New Clinical Practice Guidelines on Pheochromocytomas

CHICAGO – Genetic testing has jumped to the fore in the management of patients diagnosed as having a pheochromocytoma or paraganglioma, according to new clinical practice guidelines released by the Endocrine Society.

Indeed, the new guidelines call for genetic testing to be considered seriously in all patients with a proven pheochromocytoma or paraganglioma (PPGL), Dr. Jacques W. M. Lenders said in presenting highlights of the new guidelines at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.

"We recommend that all patients with PPGLs should be engaged in shared decision making for genetic testing. I don’t say that we should do genetic testing in everybody, but we should consider it and engage the patient in the final decision," said Dr. Lenders, who chaired the practice guidelines task force.

The strong emphasis on genetic testing arises from evidence that roughly one-third of all PPGLs are associated with germline mutations. Moreover, susceptibility mutations are present in 12% of patients with absolutely no suggestion of a positive family history. Some of these mutations – for example, those involving succinate dehydrogenase B (SDHB) – are associated with a high risk of metastasis and unfavorable prognosis. Thus, gene-testing results can have a major impact on patients with PPGL as well as their relatives.

Nonetheless, genetic testing in patients with PPGLs remains controversial.

"I must say, we on the guideline task force spent considerable time on what and how to do it," said Dr. Lenders, who is professor and deputy chair of internal medicine at Radboud University in Nijmegen, the Netherlands.

Since simultaneous testing for all the known culprit genes remains for now too expensive to be cost effective, the guidelines include a clinical feature–driven decisional algorithm designed to establish the priorities for genetic testing in a given patient with proven PPGL.

For example, patients with a metastatic PPGL should be tested for SDHB mutations, while those with a paraganglioma should undergo testing for succinate dehydrogenase mutations, according to the guidelines, published in full in concert with ICE/ENDO 2014 (J. Clin. Endocrinol. Metab. 2014;1915-42).

Dr. Lenders noted that PPGLs are uncommon tumors. It is estimated that 0.1%-1% of patients being treated for hypertension have pheochromocytomas, which are adrenal tumors resulting in excess production of epinephrine and norepinephrine. Symptoms can include paroxysmal severe headache, tachycardia, anxiety, and excessive sweating, along with tough-to-control hypertension.

While pheochromocytomas are typically benign, malignant transformation occurs in up to 17% of cases. And although a complete cure is often possible with timely therapy, the fact is that on average a 3-year delay transpires between symptomatic presentation and diagnosis of PPGL. Also, studies show that failure to appropriately follow up on a positive biochemical test is common in clinical practice; as a consequence, PPGLs are often overdiagnosed. For these reasons, Endocrine Society officials deemed PPGLs a priority area in need of practice guidelines.

In addition to routine consideration of genetic testing, other recommendations include:

• Diagnostic biochemical testing: Initial testing should include measurement of plasma free or urinary fractionated metanephrines, preferably using liquid chromatography with electrochemical or mass spectrometric laboratory methods. Immunoassays, although popular in Europe, haven’t yet been adequately validated. In measuring plasma metanephrines, the blood draw should be done with the patient in supine position, using reference standards established in the same position.

"False-positive test results are a major problem in daily clinical practice, and they outweigh by far the number of true-positive test results. That’s very important to realize," the endocrinologist said.

One common cause of false-positive test results are medications that trigger elevated metanephrine levels, according to guideline panelist Dr. William F. Young Jr., professor of medicine and chair of the department of endocrinology, diabetes, metabolism and nutrition at the Mayo Clinic, Rochester, Minn. The top three offending drugs in his experience are tricyclic antidepressants, antipsychotic agents, and levodopa. The guidelines list others, he added.

• Imaging: Once clear biochemical evidence of a PPGL is established, CT is preferred over MRI in order to locate the tumor because of its superior spatial resolution in the thorax, abdomen, and pelvis. ¹⁸F-fluorodeoxyglucose positron emission tomography/CT scanning is preferred over ¹²³I-metaiodobenzylguanidine (MIBG) scintigraphy in patients with known metastatic PPGL. ¹²³I-MIBG is best reserved for functional imaging in patients with metastatic PPGL who are being considered for radiotherapy using ¹³¹I-MIBG, in patients with an unusually large primary tumor, and in other special circumstances.

• Perioperative medical management: Preoperative blockade with an alpha-adrenergic–receptor blocker beginning 7-14 days before surgery is recommended together with a high-sodium diet and increased fluid intake as the best means of reducing the risk of perioperative cardiovascular problems.

• Surgery: Minimally invasive adrenalectomy is appropriate for most pheochromocytomas; open resection is best reserved for those tumors which are invasive or greater than 6 cm in size. The guidelines recommend open resection for paragangliomas, although laparoscopic surgery is described as reasonable for those which are small, noninvasive, and favorably located. Partial adrenalectomy is advised for patients with a hereditary pheochromocytoma and in other special circumstances.

• Team approach: Because PPGLs are uncommon, they are best managed by multidisciplinary teams at centers of expertise. That’s particularly important in nonstraightforward cases, such as those involving pregnancy, metastasis, diagnostic uncertainty, or surgical complexity, according to the guideline panelists.

All Endocrine Society clinical practice guidelines are funded by the society without any corporate support. Dr. Lenders reported having no financial conflicts.

[email protected]

CHICAGO – Genetic testing has jumped to the fore in the management of patients diagnosed as having a pheochromocytoma or paraganglioma, according to new clinical practice guidelines released by the Endocrine Society.

Indeed, the new guidelines call for genetic testing to be considered seriously in all patients with a proven pheochromocytoma or paraganglioma (PPGL), Dr. Jacques W. M. Lenders said in presenting highlights of the new guidelines at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.

"We recommend that all patients with PPGLs should be engaged in shared decision making for genetic testing. I don’t say that we should do genetic testing in everybody, but we should consider it and engage the patient in the final decision," said Dr. Lenders, who chaired the practice guidelines task force.

The strong emphasis on genetic testing arises from evidence that roughly one-third of all PPGLs are associated with germline mutations. Moreover, susceptibility mutations are present in 12% of patients with absolutely no suggestion of a positive family history. Some of these mutations – for example, those involving succinate dehydrogenase B (SDHB) – are associated with a high risk of metastasis and unfavorable prognosis. Thus, gene-testing results can have a major impact on patients with PPGL as well as their relatives.

Nonetheless, genetic testing in patients with PPGLs remains controversial.

"I must say, we on the guideline task force spent considerable time on what and how to do it," said Dr. Lenders, who is professor and deputy chair of internal medicine at Radboud University in Nijmegen, the Netherlands.

Since simultaneous testing for all the known culprit genes remains for now too expensive to be cost effective, the guidelines include a clinical feature–driven decisional algorithm designed to establish the priorities for genetic testing in a given patient with proven PPGL.

For example, patients with a metastatic PPGL should be tested for SDHB mutations, while those with a paraganglioma should undergo testing for succinate dehydrogenase mutations, according to the guidelines, published in full in concert with ICE/ENDO 2014 (J. Clin. Endocrinol. Metab. 2014;1915-42).

Dr. Lenders noted that PPGLs are uncommon tumors. It is estimated that 0.1%-1% of patients being treated for hypertension have pheochromocytomas, which are adrenal tumors resulting in excess production of epinephrine and norepinephrine. Symptoms can include paroxysmal severe headache, tachycardia, anxiety, and excessive sweating, along with tough-to-control hypertension.

While pheochromocytomas are typically benign, malignant transformation occurs in up to 17% of cases. And although a complete cure is often possible with timely therapy, the fact is that on average a 3-year delay transpires between symptomatic presentation and diagnosis of PPGL. Also, studies show that failure to appropriately follow up on a positive biochemical test is common in clinical practice; as a consequence, PPGLs are often overdiagnosed. For these reasons, Endocrine Society officials deemed PPGLs a priority area in need of practice guidelines.

In addition to routine consideration of genetic testing, other recommendations include:

• Diagnostic biochemical testing: Initial testing should include measurement of plasma free or urinary fractionated metanephrines, preferably using liquid chromatography with electrochemical or mass spectrometric laboratory methods. Immunoassays, although popular in Europe, haven’t yet been adequately validated. In measuring plasma metanephrines, the blood draw should be done with the patient in supine position, using reference standards established in the same position.

"False-positive test results are a major problem in daily clinical practice, and they outweigh by far the number of true-positive test results. That’s very important to realize," the endocrinologist said.

One common cause of false-positive test results are medications that trigger elevated metanephrine levels, according to guideline panelist Dr. William F. Young Jr., professor of medicine and chair of the department of endocrinology, diabetes, metabolism and nutrition at the Mayo Clinic, Rochester, Minn. The top three offending drugs in his experience are tricyclic antidepressants, antipsychotic agents, and levodopa. The guidelines list others, he added.

• Imaging: Once clear biochemical evidence of a PPGL is established, CT is preferred over MRI in order to locate the tumor because of its superior spatial resolution in the thorax, abdomen, and pelvis. ¹⁸F-fluorodeoxyglucose positron emission tomography/CT scanning is preferred over ¹²³I-metaiodobenzylguanidine (MIBG) scintigraphy in patients with known metastatic PPGL. ¹²³I-MIBG is best reserved for functional imaging in patients with metastatic PPGL who are being considered for radiotherapy using ¹³¹I-MIBG, in patients with an unusually large primary tumor, and in other special circumstances.

• Perioperative medical management: Preoperative blockade with an alpha-adrenergic–receptor blocker beginning 7-14 days before surgery is recommended together with a high-sodium diet and increased fluid intake as the best means of reducing the risk of perioperative cardiovascular problems.

• Surgery: Minimally invasive adrenalectomy is appropriate for most pheochromocytomas; open resection is best reserved for those tumors which are invasive or greater than 6 cm in size. The guidelines recommend open resection for paragangliomas, although laparoscopic surgery is described as reasonable for those which are small, noninvasive, and favorably located. Partial adrenalectomy is advised for patients with a hereditary pheochromocytoma and in other special circumstances.

• Team approach: Because PPGLs are uncommon, they are best managed by multidisciplinary teams at centers of expertise. That’s particularly important in nonstraightforward cases, such as those involving pregnancy, metastasis, diagnostic uncertainty, or surgical complexity, according to the guideline panelists.

All Endocrine Society clinical practice guidelines are funded by the society without any corporate support. Dr. Lenders reported having no financial conflicts.

[email protected]

CHICAGO – Genetic testing has jumped to the fore in the management of patients diagnosed as having a pheochromocytoma or paraganglioma, according to new clinical practice guidelines released by the Endocrine Society.

Indeed, the new guidelines call for genetic testing to be considered seriously in all patients with a proven pheochromocytoma or paraganglioma (PPGL), Dr. Jacques W. M. Lenders said in presenting highlights of the new guidelines at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.

"We recommend that all patients with PPGLs should be engaged in shared decision making for genetic testing. I don’t say that we should do genetic testing in everybody, but we should consider it and engage the patient in the final decision," said Dr. Lenders, who chaired the practice guidelines task force.

The strong emphasis on genetic testing arises from evidence that roughly one-third of all PPGLs are associated with germline mutations. Moreover, susceptibility mutations are present in 12% of patients with absolutely no suggestion of a positive family history. Some of these mutations – for example, those involving succinate dehydrogenase B (SDHB) – are associated with a high risk of metastasis and unfavorable prognosis. Thus, gene-testing results can have a major impact on patients with PPGL as well as their relatives.

Nonetheless, genetic testing in patients with PPGLs remains controversial.

"I must say, we on the guideline task force spent considerable time on what and how to do it," said Dr. Lenders, who is professor and deputy chair of internal medicine at Radboud University in Nijmegen, the Netherlands.

Since simultaneous testing for all the known culprit genes remains for now too expensive to be cost effective, the guidelines include a clinical feature–driven decisional algorithm designed to establish the priorities for genetic testing in a given patient with proven PPGL.

For example, patients with a metastatic PPGL should be tested for SDHB mutations, while those with a paraganglioma should undergo testing for succinate dehydrogenase mutations, according to the guidelines, published in full in concert with ICE/ENDO 2014 (J. Clin. Endocrinol. Metab. 2014;1915-42).

Dr. Lenders noted that PPGLs are uncommon tumors. It is estimated that 0.1%-1% of patients being treated for hypertension have pheochromocytomas, which are adrenal tumors resulting in excess production of epinephrine and norepinephrine. Symptoms can include paroxysmal severe headache, tachycardia, anxiety, and excessive sweating, along with tough-to-control hypertension.

While pheochromocytomas are typically benign, malignant transformation occurs in up to 17% of cases. And although a complete cure is often possible with timely therapy, the fact is that on average a 3-year delay transpires between symptomatic presentation and diagnosis of PPGL. Also, studies show that failure to appropriately follow up on a positive biochemical test is common in clinical practice; as a consequence, PPGLs are often overdiagnosed. For these reasons, Endocrine Society officials deemed PPGLs a priority area in need of practice guidelines.

In addition to routine consideration of genetic testing, other recommendations include:

• Diagnostic biochemical testing: Initial testing should include measurement of plasma free or urinary fractionated metanephrines, preferably using liquid chromatography with electrochemical or mass spectrometric laboratory methods. Immunoassays, although popular in Europe, haven’t yet been adequately validated. In measuring plasma metanephrines, the blood draw should be done with the patient in supine position, using reference standards established in the same position.

"False-positive test results are a major problem in daily clinical practice, and they outweigh by far the number of true-positive test results. That’s very important to realize," the endocrinologist said.

One common cause of false-positive test results are medications that trigger elevated metanephrine levels, according to guideline panelist Dr. William F. Young Jr., professor of medicine and chair of the department of endocrinology, diabetes, metabolism and nutrition at the Mayo Clinic, Rochester, Minn. The top three offending drugs in his experience are tricyclic antidepressants, antipsychotic agents, and levodopa. The guidelines list others, he added.

• Imaging: Once clear biochemical evidence of a PPGL is established, CT is preferred over MRI in order to locate the tumor because of its superior spatial resolution in the thorax, abdomen, and pelvis. ¹⁸F-fluorodeoxyglucose positron emission tomography/CT scanning is preferred over ¹²³I-metaiodobenzylguanidine (MIBG) scintigraphy in patients with known metastatic PPGL. ¹²³I-MIBG is best reserved for functional imaging in patients with metastatic PPGL who are being considered for radiotherapy using ¹³¹I-MIBG, in patients with an unusually large primary tumor, and in other special circumstances.

• Perioperative medical management: Preoperative blockade with an alpha-adrenergic–receptor blocker beginning 7-14 days before surgery is recommended together with a high-sodium diet and increased fluid intake as the best means of reducing the risk of perioperative cardiovascular problems.

• Surgery: Minimally invasive adrenalectomy is appropriate for most pheochromocytomas; open resection is best reserved for those tumors which are invasive or greater than 6 cm in size. The guidelines recommend open resection for paragangliomas, although laparoscopic surgery is described as reasonable for those which are small, noninvasive, and favorably located. Partial adrenalectomy is advised for patients with a hereditary pheochromocytoma and in other special circumstances.

• Team approach: Because PPGLs are uncommon, they are best managed by multidisciplinary teams at centers of expertise. That’s particularly important in nonstraightforward cases, such as those involving pregnancy, metastasis, diagnostic uncertainty, or surgical complexity, according to the guideline panelists.

All Endocrine Society clinical practice guidelines are funded by the society without any corporate support. Dr. Lenders reported having no financial conflicts.

[email protected]