Pheochromocytoma and Paraganglioma: Recent Progress and New Vistas for Improved Patient Care

 

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This special issue of Hormone Metabolic Research, together with a parallel issue of Endocrine Pathology [1], provides state-of-the-art reviews and reports on selected original research findings presented at the September 2011 International Symposium on Pheochromocytoma and Paraganglioma (ISP2011). This symposium, hosted by Pierre-Francois Plouin and Anne-Paule Gimenez-Roqueplo at Paris, France, attracted a record attendance following earlier meetings at Cambridge in the United Kingdom in 2008 and Bethesda, Maryland, USA in 2005. These series of symposia are organized under the auspices of the Pheochromocytoma and paraganglioma RESearch Support ORganization (PRESSOR, http://www.pressor.org), which was established in the Spring of 2004 following an initial workshop held in the Fall of 2003 at Cold Spring Harbor at the behest of James Watson and William Manger.

This past decade has seen enormous strides in the diagnosis and management of patients with pheochromocytomas and paragangliomas. Up until the turn of the 21^st century it was widely taught that 10% of the tumors had a hereditary basis associated with 3 familial syndromes: neurofibromatosis type 1 (NF1), multiple endocrine neoplasia type 2 (MEN 2), and von Hippel-Lindau (VHL) syndrome. Since then, as reviewed by Gimenez-Roqueplo, Dahia, and Robledo [2], 7 more tumor susceptibility genes have been identified, so that for the time being these tumors should be recoined the “10 gene tumor” rather than the “10% tumor”. Four of the 10 tumor susceptibility genes were identified since ISP2008, illustrating the accelerating pace of progress in the area. The 2 most recently identified genes include those encoding transmembrane protein 127, identified by Dahia’s group in San Antonio, Texas [3], and MYC associated factor X, identified by Robledo’s group in Madrid, Spain [4].

The coming years will surely see identification of further tumor susceptibility genes for hereditary pheochromocytomas and paragangliomas. In the mean time these tumors are now well established as having one of richest hereditary components among all neoplasms, opening up many new and wide ranging avenues for improved understanding of tumor biology in general. As illustrated by the 40% of the articles in this volume that focus on hereditary aspects of chrom­affin cell tumors [2] [5] [6] [7] [8] [9] [10], advances in genetics have provided a major push for the field and a magnet for attracting funding and drawing new young and talented investigators to studies directed at chromaffin cell tumors. Also apparent at ISP2011 are the vital contributions of women scientists who are now leading the field, particularly in genetics, tumor biology and model systems.

With the increasing identification of more and more tumor susceptibility genes there has been a growing need to establish procedures both to streamline genetic testing and manage patients with identified mutations. Consideration of the phenotypic features of tumors – such as their locations, biochemical profiles, immunohistochemical characteristics, age of presentation, and presence of metastases – can all be used to guide selection of genes for testing of possible underlying mutations. Important also are considerations of how to manage patients with identified mutations, including their most appropriate follow-up and the testing of other family members at risk for mutations. As covered by Lahlou-Laforet and colleagues [9], genetic counseling must proceed with particular care for presymptomatic testing in children and in whom a multidisciplinary team approach can facilitate communication and subsequent follow-up. Screening for tumors at an early age in those with identified mutations is important for early diagnosis and treatment, thereby potentially minimizing life-threatening complications, including malignancy in carriers of mutations of succinate dehydrogenase subunit B (SDHB) [ [2] [11].

As reviewed by Amar et al. [12], long-term periodic follow-up is not only required for patients identified with germline mutations of tumor susceptibility genes, but also for all patients operated for sporadic pheochromocytomas and paragangliomas in whom there is a risk for recurrent and malignant disease. With advances over recent years, the questions now being addressed are not only how often follow-up screening for tumors should be carried out, but also how patients should be stratified for follow-up testing and in what form this should be carried out.

Patients with large primary tumors, tumors at extra-adrenal locations or due to SDHB mutations are at increased risk for metastatic disease [11] [13] [14]. Such patients should therefore be screened more carefully for possible metastases than other patients, such as those with smaller tumors at adrenal locations. Patients with SDHB mutations in particular tend to have large extra-adrenal tumors that contain minimal quantities of catecholamines and significant amounts of dopamine [11]. Screening in these patients should therefore include measurements of methoxytyramine, but because some tumors produce negligible catecholamines considerations should also be given to measurements of chromogranin A and periodic head to pelvic imaging. With such advances in management it can be anticipated that tumors previously often missed with ensuing deadly consequences will now become increasingly diagnosed at an earlier stage when a complete cure is more likely.

In addition to advances in genetics, the last decade has also seen important advances in diagnostics, both in biochemical testing and tumor localization. While emphasis on measurements of plasma and urine metanephrines is now well embedded in diagnostic decision making, new developments are showing how heterogeneity in biochemical profiles can also be linked to underlying mutations and associated phenotypic features [14]. For example, patients with MEN 2 and NF1 are characterized with pheochromocytomas that produce adrenaline, best reflected by increased plasma concentrations or urinary outputs of its O-methylated metabolite, metanephrine. In contrast, tumors due to mutations of VHL, SDHB, and SDHD are not associated with significantly increased plasma concentrations or urinary outputs of metanephrine. In VHL syndrome the tumors are characterized by solitary increases in normetanephrine, the metabolite of noradrenaline, while in patients with tumors due to SDHB and SDHD mutations there are often additional or solitary increases in methoxytyramine, the metabolite of dopamine. The latter increases are also associated with a higher likelihood of malignancy [11].

As outlined in the review article in this issue by Timmers et al. [15], underlying mutations also impact functional imaging characteristics of tumors. While imaging by ¹²³I-meta-iodobenzylguanidine scintigraphy and ¹⁸F-6-fluorodopamine or ¹⁸F-6-fluorodihydroxphenylalanine positron emission tomography (PET) has good sensitivity for localization of adrenal pheochromocytomas, these functional imaging modalities often fall short for localization of paragangliomas and particularly metastases associated with mutations of the SDHB gene. For the latter ¹⁸F-fluorodeoxyglucose PET is recommended, apparently this reflecting both increased energy demands and the relatively immature nature of the tumors and accompanying loss of expression of components responsible for catecholamine transport and storage.

As Timmers and colleagues [15] further outline, it is likely that future use of functional imaging will increasingly move beyond localization and identification to tumor characterization for guiding personalized therapy. Illustrating that this time is already here, Spetz and colleagues outline how functional imaging may be used to guide radiotherapy of malignant PPGLs with either ¹³¹I-meta-iodobenzylguanidine (¹³¹I-MIBG) or somatostatin analogues [16]. As also outlined in the report by Zovato et al. [17], use of radiolabeled somatostatin analogues for therapy of mediastinal and head and neck paragangliomas resulted in partial responses with minimal side-effects in 4 patients evaluated and may offer an alternative to surgical resection and external beam radiation therapy. In another report, Fishbein and colleagues describe how targeted external beam radiotherapy can be combined with ¹³¹I-MIBG radiotherapy for control of bulky lesions in patients with metastatic disease [18].

In addition to improvements in patient management, elucidation of the rich hereditary background of pheochromocytomas and paragangliomas also provides fertile ground for new understanding of tumor biology that also impacts numerous other more common neoplastic conditions. This concept is well illustrated in the review by Cascon and Tennant [19], which outlines the various pathways now identified to play central roles in chromaffin cell tumorigenesis. Activation of hypoxia-angiogenic pathways, either secondary to mutations of key regulatory components, such as the VHL protein, or defects in mitochondrial energy pathways, such as those involving succinate dehydrogenase, are well recognized in numerous other neoplastic conditions. For example, fumarate hydratase mutations contribute to renal cancer and leiomyomas, whereas mutations of isocitrate dehydrogenase genes, also impacting energy metabolite pathways, have now well established roles in leukemia and gliomas [20].

Elucidation of the pathways of tumorigenesis in patients with pheochromocytomas or paragangliomas is opening up new vistas for targeted therapies of malignancy [13] [21] [22]. This and associated advances in new experimental model systems outlined by Korpershoek et al. [23] can be expected to provide new opportunities for clinical trials. In parallel there has also been considerable progress in collaborative international multicenter initiatives that provide the necessary long-term infrastructure to ensure that such trials can be rapidly implemented. The FIRSTMAPPP trial (First International Randomized Study in Malignant Progressive Pheochromocytoma and Paraganglioma, http://clinicaltrials.gov/ct2/show/NCT01371201) represents one such initiative that arose through a banding together of members of the PRESSOR consortium and the European Network for the Study of Adrenal Tumors (ENS@T, http://www.ensat.org).

Thus, from the original meeting instigated in 2003 by Drs Watson and Manger at Cold Spring Harbor to foster hope for patients with malignant pheochromocytoma and paraganglioma, there is now real progress towards addressing a primary goal of the PRESSOR consortium to develop and implement effective treatments for malignant pheochromocytoma. These efforts are now strongly based under ENS@T in Europe, where the community spirit of the European Union and associated funding opportunities encourages synergistic partnering and multicenter research collaborations to promote more effective and efficient translation of basic research to clinical practice than otherwise possible under single investigator or center associated programs of support. This provides a model for investigators and funding agencies in other Nations to follow. Indeed it is a model that is in fact already being emulated elsewhere, in particular Japan. Thus, as described at ISP2011 by Dr. Mitsuhide Naruse, in Japan there is now an established consortium of 110 clinicians and investigators focused on research and improving diagnosis, management and treatment of patients with pheochromocytoma (http://poppy.ac/pheochromocytoma).

In the United States moves are now also afoot for coordinated approaches to speed discoveries at the bench to treatments for patients. In a new National Institutes of Health (NIH) initiative, unveiled on December 23, 2011 (http://nih.gov/news/health/dec2011/od-23.htm), a new NIH Center is being established with a program to encourage and speed the development of new drugs for rare and neglected diseases, with funding directed to national consortia of medical research institutions working together to improve the way clinical and translational research is conducted nationwide.

Undoubtedly, recognition of Japanese efforts in establishing a local network was largely responsible for choice of Kyoto, Japan as the next ISP venue in the fall of 2014. With accelerating rate of progress in the field it can be expected that we will see many more scientific breakthroughs and achievements at ISP2014 in Japan. In the mean time, the present series of articles outlined in this special issue of Hormone and Metabolic Research and a parallel issue of Endocrine Pathology serves to whet our appetite for these further advances to come.

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