression of pheochromocytoma, and to mechanisms that underlie distinctive phenotypes. Rat pheochromocytomas are common, in contrast to their human counterparts, and their frequency is increased by a variety of genotoxic or nongenotoxic agents. Toxicological studies of rats are therefore a potentially rich source of information on pheochromocytoma biology. To compare the molecular profiles of rat and human pheochromocytomas and to identify pathways potentially involved in pathogenesis of rat pheochromocytomas, we conducted a gene expression profiling study comparing 31 pheochromocytomas obtained from the National Toxicology Program to normal adult rat adrenal medulla. The microarray chips were generated from 31,769-oligomer set representing over 27,200 unique Mouse Ensembl genes. The analysis showed over 1,900 genes that were up- or downregulated in the tumors. More than half of the former are involved in protein synthesis and signal transduction, including oncogenes of the RAS family and several heat shock proteins and chaperones. Downregulated genes included receptors and tumor-suppressor genes, including NF2 and Dmbt1. Specific genes related to neuroendocrine function were either upregulated or downregulated in subsets of tumors. Cross-comparison with a human pheochromocytoma database showed greater than 60% correlation. Results of this study reveal both generic and specific parallels between rat and human pheochromocytomas.

Adrenal Gland Neoplasms↗
PubMed2006

Topographic molecular profile of pheochromocytomas: role of somatic down-regulation of mismatch repair.

CONTEXT AND OBJECTIVE: Despite extensive molecular investigation of adrenal pheochromocytomas, no information is available on their molecular and mismatch repair (MMR) profiles by topographic compartments. DESIGN AND SETTING: Microdissected samples from the peripheral and internal zones of 143 pheochromocytomas from a referral hospital (95 sporadic and 48 associated with multiple endocrine neoplasia type 2A) were selected for loss of heterozygosity and single nucleotide polymorphism analyses. Five polymorphic DNA regions from TP53, RB1, WT1, and NF1 were systematically studied by PCR-denaturing gradient gel electrophoresis. PATIENTS, OUTCOME MEASURES, AND INTERVENTIONS: Pheochromocytomas were classified as malignant (16 sporadic tumors with distant metastases), locally invasive (30 sporadic tumors showing retroperitoneal infiltration only), and benign (all remaining tumors). Statistical differences were evaluated using Fisher's exact test. MMR was assessed by MLH1/MSH2 sequencing and immunostaining in pheochromocytomas with two or more abnormal microsatellites. No interventions were performed in this study. RESULTS: Loss of heterozygosity/single nucleotide polymorphism involved TP53 in 40 of 134 informative cases (29.9%), RB1 in 22 of 106 informative cases (20.8%), WT1 in 32 of 120 informative cases (26.7%), and NF1 in 32 of 80 informative cases (40.0%). More genetic abnormalities involving the peripheral compartment were revealed in 34 pheochromocytomas (23.8%): 12 of 16 malignant, 10 of 30 locally invasive, and 12 of 97 benign. Multiple and coexistent genetic abnormalities characterized malignant pheochromocytomas (P < 0.001), whereas locally invasive pheochromocytomas showed a significantly higher incidence of NF1 alterations (P < 0.001). No mutations were identified in MLH1/MSH2, but MMR proteins significantly decreased in peripheral compartments. CONCLUSIONS: Multiple microsatellite alterations and topographic intratumor heterogeneity characterize malignant pheochromocytomas, suggesting a multistep tumorigenesis through somatic topographic down-regulation of MMR proteins. Locally invasive pheochromocytomas reveal topographic heterogeneity and single-locus microsatellite alterations, especially involving NF1.

Adrenal Gland Neoplasms↗
PubMed1990

Increased circulating concentration of the N-terminus of the atrial natriuretic factor prohormone in persons with pheochromocytomas.

To investigate the possible relationship of hypertension and the N-terminus of the atrial natriuretic factor (ANF) prohormone which contains two peptides [i.e. pro ANF-(1-30) and pro-ANF-(31-67)] with blood pressure-lowering effects, we examined the circulating levels of the N-terminus of the ANF prohormone in three patients with pheochromocytomas before surgery, during an increase in their blood pressure with surgical manipulation of their tumors, and after surgery when their blood pressures returned to normal. The circulating levels of the whole N-terminus [amino acids 1-98; pro-ANF-(1-98)] and pro-ANF-(31-67) from the midportion of the N-terminus of the ANF prohormone were increased 2-fold in patients with both extraadrenal and intraadrenal pheochromocytomas. In both the intraadrenal and extraadrenal patients N-terminus [pro-ANF-(1-98)] and pro-ANF-(31-67) circulating levels increased further during surgical manipulation and returned to normal after surgical removal of their respective tumors. Each of these pheochromocytomas was found to have pro-ANF-(1-30) and -(31-67)-binding sites that were functional, since they could enhance the guanylate cyclase-cGMP system 2-fold in these pheochromocytomas. The entire 126 amino acids of the prohormone were present within each of the pheochromocytomas, since both the whole N-terminus and C-terminus (i.e. ANF) of the prohormone were present. Examination of the pheochromocytomas by electron microscopy revealed electron-dense granules similar to those in the heart, which have been associated with the synthesis and storage of the ANF prohormone. We conclude that 1) the whole N-terminus [pro-ANF-(1-98)] and pro-ANF-(31-67) of the ANF prohormone circulate at higher concentrations in persons with pheochromocytomas and return to normal with removal of the tumors; 2) pheochromocytomas contain specific binding sites for pro-ANF-(1-30) and -(31-67); 3) these binding sites are functional, since pro-ANF-(1-30) and -(31-67) could enhance the enzyme guanylate cyclase within these tumors; and 4) the entire 126 amino acids of the ANF prohormone are present within these tumors, which have electron-dense granules associated with polypeptide hormone synthesis, suggesting that the ANF prohormone is being synthesized within the pheochromocytomas.

Adolescent↗
PubMed2000

Differential genetic alterations in von Hippel-Lindau syndrome-associated and sporadic pheochromocytomas.

Pheochromocytomas arise sporadically and as a component tumor of the inherited cancer syndromes von Hippel-Lindau disease (VHL), multiple endocrine neoplasia type 2 (MEN 2), and type 1 neurofibromatosis. Germline mutations of the VHL tumor suppressor gene (VHL) are responsible for VHL, and germline RET protooncogene mutations are associated with MEN 2. The present study was conducted to examine a large series of 36 VHL-related pheochromocytomas for somatic VHL and RET gene alterations and loss of heterozygosity (LOH) of markers on chromosome arms 1p, 3p, and 22q. For comparison, the same analyses were performed in 17 sporadic pheochromocytomas. We found no somatic intragenic mutations within VHL and RET in any VHL or sporadic pheochromocytoma, and no pheochromocytoma demonstrated upstream VHL gene hypermethylation. Of interest, we found significantly different LOH frequencies at 3 loci between sporadic and VHL tumors; the more than 91% LOH of markers on 3p and the relatively low frequencies of LOH at 1p and 22q (15% and 21%, respectively) in VHL pheochromocytomas argue for the importance of VHL gene dysregulation and dysfunction in the pathogenesis of almost all VHL pheochromocytomas. In contrast, the relatively low frequency of 3p LOH (24%; P: << 0.0001) and the lack of intragenic VHL alterations compared with the high frequency of 1p LOH (71%; P: = 0.0003) and the moderate frequency of 22q LOH (53%) in sporadic pheochromocytomas argue for genes other than VHL, especially on 1p, that are significant for sporadic tumorigenesis and suggest that the genetic pathways involved in sporadic vs. VHL pheochromocytoma genesis are distinct.

Adrenal Gland Neoplasms↗
PubMed2003

A comparative immunohistochemical study of spontaneous and chemically induced pheochromocytomas in B6C3F1 mice.

Spontaneously occurring and chemically induced pheochromocytomas are rare in mice. That the mouse pheochromocytoma is a more appropriate animal model than that of the rat for study of human medullary adrenal tumors has been suggested. The expression of phenylethanolamine-N-methyltransferase (PNMT), the enzyme responsible for production of epinephrine from norepinephrine, is common to both mouse and human pheochromocytomas. This investigation assessed the expression of the immunohistochemical markers PNMT, tyrosine hydroxylase (TH), and chromogranin A (CGA) in spontaneously occurring and chemically induced pheochromocytomas in the B6C3F1 mouse. Spontaneous tumors were derived from control animals from 10 different studies and the pheochromocytomas from treated groups from 4 different studies. All tumors were positive for maximal TH expression. A highly significant difference in PNMT expression (p < 0.01) occurred between spontaneously occurring pheochromocytomas classified as benign or "malignant" by the criteria of toxicologic pathology. Chemically induced tumors showed intermediate PNMT staining. A marked reduction in CGA expression occurred in pheochromocytomas induced by technical grade pentachlorophenol, compared to the other three chemicals and the spontaneously occurring tumors. These findings suggest that immunohistochemistry is a reliable tool in investigating the functional capabilities of pheochromocytomas in mice. PNMT expression is a tightly regulated component of the chromaffin cell phenotype and appears to be readily lost in mouse pheochromocytomas, particularly those with aggressive characteristics.

Adrenal Gland Neoplasms↗
PubMed1999

Regulation of neuropeptide Y mRNA expression in cultured human pheochromocytoma cells.

The expression of the neuropeptide Y (NPY) gene varies considerably in human pheochromocytomas, but the mechanisms for this variation have not been clarified. To investigate the regulation pattern of the NPY gene in human pheochromocytomas, we screened 16 pheochromocytomas and 9 normal adrenal tissues with Northern blots. The expression level of NPY mRNA in normal adrenal medulla was low and relatively constant, while the pheochromocytomas showed a very wide variation in NPY mRNA levels in both malignant and benign tumors. This indicates that NPY gene expression is not correlated with malignancy in pheochromocytomas. In primary cultures of human pheochromocytoma cells, nerve growth factor treatment (causing neuronal differentiation) increased NPY mRNA accumulation 2- to 5-fold (P < 0.05). NPY mRNA levels were also induced by protein kinase modulators (Bu)(2)cAMP and staurosporine in the cultures (P < 0.05). In contrast, treatment with dexamethasone and IGF-II (causing or linked with chromaffin differentiation) reduced NPY mRNA accumulation (P < 0.05). These data show that the regulation pattern of NPY mRNA expression in cultured human pheochromocytoma cells is different from that previously described in rat pheochromocytoma PC12 cells. Regulation of NPY mRNA expression in primary cultures by these differentiating factors suggests that the expression of NPY mRNA in pheochromocytoma tissues may be associated with the neuronal differentiation of the tumor cells affected by multiple factors.

Adrenal Gland Neoplasms↗
PubMed2005

Comparison of CT findings in symptomatic and incidentally discovered pheochromocytomas.

OBJECTIVE: The objective of our study was to determine the prevalence of incidental pheochromocytomas, whether their imaging characteristics differ from those of pheochromocytomas in symptomatic patients, and whether they differ from adenomas using CT densitometry. MATERIALS AND METHODS: The records from 335 adrenalectomies performed at our institution from 1995 to 2002 were reviewed, and 71 pheochromocytomas were identified. Thirty-three patients had CT examinations performed at our institution that were available for retrospective review. From electronic and hard-copy medical records, patient age and sex, the indications for imaging, and biochemistry activity were recorded. Pheochromocytomas were classified as symptomatic or incidental on the basis of clinical presentation. These groups were compared for differences in patient age, adrenal mass volume and maximal diameter based on CT dimensions, attenuation on unenhanced CT, attenuation on enhanced CT during the portal phase, the presence of calcifications, low attenuation or cystic changes, biochemical activity, and hypertension. Statistical significance was assessed with the Student's t test or chi-square test, as appropriate. RESULTS: Nineteen incidental (57.6%) and 14 symptomatic (42.4%) adrenal pheochromocytomas were in the study. There was a significant difference between the two groups as to whether hypertension was present (incidental, 10/19 [52.6%]; symptomatic, 14/14 [100%]; p = 0.0025). We found a trend toward calcification present in more symptomatic patients (incidental, 0/19 [0%]; symptomatic, 4/14 [28.6%]; p = 0.0670). No statistically significant difference was noted in the mean patient age (incidental, 51.7 years; symptomatic, 45.9 years), mean volume of the mass (incidental, 74.0 cm(3); symptomatic, 78.2 cm(3)), mean maximal diameter of the mass (incidental, 5.26 cm; symptomatic, 5.33 cm), mean attenuation on unenhanced CT (incidental, 36.6 H; symptomatic, 34.2 H), mean attenuation on enhanced CT (incidental, 93.7 H; symptomatic, 104.3 H), necrosis score or biochemical activity (incidental, 17/18 [94.4%]; symptomatic, 12/14 [85.7%]). No attenuation value of any pheochromocytoma was less than 10 H on unenhanced CT (median, 35 H; range, 17-59 H). CONCLUSION: In our study population, 57.6% of the pheochromocytomas were incidental, more than in most reported series. A history of hypertension was more frequent in the symptomatic group (p = 0.0025), but no radiologic parameters that allow differentiation of incidental and symptomatic pheochromocytomas were found. None of the pheochromocytomas had attenuation values of less than 10 H on unenhanced CT scans.

Adrenal Gland Neoplasms↗
PubMed1992

Consistent association of 1p loss of heterozygosity with pheochromocytomas from patients with multiple endocrine neoplasia type 2 syndromes.

Pheochromocytomas and medullary thyroid cancers (MTCs) are neuroendocrine tumors which arise sporadically or as part of the multiple endocrine neoplasia type 2 (MEN-2) hereditary syndromes. The most consistent molecular genetic abnormality which has been described in these tumors is loss of heterozygosity (LOH) of the short arm of chromosome 1 (1p). This finding is particularly interesting because the predisposition gene for the hereditary form of these tumors has been mapped to chromosome 10, but LOH on chromosome 10 in MEN-2 tumors is found rarely. We have used a battery of 1p DNA probes to elucidate the region of loss of 1p in 18 pheochromocytomas and 27 MTCs. Using restriction fragment length polymorphism analysis, we identified loss of all or a portion of 1p in 12 of 18 pheochromocytomas. 1p LOH was identified in nine of nine pheochromocytomas in MEN-2A and -2B patients, compared with only two of seven sporadic pheochromocytomas. We also found 1p LOH in one of two von Hippel-Lindau patients. LOH on 1p was noted in only three of 24 informative MTCs, and these were from patients with MEN-2A. In most of the pheochromocytomas, the entire short arm of chromosome 1p appears to have been lost; however, in three of the non-MEN pheochromocytomas and in three MEN-2A MTCs, the region of loss is smaller, allowing estimation of the smallest region of overlap. The combined data for MTCs and pheochromocytomas suggest that the smallest region of overlap of LOH is bounded by D1S15 (1pter-p22) and D1Z2 (1P36.3), excluding a region around MYCL (1p32). Although other regions of 1p should not be completely ruled out, the data suggest that this region may harbor a tumor suppressor gene or genes whose inactivation is important in the development of these tumors. Furthermore, the strong association between 1p LOH and the MEN-2 syndromes, especially in pheochromocytomas, suggests a relationship between the predisposition gene on chromosome 10 and the loss of the suppressor gene on 1p. Alternatively, other loci may be more important in sporadic disease.

Adrenal Gland Neoplasms↗
PubMedDate not supplied

[Pheochromocytoma: role of preoperative diagnosis in the assessment of malignancy risk and in the choice of surgical approach].

Pheochromocytomas are malignant in 5-26% of the cases. Differential diagnosis with benign lesions can be difficult even on a pathological basis. Local invasion and distant metastasis are the only well established indicators of malignancy. It has been reported that the risk of malignancy increases with the lesion size. Despite safe laparoscopic adrenalectomy (LA) has been reported for lesions up to 10 cm, it is considered hazardous for pheochromocytoma larger than 6 cm, because of the risk of malignancy and iatrogenic pheochromocytomatosis. We evaluated the possibility to pre-operatively recognize pheochromocytomas at risk of being malignant that should not be selected for LA. The medical records of all the patients who underwent adrenalectomy for pheochromocytoma were reviewed. All the preoperatively available data (demographic, clinical, biochemical and radiological) were recorded as well as final pathological diagnosis. Comparative analysis of patients with benign and malignant pheochromocytomas was performed. Sixty-three adrenalectomies for pheochromocytoma were performed in 60 patients. Fifty-seven benign and 6 malignant pheochromocytomas were identified. No significant difference was found between patients with malignant and benign lesions concerning age, gender, family history, symptoms, laboratory and radiological findings. In particular, no significant difference was found for lesion size between the benign (63.3 +/- 30.6 mm, range, 20-150) and the malignant group (48.6 +/- 16.5 mm; range, 30-70). The largest diameter recorded for a malignant lesion was 70 mm. No preoperatively available data can reliably differentiate between benign and malignant pheochromocytomas. All malignant lesions in this series were smaller than 7 cm. Thus, pheochromocytoma size does not seem a reliable predictor of malignancy. In absence of the evidence of gross local invasion or metastatic disease, LA can be safely proposed also for large lesions. Conversion is mandatory in presence of local invasion or difficult dissection that could involve inadequate resection.

Adrenal Gland Neoplasms↗
PubMed1986

Desensitization of aortic smooth muscle contraction in rats harboring pheochromocytoma.

Desensitization of smooth muscle contraction was studied in aortic ring segments obtained from New England Deaconness Hospital rats harboring pheochromocytomas, a norepinephrine-secreting tumor. Rats were studied 5 to 6 weeks after implantation of the pheochromocytoma, by which time severe hypertension had developed. Aortic ring segments from the pheochromocytoma rats were significantly less sensitive to the alpha-1 adrenergic agonist phenylephrine [log10 (ED50) = -7.21 +/- 0.09 vs. -7.63 +/- 0.11 in controls). In addition, the maximal force of contraction induced by phenylephrine was decreased in the aortas from pheochromocytoma rats (1.31 +/- 0.15 g) compared to controls (2.17 +/- 0.23 g). The potency of the thromboxane A2 receptor agonist U-46,619 was decreased in the aortic ring segments from pheochromocytoma rats compared to controls, although it elicited a similar maximal force of contraction. Desensitization of alpha receptor-mediated contraction was prevented by treating the pheochromocytoma-bearing rats with the reversible alpha adrenergic antagonist phentolamine (200 micrograms/kg/hr) via osmotic minipumps for 2 weeks. However, phentolamine did not decrease the hypertension in these rats. Also, large doses of the irreversible alpha adrenergic antagonist phenoxybenzamine (4 mg/kg/day i.p.) did not decrease blood pressure in rats harboring pheochromocytoma or did the drug completely block aortic alpha receptors in these rats as it did in controls. The results indicate that pheochromocytoma induces heterologous desensitization of smooth muscle contraction in rat aorta. The desensitization is due to direct effects of catecholamines unrelated to hypertension. The New England Deaconess Hospital rat harboring pheochromocytoma is an interesting model to study the effects of high concentrations of plasma catecholamines on smooth muscle contraction.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1985

[von Hippel-Lindau disease--hemangioblastoma associated with pheochromocytoma].

The association of a pheochromocytoma with von Hippel-Lindau disease is uncommon. We had a family with eight patients affected by von Hippel-Lindau disease, of whom five had hemangioblastoma of the central nervous system and seven had pheochromocytoma. As other lesions, retinal angiomatosis, spinal A-V malformation and spinal hemangioma were included in this family. In this paper five hemangioblastomas, four of whom had the association of hemangioblastoma and pheochromocytoma, are presented and clinical features of hemangioblastoma associated with pheochromocytoma are discussed, comparing to the 16 reported cases that had the association of hemangioblastoma and pheochromocytoma. The mean age of our own five cases at the onset of clinical symptoms was 32.2 years (ranging from 24 to 41 years) and that of reported 16 cases was 33.9 years (ranging from 18 to 55 years). These ages are slightly younger than that of sporadic hemangioblastoma. On the other hand, the mean age at the onset of pheochromocytoma was 28.3 years in our cases and 31.0 years in reported cases. This may suggest that hemangioblastoma when it is associated with pheochromocytoma presents its symptoms several years after the signs and symptoms of pheochromocytoma are manifested. In our cases a male to female ratio was 4:1 and in reported ones it was 9:7, showing that hemangioblastoma associated with pheochromocytoma as well as sporadic hemangioblastoma is likely to occur more in male.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Gland Neoplasms↗
PubMed1983

Rare forms of pheochromocytoma in children.

Two cases of pheochromocytomas in multiple locations are described. In the first case, a 5-year-old girl had surgery for a pheochromocytoma that was nonsecreting but had obstructed the renal artery. Ten years later, hypertension recurred and 2 adrenal pheochromocytomas, one on the left and one on the right side, were discovered. In addition, a papillary angioma was present in the fundus of the right eye, which indicated a phacomatosis. The child was cured. In the second case, another 5-year-old girl had a secreting pheochromocytoma in the upper thoracic region. Six months after extirpation of the tumour, a second pheochromocytoma was found in the right adrenal gland. These findings indicate 4 points of interest: 1. The thoracic localization. This prompted a review of all the available literature with the conclusion that this form of tumour is extremely rare. 2. The association of a pheochromocytoma and renal arterial stenosis. This has been observed by a number of other authors as well. 3. The coincidence of a pheochromocytoma as part of a phacomatosis and pheochromocytomas associated with Sipple's syndrome. 4. The multiple tumour sites. The necessity of generalized examinations in patients with pheochromocytomas to determine the presence of a phacomatosis or Sipple's syndrome is apparent.

Adolescent↗
PubMed1998

Elevated levels of telomerase activity in malignant pheochromocytoma.

BACKGROUND: Although malignant pheochromocytoma is a life-threatening illness, there is no excretory profile that is predictive of malignancy. Reliable prediction of malignant behavior on the basis of histopathology is also notoriously difficult. Although DNA ploidy can be a helpful indicator, aneuploidy per se is not considered to be a specific marker of malignancy. Mutations in p53 have been reported to occur frequently in cases of benign pheochromocytoma. Thus, molecular analysis of this protein is not a useful diagnostic tool. The authors analyzed telomerase activity in benign and malignant pheochromocytomas and assessed its utility as a prognostic marker. METHODS: Telomerase activity was estimated in 16 benign pheochromocytomas, 3 malignant pheochromocytomas, and 16 normal adrenal medullae by the fluorescence-based telomeric repeat amplification protocol. The telomerase activities of each group of samples were compared. RESULTS: No telomerase activity was detected in any of the normal adrenal medullae or the benign pheochromocytomas. By contrast, all of the three malignant pheochromocytomas had elevated telomerase activity. The telomerase activity in each tumor was determined to be 87.6 units, 71.2 units, and 180.3 units, respectively. CONCLUSIONS: The expression of telomerase activity in pheochromocytoma clearly suggests the malignant behavior of the component cells. Analysis of telomerase activity appears to be a powerful tool for the diagnosis of malignant pheochromocytoma.

Adrenal Gland Neoplasms↗
PubMed2002

Germ-line mutations in nonsyndromic pheochromocytoma.

BACKGROUND: The group of susceptibility genes for pheochromocytoma that included the proto-oncogene RET (associated with multiple endocrine neoplasia type 2 [MEN-2]) and the tumor-suppressor gene VHL (associated with von Hippel-Lindau disease) now also encompasses the newly identified genes for succinate dehydrogenase subunit D (SDHD) and succinate dehydrogenase subunit B (SDHB), which predispose carriers to pheochromocytomas and glomus tumors. We used molecular tools to classify a large cohort of patients with pheochromocytoma with respect to the presence or absence of mutations of one of these four genes and to investigate the relevance of genetic analyses to clinical practice. METHODS: Peripheral blood from unrelated, consenting registry patients with pheochromocytoma was tested for mutations of RET, VHL, SDHD, and SDHB. Clinical data at first presentation and follow-up were evaluated. RESULTS: Among 271 patients who presented with nonsyndromic pheochromocytoma and without a family history of the disease, 66 (24 percent) were found to have mutations (mean age, 25 years; 32 men and 34 women). Of these 66, 30 had mutations of VHL, 13 of RET, 11 of SDHD, and 12 of SDHB. Younger age, multifocal tumors, and extraadrenal tumors were significantly associated with the presence of a mutation. However, among the 66 patients who were positive for mutations, only 21 had multifocal pheochromocytoma. Twenty-three (35 percent) presented after the age of 30 years, and 17 (8 percent) after the age of 40. Sixty-one (92 percent) of the patients with mutations were identified solely by molecular testing of VHL, RET, SDHD, and SDHB; these patients had no associated signs and symptoms at presentation. CONCLUSIONS: Almost one fourth of patients with apparently sporadic pheochromocytoma may be carriers of mutations; routine analysis for mutations of RET, VHL, SDHD, and SDHB is indicated to identify pheochromocytoma-associated syndromes that would otherwise be missed.

Adolescent↗
PubMed1995

Loss of heterozygosity on the short arm of chromosome 3 in sporadic, von Hippel-Lindau disease-associated, and familial pheochromocytoma.

Pheochromocytomas occur sporadically and are associated with several dominantly inherited cancer syndromes, including von Hippel-Lindau (VHL) disease. We examined 14 pheochromocytomas (four from VHL patients, nine from sporadic patients, and one from a patient with familial pheochromocytoma) for loss of heterozygosity on chromosome arm 3p by using the polymerase chain reaction and restriction fragment length polymorphisms at eight loci. Loss of heterozygosity was detected in 8 of 14 pheochromocytomas examined: in three of the four VHL-associated tumors, in four of the nine sporadic tumors, and in the familial pheochromocytoma-associated tumor. Deletion of the inherited wild-type VHL allele was demonstrated in both informative VHL-associated pheochromocytomas, demonstrating involvement of VHL in pheochromocytoma development. However, because VHL mutations have not been detected in sporadic pheochromocytomas, VHL and/or another chromosome arm 3p gene may be involved in the etiology of these tumors.

Adrenal Gland Neoplasms↗
PubMed1996

Laparoscopic approach to pheochromocytoma: hemodynamic changes and catecholamine secretion.

This study compares the outcome of laparoscopic adrenalectomy (LpA) in 23 patients using CO2 insufflation with the outcome of this procedure in another 8 patients with pheochromocytoma (7 unilateral, 1 bilateral) using helium for pneumoperitoneum. The adrenal lesions in the first group included nonfunctional adenoma (n = 3), aldosterone adenoma (n = 11), Cushing's adenoma (n = 6), and Cushing's disease (n = 3). The latter patients were compared with a third group of 8 patients with pheochromocytoma undergoing conventional transabdominal adrenalectomy (CTA). With both procedures, intraoperative changes in plasma catecholamine levels were studied during pheochromocytoma removal and the changes correlated with intraoperative cardiovascular derangements. LpA was successfully performed in 95% of patients with adrenal lesions and in 100% of patients with pheochromocytoma. There was no significant difference in laparoscopic adrenalectomy for pheochromocytoma compared to that for other adrenal lesions in terms of operative time, blood loss, hospital stay, analgesic requirements, and return to normal activity. The outcome was less favorable in pheochromocytoma patients undergoing CTA. The largest increase of catecholamine levels in pheochromocytoma patients occurred during tumor manipulation with both LpA (17.4-fold for epinephrine and 8.6-fold for norepinephrine) and CTA (34.2-fold for epinephrine and 13.7-fold for norepinephrine), but cardiovascular instability was associated only with CTA. LpA may become the technique of choice for surgical removal of adrenal lesions and may also become the preferred method for removing pheochromocytoma.

Activities of Daily Living↗
PubMed1992

Value of the plasma norepinephrine/3,4-dihydroxyphenylglycol ratio for the diagnosis of pheochromocytoma.

PURPOSE: The purpose of this study was to assess whether the plasma norepinephrine/3,4-dihydroxyphenylglycol ratio (NE/DHPG) is of diagnostic relevance for patients with a pheochromocytoma. SUBJECTS AND METHODS: In 18 patients with a histologically proven pheochromocytoma and in nine patients with congestive heart failure, plasma levels of NE, epinephrine (EPI), and DHPG (radioenzymatic method) were determined after 20 minutes of supine rest. In 10 healthy subjects, the plasma catecholamine responses to active standing (5 minutes) and mental arithmetic (5 minutes) were measured. From the plasma NE and DHPG levels, the plasma NE/DHPG ratio was calculated. In order to analyze whether NE or EPI was the major secreted catecholamine, the patients with a pheochromocytoma were divided into two groups based on the increase of plasma NE above normal relative to that of EPI: Group 1 included patients with increased plasma NE or increased plasma NE and EPI. Group 2 included patients with increased plasma EPI in combination with a nearly normal NE. RESULTS: Both active standing and mental arithmetic increased the plasma NE/DHPG ratio by 105% and 13.6%, respectively, but in all subjects the ratio did not exceed 1.0. Patients with heart failure demonstrated a threefold higher plasma NE/DHPG ratio than did healthy subjects, and the ratio also did not exceed 1.0. The plasma NE/DHPG ratio was about seven to eight times higher in Group 1 (mean: 1.62, range: 0.81 to 2.84) than in Group 2 (mean: 0.24, range: 0.12 to 0.68). Nearly all patients in Group 1 had a NE/DHPG ratio that was higher than 1.0. In contrast, five of six samples of Group 2 demonstrated a NE/DHPG ratio within the normal range. The calculated positive and negative predictive values of a basal plasma catecholamine level were higher than that for the plasma NE/DHPG ratio. CONCLUSIONS: In contrast to earlier reports, a normal plasma NE/DHPG ratio does not exclude the presence of a pheochromocytoma. In patients with a pheochromocytoma that produces EPI predominantly, this ratio may be normal. On the other hand, in patients with congestive heart failure, the plasma NE/DHPG ratio is increased, although there is no clear overlap with values of patients with a pheochromocytoma. Although the prevalence of pure EPI-producing pheochromocytomas is low, the plasma NE/DHPG ratio should be used with caution in the diagnostic evaluation of patients with a suspected pheochromocytoma.

Adrenal Gland Neoplasms↗
PubMed2005

Peripartum hypertension from pheochromocytoma: a rare and challenging entity.

BACKGROUND: Pheochromocytoma, a rare and usually curable cause of hypertension, is characterized by symptoms and signs related to increased catecholamine secretion. Pregnancy can elicit clinical manifestations of otherwise unrecognized pheochromocytoma. METHODS AND RESULTS: Four women, ranging in age from 27 to 37 years, were referred to the hypertension clinic with the following presentations: 1) a 35-year-old woman, diagnosed with gestational hypertension and headaches during the third trimester of her pregnancy and 5 months after delivery, was hospitalized with pulmonary edema. Echocardiography revealed severe dilated left ventricular (LV) dysfunction. Cardiac function was normalized after surgical resection of a pheochromocytoma from her left adrenal; 2) a 37-year-old woman suffered from preeclampsia, persistent hypertension and orthostatic hypotension after a cesarean section. A diagnostic work-up revealed a catecholamine-secreting paraganglioma in the retroperitoneum. The patient underwent a laparosopic resection of the tumor; 3) a 27-year-old woman suffered from hypertension and episodes of palpitations, sweating, and dyspnea in the first trimester of her pregnancy. An ultrasound revealed a 5-cm mass in the left adrenal. She underwent a left adrenalectomy at the 17th week of pregnancy, which confirmed the diagnosis of pheochromocytoma; 4) a 34-year-old woman, at the 26th week of pregnancy, presented with an acute loss of vision and blood pressure of 230/140 mm Hg. Fundoscopy showed papilledema with soft exudates in both eyes. Chemical studies were positive and imaging revealed a left adrenal pheochromocytoma. Despite aggressive medical treatment, fetal distress mandated a laparotomy at the end of the 28th week of pregnancy. A healthy newborn was delivered and resection of the adrenal tumor confirmed the diagnosis of pheochromocytoma. CONCLUSIONS: Although rare, pheochromocytoma can cause severe peripartum hypertension. Screening for pheochromocytoma, ideally with plasma-free metanephrines, should be considered in cases of peripartum hypertension.

Adrenal Gland Neoplasms↗