Details associated with Recommendations:

Biochemical Diagnosis and Localization Details

Initial biochemical testing for pheochromocytoma should include measurements of plasma free metanephrines or urinary fractionated metanephrines.

This important recommendation agreed upon by all attending participants at the breakout and final discussion sessions of ISP2005 does not exclude additional use of other tests, but does represent a move away from reliance on measurements of urinary or plasma catecholamines, urinary total metanephrines and urinary vanillylmandelic acid. Thus, if other tests are used during initial testing, these should always be used in conjunction with measurements of fractionated metanephrines (normetanephrine and metanephrine) measured in plasma or urine.

The importance of measurements of urinary or plasma fractionated metanephrines for the diagnosis of pheochromocytoma is based on research establishing that pheochromocytomas contain catechol-O-methyltransferase, the presence of this enzyme resulting in metabolism of catecholamines to metanephrines within tumor cells. Production of metanephrines within tumor cells is continuous and more accurately reflects tumor mass than release of catecholamines, which can occur episodically or not at all in non-secretory tumors. Consistent with these concepts it has now been established by four independent groups of investigators that measurements of plasma metanephrines provides superior diagnostic sensitivity over measurements of plasma or urinary catecholamines for detection of pheochromocytoma. A further study presented at ISP2005 by Dr. Robert Peaston (Freeman Hospital, Newcastle upon Tyne, United Kingdom) provided further documentation by a fifth group that measurements of plasma metanephrines provide improved accuracy over urinary catecholamines for the diagnosis of the tumor (Table 1).

Several studies involving measurements of urinary fractionated metanephrines have similarly indicated that these tests provide superior diagnostic sensitivity over urinary or plasma catecholamines, urinary vanillymandelic acid, or total metanephrines, the latter measured as the combined sum of normetanephrine and metanephrine by early spectrophotometric methods. Taken together, the weight of accumulating evidence clearly indicates that measurements of fractionated metanephrines in urine or plasma provide superior diagnostic sensitivity over urinary or plasma measurements of catecholamines and other catecholamine metabolites. [recommendation]
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Reference intervals for initial tests of plasma or urinary fractionated metanephrines should be established primarily to ensure optimum diagnostic sensitivity, with specificity a secondary consideration

This recommendation is based on considerations of the relative importance of diagnostic sensitivity and specificity for detecting pheochromocytomas. Because missing these tumors can have deadly consequences, one of the most important considerations in choice of initial test is a high level of reliability that the test will provide a positive result in that rare patient with the tumor. This conversely also provides confidence that a negative result reliably excludes the tumor, thus avoiding the need for multiple or repeat biochemical testing or even costly and unnecessary imaging studies to rule out the tumor. Measurements of plasma free metanephrines or urinary fractionated metanephrines provide tests with suitably high diagnostic sensitivity. However, maintaining this sensitivity requires use of appropriately established reference intervals. For example, since plasma concentrations of free metanephrines are increased by assumption of upright posture, reference intervals for these analytes should be established in samples taken after at least 20 minutes in the supine position. [recommendation]
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Testing algorithms should not simply rely on a binary approach for test interpretation (i.e., whether a test result is negative or positive), but should instead take advantage of the continuous nature of biochemical test results

This recommendation followed recognition that emphasis on high diagnostic sensitivity typically necessitates a trade-off in suboptimal diagnostic specificity. This recommendation represents a move away from over-reliance on a given reference interval for drawing a line about whether a disease is or is not present, and a move towards different decision levels for assessing the relative probability of disease. For example, while a single elevation of urinary or plasma normetanephrine of slightly above the upper reference intervals may only marginally increase the pre-to post-test probability of pheochromocytoma, an elevation of more than 4-fold above those intervals is associated with close to 100% probability of the tumor. In the latter situation more emphasis may be placed on immediately locating the tumor, whereas in the former situation involving test results in the "grey area", there is more of a need to first exclude a false-positive result.[recommendation]
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Interpretation of positive test results in the "grey area" requires consideration - and where possible elimination - of causes of false-positive results before further confirmatory testing is initiated

Due to myriad conditions and medications that can lead to false-positive results, no specific precautions were outlined that should be considered during biochemical testing to minimize or avoid false-positive results or drug-interferences. Ideally, such precautions should be considered before initial testing, but it was recognized that this is not always possible or practical. For example, to minimize false-positive results for measurements of plasma free metanephrines, blood samples should ideally be collected after 20 minutes of supine rest. However, because blood sampling is routinely carried out with patients in the seated position, the ideal supine sampling position is often not practical. It was therefore proposed that where blood sampling in the seated position returns positive results in the "grey area", repeat testing should be carried out with blood samples collected after 20 minutes of supine rest, where necessary carried out by clinical staff not subject to the same restrictions as phlebotomy technicians.

Medications represent common causes of false-positive results, either through direct analytical interference with techniques used to measure catecholamines and catecholamine metabolites, or through pharmacological influences on actual plasma or urinary levels. The former causes tend to be method-specific and variable from laboratory to laboratory, making general recommendations on what medications to avoid largely inappropriate. Among the latter causes, tricyclic antidepressants and the ?-adrenoceptor blocker, phenoxybenzamine, may be responsible for close to 50% of all false-positive elevations of plasma and urinary norepinephrine and normetanephrine. Repeat testing after discontinuation of suspect medications can be used to exclude these as causes of false-positive results. Use of confirmatory follow-up tests, such as urinary fractionated metanephrines to support patterns of increases in initial measurements of plasma metanephrines, or vice-versa, were outlined as other approaches to exclude false-positive results, particularly where there is concern about analytical validity.

In all approaches involving multiple tests of catecholamine excess, due consideration should also be given to the inter-dependence of the various analytes which may compromise Bayesian approaches to clinical decision-making. A false-positive elevation of urinary normetanephrine due to sympathetic activation is also likely to be associated with false-positive elevations of urinary and plasma norepinephrine and plasma normetanephrine. Thus, while elevations in the latter analytes measured in follow-up tests may serve to confirm the validity of the initial elevated urinary normetanephrine, those additional positive test results do not always provide increased evidence of a pheochromocytoma any more than they provide increased evidence for sympathetic activation. In such situations suppression tests using clonidine or pentolinium can be useful for distinguishing true-positive results due to a pheochromocytoma from false-positive results due to sympathetic activation [recommendation]
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Imaging studies to search for a pheochromocytoma should usually only be initiated once biochemical or other evidence of the tumor is reasonably compelling

In general, participants at ISP2005 felt strongly that localization of pheochromocytoma should usually only be initiated once the clinical evidence for the tumor is reasonably compelling. For most patients where initial suspicion is based on signs and symtoms, such evidence may include strongly positive biochemical test results or when results are not strongly positive, repeated testing after ruling out causes of false-positive results. In patients where the risk of pheochromocytoma is high because of a hereditary predisposition or a previous history of the tumor, imaging studies may be warranted even when biochemical evidence of a pheochromocytoma is less than compelling. In some such patients, imaging studies may be appropriate as part of a periodic surveillance plan, not only for pheochromocytoma, but also to check for other tumors (e.g., kidney tumors in VHL syndrome). [recommendation]
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Anatomic imaging studies - CT or MRI - provide the most appropriate tools for initial localization of a pheochromocytoma. Although additional functional imaging studies may not always be called for, such studies can be useful to prove that a localized mass is indeed a pheochromocytoma and to correctly detect any extension of disease, not identified by anatomic imaging.

Except for children and pregnant women or rarely in patients with allergies to contrast medium, there was no consensus about whether to use CT or MRI for the initial localization of a tumor. It was concluded that this depends largely on institutional preference and expertise. Both imaging modalities have excellent sensitivity for detection of adrenal tumors, but lack adequate specificity for unequivocally confirming a mass as a pheochromocytoma. Neither CT nor MRI can distinguish with clear certainty a functional from a non-functional tumor.

Although it was recognized that functional imaging may not always be necessary once a tumor is located by CT or MRI, it was generally agreed that such studie scan be useful. The functional imaging test of choice is currently [123I]-MIBG scintigraphy. Participants agreed that additional functional imaging studies should be performed in most cases of biochemically-proven pheochromocytoma for two main reasons: (1) to prove that the tumor is indeed a pheochromocytoma; and (2) to correctly detect any extension of disease, not identified by anatomic imaging (e.g., presence of multifocal or bilateral disease or metastatic lesions), which may guide an appropriate therapeutic plan. It should be noted that this recommendation was based on expert opinion, as data for or against the use of routine functional imaging are limited.

Decisions about imaging should also take into account prior knowledge of the patient. For example, in some patients at risk for extra-adrenal tumors due to germ-line mutations of SDHB and SDHD genes or a previous history of paraganglioma, it may be appropriate to include [123I]-MIBG scintigraphy with CT or MRI as part of the initial imaging evaluation. Exceptions where [123I]-MIBG scintigraphy may not be necessary include solitary adrenal masses of less than 5 cm associated with elevations of plasma or urinary epinephrine or its metabolite, metanephrine. This suggestion was based on the perception that malignant disease mainly occurs in association with large norepinephrine-predominant tumors, as well as findings that practically all epinephrine-producing pheochromocytomas - including those in patients with MEN 2 - are found in the adrenal gland or are recurrences of previously resected adrenal tumors.

Although no firm recommendations were directed to the use of other functional imaging modalities, these it was recognized hold considerable promise, and have already been demonstrated to be of value in the localization of certain cases of the tumor. [recommendation]
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Genetics Details

There are now reasonable arguments for more widespread genetic testing than previously practiced; however, it is currently neither appropriate nor cost-effective to test every disease-causing gene in every patient with a pheochromocytoma. Rather, the decision to test, and which genes to test, requires judicious consideration of numerous factors.

The recommendation for more widespread genetic testing than has been previously practiced is based on growing recognition of the relatively high prevalence of unsuspected mutations in patients with pheochromocytoma, combined with accumulating evidence that the overall hereditary predisposition for pheochromocytoma is at least between 20-30%.

Nevertheless, with a view to the currently high cost of genetic testing and continuing uncertainty in prevalence of unsuspected mutations it was also recommended that it is neither appropriate nor currently cost-effective to test 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.

A complete clinical work-up and a specialized genetic consultation was recommended as vitally important to ascertain any family history, outline potential repercussions of genetic testing and obtain appropriate informed consent. Since hereditary tumors usually occur at a younger age than sporadic tumors, age at presentation was recognized as an important factor to consider when deciding to test for disease-causing genes. Findings that at least 36% of pheochromocytomas or paragangliomas in children occur secondarily to germline mutations underscore the potential importance of genetic testing in pediatric patients with these tumors.

Apart from the obvious clinical manifestations that may indicate a specific hereditary syndrome (e.g. medullary thyroid cancer in patients with MEN 2), it was further recommended that the decision to test a particular gene should take into consideration tumor location, the presence of metastases and the type of catecholamine produced by tumors. Although mutations of 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. Testing for SDHD and SDHB gene mutations in patients with extra-adrenal tumors can therefore be particularly revealing; furthermore, because SDHB mutations carry a high risk for malignant disease, testing for such mutations in patients with metastases, especially from an extra-adrenal paraganglioma, is particularly warranted. [recommendation]
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Pheochromocytomas are neuroendocrine tumors derived from catecholamine-producing chromaffin cells of the adrenal medulla, whereas extra-adrenal paragangliomas arise from chromaffin cells of the extra-adrenal paraganglia (a pheochromocytoma is an intra-adrenal paraganglioma).

It was agreed to adopt the 2004 WHO classification of endocrine tumors where pheochromocytomas are defined as tumors arising from catecholamine-producing chromaffin cells in the adrenal medulla. According to this classification, closely related tumors of extra-adrenal sympathetic and parasympathetic paraganglia are classified as extra-adrenal paragangliomas. The recommendation to adopt this simplified definition was based on the need for international standardization. However, as long as the histopathological and clinical entities are well-defined and accounted for, for purposes of genetic testing the two types of tumors should often be considered together because they often have a common genetic basis. [recommendation]

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Management Details

All patients with a biochemically positive pheochromocytoma or paraganglioma should receive appropriate preoperative medical management to block the effects of released catecholamines.

The high variability in the clinical presentation of pheochromocytoma make it unlikely that any single medical management or treatment strategy will be optimal for every patient. Because of this and in light of varying practices and international differences in available or approved therapies, and without evidence-based studies comparing different therapies, there was no specific recommendation about preferred drugs for preoperative blockade. Nevertheless, it was recommended that preoperative administration of antihypertensive drugs was a prudent consideration for all patients with catecholamine-producing pheochromocytomas and paragangliomas. This recommendation is regardless of whether patients may be normotensive and asymptomatic, as may be the situation in some patients presenting with an incidentaloma or where a pheochromocytoma is diagnosed during routine periodic screening because of a hereditary predisposition. The only exceptions might be tumors that do not produce or contain norepinephrine or epinephrine (e.g., non-functional head and neck paragangliomas, tumors that solely produce dopamine). [recommendation]
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All patients should receive appropriate follow-up after surgical resection of a pheochromocytoma or paraganglioma.

Because of possible remaining or recurrent disease and since it is currently impossible to accurately predict malignant potential of a resected tumor, it was recommended that all patients should receive appropriate follow-up after surgical resection of a pheochromocytoma or paraganglioma. Follow-up should include repeat biochemical testing after appropriate recovery from surgery to check for remaining disease and periodic follow-up thereafter to check for recurrent disease.

In the immediate post-operative period, patients should be monitored for 24-48 hours after surgery for cardiovascular and metabolic instability. Hypoglycemia can be a problem that should be promptly diagnosed and treated by infusion of 5% glucosedextrose. There was general agreement that biochemical testing should be repeated after about 14 days from surgery in order to check for remaining disease. If results of biochemical tests are entirely normal, resection is probably complete and those patients with sporadic disease are likely cured. Importantly, however, normal post-operative biochemical test results do not exclude remaining microscopic disease so that regular follow-up to check for recurrences remains necessary. It is therefore misleading to inform patients who have undergone a successful resection that they are cured. There were no specific recommendations about the frequency and duration of long-term follow-up, which may depend on relative likelihood of recurrent or metastatic disease. For example, annual biochemical testing throughout life can be especially important for extra-adrenal or large (> 5 cm) adrenal tumors where there is higher risk of malignancy. However, since there is currently no method based on pathological examination of a resected tumor to establish potential for malignancy or recurrence, long-term periodic follow-up currently remains important for all cases of pheochromocytoma or paraganglioma. [recommendation]
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Concerted efforts are required to identify new targets for treatment of metastatic pheochromocytoma and set up multicenter clinical trials to examine and compare existing and new therapies.

Although several therapeutic options exist for patients with metastatic pheochromocytoma, all are limited and there is no cure. Because of this and the lack of suitably sized, evidence-based trials, no recommendations were reached about optimal therapies to treat malignant pheochromocytoma. Instead, it was recommended that concerted efforts are required to identify new targets for treatment of metastatic pheochromocytoma. Additionally well organized and coordinated multicenter clinical trials should be set up to examine and compare existing and new therapies.

As a step towards realization of the first goal, a database of gene expression profiles in different forms of pheochromocytoma - including metastases and primary tumors from which metastases developed - was made available to PRESSOR members at ISP2005. [recommendation]

Pathology Details

The principal objectives of the pathology examination are to distinguish primary or metastatic pheochromocytomas and extra- adrenal paragangliomas from other types of tumors and to identify features suggestive malignancy or hereditary disease. The pathologist also plays a critical role in tissue procurement, assuring that appropriate samples are procured and that sampling does not compromise assessment of the specimen for purposes of patient care.

It is currently agreed that the only definitive criterion for malignancy is the presence of metastases. However, some evidence suggests that multifactorial analyses may help to identify tumors that pose a significant risk of metastasis. Several formal scoring systems that derive numerical grades based on invasion, histological growth patterns, cytological features, mitotic activity and other characteristics have been proposed. There was no consensus on the adoption of a formal scoring system, but it was recommended that reporting of pathology specimens conform to templates or checklists for minimal standard reporting endorsed by pathology associations. The templates list the major elements of the proposed scoring systems and permit reporting of additional optional elements. Recommendations for reporting of pheochromocytomas and extra-adrenal paragangliomas are available on the website of the Association of Directors of Anatomic and Surgical Pathology (ADASP) of the United States (www.adasp.org). The website of the Royal College of Pathologists of the United Kingdom (http://www.rcpath.org/) provides a more detailed synoptic reporting template, as well as excellent instructions for gross and microscopic examinations of the specimens and their rationale (Royal College of Pathology "Standards and Datasets for Reporting Cancers").

Clues to the presence of hereditary disease that must be documented include multicentricity or the presence of accompanying adrenal medullary hyperplasia (the latter most often seen in MEN2). However, they are not always present. Specific morphological findings recently been reported in association with VHL disease may also be inconsistent. [recommendation]