Page 2 - Long-term surveillance following resection of pheochromocytoma

BPR: Pheochromocytoma followup

Surgery: Pheochromocytoma tion of a hereditary syndrome allows for earlier diagnosis
confirmed on pathology and treatment of pheochromocytomas and other syndromic
manifestations in relatives.
Positive Disease-specific followup
Referral for genetic counselling
recommendations
Recommendation 1: We recommend all patients with
PPGLs be considered for referral for genetic testing (Strong
Repeat urine/plasma Positive Imaging to rule out tumor
metanephrines after surgery persistence/metastasis recommendation, Moderate-quality evidence).
Negative
Annual surveillance with Positive Imaging to rule out Perioperative workup
urinary/plasma metanephrines recurrence
Traditionally, biochemical testing for pheochromocytomas
Low-risk patient High-risk patient
was done by measurements of urine cathecolamines, often
Followup for at Consider lifelong in conjunction with catecholamine metabolites, such as van-
least 10 years followup
illylmandelic acid and metanephrines. Advances in assay
Fig. 1. Algorithm for followup of pheochromocytoma. technology and our understanding of catecholamine metab-
olism have led to a newer emphasis on measurements of
community. Therefore, recommendations from this guideline urine and plasma metanephrines, including normetaneph-
were endorsed or adapted to a Canadian urology context. rine and metanephrine, as well as methoxytyramine, a dopa-
Of the 11 recommendations from the European Society of mine metabolite. Compared to cathecolamines, measure-
Endocrinology, two were excluded, as they were deemed not ment of metanephrines is advantageous in detecting tumors
applicable and beyond the scope of our review; four were that release catecholamines, episodically in low amounts,
adopted with modifications to better suit a Canadian urolo- and they are a more specific marker for catecholamine pro-
gist’s context; and five were adopted without modification. duced in chromaffin cells and associated tumors. 12
Other statements were based on a systematic review of the Lenders et al provided early evidence that plasma-free
literature and one clinical principle was added. metanephrines had a superior diagnostic sensitivity and
equivalent specificity compared to the other tests. This
13
Recommendations was supported by a larger National Institutes of Health multi-
center cohort study published in 2002 involving over 800
patients, which compared plasma metanephrines vs. plasma
Genetic testing catecholamines, urinary cathetholamines, urinary total and
fractionated metanephrines, and urinary vanillylmandelic
14
Pheochromocytomas and paragangliomas (PPGLs) carry a acid. They reported a sensitivity of 99% for plasma-free
higher degree of heritability than most solid tumors. In the metanephrines vs. a sensitivity of 64–97% for the other bio-
past 15 years, germline mutations in a dozen genes have chemical tests. The specificity of plasma-free metanephrines
been identified and it is estimated that approximately 40% of was 89%. Given these findings, they concluded that plasma-
patients carry a causal germline mutation. Hereditary disease free metanephrines provided the best test for excluding or
linked with pheochromocytomas include neurofibromatosis confirming pheochromocytoma. There have been multiple
type 1 (caused by mutations in NF1), multiple endocrine subsequent studies confirming the high diagnostic accuracy
neoplasia type 2 (MEN2; linked with mutations in RET), for plasma-free metanephrines.
von Hippel-Lindau disease (associated with mutations in In 2007, Perry et al showed that urine fractionated
VHL), hereditary paraganglioma (caused by mutations in the metanephrines measured by mass spectrometry provided
SDHx group of genes [SDHA, SDHB, SDHC, SDHD, and a sensitivity of 97% and specificity of 91% for the diag -
SDHAF2]), familial pheochromocytoma (caused by muta- nosis of pheochromocytomas and paragangliomas, results
tions in TMEM127 or MAX), polycythemia paraganglioma comparable to those reported of plasma metanephrines in
syndrome (associated with mutations in EPAS1 [also known other studies. There has not been a direct comparison of
15
as HIF2A]) or hereditary leiomyomatosis and renal cell can- plasma metanephrines vs. urinary fractionated metaneph-
cer syndrome (linked with mutations in FH). 11 rines measured by mass spectrometry, and thus it remains
Identification of an underlying mutation is critical in unclear if one test is superior to the other. It is important to
guiding patient management and genetic counselling. For highlight that these studies have been done in the diagnostic
example, patients with mutations in SDHB can develop par- phase (i.e., pre-resection) and have been extrapolated to be
ticularly aggressive and rapidly progressing pheochromocy- accurate in the setting of monitoring for disease recurrence.
tomas/paragangliomas, as well as other renal cancers and In patients with elevated metanephrines preoperatively,
gastrointestinal stromal tumours. Furthermore, identifica- metanephrine determinations should be repeated postopera-
11

CUAJ • December 2019 • Volume 13, Issue 12 373