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PubMed1995

Characterization of Pheochromocytomas in a Mouse Strain with a Targeted Disruptive Mutation of the Neurofibromatosis Gene Nf1.

Patients with neurofibromatosis type 1 (NF1) show an increased frequency of pheochromocytomas. The NF1 gene encodes a GTPase-activating protein that controls the activity of ras proteins in intracellular signaling. A mouse strain with a knockout mutation of Nf1, the murine counterpart of NF1, has recently been constructed. This mutation, designated Nf1(n31), has been shown to be associated with the frequent development of pheochromocytomas in heterozygous animals. Pheochromocytomas are extremely rare in wild-type mice. We have characterized the tumors to assess their relevance as a model for human pheochromocytomas. The frequency of pheochromocytomas was determined in inbred compared to outbred mice carrying the Nf1(31) mutation. Paraffin sections of pheochromocytomas from seven mice were stained immunohistochemically for the catecholamine biosynthetic enzymes, tyrosine hydroxylase (TH), and phenylethanolamine-N-methyltransferase (PNMT) to infer their profiles of catecholamine synthesis, and for chromogranin A (CGA) to infer their content of secretory granules. Cultured cells from a representative tumor were studied in vitro to assess proliferation and neuronal differentiation. Pheochromocytomas arose in approx 15% of Nf1(n31) mice with a mixed genetic background, but were absent in inbred mice. Approximately one-fourth of the tumors were bilateral. The tumors exhibited variable morphology. All included cells that appeared well differentiated and resembled normal chromaffin cells in that they expressed TH, PNMT, and CGA. Focal neuronal differentiation was also observed. In cell culture, the tumor cells ceased to proliferate and the majority underwent terminal differentiation into TH-positive cells with neuronal morphology. The phenotype of pheochromocytomas in mice with the Nf1(31) mutation resembles that of human pheochromocytomas, particularly with respect to their ability to produce epinephrine, as inferred from positive staining for PNMT. The tumors also resemble both normal and neoplastic human adrenal medulla with respect to their extensive differentiation into neuron-like cells in vitro. This change in phenotype may be related to ras activation. These neoplasms may be valuable both as models for the pathobiology of adrenal medullary neoplasia, and as a source of epinephrine-producing pheochromocytoma cell lines, for which adequate models currently do not exist.

Journal Article↗
PubMed1999

Composite Pheochromocytoma-Ganglioneuroma of the Adrenal Gland: An Uncommon Entity with Distinctive Clinicopathologic Features.

Background: Adrenal composite pheochromocytoma-ganglioneuroma is uncommon. The aim of this study is to investigate the characteristics of patients with this tumor. Methods: Histologic features of 46 pheochromocytomas diagnosed over a 28-year period (1971-1998) were reviewed. The clinical records, pathologic features, and ploidy patterns of patients with composite pheochromocytoma-ganglioneuroma were studied. Cases reported in the literature were also reviewed and compared with typical pheochromocytomas. Results: Four patients (two men; two women) with composite pheochromocytoma-ganglioneuromas were found. The tumors comprised 8.7% of pheochromocytomas. The two male patients with composite tumors were younger than the two female patients (age = 32, 52 vs 73, 75, respectively). The radiologic, gross, and microscopic appearances of the tumors were heterogeneous. One patient had malignant tumor with distant metastases. Flow cytometric analysis showed that the pheochromocytoma component was aneuploid and the ganglioneuroma portion was diploid. A review of the literature showed 31 adrenal composite pheochromocytoma-ganglioneuromas. Composite tumors were seen in older patients and were bigger than typical pheochromocytomas. Conclusion: Composite pheochromocytoma-ganglioneuromas had distinctive clinicopathologic features. Life-long clinical and biochemical follow-up of these patients is essential in view of the non-diploid DNA pattern.

Journal Article↗
PubMedDate not supplied

Pheochromocytoma.

OBJECTIVE: To characterize the symptoms associated with pheochromocytoma and discuss the diagnosis and management of this tumor. METHODS: We review the clinical manifestations in patients with pheochromocytoma, the biochemical and imaging studies recommended for diagnosis and localization of the tumor, and the available strategies for treatment. RESULTS: Pheochromocytoma is a tumor of chromaffin cells that originates in either the adrenal medulla or the extra-adrenal sympathetic tissues. It is usually unilateral and benign. Frequent initial symptoms include headache, sweating, and palpitations, with or without increased blood pressure. In many patients, hypertension is accelerated during a paroxysm. Pheochromocytoma may also occur as a part of multiple endocrine neoplasia type IIA and B. Several common syndromes, such as panic disorders and hyperthyroidism, may mimic pheochromocytoma; however, pheochromocytoma should be suspected in the presence of hypertension, tachycardia, and throbbing headache, especially occurring as paroxysmal episodes. The physiologic diagnosis of pheochromocytoma is established by biochemical tests of levels of plasma and urinary catecholamines or their metabolites (or both). In most patients, anatomic localization is achieved with computed tomography or magnetic resonance imaging, metaiodobenzylguanidine scintigraphy, labeled somatostatin scans, or positron emission tomography. The management preferentially includes surgical removal of the pheochromocytoma after preparation with appropriate medical therapy to avoid hypertensive crisis during the perioperative period. Patients with contraindications to a major surgical procedure or with malignant pheochromocytoma and metastatic disease, however, may be treated with multiple drugs--for example, alpha- and beta-adrenergic blockers and direct vasodilators to neutralize the effects of high levels of circulating catecholamines and alpha-methyl-metatyrosine to inhibit catecholamine synthesis. CONCLUSION: The presence of suggestive clinical features in patients with hypertension should prompt clinicians to undertake appropriate diagnostic testing because surgical resection of a pheochromocytoma will yield a cure in many cases.

Journal Article↗
PubMed2003

Von Hippel-Lindau gene alterations in sporadic benign and malignant pheochromocytomas.

The Von Hippel-Lindau (VHL) gene product has a wide spectrum of tissue-specific functions, and specific germline mutations are associated with clinical phenotypes in VHL disease. In particular, missense mutations are correlated with the susceptibility to pheochromocytomas. An association between VHL aberrations and prognosis has been suggested in renal clear cell carcinoma but has not been studied in pheochromocytomas. We studied the frequency and spectrum of VHL alterations in apparently sporadic pheochromocytomas in relation to the clinical behavior in 72 patients, including 48 patients with clinically benign and 24 patients with malignant pheochromocytomas. Single-strand conformation polymorphism (SSCP) analysis followed by DNA sequencing, loss of heterozygosity analysis of the VHL locus and immunohistochemistry for VHL protein expression were used to investigate somatic VHL gene alterations. In 2 patients, 1 with a malignant tumor, germline mutations were identified in the stop codon. Tumor-specific intragenic VHL mutations and accompanying loss of heterozygosity were identified in 2 (4.3%) of 47 sporadic benign pheochromocytomas compared to 4 (17.4%) of 23 malignant tumors (p = 0.064). Only one of these mutations has been previously described, in a renal clear cell carcinoma. Expression of the VHL protein was observed in all pheochromocytomas. No distinction in the nature of VHL alterations between benign and malignant pheochromocytomas and no correlation with histopathologic or clinical features was observed. We report novel VHL mutations in sporadic pheochromocytomas, which are slightly correlated with malignancy. VHL mutations may have some impact on the malignant transformation of pheochromocytomas.

Adolescent↗
PubMed1990

Evaluation of clonidine suppression and various provocation tests in the diagnosis of pheochromocytoma.

Recent investigations have shown that the widely used clonidine suppression test is sometimes fallible for the diagnosis of pheochromocytoma. A comparative assessment was made of the following suppression and provocation tests, the clonidine suppression test, and the glucagon, metoclopramide, and naloxone provocation tests. The assessment was performed in 6 patients with pheochromocytoma and in 19 patients without pheochromocytoma who were initially suspected of harboring a tumor. BP response did not predict the presence of pheochromocytoma in any test. Plasma norepinephrine (NE) concentrations determined at 120 and 180 min after oral 150 micrograms of clonidine gave false negative results in 2 of the 5 patients with pheochromocytoma tested. Both plasma NE and epinephrine (E) concentrations were measured before and sequentially after each provocative agent. Neither NE nor E responded to 1 mg of glucagon iv in 2 of the 4 patients with pheochromocytoma tested. Determination of the peak level, peak increment, and % peak increment of NE and E following 10 mg of naloxone iv did not distinguish the two groups. The % peak increments of both NE and E in all 4 patients with pheochromocytoma given 5 mg of metoclopramide iv exceeded the mean + 3 SD values of the patients without pheochromocytoma (25 + 28% for NE, and 25 + 42% for E). These results suggested that, when performed with judicious patient selection (ambiguous plasma or urinary catecholamine levels), the measurement of plasma catecholamines in response to metoclopramide can be a useful adjunctive tool in the diagnosis of pheochromocytoma.

Adrenal Gland Neoplasms↗
PubMed2005

Pheochromocytoma in von Hippel-Lindau disease and neurofibromatosis type 1.

Clinical and genetic understanding of chromaffin tumors has been greatly enhanced in the last few years. Although some pheochromocytoma genes may still be unknown, the role of RET, VHL, SDHB, SDHD and NF1 genes is unequivocal and phenotypes are also being better characterized. The loss of function of VHL and NF1 genes can lead to a variety of tumors including phechromocytoma and their mechanism of action is under intensive investigation. Many different mutations are responsible for VHL gene inactivation but only missense mutations have been described so far in families with pheochromocytoma. Because of its large size extensive mutation analysis of the NF1 gene has seldom been performed, and mutations have only been identified in about 15% of patients. Several point mutations have been found in exon 31. Differences in pheochromocytoma phenotype in VHL or NF1 are not very pronounced, but it may be of some interest to consider the two groups separately. In VHL, pheochromocytoma has an earlier onset than in sporadic forms, it is often multiple, and malignancy is less frequent. The mean age of diagnosis is 28 years, the youngest patient being 5 years old. In NF1 patients pheochromocytoma phenotype is similar to sporadic forms. The mean age of pheochromocytoma onset is 42 years; 84% of patients have solitary adrenal tumors, 9.6% have bilateral adrenal disease and 6.1% have ectopic pheochromocytomas; malignant pheochromocytomas were identified in 11.5% of the cases. The group of pheochromocytoma susceptibility genes includes, along with the tumor suppressor genes VHL and NF1, the proto-oncogene RET and the genes encoding succinate dehydrogenase subunit D and succinate dehydrogenase subunit B. Whether there is a common pathway among these different genes is still a matter of debate.

Adrenal Gland Neoplasms↗
PubMed2004

Surgical management of hereditary pheochromocytoma.

BACKGROUND: Surgical treatment of hereditary pheochromocytoma remains controversial because of the need for lifelong corticosteroid therapy and the risk of Addisonian crisis associated with bilateral total adrenalectomy. We examined our large series of patients with hereditary pheochromocytoma to evaluate postsurgical outcomes, particularly in those who underwent cortical-sparing adrenalectomy. STUDY DESIGN: We retrospectively reviewed the outcomes of all patients with histopathologic diagnoses of hereditary pheochromocytoma treated at our institution from 1962 to 2003. Familial disease was initially determined by pedigree analysis, genetic testing, or both for multiple endocrine neoplasia (MEN) types 1, 2A, or 2B; von Hippel-Lindau disease (VHL); neurofibromatosis type 1 (NF-1); or familial paraganglioma syndrome (FP). RESULTS: Adrenal pheochromocytomas were present in 56 of 59 patients (95%): MEN2A (39), MEN2B (7), VHL (6), MEN1 (2), NF-1 (2). Paragangliomas (extraadrenal pheochromocytomas) were present in the remaining 3 of 59 patients (5%): FP (2) and NF-1 (1). Thirty-eight of 56 patients with pheochromocytomas had cumulative operations resulting in total or subtotal bilateral adrenalectomy. Acute adrenal insufficiency (Addisonian crisis) occurred in 4 of these 38 patients (11%). Cortical-sparing adrenalectomy was performed in 26 patients who underwent bilateral adrenal resection; 17 (65%) were corticosteroid independent at a median followup of 71 months. Recurrent pheochromocytoma developed in an adrenal remnant in 3 of 30 patients (10%) who underwent unilateral or bilateral cortical-sparing procedures. Metastatic disease did not develop in any patient with pheochromocytoma, but has occurred in two of three patients with paragangliomas. CONCLUSIONS: Our data suggest that a cortical-sparing adrenalectomy can successfully avoid the need for corticosteroid replacement in the majority of patients who undergo a bilateral adrenalectomy. Long-term followup should include monitoring of the remnant gland for recurrent pheochromocytoma with yearly biochemical screening studies.

Addison Disease↗
PubMed2003

VEGF in 105 pheochromocytomas: enhanced expression correlates with malignant outcome.

Pheochromocytomas are rare sympathoadrenal tumors that are highly vascular. Their malignancy is extremely difficult to estimate on the basis of histopathological features. Vascular endothelial growth factor (VEGF) is one of the most important angiogenic factors involved in both tumor growth and metastasis. In our search for new prognostic markers, we investigated the expression of VEGF in normal adrenal gland, in 105 primary pheochromocytomas, and in 6 metastases by using immunohistochemistry and Northern blot analysis. We also calculated the microvessel density of these tumors by staining the endothelial cells with monoclonal CD34 antibody. VEGF messenger ribonucleic acid was found in all pheochromocytomas studied. Immunohistochemically, VEGF was not found in normal adrenal medullary cells. Interestingly, all malignant pheochromocytomas (n=8), regardless of their primary location, had strong or moderate VEGF immunoreactivity, while most benign adrenal pheochromocytomas (26 of 37, 70.3%) were either negative or only weakly positive. The staining was heterogenous in extraadrenal pheochromocytomas as well as in a group of tumors that had histologically suspicious features but had not metastasized, here called borderline tumors (n=29). The microvessel density varied greatly in all of the tumor groups, and no statistical difference was found between these groups. Here we report moderate to strong VEGF expression in malignant pheochromocytomas, and negative or weak expression in benign adrenal pheochromocytomas. Normal medullary cells are immunohistochemically negative. Thus, low VEGF expression in pheochromocytomas favors a benign diagnosis.

Adolescent↗
PubMed2002

Neurofibromin and NF1 gene analysis in composite pheochromocytoma and tumors associated with von Recklinghausen's disease.

Composite tumor of pheochromocytoma and neuroblastoma, or ganglioneuroma, or ganglioneuroblastoma (composite pheochromocytoma), also known as mixed neuroendocrine and neural tumor, are sometimes combined with neurofibromatosis type 1 (NF1). To better understand the relationship between NF1 and composite pheochromocytoma, an immunohistochemical study using anti-neuro-fibromin that is an NF1 gene product and DNA sequence of NF1 Exon 31 were carried out in five cases of composite pheochromocytoma and in various tumors from five patients with NF1. Neurofibromin was not expressed in Schwann cells and sustentacular cells of composite pheochromocytomas and was very weakly or negatively expressed in neurofibroma of NF1 patients. However, it was strongly expressed in ganglionic cells and pheochromocytoma cells of the composite pheochromocytomas and also in mucosal ganglioneuromas, a gangliocytic paraganglioma, and in pheochromocytomas from the patients with NF1. Although there was no mutation in NF1 Exon 31, it could not be ruled out that there were mutations in other sites of the NF1 gene. Neurofibromin insufficiency may induce abnormal proliferation of Schwann cells in composite pheochromocytomas as well as in neurofibromatosis.

Adrenal Gland Neoplasms↗
PubMed2001

Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma.

The pheochromocytomas are an important cause of secondary hypertension. Although pheochromocytoma susceptibility may be associated with germline mutations in the tumor-suppressor genes VHL and NF1 and in the proto-oncogene RET, the genetic basis for most cases of nonsyndromic familial pheochromocytoma is unknown. Recently, pheochromocytoma susceptibility has been associated with germline SDHD mutations. Germline SDHD mutations were originally described in hereditary paraganglioma, a dominantly inherited disorder characterized by vascular tumors in the head and the neck, most frequently at the carotid bifurcation. The gene products of two components of succinate dehydrogenase, SDHC and SDHD, anchor the gene products of two other components, SDHA and SDHB, which form the catalytic core, to the inner-mitochondrial membrane. Although mutations in SDHC and in SDHD may cause hereditary paraganglioma, germline SDHA mutations are associated with juvenile encephalopathy, and the phenotypic consequences of SDHB mutations have not been defined. To investigate the genetic causes of pheochromocytoma, we analyzed SDHB and SDHC, in familial and in sporadic cases. Inactivating SDHB mutations were detected in two of the five kindreds with familial pheochromocytoma, two of the three kindreds with pheochromocytoma and paraganglioma susceptibility, and 1 of the 24 cases of sporadic pheochromocytoma. These findings extend the link between mitochondrial dysfunction and tumorigenesis and suggest that germline SDHB mutations are an important cause of pheochromocytoma susceptibility.

Amino Acid Sequence↗
PubMed2002

Laparoscopic adrenalectomy for pheochromocytoma: morbidity compared with adrenalectomy for tumors of other pathology.

PURPOSE: We report our experience with laparoscopic adrenalectomy in nine patients with pheochromocytoma and compare the morbidity with that of laparoscopic adrenalectomy for tumors of other pathology. PATIENTS AND METHODS: Between January 1997 and November 1999, nine patients underwent laparoscopic surgery for pheochromocytoma via a transperitoneal approach. Of the patients, eight had solitary tumors, and one presented with bilateral pheochromocytomas. The mean size of the tumors was 5.4 cm. The surgical outcomes of the 9 patients were compared with those of 28 patients with adrenal tumors of other pathology (primary aldosteronism in 15 patients, Cushing syndrome in 6, and nonfunctioning adenoma in 7) who underwent transperitoneal laparoscopic adrenalectomy during the same period. The mean size of the adrenal tumors of other pathology was 2.4 cm. RESULTS: In eight of the nine patients with pheochromocytoma, laparoscopic adrenalectomy was successful. The procedure was converted to open surgery in the patient with bilateral tumors because of uncontrollable hemorrhage. A hypertensive crisis with the systolic blood pressure >200 mm Hg occurred in 6 patients (67%), but the episode could be controlled by temporary discontinuation of tumor manipulation, administration of drugs, or both. In adrenalectomy for pheochromocytoma, the mean operative time was longer (199 v 177 minutes) and the mean estimated blood loss was greater (360 v 54 mL) than for tumors of other pathology. Blood transfusion was given to two patients with pheochromocytoma but to no patient with tumors of other pathology. The patients with adrenal tumors of other pathology could resume normal activity earlier (mean 18 v 26 days) than those with pheochromocytoma. CONCLUSION: The operation is more difficult and the morbidity is higher in laparoscopic adrenalectomy for pheochromocytoma than that for tumors of other pathology. An experienced team of surgeons with advanced laparoscopic skills and anesthesiologists is mandatory. In large tumors, great caution should be taken for intraoperative complications. Nevertheless, laparoscopic adrenalectomy is not contraindicated for pheochromocytoma and can be performed safely.

Adrenal Gland Neoplasms↗
PubMed1976

Adrenal medullary disease in multiple endocrine neoplasia, type 2: pheochromocytoma and its precursors.

Multiple endocrine neoplasia, type 2 (MEN-type 2), designates the syndrome of medullary thyroid carcinoma, pheochromocytoma, and occasional parathyroid hyperplasia. The thyroid carcinoma, which is usually bilateral and multicentric, is preceded by multifocal C-cell hyperplasia. The adrenal gland manifests pheochromocytoma, which is frequently bilateral and multicentric, and may be malignant. To test the hypothesis that diffuse adrenal medullary hyperplasia is a precursor of pheochromocytoma in this syndrome, we studied the adrenal glands of 19 patients who had MEN-type 2. The findings in the adrenal medulla in these 19 patients were: synchronous bilateral pheochromocytoma in 9 (metastatic in 3); asynchronous bilateral pheochromocytoma in 1 (metastatic); unilateral pheochromocytoma with contralateral diffuse and nodular hyperplasia in 2; unilateral pheochromocytoma with contralateral diffuse hyperplasia in 2; unilateral pheochromocytoma in 1; bilateral nodular hyperplasia in 1; bilateral diffuse hyperplasia in 1; and no abnormality in 2. This spectrum of adrenal medullary pathology suggests that diffuse and nodular medullary hyperplasia are precursors of pheochromocytoma in MEN-type 2.

Adrenal Gland Neoplasms↗
PubMed2001

Increased expression of tenascin in pheochromocytomas correlates with malignancy.

Tenascin is a significant extracellular matrix glycoprotein, which is upregulated in various neoplasias and pathologic processes. Pheochromocytomas are rare tumors of the sympathoadrenal system, whose malignancy is almost impossible to predict. There are no histologic or chemical markers available that would define the malignant behavior of these tumors, except the discovery of metastases. In our search for new markers, we investigated the immunohistochemical expression of tenascin in a large number of pheochromocytomas and paragangliomas. Seven tumors were metastasized and were thus considered malignant. Normal adrenal medulla was tenascin negative. A striking difference was seen between malignant and benign pheochromocytomas. All malignant pheochromocytomas expressed stromal tenascin strongly or moderately, whereas most benign pheochromocytomas (28 of 37, 70%) showed no or only weak immunopositivity. The staining was strong or moderate also in 13 of 28 (46%) of the tumors that showed histologically suspicious features, here called borderline tumors. Paragangliomas showed a more heterogeneous staining pattern, and no significant difference was found between benign and malignant paragangliomas. To our knowledge, this is the first study to demonstrate the expression of tenascin in pheochromocytomas and particularly the enhanced expression in malignant pheochromocytomas. We therefore suggest that tenascin may be associated with the malignant transformation and metastasis of pheochromocytomas. It is also a potential marker predicting more aggressive behavior in pheochromocytomas.

Adolescent↗
PubMed2004

Expression of chromogranins A, B, and C (secretogranin II) in human adrenal medulla and in benign and malignant pheochromocytomas An immunohistochemical study with region-specific antibodies.

In a recent immunohistochemical study of pheochromocytomas, a difference was observed between benign and malignant pheochromocytomas in their expression in different parts of the chromogranin (Cg) A molecule. The purpose of the present study was to extend the investigations by including two other members of this Cg family, CgB and C. Twenty-five patients operated on for clinicopathologically benign pheochromocytomas, and four for metastasizing pheochromocytomas, were studied. Expression of the different Cg regions was studied immunohistochemically by means of region-specific antibodies: four raised against CgA epitopes, five against CgB, and two against CgC. Adrenal medulla parenchyma from three surgical adrenalectomy specimens was used as non-neoplastic control. All cells of normal adrenal medulla were immunoreactive to all 11 region-specific Cg antibodies. In the pheochromocytomas, variations in the expression pattern occurred, but no significant quantitative differences were noted between benign and malignant tumours. Nevertheless, in all four malignant pheochromocytomas, the antibodies raised against the C-terminal regions of both CgB and CgC visualised a noticeable population of large spindle-shaped tumour cells, characterised by elongated processes. This cell type occurred in all four malignant pheochromocytomas but only in one benign tumour. Their structure and immunoreactivity differed from those of the sustentacular cells in the pheochromocytoma parenchyma. The use of region-specific antibodies raised against epitopes in the C-terminal region of CgB and CgC can facilitate the diagnosis of malignant pheochromocytoma.

Adrenal Gland Neoplasms↗
PubMed2004

The genetic basis of pheochromocytoma.

Until very recently, the majority of hereditary pheochromocytomas were related to the MEN 2 and the VHL. In rare instances, hereditary pheochromocytoma was reported in patients with NF1. In addition, nonsyndromic hereditary pheochromocytomas have been reported. Recently, three more genes (SDHD, SDHB, and SDHC) which are all related subunits of the mitochondrial complex II have been identified to cause susceptibility to pheochromocytoma and/or paraganglioma. Hence, mutation analysis of VHL, RET, SDHB, and SDHD is generally recommended in patients with pheochromocytoma regardless of their family history or other features suggestive for a hereditary form. Mutation analysis should start with VHL and RET. However, in the presence of extra-adrenal pheochromocytoma, it may be more useful to screen for VHL, SDHD and SDHB mutations. It is of interest that various different genes can lead to one type of tumor formation. A common pathway (i.e. oxygen sensing) has been shown for VHL and SDHX. However, although several genes that are involved in the pathogenesis of hereditary pheochromocytoma are known, the precise molecular steps in tumorigenesis are widely unknown. In addition, recent data in MEN 2 pheochromocytomas point to a 'second hit' mechanism as a trigger for tumor formation. The molecular pathogenesis of sporadic pheochromocytomas remains obscure [114].

Adrenal Gland Neoplasms↗
PubMed1997

Tumor recurrence and hypertension persistence after successful pheochromocytoma operation.

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.

Adult↗
PubMed2001

6-[18F]fluorodopamine positron emission tomographic (PET) scanning for diagnostic localization of pheochromocytoma.

The diagnosis and treatment of pheochromocytoma depend critically on effective means to localize the tumor. Computed tomography and magnetic resonance imaging have good sensitivity but poor specificity for detecting pheochromocytoma, and nuclear imaging approaches such as (131)I-metaiodobenzylguanidine scintigraphy have limited sensitivity. Here we report initial results using 6-[(18)F]fluorodopamine positron emission tomography (PET) scanning in the diagnostic localization of pheochromocytoma. Twenty-eight patients with known or clinically suspected pheochromocytoma underwent PET scanning after intravenous injection of 6-[(18)F]fluorodopamine. Of the 28 patients, 9 had surgical confirmation of the tumor, 8 had previously diagnosed metastatic pheochromocytoma, and 11 had plasma levels of metanephrines that were within normal limits. All 9 patients with surgically proven pheochromocytoma had abnormal 6-[(18)F]fluorodopamine PET scans that identified the tumors. All 8 patients with metastatic pheochromocytoma had extra-adrenal sites of 6-[(18)F]fluorodopamine-derived activity. Of the 11 patients with normal plasma levels of metanephrines, 9 had negative 6-[(18)F]fluorodopamine PET scans, 1 had extra-adrenal foci of 6-[(18)F]fluorodopamine-derived activity, and 1 had symmetric uptake of 6-[(18)F]fluorodopamine in the region of the adrenal glands. In patients with known disease, 6-[(18)F]fluorodopamine PET scanning can detect and localize pheochromocytomas with high sensitivity. In patients in whom the diagnosis of pheochromocytoma is considered but excluded because of negative plasma metanephrine results, 6-[(18)F]fluorodopamine PET scans are consistently negative. These findings justify a clinical trial of 6-[(18)F]fluorodopamine PET scanning as a diagnostic tool.

Adrenal Gland Neoplasms↗
PubMed2006

Expression of mRNAs for succinate dehydrogenase subunits and related genes in pheochromocytoma.

Mutations in the genes encoding succinate dehydrogenase (SDH) have been associated with susceptibility to pheochromocytoma. However, few reports have examined the level of SDH mRNAs expression. In this study, we examined the level of expression of mRNAs encoding SDHB, SDHC, and SDHD in pheochromocytoma, pheochromocytoma subgroups, and normal adrenal gland, and compared the expression of these genes to the level of expression of related genes in the same tissues. The mean relative level of expression of SDHB, SDHC, SDHD and VHL mRNA was 28.7+/-6.2%, 16.6+/-4.8%, 214+/-47.5% and 25.9+/-8.2%, respectively, in pheochromocytoma tissues compared to normal adrenal gland. Furthermore, the mean relative level of the RET proto-oncogene mRNA was 707+/-149% in pheochromocytoma compared to normal adrenal gland. The level of expression of the SDH genes was highly correlated in each individual sample (P<0.0001). The level of expression of the SDH mRNAs correlated with the level of VHL mRNA (P<0.0001), but not with the level of RET mRNA. The level of SDH mRNAs expression also correlated with the expression of phenylethanolamine N-methyl transferase (PNMT), an adrenaline synthesizing enzyme (P<0.01), which may explain the correlation between SDH expression and adrenaline content (P<0.05). The level of SDH mRNAs expression correlated strongly with the expression of VEGF mRNA (P<0.0001). In multiple endocrine neoplasia (MEN) 2a, the expression of the SDH genes and VHL mRNA was significantly higher than that observed in adrenal or extra-adrenal pheochromocytoma. The expression of the corticotropin-releasing hormone (CRH) mRNA was significantly higher in extra-adrenal pheochromocytoma than in adrenal pheochromocytoma or MEN2a. Thus, tumor-specific gene expression exists in pheochromocytoma, which may explain the characteristics of the tumor.

Adolescent↗