Review

Correspondence *Department of Pathology, Tufts – New England Medical Center, 750 Washington Street, Boston, MA 02111, USA

Email atischler@tufts-nemc.org

Introduction

The 2004 WHO classification of endocrine tumors defines pheochromocytoma as a tumor arising from catecholamine-producing chromaffin cells in the adrenal medulla—an intra-adrenal paraganglioma. Closely related tumors of extra-adrenal sympathetic and parasympathetic paraganglia are classified as extra-adrenal paragangliomas. Although arbitrary, this nomenclature serves to emphasize the distinctive properties of tumors in different locations. In contrast to adrenal and extra-adrenal sympathetic paragangliomas, those from parasympathetic tissue (mainly in the head and neck) rarely produce significant amounts of catecholamines.

Improvements in diagnosis, localization, management, and treatment of pheochromocytomas and catecholamine-producing paragangliomas are being driven by recent leaps in understanding of the genetics and biology of these tumors, coupled with advances in analytical chemistry, genomics, molecular biology, biotechnology, and nuclear medicine. Ineffective treatments for malignant tumors, inadequate methods to distinguish malignant from benign disease, and a lack of consensus on how to apply recent scientific and medical advances to improve diagnosis and patient management remain important unresolved problems.

This article reviews progress and outlines recommendations for improved clinical evaluation and care of patients with catecholamine-producing paragangliomas; it is based on presentations and moderated 'break-out' discussion sessions at the First International Symposium on Pheochromocytoma (ISP) held on 20–23 October, 2005, at Bethesda, MD, USA. Break-out sessions were designed to foster resolution of outstanding issues and problems in the form of recommendations addressing a series of questions (Box 1) formulated by key opinion leaders in the field, with input from patients and their support-group representatives and final agreement at a general session in which all attendees could be present. Here, we will discuss each of these questions in turn.

Considering the absence of large, randomized, double-blind, multicenter clinical trials fulfilling firm, high-level evidence-based criteria, recommendations from a consensus of experts from around the world seemed appropriate to provide guidance for the clinical community. During the course of discussions, it became clear that strict guidelines are rendered inappropriate by variability in the presentation of tumors and international differences in medical approaches or the availability of tests and therapies. Recommendations are, therefore, intended to complement sound clinical judgment, and are not intended as rigid mandates.

This article attempts to provide an unbiased overview of the consensus recommendations from the break-out sessions of the ISP. It acknowledges that there are numerous opinions and approaches and is not meant to favor any specific point of view, including those of the authors. Because of the limitations of space and the number of references, many ramifications of the topics and discussions are not dealt with in detail. Comprehensive reviews of the literature related to management and diagnosis of pheochromocytoma are available elsewhere.

Biochemical diagnosis

Pheochromocytomas and extra-adrenal paragangliomas are rare, and often overlooked, causes of hypertension. The crucial first step is therefore to consider these tumors when thinking of possible diagnoses. Confirming the diagnosis requires biochemical evidence of inappropriate catecholamine production. Measurement of urinary catecholamine levels has traditionally been the most widely used test, but measurement of urinary catecholamine metabolites or plasma catecholamines has also been recommended.^{1, 2, 3}

Previous recommendations on preferred biochemical tests—more often based on institutional experience than evidence-based medicine—are now being reconsidered in light of technical advances and improved understanding of catecholamine metabolism.⁴ It is now clear that catecholamines are metabolised within chromaffin cells to metanephrines (i.e. norepinephrine to normetanephrine and epinephrine to metanephrine). This intratumoral process occurs independently of catecholamine release, which can occur intermittently or at low rates. Consistent with these concepts, studies have confirmed that measurements of fractionated metanephrines (i.e. normetanephrine and metanephrine measured separately) in urine or plasma provide superior diagnostic sensitivity to measurements of the parent catecholamines.^{5, 6, 7, 8, 9, 10, 11}

An important recommendation derived from the above considerations, and endorsed by those at the ISP, was that initial testing for pheochromocytoma should include measurements of fractionated metanephrines in urine or plasma, or both, as available. There was no consensus on whether plasma or urine measurements should be the preferred test. Plasma metanephrines are usually measured in their free form, as produced by tumors, whereas urinary metanephrines are commonly measured after a deconjugation step and largely represent sulfate-conjugates produced by an enzyme localized mainly to gastrointestinal tissues. This might explain the diagnostic advantages of plasma measurement compared with urinary measurement reported by two groups.^{8, 11} The reported differences are, nevertheless, relatively small compared with the advantages of either test to tests for the parent catecholamines. Other factors, as outlined in Box 2, might be more important to consider in the choice of plasma or urinary measurements of fractionated metanephrines.

Box 2 Considerations affecting the choice of urinary fractionated metanephrines versus plasma free metanephrines for diagnosis of pheochromocytoma and paraganglioma.

Two further related recommendations arose from the discussion session on biochemical diagnosis: first, reference intervals for plasma and urinary metanephrines should primarily ensure optimum diagnostic sensitivity, with specificity a secondary consideration—this is mainly to avoid the deadly consequences of a missed diagnosis; and second, testing algorithms should not simply rely on a binary approach for test interpretation (i.e. a result being positive or negative), but should take advantage of the continuous nature of biochemical test results.

The latter recommendation is based on recognition that high diagnostic sensitivity is invariably associated with a trade-off in specificity, making it troublesome to distinguish true-positive from false-positive results. Clinical decision-making should, therefore, take into account the extent of the elevation in biochemical test results (Figure 1). Although an elevation of plasma or urinary normetanephrine slightly above the respective upper reference interval might only marginally increase the post-test probability of pheochromocytoma, an elevation of more than fourfold above the reference interval is associated with a close to 100% probability of the presence of the tumor.¹² The actual level of the abnormal result should, therefore, be used to determine the need for immediate tumor localization studies versus additional biochemical investigations.

Figure 1 Scatterplots showing the distributions for plasma concentrations (A) or urinary outputs (B) of normetanephrine versus metanephrine in patients with confirmed pheochromocytoma or paraganglioma (gray squares) compared with patients in whom tumors were excluded (gray dots).

The vertical and horizontal dashed lines, respectively, illustrate the upper reference limits for plasma concentrations of normetanephrine and metanephrine (0.61 nmol/l and 0.31 nmol/l) (A) and urinary outputs of normetanephrine and metanephrine (1.7 mol/day and 0.7 mol/day) (B) used to determine whether the results are negative or positive (a binary approach to test interpretation). With some exceptions, a tumor can be excluded if both normetanephrine and metanephrine concentrations fall below the upper limits. Exceptions include patients with tumors that produce only dopamine—for whom diagnosis might be based on isolated elevation of methoxytyramine (a metabolite of dopamine)—or patients with very small or microscopic tumors (<1 cm diameter) and no other biochemical evidence or signs or symptoms of catecholamine excess. The gray areas beyond the upper limits indicate areas in which positive results are of insufficient magnitude to enable false-positive and true-positive results to be reliably distinguished, but for which the probability of a tumor increases with increasing magnitude of the result (a continuous approach to test interpretation). Beyond the boundary of gray areas the probability of a tumor approaches 100%.

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If there is difficulty in distinguishing false-positive from true-positive results, it was generally agreed by the panel of experts that further biochemical testing is warranted before proceeding to localization studies. There was, however, no specific recommendation on what form this should take, although it was agreed that causes of false-positive results owing to medications and other factors should be considered. For testing involving measurements of plasma metanephrines, a seated posture during sampling was identified as a factor likely to increase the occurrence of false-positive results for that test. It was, therefore, recommended that blood samples should ideally be collected from patients in the supine position or repeated with sampling in the supine position if initial sampling in the seated position returns positive results in the 'gray area'.

Tumor localization

The panel of experts at the ISP felt strongly that localization of pheochromocytoma or paraganglioma should only be initiated if the clinical evidence for the presence of tumor is reasonably compelling. If suspicion is derived from signs and symptoms of catecholamine excess, biochemical test results should be strongly positive. If the pretest probability of a tumor is higher, such as in patients with a hereditary predisposition or previous history of the tumor, less compelling biochemical evidence might justify imaging studies.

Several other considerations also impact on localization studies. First, because of periodic surveillance of patients with a hereditary predisposition to catecholamine-producing tumors—including recently discovered disease-causing genes (see below)—there are further requirements to localize tumors of extremely small size or at unusual locations. Second, because of widespread use of anatomic imaging studies, adrenal incidentalomas have become an important clinical entity for which pheochromocytoma must be considered, regardless of signs and symptoms. Third, knowledge of the relationship between adrenal and extra-adrenal tumor locations according to genotype or biochemical phenotype calls for selection of appropriate imaging studies that result in decreased costs, radiation exposure, and the time required for tumor localization.

Except for children, pregnant women, and, rarely, patients with an allergy to contrast medium, there was no consensus on whether CT or MRI is preferred for initial localization of a tumor. This largely depends on the institutional preference and local expertise. Regardless of whether CT or MRI is used, there was a general agreement that imaging studies should initially focus on the abdomen and pelvis. If a tumor is not found, chest and neck images should be obtained, but with recognition that metastatic lesions in long bones can be missed.

Although CT and MRI have excellent sensitivity for detecting most catecholamine-producing tumors, these anatomic imaging approaches lack the specificity required to unequivocally identify a mass as a pheochromocytoma or paraganglioma. The higher specificity of functional imaging—the test of choice is currently ¹²³I-labeled meta-iodobenzylguanide (MIBG) scintigraphy—offers an approach to overcome the limitations of anatomic imaging.^{13, 14} The panel of experts agreed that functional imaging is useful. Differences in opinion were, however, expressed regarding whether functional imaging should be used for all tumors and in what sequence the modality should be used in relation to anatomic imaging.

Two main reasons warrant the use of functional imaging: first, the modality provides a method to more correctly distinguish pheochromocytomas or paragangliomas from other lesions; and second, it enables determination of the extent of disease, including the presence of multiple tumors or metastases. Exceptions for which functional imaging might not be required include adrenal tumors of <5 cm in diameter that are associated with a significant elevation of plasma or urine metanephrine levels. This is because such small tumors rarely metastasise and epinephrine-producing tumors are almost always located in the adrenal gland.¹⁵ If diagnostic doubt remains after all of the conventional imaging studies have been performed, venous catheter studies looking for 'hot spots' of catecholamines or metanephrines can occasionally be helpful, in addition to an examination of the ratio of epinephrine to norepinephrine in the adrenal veins.

Despite the advantages of ¹²³I-labeled MIBG scintigraphy, its sensitivity is less than optimal, especially for detection of metastases. The use of other functional imaging modalities is, therefore, occasionally necessary. PET imaging using 6-[¹⁸F]-fluorodopamine, [¹⁸F]-dihydroxyphenylalanine, [¹¹C]-hydroxyephedrine, or [¹¹C]-epinephrine are very promising, new, specific radionuclide localization techniques for pheochromocytoma.^{16, 17, 18, 19, 20, 21} Several recent studies have demonstrated superiority of these techniques to ¹²³I-labeled or ¹³¹I-labeled MIBG scintigraphy.¹⁷ Octreoscan and [¹⁸F]-fluorodeoxyglucose PET are other imaging options.^{14, 22} These studies are not recommended for initial localization, but should be reserved for patients with negative ¹²³I-labeled MIBG scintigraphy or rapidly growing tumors that have a high metabolic rate or express somatostatin receptors.^{23, 24}

Genetics

Hereditary catecholamine-producing pheochromocytomas and paragangliomas can be caused by germ-line mutations in any one of five genes identified to date: the rearranged during transfection (RET) proto-oncogene, in which mutations lead to multiple endocrine neoplasia type 2 (MEN2); the von Hippel–Lindau (VHL) gene, in which mutations lead to VHL syndrome; the neurofibromatosis type I (NF1) gene, which is associated with von Recklinghausen's disease; and genes encoding succinate dehydrogenase subunits D (SDHD) and B (SDHB), which are associated with familial nonsyndromic pheochromocytomas or paragangliomas.^{25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36} Mutation in a sixth gene encoding succinate dehydrogenase subunit C, SDHC, have so far been reported only in parasympathetic paragangliomas.

Mutation testing, now routinely available for four of the above genes (RET, VHL, SDHB, and SDHD), demonstrates that germ-line mutations are responsible for well in excess of the 10% of tumors previously thought to be hereditary.^{15, 37, 38, 39} Most importantly, 7.5–27.0% of tumors without an obvious syndrome or family history result from otherwise unsuspected germ-line mutations in one of these four genes (Table 1).^{29, 31, 36, 40, 41} The overall hereditary predisposition for pheochromocytoma is, therefore, estimated to be approximately 20–30%. The high prevalence of unsuspected mutations indicates a need for more widespread genetic testing of patients with these tumors than is currently practiced.

Table 1 Relative frequency of genetic mutations in nonfamilial pheochromocytoma and paraganglioma from different European groups presented during the First International Symposium on Pheochromocytoma, which was held on 20–23 October, 2005, at Bethesda, MD, USA.

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The panel of experts at the ISP agreed that, although there is now a reasonable argument for more widespread genetic testing, it is neither appropriate nor currently cost-effective to test for every disease-causing gene in every patient with a pheochromocytoma or paraganglioma. Rather, it was stressed that the decision to test, and which genes to test, requires judicious consideration of numerous factors, several of which are noted in Figure 2.

Figure 2 Algorithm for genetic testing for genes associated with pheochromocytoma.

The algorithm should be applied if there is a family history of pheochromocytoma, the patient is <50 years old, or there are multiple, malignant, or bilateral tumors. The biochemical phenotype of a tumor should also be considered in selection of the most appropriate genes to test. The term 'multiple' in the figure indicates tumors in separate anatomic locations. Patients with multiple endocrine neoplasia type 2 might have multiple tumors in a single adrenal gland. It should be considered that multiple or bilateral tumors often do not occur simultaneously. Abbreviations: RET, rearranged during transfection; SDHB, succinate dehydrogenase subunit B gene; SDHD, succinate dehydrogenase subunit D gene; VHL, von Hippel–Lindau gene.

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The panel underlined the importance of a complete clinical work-up and specialized genetic consultation to collect family history, outline potential repercussions of genetic testing, and obtain appropriate informed consent. A detailed medical and family history can be particularly important in pointing to an underlying hereditary condition. In the absence of any family history of pheochromocytoma or paraganglioma, descriptions of sudden death owing to incompletely explained cardiovascular events in family members could suggest an increased probability of hereditary disease, particularly because it is currently considered that at least 50% of catecholamine-producing tumors remain undiagnosed until death. Clinical manifestations in the patient or other family members might also signal a particular disease-causing gene (e.g. a VHL gene mutation suggested by findings of subtle retinal vascular lesions).

Because hereditary tumors usually occur at a younger age than sporadic tumors, age at presentation is an important factor to consider when deciding to test for disease-causing genes.^{31, 32} Findings that at least 36% of pheochromocytomas or paragangliomas in children occur secondary to germ-line mutations underscore the potential importance of genetic testing in pediatric patients with these tumors.⁴² Young adults with apparently sporadic tumors are likely to harbor occult germ-line mutations more often than elderly patients with these tumors; however, advanced age at presentation does not preclude familial disease, as evident from the case of a 73-year-old woman with an apparently sporadic pheochromocytoma who was serendipitously tested and found to have MEN2A, leading to the discovery of medullary thyroid carcinoma in a relative.⁴³

Except for the obvious clinical manifestations that can indicate a specific hereditary syndrome (e.g. medullary thyroid cancer in patients with MEN2), the panel of experts recommended that the decision to test for a particular gene might benefit from consideration of tumor location, presence of metastases, and type of catecholamine produced by the tumor. Although mutations of the SDHB and SDHD genes are occasionally associated with solitary adrenal tumors, patients with these mutations most commonly present with extra-adrenal paragangliomas, often with multifocal disease.^{28, 29, 39, 40, 41, 44} Testing for SDHD and SDHB gene mutations in patients with extra-adrenal tumors can, therefore, be particularly revealing; furthermore, because SDHB gene mutations carry a high risk of malignant disease, testing for such mutations in patients with metastases, especially related to extra-adrenal paragangliomas, is particularly warranted (Figure 2).^{29, 40, 41}

By contrast, malignant disease and extra-adrenal tumors are rare in MEN2, so testing for RET gene mutations is unlikely to be rewarding in these situations; furthermore, because pheochromocytomas in patients with MEN2 always produce epinephrine, it is inappropriate to test for RET gene mutations in tumors characterized by an increase in urinary or plasma normetanephrine but not metanephrine.⁴⁵ This differs from pheochromocytomas in VHL syndrome, which do not produce significant amounts of epinephrine, indicating that testing for VHL mutations is inappropriate for tumors characterized by an increase in plasma or urinary metanephrine, with or without an increase in normetanephrine.⁴⁵

Patient management

The correct clinical management of patients with pheochromocytoma relies on a close collaboration between different specialists.^{38, 46, 47, 48, 49} In most patients, the tumor is cured by surgery. Exposure to high levels of circulating catecholamines during surgery could cause hypertensive crises and arrhythmias, which can occur even if patients are preoperatively normotensive and asymptomatic. It was, therefore, recommended that all patients with a biochemically positive pheochromocytoma or paraganglioma should receive appropriate preoperative medical management to block the effects of released catecholamines.

Because of wide-ranging practices and international differences in available or approved therapies, and without evidence-based studies comparing different therapies, there was no specific recommendation on the preferred drugs for preoperative blockade; -adrenoceptor antagonists,^{46, 47, 49} calcium-channel blockers, or angiotensin-receptor blockers have all been recommended and appear useful.⁵⁰ For tachyarrhythmias, -adrenoceptor or calcium-channel blockers were recommended.⁴⁶ It was emphasised that if -adrenoceptor blockers are used, they should be used only after adequate pretreatment with -adrenoceptor antagonists. Volume expansion was also recommended before and after surgery.

It was recommended that only experienced surgeons perform the surgery, and that the approach take into account the type, site, size, and hereditary background of the tumor.⁵¹ The use of laparoscopy as the surgical method of choice for most abdominal pheochromocytomas or paragangliomas is recommended for primary or multiple smaller tumors.⁵² Currently, tumors up to approximately 10 cm can be removed by laparoscopy. An adrenal-cortex-sparing procedure to prevent permanent glucocorticoid deficiency can be an important consideration in hereditary cases in which bilateral disease is probable. The choice of cortex-sparing surgery should be balanced by the consideration that this will increase the risk of tumor recurrence.^{53, 54, 55, 56}

There was general agreement that biochemical testing should be repeated approximately 14 days following surgery to check for remaining disease. Importantly, normal postoperative biochemical test results do not exclude remaining microscopic disease, so patients should not be misinformed that they are cured and no further follow-up is necessary. As outlined by patient representatives at the ISP, the lack of recommendations on follow-up seems to remain a significant problem. Although follow-up is especially important for patients identified with mutations in disease-causing genes, there is currently no method of follow-up on the basis of pathologic examination of a resected tumor that can rule out the potential for malignancy or recurrence. Long-term periodic follow-up, therefore, remains recommended for all cases of pheochromocytoma or paraganglioma.

Pathology

Pathologic examination should distinguish primary or metastatic pheochromocytomas and paragangliomas from other endocrine or nonendocrine tumors and flag tumors with features suggestive of malignancy or hereditary disease. The latter might include multicentricity, accompanying adrenal medullary hyperplasia, or morphologic findings reported in association with VHL syndrome;⁵⁷ however, these are not always present.

To be optimally informative, pathology reports must use consistent definitions and incorporate standard elements. The 2004 WHO criteria⁵⁸ define malignancy by the presence of metastases, not local invasion. Even extensive invasion—although potentially lethal—is a poor predictor of metastases, and a lack of apparent invasion does not preclude the development of metastases. The two types of aggressive behavior might, therefore, have different biological underpinnings, requiring different treatment, and should be clearly distinguished in pathology reports.

No histologic feature can—by itself—identify metastatic potential, including capsular or vascular invasion, cytologic atypia, or areas resembling pediatric neuroblastoma; however, some evidence suggests that multifactorial analyses can help to identify tumors with a significant risk of metastasis. Several scoring systems derived from invasion, histologic growth patterns, cytologic features, mitotic activity, and other characteristics have been proposed.^{59, 60, 61} One system reportedly predicts both metastatic potential and the clinical course of patients who develop metastases.⁵⁹ A seminal study by Linnoila et al.⁶⁰ showed that >70% of sympathoadrenal paragangliomas could be classified correctly on the basis of four factors: extra-adrenal location, coarse nodularity, confluent necrosis, and absence of hyaline globules. Unfortunately, a number of subsequent papers addressing the assessment of malignancy blur the distinction between intra-adrenal and extra-adrenal tumors, so the powerful independent predictive value of the anatomic site is obscured. Large tumor size (>5 cm) shows some correlation to metastatic potential in some studies, although possibly not as an independently useful criterion.^{15, 59, 60, 61}

There is currently no consensus on adoption of a formal scoring system; however, it is recommended that pathology reports conform to templates or checklists for minimal standard reporting that are endorsed by several pathology associations. The templates list the major elements of the proposed scoring systems and permit additional optional elements. The listing of potentially unfavorable findings will presumably flag a tumor for some type of follow-up, but the nature of the required follow-up remains unclear.

The Association of Directors of Anatomic and Surgical Pathology (ADASP) oversees standardization of pathology reporting in the US. ADASP recommendations for reporting of major tumor types are available in pathology journals, in textbooks,⁶² and on the organization's website.⁶³ The protocols, including those for adrenal gland⁶⁴ and extra-adrenal paragangliomas,⁶² were recently updated to generate checklists compliant with the 2004 requirements for accreditation of cancer centers in the US by the American College of Surgery Commission on Cancer. In the UK, the Royal College of Pathologists has recently finalized a more detailed synoptic reporting template,⁶⁵ based, primarily, on the report by Linnoila et al.⁶⁰

Pathology practice currently rests mostly on the interpretation of conventional histologic sections stained with hematoxylin and eosin, with ancillary application of immunohistochemistry principally as required for differential diagnosis. Immunohistochemistry has been used as an ancillary technique for assessment of malignant potential, with mixed results.⁶⁶ Staining for the proliferation marker Ki-67, which is demonstrated in paraffin sections using the monoclonal antibody MIB-1, is most consistently correlated to malignancy^{59, 67} and is incorporated into the most recently proposed scoring system;⁵⁹ however, studies of MIB-1 labeling lack methodological consistency and many papers do not provide sufficient methodological detail to permit replication. The Ki-67 labeling index might provide useful information as an optional component of the pathology report, but at present it must be interpreted in the context of individual pathologists' methods and experience.

Malignant pheochromocytoma

The incidence of metastatic pheochromocytoma ranges (depending on the genetic background and tumor localization) from 3% to 36%.^{15, 68, 69, 70, 71} The survival rate depends on the location of metastatic lesions. Short-term survivors (<5 years) tend to be patients with metastatic lesions in the liver and lungs, whereas long-term survivors are those with metastatic lesions in bones. The overall 5-year survival rate varies between 34% and 60%.^{69, 72} This poor prognosis emphasises the need to adequately identify either those with already existing metastatic disease or, preferably, those who might develop metastases. The latter depends largely on the future discovery of genes and their products that determine metastatic potential and organ specificity. Currently, except for the presence of the SDHB gene mutation, there are no reliable markers to suggest a high probability of the development of metastatic pheochromocytoma if a primary tumor is found. Leads from proteomic and genomic studies offer promise for future development of prognostic biomarkers.^{66, 73}

Although several therapeutic options exist for patients with metastatic pheochromocytoma, all options are limited and there is no cure. Reduction of tumor size palliates symptoms, but a survival advantage of debulking is unproven. A reduced tumor burden can facilitate subsequent radiotherapy or chemotherapy. External-beam irradiation of bone metastases and radiofrequency ablation of lesions are treatment alternatives. Chemotherapy with a combination of cyclophosphamide, vincristin, and dacarbazine can provide tumor regression and symptom relief in up to 50% of patients, but the responses are usually short-lived.^{74, 75, 76, 77} To date, ¹³¹I-labeled MIBG therapy is the single most valuable adjunct to surgical treatment of malignant pheochromocytomas.⁷⁸ As a single agent, ¹³¹I-labeled MIBG has a limited efficacy of cure, and there is no consensus on what doses to use for treating either bone or organ metastases. Multicenter studies are required to reach a consensus on the efficacy of high-dose versus fractionated medium doses of ¹³¹I-labeled MIBG and monotherapy versus combination therapy with other radionuclides or modes of chemotherapy.⁷⁹

Conclusion

It is, generally, agreed that converging technologic advances will continue to radically affect the management of patients with pheochromocytoma or paraganglioma. To be optimally useful and cost-effective, new technologies will need to be thoughtfully integrated with one another and older diagnostic and therapeutic modalities. New biochemical testing methods, involving mass spectrometry, are becoming available at many centers.^{80, 81, 82, 83} Future test reporting should also be improved, to indicate changes in pretest to post-test probabilities of disease for individual patients, to further guide clinical decision-making. For diagnostic imaging, it is probable that combining PET with CT will provide the definitive tool in the near future. The combined methods will increase the accuracy of tumor localization, provide proof that a tumor is, indeed, a pheochromocytoma or paraganglioma, and be useful in monitoring the response to treatment.

Currently, there is no cure for malignant pheochromocytoma or paraganglioma and no reliable histopathologic markers exist to diagnose malignancy or assess prognosis. Establishing the pathways of tumorigenesis and malignancy is an important objective that will be facilitated by advances in understanding the function and genetic basis of these tumors and the wealth of information available on normal chromaffin cell biology; however, histopathology is a time-tested and relatively inexpensive diagnostic tool. Pathology scoring systems reported to correlate to the metastatic potential of tumors and patients' clinical courses in retrospective studies should be prospectively validated and strengthened by judicious introduction of new immunohistochemical and molecular markers. The future role of pathology, perhaps in combination with genetic testing,^{66, 67} might involve more definitive assessment of malignancy, genotype–phenotype correlation, and identification of targets for therapy.

Gene expression and proteomic profiling will facilitate the search for new diagnostic and prognostic markers and will present new targets for the treatment of malignancy. Superarrays, using limited numbers of disease-specific genes, could help to quickly and accurately diagnose a tumor and assess its behavior and prognosis. Genes that are as yet unidentified will probably be found to cause hereditary pheochromocytoma or paraganglioma and increase the proportion of hereditary cases above that which has been already estimated. Finally, new animal models of familial and metastatic pheochromocytoma or paraganglioma will provide essential tools to test new approaches for diagnosis and treatment of tumors and the eradication of tumor precursors.

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