Jacques W M Lenders, Michiel N Kerstens, Laurence Amar, Aleksander Prejbisz, Mercedes Robledo, David Taieb, Karel Pacak, Joakim Crona, Tomáš Zelinka, Massimo Mannelli, Timo Deutschbein, Henri J L M Timmers, Frederic Castinetti, Henning Dralle, Jřri Widimský, Anne-Paule Gimenez-Roqueplo, Graeme Eisenhofer
Genetics, diagnosis, management and future directions of research of phaeochromocytoma and paraganglioma: a position statement and consensus of the Working Group on Endocrine Hypertension of the European Society of Hypertension.
J Hypertens. 2020 Aug;38(8):1443-1456. doi: 10.1097/HJH.0000000000002438.
Abstract/Text
: Phaeochromocytoma and paraganglioma (PPGL) are chromaffin cell tumours that require timely diagnosis because of their potentially serious cardiovascular and sometimes life- threatening sequelae. Tremendous progress in biochemical testing, imaging, genetics and pathophysiological understanding of the tumours has far-reaching implications for physicians dealing with hypertension and more importantly affected patients. Because hypertension is a classical clinical clue for PPGL, physicians involved in hypertension care are those who are often the first to consider this diagnosis. However, there have been profound changes in how PPGLs are discovered; this is often now based on incidental findings of adrenal or other masses during imaging and increasingly during surveillance based on rapidly emerging new hereditary causes of PPGL. We therefore address the relevant genetic causes of PPGLs and outline how genetic testing can be incorporated within clinical care. In addition to conventional imaging (computed tomography, MRI), new functional imaging approaches are evaluated. The novel knowledge of genotype-phenotype relationships, linking distinct genetic causes of disease to clinical behaviour and biochemical phenotype, provides the rationale for patient-tailored strategies for diagnosis, follow-up and surveillance. Most appropriate preoperative evaluation and preparation of patients are reviewed, as is minimally invasive surgery. Finally, we discuss risk factors for developing metastatic disease and how they may facilitate personalised follow-up. Experts from the European Society of Hypertension have prepared this position document that summarizes the current knowledge in epidemiology, genetics, diagnosis, treatment and surveillance of PPGL.
Svenja Nölting, Nicole Bechmann, David Taieb, Felix Beuschlein, Martin Fassnacht, Matthias Kroiss, Graeme Eisenhofer, Ashley Grossman, Karel Pacak
Personalized management of pheochromocytoma and paraganglioma.
Endocr Rev. 2021 Jun 19;. doi: 10.1210/endrev/bnab019. Epub 2021 Jun 19.
Abstract/Text
Pheochromocytomas/paragangliomas are characterized by a unique molecular landscape that allows their assignment to clusters depending on underlying genetic alterations. With around 30-35% of Caucasian patients (a lower percentage in the Chinese population) showing germline mutations in susceptibility genes, pheochromocytomas/paragangliomas have the highest rate of heritability among all tumors. A further 35-40% of Caucasian patients (a higher percentage in the Chinese population) are affected by somatic driver-mutations. Thus, around 70% of all patients with pheochromocytoma/paraganglioma can be assigned to one of three main molecular clusters with different phenotypes and clinical behavior. Krebs cycle/VHL/EPAS1-related cluster 1 tumors tend to a noradrenergic biochemical phenotype, and require very close follow-up due to the risk of metastasis and recurrence. In contrast, kinase signaling-related cluster 2 tumors are characterized by an adrenergic phenotype and episodic symptoms, with generally a less aggressive course. The clinical correlates of patients with Wnt signaling-related cluster 3 tumors are currently poorly described, but aggressive behavior seems likely. In this review, we explore and explain why cluster-specific (personalized) management of pheochromocytoma/paraganglioma is essential to ascertain clinical behavior and prognosis, guide individual diagnostic procedures (biochemical interpretation, choice of the most sensitive imaging modalities), and personalized management and follow-up. Although cluster-specific therapy of inoperable/metastatic disease has not yet entered routine clinical practice, we suggest that informed personalized genetic-driven treatment should be implemented as a logical next step. This review amalgamates published guidelines and expert views within each cluster for a coherent individualized patient management plan.
© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.
Joakim Crona, David Taïeb, Karel Pacak
New Perspectives on Pheochromocytoma and Paraganglioma: Toward a Molecular Classification.
Endocr Rev. 2017 Dec 1;38(6):489-515. doi: 10.1210/er.2017-00062.
Abstract/Text
A molecular biology-based taxonomy has been proposed for pheochromocytoma and paraganglioma (PPGL). Data from the Cancer Genome Atlas revealed clinically relevant prognostic and predictive biomarkers and stratified PPGLs into three main clusters. Each subgroup has a distinct molecular-biochemical-imaging signature. Concurrently, new methods for biochemical analysis, functional imaging, and medical therapies have also become available. The research community now strives to match the cluster biomarkers with the best intervention. The concept of precision medicine has been long awaited and holds great promise for improved care. Here, we review the current and future PPGL classifications, with a focus on hereditary syndromes. We discuss the current strengths and shortcomings of precision medicine and suggest a condensed manual for diagnosis and treatment of both adult and pediatric patients with PPGL. Finally, we consider the future direction of this field, with a particular focus on how advanced molecular characterization of PPGL can improve a patient's outcome, including cures and, ultimately, disease prevention.
Copyright © 2017 Endocrine Society.
Aikaterini Geroula, Timo Deutschbein, Katharina Langton, Jimmy Masjkur, Christina Pamporaki, Mirko Peitzsch, Stephanie Fliedner, Henri J L M Timmers, Stefan R Bornstein, Felix Beuschlein, Anthony Stell, Andrzej Januszewicz, Aleksander Prejbisz, Martin Fassnacht, Jacques W M Lenders, Graeme Eisenhofer
Pheochromocytoma and paraganglioma: clinical feature-based disease probability in relation to catecholamine biochemistry and reason for disease suspicion.
Eur J Endocrinol. 2019 Oct;181(4):409-420. doi: 10.1530/EJE-19-0159.
Abstract/Text
Objective: Hypertension and symptoms of catecholamine excess are features of pheochromocytomas and paragangliomas (PPGLs). This prospective observational cohort study assessed whether differences in presenting features in patients tested for PPGLs might assist establishing likelihood of disease.
Design and methods: Patients were tested for PPGLs because of signs and symptoms, an incidental mass on imaging or routine surveillance due to previous history or hereditary risk. Patients with (n = 245) compared to without (n = 1820) PPGLs were identified on follow-up. Differences in presenting features were then examined to assess the probability of disease and relationships to catecholamine excess.
Results: Hyperhidrosis, palpitations, pallor, tremor and nausea were 30-90% more prevalent (P < 0.001) among patients with than without PPGLs, whereas headache, flushing and other symptoms showed little or no differences. Although heart rates were higher (P < 0.0001) in patients with than without PPGLs, blood pressures were not higher and were positively correlated to BMI, which was lower (P < 0.0001) in patients with than without PPGLs. From these differences in clinical features, a score system was established that indicated a 5.8-fold higher probability of PPGLs in patients with high than low scores. Higher scores among patients with PPGLs were associated, independently of tumor size, with higher biochemical indices of catecholamine excess.
Conclusions: This study identifies a complex of five signs and symptoms combined with lower BMI and elevated heart rate as key features in patients with PPGLs. Prevalences of these features, which reflect variable tumoral catecholamine production, may be used to triage patients according to likelihood of disease.
厚生労働省難治性疾患克服研究事業 「褐色細胞腫の実態調査と診療指針の作成」研究班：褐色細胞腫診療指針2010．2010；14-16．.
名和田新ほか：副腎ホルモン産生異常症の全国疫学調査，厚生省特定疾患「副腎ホルモン産生異常症」調査研究班平成10年研究報告書．1995；11-55．.
Smita K Baid, Edwin W Lai, Robert A Wesley, Alex Ling, Henri J L M Timmers, Karen T Adams, Anna Kozupa, Karel Pacak
Brief communication: radiographic contrast infusion and catecholamine release in patients with pheochromocytoma.
Ann Intern Med. 2009 Jan 6;150(1):27-32.
Abstract/Text
BACKGROUND: Contrast-enhanced computed tomography (CT) is useful for localizing pheochromocytoma. However, in patients with suspected pheochromocytoma, CT is often canceled or not performed because of the strong belief that intravenous contrast may induce hypertensive crisis.
OBJECTIVE: To examine whether intravenous low-osmolar contrast administration during CT induces catecholamine release that increases blood pressure or heart rate.
DESIGN: Prospective study.
SETTING: Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland.
PARTICIPANTS: 22 patients with pheochromocytoma (15 nonadrenal and 7 adrenal) and 8 unmatched control participants without pheochromocytoma.
MEASUREMENTS: Plasma catecholamine levels, blood pressure, and heart rate.
RESULTS: Plasma catecholamine levels within and between groups did not significantly differ before and after intravenous administration of low-osmolar CT contrast. Patients with pheochromocytoma experienced a clinically and statistically significant increase in diastolic blood pressure that was not accompanied by corresponding increases in plasma catecholamine levels. The difference became non-statistically significant after adjustment for use of alpha- and beta-blockers.
LIMITATION: The study lacked a placebo group, and the sample was relatively small.
CONCLUSION: Intravenous low-osmolar contrast-enhanced CT can safely be used in patients with pheochromocytoma who are not receiving alpha- or beta-blockers.
FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Development, National Institutes of Health.
P P Stein, H R Black
A simplified diagnostic approach to pheochromocytoma. A review of the literature and report of one institution's experience.
Medicine (Baltimore). 1991 Jan;70(1):46-66.
Abstract/Text
Pheochromocytoma is an unusual but potentially devastating tumor. Although a high index of suspicion is necessary, the likelihood of a pheochromocytoma is lower in the absence of the typical symptoms and findings. Nonetheless, screening must be broadened to include patients with a lower risk of the disease, such as those with resistant or labile hypertension who are minimally symptomatic. Extensive diagnostic evaluations should be reserved for those whose clinical or laboratory findings are more suggestive. Symptoms in a group of patients in whom a pheochromocytoma was seriously considered but excluded overlap symptoms in patients with a pheochromocytoma. Certain symptoms are useful: flushing to suggest a non-pheochromocytoma illness; visual symptoms, flank pain, and pallor to suggest that a pheochromocytoma is more likely. Combinations of symptoms can be of value: 2 or more symptoms from the triad of headache, palpitations, and diaphoresis were present in the majority of pheochromocytoma patients, but in a smaller number of non-pheochromocytoma patients. The presence of the entire triad is more specific, but less sensitive. New hypertension, or hypertension associated with unexplained orthostatic hypotension, are suggestive of an underlying pheochromocytoma. Twenty-four-hour urine studies are consistently abnormal in patients with a pheochromocytoma, but are also elevated in a significant proportion of non-pheochromocytoma patients. Values greater then 1.5-2-fold above the upper limit of normal are very suggestive that a pheochromocytoma is present, and warrant a more intensive subsequent evaluation. Imaging studies are reliable in the diagnosis of pheochromocytoma, and can help to confirm or exclude the disease. Patients with a higher clinical likelihood and any elevated urinary testing, or with a lower clinical likelihood and persistently and/or significantly elevated urinary testing, should have imaging studies performed. This combination of clinical screening, 24-hour urinary testing, and imaging studies is a useful and reliable approach to patients suspected of harboring a pheochromocytoma.
K Pacak, W M Linehan, G Eisenhofer, M M Walther, D S Goldstein
Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma.
Ann Intern Med. 2001 Feb 20;134(4):315-29.
Abstract/Text
Pheochromocytoma is a rare but important tumor of chromaffin cells that is frequently considered in the evaluation of hypertension, arrhythmias, or panic disorder and in the follow-up of patients with particular genetic diseases. This report provides an update about the genetics, neurochemical diagnosis, localization by imaging, and surgical management of pheochromocytoma. Specific mutations of the RET proto-oncogene cause familial predisposition to pheochromocytoma in multiple endocrine neoplasia type II, and mutations in the von Hippel-Lindau tumor suppressor gene cause familial disposition to pheochromocytoma in von Hippel-Lindau disease. Recent findings demonstrating extraordinarily high sensitivity of plasma levels of metanephrines for detecting pheochromocytoma have led to an algorithm for clinical diagnostic steps. Nuclear imaging approaches, such as(123) I-metaiodobenzylguanidine scintigraphy and 6-[(18) F]fluorodopamine positron emission tomography, enhance both diagnosis and localization of the tumor, as described in an algorithm for patients with positive biochemical test results. Since pheochromocytoma is often benign, surgical resection by laparoscopic adrenalectomy can be curative. Areas requiring further work include determining appropriate follow-up of patients with familial pheochromocytoma, elucidating the bases for phenotypic differences, improving both specificity and sensitivity of biochemical tests, optimizing cost-effectiveness of diagnostic imaging, and testing the risk for tumor recurrence after partial adrenalectomy.
P F Plouin, P Degoulet, A Tugayé, M B Ducrocq, J Ménard
[Screening for phaeochromocytoma : in which hypertensive patients? A semiological study of 2585 patients, including 11 with phaeochromocytoma (author's transl)].
Nouv Presse Med. 1981 Mar 7;10(11):869-72.
Abstract/Text
In an attempt to find out whether phaeochromocytoma could be screened by questioning, the authors have recorded in a population of 2585 hypertensive patients the symptoms known to be most frequently associated with the tumour, i.e. headaches, palpitations and sweating attacks. Since 72.4% of the entire population reported one or another of these complaints, no single symptom could be taken as suggestive of phaeochromocytoma. However, only 6.5% of the patients reported all three symptoms and could therefore be considered as forming a subgroup likely to have the tumour. Patients in this subgroup differed from the others in the predominance of females (p less than 0.01), the higher frequency of anxiety (p less than 0.01) and above all, the higher incidence of phaeochromocytoma (5.9% as against 0.04%; p less than 0.01). The symptomatic triad (headaches, palpitations, sweating attacks) has a specificity of 93.8%, a sensitivity of 90.9% and an exclusion value of 99.9% for the diagnosis of phaeochromocytoma. Its presence in hypertensive patients justifies systematic assays of blood or urinary catecholamines. In its absence, the probability of phaeochromocytoma is inferior to 1 in 1 000.
Agnès La Batide-Alanore, Gilles Chatellier, Pierre-François Plouin
Diabetes as a marker of pheochromocytoma in hypertensive patients.
J Hypertens. 2003 Sep;21(9):1703-7. doi: 10.1097/01.hjh.0000084729.53355.ce.
Abstract/Text
OBJECTIVE: To assess the prevalence of diabetes in patients with pheochromocytoma and the probability of pheochromocytoma occurring in hypertensive patients with or without diabetes.
SETTING: A tertiary, referral hypertension department.
PATIENTS AND METHODS: We compared age, body mass index and the frequency of diabetes in 191 patients with pheochromocytoma and a random sample of 880 patients with essential hypertension. Diabetes was defined as current antihyperglycemic treatment or two fasting blood glucose concentrations >or= 7 mmol/l. For patients with pheochromocytoma, we also recorded plasma catecholamine concentrations, the urinary excretion of metanephrines, and tumor characteristics.
RESULTS: Diabetes was present in 68 (35.6%) patients with pheochromocytoma and 192 (21.8%) patients with essential hypertension (P < 0.001). Pheochromocytoma patients with or without diabetes did not differ in body mass index, plasma noradrenaline concentration, metanephrine excretion or tumor characteristics. Age, duration of hypertension and plasma adrenaline concentration were significantly and independently associated with diabetes in patients with pheochromocytoma. They were younger, more likely to be female and had a lower body mass index than those with essential hypertension (P < 0.01). After adjustment for these three variables, the odds ratio for pheochromocytoma in hypertensive patients with diabetes was 5.5 (95% confidence interval, 3.5-8.7). For patients younger than the age of 51 years with a body mass index < 25 kg/m2, the odds ratio was 18.9 (95% confidence interval, 5.9-58.8).
CONCLUSION: Diabetes is present in one in three patients with pheochromocytoma. In young patients with hypertension and normal body weight, the presence of diabetes is a clinical clue to the diagnosis of pheochromocytoma.
Jacques W M Lenders, Karel Pacak, McClellan M Walther, W Marston Linehan, Massimo Mannelli, Peter Friberg, Harry R Keiser, David S Goldstein, Graeme Eisenhofer
Biochemical diagnosis of pheochromocytoma: which test is best?
JAMA. 2002 Mar 20;287(11):1427-34.
Abstract/Text
CONTEXT: Diagnosis of pheochromocytoma depends on biochemical evidence of catecholamine production by the tumor. However, the best test to establish the diagnosis has not been determined.
OBJECTIVE: To determine the biochemical test or combination of tests that provides the best method for diagnosis of pheochromocytoma.
DESIGN, SETTING, AND PARTICIPANTS: Multicenter cohort study of patients tested for pheochromocytoma at 4 referral centers between 1994 and 2001. The analysis included 214 patients in whom the diagnosis of pheochromocytoma was confirmed and 644 patients who were determined to not have the tumor.
MAIN OUTCOME MEASURES: Test sensitivity and specificity, receiver operating characteristic curves, and positive and negative predictive values at different pretest prevalences using plasma free metanephrines, plasma catecholamines, urinary catecholamines, urinary total and fractionated metanephrines, and urinary vanillylmandelic acid.
RESULTS: Sensitivities of plasma free metanephrines (99% [95% confidence interval [CI], 96%-100%]) and urinary fractionated metanephrines (97% [95% CI, 92%-99%]) were higher than those for plasma catecholamines (84% [95% CI, 78%-89%]), urinary catecholamines (86% [95% CI, 80%-91%]), urinary total metanephrines (77% [95% CI, 68%-85%]), and urinary vanillylmandelic acid (64% [95% CI, 55%-71%]). Specificity was highest for urinary vanillylmandelic acid (95% [95% CI, 93%-97%]) and urinary total metanephrines (93% [95% CI, 89%-97%]); intermediate for plasma free metanephrines (89% [95% CI, 87%-92%]), urinary catecholamines (88% [95% CI, 85%-91%]), and plasma catecholamines (81% [95% CI, 78%-84%]); and lowest for urinary fractionated metanephrines (69% [95% CI, 64%-72%]). Sensitivity and specificity values at different upper reference limits were highest for plasma free metanephrines using receiver operating characteristic curves. Combining different tests did not improve the diagnostic yield beyond that of a single test of plasma free metanephrines.
CONCLUSION: Plasma free metanephrines provide the best test for excluding or confirming pheochromocytoma and should be the test of first choice for diagnosis of the tumor.
地曳和子ほか：褐色細胞腫の診断におけるメタネフリンおよびノルメタネフリン測定の意義．日本内分泌学会誌 1998；64：707-716．.
Noriko Kimura, Ryoichi Takayanagi, Nae Takizawa, Eiji Itagaki, Takayuki Katabami, Narihiko Kakoi, Hiromi Rakugi, Yukihiro Ikeda, Akiyo Tanabe, Takeshi Nigawara, Sadayoshi Ito, Itaru Kimura, Mitsuhide Naruse, Phaeochromocytoma Study Group in Japan
Pathological grading for predicting metastasis in phaeochromocytoma and paraganglioma.
Endocr Relat Cancer. 2014 Jun;21(3):405-14. doi: 10.1530/ERC-13-0494. Epub 2014 May 6.
Abstract/Text
Phaeochromocytomas (PHEO) and paragangliomas are rare catecholamine-producing tumours. Although 10-30% of these tumours metastasise, histopathological criteria to discriminate malignant from benign tumours have not been established; therefore, reliable histopathological markers predicting metastasis are urgently required. A total of 163 tumours, including 40 metastatic tumours, collected by the Phaeochromocytoma Study Group in Japan (PHEO-J) were analysed using a system called grading system for adrenal phaeochromocytoma and paraganglioma (GAPP). The tumours were scored based on GAPP criteria as follows: histological pattern, cellularity, comedo-type necrosis, capsular/vascular invasion, Ki67 labelling index and catecholamine type. All tumours were scored from 0 to 10 points and were graded as one of the three types: well-differentiated (WD, 0-2 points), moderately differentiated (MD, 3-6 points) and poorly differentiated (PD, 7-10 points). GAPP scores of the non-metastatic and metastatic groups were 2.08±0.17 and 5.33±0.43 (mean±s.e.m., P<0.001) respectively. There was a significant negative correlation between the GAPP score and the interval until metastasis (r=-0.438, P<0.01). The mean number of years until metastasis after the initial operation was 5.5±2.6 years. The study included 111 WD, 35 MD and 17 PD types. The five-year survival of these groups was 100, 66.8 and 22.4% respectively. In addition, negative immunoreactivity for succinate dehydrogenase gene subunit B (SDHB) was observed in 13 (8%) MD or PD tumours and ten of the 13 (77%) had metastases. Our data indicate that a combination of GAPP classification and SDHB immunohistochemistry might be useful for the prediction of metastasis in these tumours.
Umasuthan Srirangalingam, Lisa Walker, Bernard Khoo, Fiona MacDonald, Daphne Gardner, Terence J Wilkin, Robert H Skelly, Emad George, David Spooner, John P Monson, Ashley B Grossman, Scott A Akker, Patrick J Pollard, Nick Plowman, Norbert Avril, Daniel M Berney, Jacky M Burrin, Rodney H Reznek, V K Ajith Kumar, Eamonn R Maher, Shern L Chew
Clinical manifestations of familial paraganglioma and phaeochromocytomas in succinate dehydrogenase B (SDH-B) gene mutation carriers.
Clin Endocrinol (Oxf). 2008 Oct;69(4):587-96. doi: 10.1111/j.1365-2265.2008.03274.x. Epub 2008 Apr 14.
Abstract/Text
OBJECTIVE: Phaeochromocytomas and paragangliomas are familial in up to 25% of cases and can result from succinate dehydrogenase (SDH) gene mutations. The aim of this study was to describe the clinical manifestations of subjects with SDH-B gene mutations.
DESIGN: Retrospective case-series.
PATIENTS: Thirty-two subjects with SDH-B gene mutations followed up between 1975 and 2007. Mean follow-up of 5.8 years (SD 7.4, range 0-31). Patients seen at St Bartholomew's Hospital, London and other UK centres.
MEASUREMENTS: Features of clinical presentation, genetic mutations, tumour location, catecholamine secretion, clinical course and management.
RESULTS: Sixteen of 32 subjects (50%) were affected by disease. Two previously undescribed mutations in the SDH-B gene were noted. A family history of disease was apparent in only 18% of index subjects. Mean age at diagnosis was 34 years (SD 15.4, range 10-62). 50% of affected subjects had disease by the age of 26 years. 69% (11 of 16) were hypertensive and 80% (12 of 15) had elevated secretions of catecholamines/metabolites. 24% (6 of 25) of tumours were located in the adrenal and 76% (19 of 25) were extra-adrenal. 19% (3 of 16) had multifocal disease. Metastatic paragangliomas developed in 31% (5 of 16). One subject developed a metastatic type II papillary renal cell carcinoma. The cohort malignancy rate was 19% (6 of 32). Macrovascular disease was noted in two subjects without hypertension.
CONCLUSION: SDH-B mutation carriers develop disease early and predominantly in extra-adrenal locations. Disease penetrance is incomplete. Metastatic disease is prominent but levels are less than previously reported. Clinical manifestations may include papillary renal cell carcinoma and macrovascular disease.
Henri J L M Timmers, Clara C Chen, Jorge A Carrasquillo, Millie Whatley, Alexander Ling, Bastiaan Havekes, Graeme Eisenhofer, Lucia Martiniova, Karen T Adams, Karel Pacak
Comparison of 18F-fluoro-L-DOPA, 18F-fluoro-deoxyglucose, and 18F-fluorodopamine PET and 123I-MIBG scintigraphy in the localization of pheochromocytoma and paraganglioma.
J Clin Endocrinol Metab. 2009 Dec;94(12):4757-67. doi: 10.1210/jc.2009-1248. Epub 2009 Oct 28.
Abstract/Text
CONTEXT: Besides (123)I-metaiodobenzylguanidine (MIBG), positron emission tomography (PET) agents are available for the localization of paraganglioma (PGL), including (18)F-3,4-dihydroxyphenylalanine (DOPA), (18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG), and (18)F-fluorodopamine ((18)F-FDA).
OBJECTIVE: The objective of the study was to establish the optimal approach to the functional imaging of PGL and examine the link between genotype-specific tumor biology and imaging.
DESIGN: This was a prospective observational study.
INTERVENTION: There were no interventions.
PATIENTS: Fifty-two patients (28 males, 24 females, aged 46.8 +/- 14.2 yr): 20 with nonmetastatic PGL (11 adrenal), 28 with metastatic PGL (13 adrenal), and four in whom PGL was ruled out; 22 PGLs were of the succinate dehydrogenase subunit B (SDHB) genotype.
MAIN OUTCOME MEASURES: Sensitivity of (18)F-DOPA, (18)F-FDG, and (18)F-FDA PET, (123)I-MIBG scintigraphy, computed tomography (CT), and magnetic resonance imaging (MRI) for the localization of PGL were measured.
RESULTS: Sensitivities for localizing nonmetastatic PGL were 100% for CT and/or MRI, 81% for (18)F-DOPA PET, 88% for (18)F-FDG PET/CT, 78% for (18)F-FDA PET/CT, and 78% for (123)I-MIBG scintigraphy. For metastatic PGL, sensitivity in reference to CT/MRI was 45% for (18)F-DOPA PET, 74% for (18)F-FDG PET/CT, 76% for (18)F-FDA PET/CT, and 57% for (123)I-MIBG scintigraphy. In patients with SDHB metastatic PGL, (18)F-FDA and (18)F-FDG have a higher sensitivity (82 and 83%) than (123)I-MIBG (57%) and (18)F-DOPA (20%).
CONCLUSIONS: (18)F-FDA PET/CT is the preferred technique for the localization of the primary PGL and to rule out metastases. Second best, equal alternatives are (18)F-DOPA PET and (123)I-MIBG scintigraphy. For patients with known metastatic PGL, we recommend (18)F-FDA PET in patients with an unknown genotype, (18)F-FDG or (18)F-FDA PET in SDHB mutation carriers, and (18)F-DOPA or (18)F-FDA PET in non-SDHB patients.
Alicia Algeciras-Schimnich, Carol M Preissner, William F Young, Ravinder J Singh, Stefan K G Grebe
Plasma chromogranin A or urine fractionated metanephrines follow-up testing improves the diagnostic accuracy of plasma fractionated metanephrines for pheochromocytoma.
J Clin Endocrinol Metab. 2008 Jan;93(1):91-5. doi: 10.1210/jc.2007-1354. Epub 2007 Oct 16.
Abstract/Text
CONTEXT: The initial diagnosis of pheochromocytoma relies on plasma fractionated metanephrines levels. Normal levels exclude pheochromocytoma, but positive tests have a low positive predictive value due to the disease's rarity.
OBJECTIVES: The objective of the study was to evaluate three approaches to distinguish between true-positive and false-positive tests: 1) increased cutoff for plasma fractionated metanephrines, 2) measurement of serum/plasma chromogranin A (CGA), and 3) urine fractionated metanephrine testing.
DESIGN: We studied retrospectively all Mayo Clinic patients with positive plasma fractionated metanephrine tests over a 15-month period and determined their final diagnosis based on histology, imaging, additional biochemical tests, and more than 1 yr follow-up. For a subgroup, urine fractionated metanephrine results were available. All original plasma samples were retested for CGA.
RESULTS: Of 140 patients, 40 had a chromaffin tumor confirmed and 100 excluded, indicating a positive predictive value of plasma fractionated metanephrines of 28.6%. Increasing the threshold for a positive test improved specificity to 98% but missed eight cases (20%). Incorporation of urine fractionated metanephrine testing as follow-up test achieved 80% specificity and 91% sensitivity. The corresponding figures for CGA were 71 and 87% for all patients and 89 and 87% when patients taking proton pump inhibitors were excluded.
CONCLUSIONS: Unless plasma fractionated metanephrines levels are elevated more than 4-fold above the upper limit of normal, patients with a positive plasma fractionated metanephrines test should be evaluated with urine fractionated metanephrines and serum/plasma CGA assays before being subjected to imaging or invasive diagnostic tests.
Vesna D Garovic, Marie C Hogan, Sharan K R Kanakiriya, Clive S Grant, William F Young
Labile hypertension, increased metanephrines and imaging misadventures.
Nephrol Dial Transplant. 2004 Apr;19(4):1004-6. doi: 10.1093/ndt/gfg541.
Abstract/Text
Arnold F Jacobson, Hsiaowei Deng, John Lombard, Harry J Lessig, Richard R Black
123I-meta-iodobenzylguanidine scintigraphy for the detection of neuroblastoma and pheochromocytoma: results of a meta-analysis.
J Clin Endocrinol Metab. 2010 Jun;95(6):2596-606. doi: 10.1210/jc.2009-2604. Epub 2010 Apr 14.
Abstract/Text
CONTEXT: (123)I-mIBG scintigraphy has been in clinical use for more than 20 yr for diagnostic assessment of patients with neural crest and neuroendocrine tumors. Prospective validation of the performance characteristics of this method has recently been published.
OBJECTIVE: A meta-analysis was performed to obtain best estimates of performance characteristics of (123)I-mIBG imaging for the two most common applications, evaluation of patients with neuroblastoma and pheochromocytoma.
DATA SOURCES: Articles published between 1980 and 2007 were identified from searches of multiple computer databases, including MEDLINE, BIOSIS, EMBASE, and SciSearch.
STUDY SELECTION: Primary inclusion criteria were: acceptable reference standard(s) for confirming subjects with disease (histopathology and/or a combination of imaging and catecholamine results); reference standards applied to all subjects who received (123)I-mIBG; and data on a minimum of 16 patients confirmed to have or not have the disease(s) under consideration. Two physician reviewers independently evaluated all articles against the inclusion/exclusion criteria. Twenty-two of 100 articles reviewed were included in the final analysis.
DATA EXTRACTION: The two reviewers extracted the data from eligible articles using a standardized form, capturing both study quality and efficacy information. Disagreements were resolved by consensus.
DATA SYNTHESIS: Sensitivity of (123)I-mIBG scans for detection of neuroblastoma was 97% [95% confidence interval (CI), 95 to 99%]; data were insufficient to estimate specificity. For pheochromocytoma, with application of the random-effects model, sensitivity and specificity were 94% (95% CI, 91-97%) and 92% (95% CI, 87-98%), respectively.
CONCLUSION: Based upon the literature, (123)I-mIBG scintigraphy has sensitivity and specificity greater than 90% for detection of neuroblastoma and pheochromocytoma.
Shern L Chew
Diagnosis: imaging of pheochromocytomas and paragangliomas.
Nat Rev Endocrinol. 2010 Apr;6(4):193-4. doi: 10.1038/nrendo.2010.22.
Abstract/Text
Pheochromocytomas and paragangliomas are rare tumors, but their investigation and management are complex and expensive, both in terms of time and resources. a novel prospective study systematically compared different imaging techniques, and the results provide clinicians with valuable help in deciding the appropriate imaging strategy for patients with pheochromocytomas or paragangliomas.
Alexandre Buffet, Nelly Burnichon, Judith Favier, Anne-Paule Gimenez-Roqueplo
An overview of 20 years of genetic studies in pheochromocytoma and paraganglioma.
Best Pract Res Clin Endocrinol Metab. 2020 Mar;34(2):101416. doi: 10.1016/j.beem.2020.101416. Epub 2020 Mar 10.
Abstract/Text
Paragangliomas and pheochromocytomas (PPGL) are rare neuroendocrine tumours characterized by a strong genetic determinism. Over the past 20 years, evolution of PPGL genetics has revealed that around 40% of PPGL are genetically determined, secondary to a germline mutation in one of more than twenty susceptibility genes reported so far. More than half of the mutations occur in one of the SDHx genes (SDHA, SDHB, SDHC, SDHD, SDHAF2), which encode the different subunits and assembly protein of a mitochondrial enzyme, succinate dehydrogenase. These susceptibility genes predispose to early forms (VHL, RET, SDHD, EPAS1, DLST), syndromic (RET, VHL, EPAS1, NF1, FH), multiple (SDHD, TMEM127, MAX, DLST, MDH2, GOT2) or malignant (SDHB, FH, SLC25A11) PPGL. The discovery of a germline mutation in one of these genes changes the patient's follow-up and allows genetic screening of affected families and the presymptomatic follow-up of relatives carrying a mutation.
Copyright © 2020 Elsevier Ltd. All rights reserved.
Eleonora P M Corssmit, Marieke Snel, Ellen Kapiteijn
Malignant pheochromocytoma and paraganglioma: management options.
Curr Opin Oncol. 2020 Jan;32(1):20-26. doi: 10.1097/CCO.0000000000000589.
Abstract/Text
PURPOSE OF REVIEW: Although the majority of pheochromocytoma and paraganglioma are benign, 15-17% develop metastatic disease, being present at the initial diagnosis in about 11-31% of cases. The natural course of metastasized disease is highly heterogeneous, with an overall 5-year survival rate varying between 40% and 85%. For individual patients, overall survival, progression-free survival, and clinical outcome are difficult to predict. Management of metastasized pheochromocytoma and paraganglioma is challenging. Currently available therapeutic options are surgical debulking, treatment with radiopharmaceuticals (I-MIBG, Y and Lu-DOTATATE), chemotherapy and targeted therapy.
RECENT FINDINGS: The pathogenesis of pheochromocytoma and paraganglioma (PPGL) is largely driven by genomic alterations in PPGL susceptibility genes related to three different clusters: altered pseudo-hypoxic signaling (cluster-1), altered MAP-kinase signaling (cluster-2) and altered Wnt signaling (cluster-3). Novel targeted therapies (tyrosine kinase inhibitors) and potential future therapeutic options, guided by improved knowledge about the oncogenic cluster 1-3 signaling pathways, will be discussed.
SUMMARY: Treatment of metastasized pheochromocytoma and paraganglioma remains challenging. Profiling of gene expression and methylation can serve as a powerful tool for characterizing disease clusters and for guiding targeted therapy to improve selectivity and efficacy. Current knowledge of signatures involved in molecular signaling, metabolism, and resistance mechanisms of PPGLs suggests that therapeutic regimens can be optimized to each molecular subtype.
Masato Yonamine, Koichiro Wasano, Yuichi Aita, Takehito Sugasawa, Katsutoshi Takahashi, Yasushi Kawakami, Hitoshi Shimano, Hiroyuki Nishiyama, Hisato Hara, Mitsuhide Naruse, Takahiro Okamoto, Tadashi Matsuda, Shinji Kosugi, Kazuhiko Horiguchi, Akiyo Tanabe, Atsushi Watanabe, Noriko Kimura, Eijiro Nakamura, Akihiro Sakurai, Kiyoto Shiga, Kazuhiro Takekoshi
Prevalence of Germline Variants in a Large Cohort of Japanese Patients with Pheochromocytoma and/or Paraganglioma.
Cancers (Basel). 2021 Aug 9;13(16). doi: 10.3390/cancers13164014. Epub 2021 Aug 9.
Abstract/Text
The high incidence of germline variants in pheochromocytoma and paraganglioma (PPGL) has been reported mainly in Europe, but not among Japanese populations in Asia. We aimed to study the prevalence of germline variants in Japanese PPGL patients and the genotype-phenotype correlation. We examined 370 PPGL probands, including 43 patients with family history and/or syndromic presentation and 327 patients with apparently sporadic (AS) presentation. Clinical data and blood samples were collected, and the seven major susceptibility genes (MAX, SDHB, SDHC, SDHD, TMEM127, VHL, and RET) were tested using Sanger sequencing. Overall, 120/370 (32.4%) patients had pathogenic or likely pathogenic variants, with 81/327 (24.8%) in AS presentation. SDHB was the most frequently mutated gene (57, 15.4%), followed by SDHD (27, 7.3%), and VHL (18, 4.9%). The incidence of metastatic PPGL was high in SDHB carriers (21/57, 36.8%). A few unique recurrent variants (SDHB c.137G>A and SDHB c.470delT) were detected in this Japanese cohort, highlighting ethnic differences. In summary, almost a quarter of patients with apparently sporadic PPGL in Japan harboured germline variants of the targeted genes. This study reinforces the recommendation in Western guidelines to perform genetic testing for PPGL and genotype-based clinical decision-making in the Japanese population.
P F Plouin, L Amar, O M Dekkers, M Fassnacht, A P Gimenez-Roqueplo, J W M Lenders, C Lussey-Lepoutre, O Steichen, Guideline Working Group
European Society of Endocrinology Clinical Practice Guideline for long-term follow-up of patients operated on for a phaeochromocytoma or a paraganglioma.
Eur J Endocrinol. 2016 May;174(5):G1-G10. doi: 10.1530/EJE-16-0033.
Abstract/Text
Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours. Standard treatment is surgical resection. Following complete resection of the primary tumour, patients with PPGL are at risk of developing new tumoural events. The present guideline aims to propose standardised clinical care of long-term follow-up in patients operated on for a PPGL. The guideline has been developed by The European Society of Endocrinology and based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) principles. We performed a systematic review of the literature and analysed the European Network for the Study of Adrenal Tumours (ENS@T) database. The risk of new events persisted in the long term and was higher for patients with genetic or syndromic diseases. Follow-up in the published cohorts and in the ENS@T database was neither standardised nor exhaustive, resulting in a risk of follow-up bias and in low statistical power beyond 10 years after complete surgery. To inform patients and care providers in this context of low-quality evidence, the Guideline Working Group therefore prepared recommendations on the basis of expert consensus. Key recommendations are the following: we recommend that all patients with PPGL be considered for genetic testing; we recommend assaying plasma or urinary metanephrines every year to screen for local or metastatic recurrences or new tumours; and we suggest follow-up for at least 10 years in all patients operated on for a PPGL. High-risk patients (young patients and those with a genetic disease, a large tumour and/or a paraganglioma) should be offered lifelong annual follow-up.
© 2016 European Society of Endocrinology.
Oksana Hamidi, William F Young, Lucinda Gruber, John Smestad, Qi Yan, Oscar J Ponce, Larry Prokop, Mohammad Hassan Murad, Irina Bancos
Outcomes of patients with metastatic phaeochromocytoma and paraganglioma: A systematic review and meta-analysis.
Clin Endocrinol (Oxf). 2017 Nov;87(5):440-450. doi: 10.1111/cen.13434. Epub 2017 Aug 17.
Abstract/Text
OBJECTIVE: The outcomes of patients with metastatic phaeochromocytoma (PHEO) and paraganglioma (PGL) are unclear. We performed a systematic review and meta-analysis of baseline characteristics and mortality rates of patients with metastatic PHEO and PGL (PPGL).
DESIGN: Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Scopus, Web of Science, and references of key articles were searched from inception to 2016.
PATIENTS: Studies comprised ≥20 patients with metastatic PPGL and reported baseline characteristics and follow-up data.
MEASUREMENTS: Reviewers extracted standardized data and assessed risk of bias using a modified Newcastle-Ottawa tool. Random-effects meta-analysis was used to pool event rates across studies.
RESULTS: Twenty retrospective noncomparative studies reported on 1338 patients with metastatic PHEO (685/1296, 52.9%) and PGL (611/1296, 47.1%), diagnosed at a mean age of 43.9 ± 5.2 years. Mean follow-up was 6.3 ± 3.2 years. Of 532 patients with reported data, 40.4% had synchronous metastases. Five-year (7 studies, n = 738) and 10-year (2 studies, n = 55) mortality rates for patients with metastatic PPGL were 37% (95% CI, 24%-51%) and 29% (95% CI, 17%-42%), respectively. Higher mortality was associated with male sex (RR 1.50; 95% CI, 1.11-2.02) and synchronous metastases (RR 2.43; 95% CI, 1.01-5.85).
CONCLUSIONS: Available low-quality evidence from heterogeneous studies suggests low mortality rates of patients with metastatic PPGL. Male sex and synchronous metastases correlated with increased mortality. The outcomes of patients with metastatic PPGL have been inadequately assessed, indicating the need for carefully planned prospective studies.
© 2017 John Wiley & Sons Ltd.
Oksana Hamidi, William F Young, Nicole M Iñiguez-Ariza, Nana Esi Kittah, Lucinda Gruber, Cristian Bancos, Shrikant Tamhane, Irina Bancos
Malignant Pheochromocytoma and Paraganglioma: 272 Patients Over 55 Years.
J Clin Endocrinol Metab. 2017 Sep 1;102(9):3296-3305. doi: 10.1210/jc.2017-00992.
Abstract/Text
Context: Malignant pheochromocytoma (PHEO) and paraganglioma (PGL) are rare and knowledge of the natural history is limited.
Objective: We aimed to describe baseline characteristics and outcomes of patients with malignant PHEO and PGL (PPGL) and to identify predictors of shorter survival.
Design: Retrospective review of patients with malignant PPGL evaluated from 1960 to 2016.
Setting: Referral center.
Patients: The group comprised 272 patients.
Main Outcome Measures: Baseline description, survival outcomes, and predictors of shorter survival were evaluated in patients with rapidly progressive (n = 29) and indolent disease (n = 188).
Results: Malignant PPGL was diagnosed at a median age of 39 years (range, 7 to 83 years), with synchronous metastases in 96 (35%) patients. In 176 (65%) patients, metastases developed at a median of 5.5 years (range, 0.3 to 53.4 years) from the initial diagnosis. Median follow-up was 8.2 years (range, 0.01 to 54.1 years). Median overall and disease-specific survivals were 24.6 and 33.7 years, respectively. Shorter survival correlated with male sex (P = 0.014), older age at the time of primary tumor (P = 0.0011), synchronous metastases (P < 0.0001), larger primary tumor size (P = 0.0039), elevated dopamine (P = 0.0195), and not undergoing primary tumor resection (P < 0.0001). There was no difference in the type of primary tumor or presence of SDHB mutation.
Conclusions: The clinical course of patients with malignant PPGL is remarkably variable. Rapid disease progression is associated with male sex, older age at diagnosis, synchronous metastases, larger tumor size, elevated dopamine, and not undergoing resection of primary tumor. An individualized approach to patients with metastatic PPGL is warranted.
Copyright © 2017 Endocrine Society
C Y Lo, K Y Lam, M S Wat, K S Lam
Adrenal pheochromocytoma remains a frequently overlooked diagnosis.
Am J Surg. 2000 Mar;179(3):212-5.
Abstract/Text
BACKGROUND: Adrenal pheochromocytoma is potentially lethal if undetected and is associated with long-term morbidity.
METHODS: Records of patients (11 men, 18 women) with confirmed pheochromocytoma were studied with respect to clinicopathological features and outcome.
RESULTS: Pheochromocytoma was diagnosed in 4 of 8,486 (0.05%) autopsies and accounted for 3 of the 4 immediate causes of death. Operative mortality occurred in 1 patient with undiagnosed tumor. Hypertensive-related complications occurred in 6 patients before diagnosis. Malignancy was documented in 7 patients with distant metastases (n = 4) or locally invasive tumors (n = 3). During a median follow-up of 4 years, 23 patients are alive and free of disease (79%). Four of the 6 patients (67%) who died had distant metastases compared with 2 of 23 patients (9%) without distant metastases (P = 0.04). Persistent hypertension and diabetes requiring treatment were present in 8 (35%) and 4 (17%) of 23 patients respectively.
CONCLUSIONS: Fatal complications preceded diagnosis in a significant proportion of patients with pheochromocytoma. The presence of distant metastases was associated with poor survival.
P F Plouin, J M Duclos, F Soppelsa, G Boublil, G Chatellier
Factors associated with perioperative morbidity and mortality in patients with pheochromocytoma: analysis of 165 operations at a single center.
J Clin Endocrinol Metab. 2001 Apr;86(4):1480-6. doi: 10.1210/jcem.86.4.7392.
Abstract/Text
To identify preoperative factors associated with 30-day morbidity and mortality after pheochromocytoma surgery, we carried out an external review of the records of all patients undergoing pheochromocytoma surgery from 1975 to 1997 at a single center. One hundred and forty-seven patients, including 23 with malignant tumors at the time of the first operation, underwent 165 operations. Death, resection of a neighboring organ, further surgery, secondary transfer to an intensive care unit, and any events associated with a surgical stay exceeding 10 days were defined as complications. Mortality and morbidity were 4 of 165 (2.4%) and 38 of 161 (23.6%), respectively. Morbidity included 13 spleen resections and hematomas. Spleen complications were not related to tumor location, but were probably due to the operative strategy used, a transperitoneal complete abdominal exploration including both adrenal glands. Complications were independently associated with preoperative systolic blood pressure [odds ratio (OR), 1.14/cm Hg], urinary metanephrine excretion (OR, 1.18/10 micromol x day), and with the number of operations (repeat vs. first operation OR, 5.36). In conclusion, pheochromocytoma resection consistently involves a risk of complications. Spleen damage should be prevented by complete preoperative localization studies and an elective or laparoscopic surgical approach. Careful blood pressure control should help prevent complications. Patients with high secretion tumors and those undergoing repeat intervention are at high risk of complications and should be referred to centers familiar with pheochromocytoma management.
Mitsuhide Naruse, Fumitoshi Satoh, Akiyo Tanabe, Takahiro Okamoto, Atsuhiro Ichihara, Mika Tsuiki, Takuyuki Katabami, Masatoshi Nomura, Tomoaki Tanaka, Tadashi Matsuda, Tsuneo Imai, Masanobu Yamada, Tomohiro Harada, Nobuyuki Kawata, Kazuhiro Takekoshi
Efficacy and safety of metyrosine in pheochromocytoma/paraganglioma: a multi-center trial in Japan.
Endocr J. 2018 Mar 28;65(3):359-371. doi: 10.1507/endocrj.EJ17-0276. Epub 2018 Jan 20.
Abstract/Text
To assess the efficacy, safety, and pharmacokinetics of metyrosine (an inhibitor of catecholamine synthesis) in patients with pheochromocytoma/paraganglioma (PPGL), we conducted a prospective, multi-center, open-label study at 11 sites in Japan. We recruited PPGL patients aged ≥12 years requiring preoperative or chronic treatment, receiving α-blocker treatment, having baseline urinary metanephrine (uMN) or normetanephrine (uNMN) levels ≥3 times the upper limit of normal values, and having symptoms associated with excess catecholamine. Metyrosine treatment was started at 500 mg/day and modified according to dose-adjustment criteria up to 4,000 mg/day. The main outcome measure was the proportion of patients who achieved at least 50% reduction in uMN or uNMN levels from baseline. Sixteen patients (11 males/5 females) aged 12-86 years participated. After 12 weeks of treatment and at the last evaluation of efficacy, the primary endpoint was achieved in 31.3% of all patients, including 66.7% of those under preoperative treatment and 23.1% of those under chronic treatment. Sedation, anemia, and death were reported in 1 patient each as serious adverse drug reactions during the 24-week treatment. Metyrosine was shown to be tolerated and to relieve symptoms by reducing excess catecholamine in PPGL patients under both preoperative and chronic treatment.
Hui Huang, Jame Abraham, Elizabeth Hung, Steven Averbuch, Maria Merino, Seth M Steinberg, Karel Pacak, Tito Fojo
Treatment of malignant pheochromocytoma/paraganglioma with cyclophosphamide, vincristine, and dacarbazine: recommendation from a 22-year follow-up of 18 patients.
Cancer. 2008 Oct 15;113(8):2020-8. doi: 10.1002/cncr.23812.
Abstract/Text
BACKGROUND: A long-term follow-up was conducted of 18 patients with a diagnosis of pheochromocytoma/paraganglioma treated with a combination of cyclophosphamide, vincristine, and dacarbazine (CVD).
METHODS: The study design was a nonrandomized, single-arm trial conducted at a government medical referral center. Eighteen patients with metastatic malignant pheochromocytoma/paraganglioma were studied. After controlling symptoms of catecholamine excess, patients were treated with cyclophosphamide at 750 mg/m(2), vincristine at 1.4 mg/m(2), and dacarbazine at 600 mg/m(2) on Day 1 and dacarbazine at 600 mg/m(2) on Day 2, every 21 to 28 days.
RESULTS: Combination chemotherapy with CVD produced a complete response rate of 11% and a partial response rate of 44%. Median survival from a landmark was 3.8 years for patients whose tumors responded to therapy and 1.8 years for patients whose tumors did not respond (P = .65). All patients with tumors scored as responding reported improvement in their symptoms related to excessive catecholamine release and had objective improvements in blood pressure. CVD was well tolerated with only grade I/II toxicities.
CONCLUSIONS: Combination chemotherapy with CVD produced objective tumor responses in patients with advanced malignant pheochromocytoma/paraganglioma. In this 22-year follow-up there was no difference in overall survival between patients whose tumors objectively shrank and those with stable or progressive disease. However, patients reported improvement in symptoms, had objective improvements in blood pressure, and had tumor shrinkage that made surgical resection possible. The authors conclude that CVD therapy is not indicated in every patient with metastatic pheochromocytoma/paraganglioma, but should be considered in the management of patients with symptoms and where tumor shrinkage might be beneficial.
(c) 2008 American Cancer Society.
Shiko Asai, Takuyuki Katabami, Mika Tsuiki, Yasushi Tanaka, Mitsuhide Naruse
Controlling Tumor Progression with Cyclophosphamide, Vincristine, and Dacarbazine Treatment Improves Survival in Patients with Metastatic and Unresectable Malignant Pheochromocytomas/Paragangliomas.
Horm Cancer. 2017 Apr;8(2):108-118. doi: 10.1007/s12672-017-0284-7. Epub 2017 Jan 20.
Abstract/Text
Evidence has not been established to support that combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine (CVD) improves survival in patients with malignant pheochromocytoma and paraganglioma (M-PPGL). To investigate the efficacy of CVD for this disease, we retrospectively analyzed data of 23 patients with metastatic and unresectable M-PPGL (mean age, 41.7 ± 15.4 years) who received at least 2 cycles of this regimen. The follow-up period after initiation of CVD ranged from 0.3 to 13.7 years, with a median of 3.3 years. CVD therapy achieved a complete tumor response (CR) in 1 patient (4%), a partial response (PR) in 5 (22%), stable disease (SD) in 5 (22%), and progressive disease (PD) in 13 (52%), respectively. All of the responders (CR and PR) but 6% of the non-responders (SD and PD) showed substantial biochemical improvement. The progression-free survival period in the responders was significantly longer than in the non-responders (p < 0.01). Although the overall survival and survival after the diagnosis of M-PPGL were longer in the responders than the non-responders, the difference was not statistically significant (p = 0.08). The progression-free and overall survival period were significantly longer in the non-progression group (CR, PR, and SD) than in the progression group (PD) (1.7 ± 3.3 vs. 0.3 ± 0.3 years, p < 0.01, and 4.6 ± 3.6 vs. 2.0 ± 3.7 years, p = 0.01, respectively). It is therefore suggested that CVD chemotherapy could be useful in controlling tumor progression and improving survival in patients with metastatic and progressive M-PPGL.
L Fishbein, S Ben-Maimon, S Keefe, K Cengel, D A Pryma, A Loaiza-Bonilla, D L Fraker, K L Nathanson, D L Cohen
SDHB mutation carriers with malignant pheochromocytoma respond better to CVD.
Endocr Relat Cancer. 2017 Aug;24(8):L51-L55. doi: 10.1530/ERC-17-0086. Epub 2017 May 31.
Abstract/Text
Kaoru Nomura, Hironari Kimura, Satoru Shimizu, Hitomi Kodama, Takahiro Okamoto, Takao Obara, Kazue Takano
Survival of patients with metastatic malignant pheochromocytoma and efficacy of combined cyclophosphamide, vincristine, and dacarbazine chemotherapy.
J Clin Endocrinol Metab. 2009 Aug;94(8):2850-6. doi: 10.1210/jc.2008-2697. Epub 2009 May 26.
Abstract/Text
CONTEXT: About 10% of pheochromocytomas are malignant. Exact survival has not been reported, nor has an analysis of the efficacy of chemotherapy on survival time.
OBJECTIVE: The aim of this study was to analyze the survival curves and survival times of patients with malignant pheochromocytoma and to determine the efficacy of chemotherapy on prolongation of life.
DESIGN: An inception cohort and Kaplan-Meier survival analysis was conducted.
PATIENTS AND OUTCOME MEASURES: Thirty-two patients with metastasized malignant pheochromocytoma were analyzed for survival. Twenty-five patients had undergone excision of their primary tumors. Survival curves were compared among the 16 patients in this group treated with combined chemotherapy using cyclophosphamide, vincristine and dacarbazine (CVD) and the nine patients not treated with chemotherapy.
RESULTS: The survival curve of the 32 patients declined continuously and linearly to at least 20 yr after the diagnosis of pheochromocytoma. The 50% survival rate was estimated to be 14.7 yr. In the 25 patients whose primary tumor was excised, patients who already had metastases at the time of pheochromocytoma diagnosis had better survival than those whose metastases were found later. The survival rate after diagnosis of metastasis was worse in the CVD group than in controls. When the effects of CVD were examined after stratifying several factors, female gender and adrenal origin of tumor were found to be negative prognostic factors for CVD chemotherapy.
CONCLUSION: The present study revealed a long survival time. CVD chemotherapy was not shown to extend survival, especially for women and patients with adrenal gland-derived primary tumors.
B Shapiro
Summary, conclusions, and future directions of [131I]metaiodobenzylguanidine therapy in the treatment of neural crest tumors.
J Nucl Biol Med. 1991 Oct-Dec;35(4):357-63.
Abstract/Text
The role of diagnostic [131I/123I]metaiodobenzylguanidine (*I-MIBG) scintigraphy in the management of pheochromocytoma and neuroblastoma is established, but for other neural crest tumors is less defined. Radiopharmaceutical therapy of all these tumors with large activities of suitably radiolabeled MIBG is a compelling concept. In the five years since the first workshop on 131I-MIBG therapy held in Rome, the initial therapeutic promise appears to have been maintained for neuroblastoma and pheochromocytoma. A significant fraction of patients enter partial remission but complete remission is rare and relapse frequent. To date, experience with other neuroendocrine tumors and the use of 125I in place of 131I remains limited. Many promising areas remain incompletely explored. These include development of appropriate in vitro cultures and animal models, basic pharmacological mechanisms, drug interactions, macro- and microdosimetry and human clinical trials. The latter includes determining dose-limiting toxicity of 131I- and 125I-MIBG, treatment of patients at earlier times or stages of disease, optimal integration with other therapy including granulocyte-stimulating factor and marrow transplant rescue from otherwise limiting myelotoxicity. Progress to date has been slow and painstaking, but nevertheless significant, while the future holds both challenges and promise.
Keiichiro Yoshinaga, Noboru Oriuchi, Hiroshi Wakabayashi, Yuuki Tomiyama, Megumi Jinguji, Tetsuya Higuchi, Daiki Kayano, Makoto Fukuoka, Anri Inaki, Ayane Toratani, Shozo Okamoto, Tohru Shiga, Yoichi M Ito, Masatoyo Nakajo, Masayuki Nakajo, Seigo Kinuya, Drafting Committee for Guidelines on Internal Radiotherapy with ¹³¹I-MIBG, Japanese Society of Nuclear Medicine in Oncology and Imunology, Japanese Society of Nuclear Medicine
Effects and safety of ¹³¹I-metaiodobenzylguanidine (MIBG) radiotherapy in malignant neuroendocrine tumors: results from a multicenter observational registry.
Endocr J. 2014;61(12):1171-80. doi: 10.1507/endocrj.EJ14-0211. Epub 2014 Sep 11.
Abstract/Text
Effective treatments for malignant neuroendocrine tumors are under development. While iodine-131 metaiodobenzylguanidine (¹³¹I-MIBG) radiotherapy has been used in the treatment of malignant neuroendocrine tumors, there are few studies evaluating its therapeutic effects and safety in a multicenter cohort. In the current study, we sought to evaluate the effects and safety of ¹³¹I-MIBG therapy for conditions including malignant pheochromocytoma and paraganglioma within a multicenter cohort. Forty-eight malignant neuroendocrine tumors (37 pheochromocytoma and 11 paraganglioma) from four centers underwent clinical ¹³¹I-MIBG radiotherapy. The tumor responses were observed before and 3 to 6 months after the ¹³¹I-MIBG radiotherapy in accordance with RECIST criteria. We also evaluated the data for any adverse effects. The four centers performed a total of 87 ¹³¹I-MIBG treatments on 48 patients between January 2000 and March 2009. Of the treatments, 65 were evaluable using RECIST criteria. One partial response (PR), 40 stable disease (SD), and 9 progressive disease (PD) in malignant pheochromocytoma were observed after each treatment. Fourteen SD and one PD-were observed in paraganglioma. Patients with normal hypertension (systolic blood pressure (BP) > 130 mmHg) showed significantly reduced systolic BP after the initial follow-up (n=10, 138.1±8.2 to 129.5±13.5 mmHg, P=0.03). In adult neuroendocrine tumors with a treatment-basis analysis, there were side effects following 41 treatments (47.1%) and most of them (90.2%) were minor. In this multicenter registry, PR or SD was achieved in 84.6% of the treatment occasions in adult neuroendocrine tumors through ¹³¹I-MIBG radiotherapy. This indicated that most of the ¹³¹I-MIBG radiotherapy was performed safely without significant side effects.
Anri Inaki, Tohru Shiga, Yoshito Tsushima, Megumi Jinguji, Hiroshi Wakabayashi, Daiki Kayano, Norihito Akatani, Takafumi Yamase, Yuji Kunita, Satoru Watanabe, Tomo Hiromasa, Hiroshi Mori, Kenji Hirata, Shiro Watanabe, Tetsuya Higuchi, Hiroyasu Tomonaga, Seigo Kinuya
An open-label, single-arm, multi-center, phase II clinical trial of single-dose [131I]meta-iodobenzylguanidine therapy for patients with refractory pheochromocytoma and paraganglioma.
Ann Nucl Med. 2021 Dec 6;. doi: 10.1007/s12149-021-01699-0. Epub 2021 Dec 6.
Abstract/Text
OBJECTIVE: In this phase II study, we aimed to investigate the efficacy and safety of single-dose [131I]meta-iodobenzylguanidine (131I-mIBG) therapy in patients with refractory pheochromocytoma and paraganglioma (PPGL).
PATIENTS AND METHODS: This study was designed as an open-label, single-arm, multi-center, phase II clinical trial. The enrolled patients were administered 7.4 GBq of 131I-mIBG. Its efficacy was evaluated 12 and 24 weeks later, and its safety was monitored continuously until the end of the study. We evaluated the biochemical response rate as the primary endpoint using the one-sided exact binomial test based on the null hypothesis (≤ 5%).
RESULTS: Seventeen patients were enrolled in this study, of which 16 were treated. The biochemical response rate (≥ 50% decrease in urinary catecholamines) was 23.5% (90% confidence interval: 8.5-46.1%, p = 0.009). The radiographic response rates, determined with CT/MRI according to the response evaluation criteria in solid tumors (RECIST) version 1.1 and 123I-mIBG scintigraphy were 5.9% (0.3%-25.0%) and 29.4% (12.4%-52.2%), respectively. The most frequent non-hematologic treatment-emergent adverse events (TEAEs) were gastrointestinal symptoms including nausea, appetite loss, and constipation, which were, together, observed in 15 of 16 patients. Hematologic TEAEs up to grade 3 were observed in 14 of 16 patients. No grade 4 or higher TEAEs were observed. All patients had experienced at least one TEAE, but no fatal or irreversible TEAEs were observed.
CONCLUSION: A single dose 131I-mIBG therapy was well tolerated by patients with PPGL, and statistically significantly reduced catecholamine levels compared to the threshold response rate, which may lead to an improved prognosis for these patients.
© 2021. The Author(s).
