Pheochromocytoma: A Genetic and Diagnostic Update

Leilani B. Mercado-Asis, MD, PhD, MPH; Katherine I. Wolf; Ivana Jochmanova, MD; David Taïeb, MD


Endocr Pract. 2018;24(1):78-90. 

In This Article

Developments in the Biochemical Evaluation of PPGL

Upon clinical suspicion of PPGL, biochemical evaluation using plasma and urinary catecholamines and their O-methylated metabolites, metanephrines (MNs), should be initiated to confirm diagnosis.[3,37] Proper adherence to suggested guidelines is paramount in collecting evidence of inappropriate catecholamine production.[45] Despite recent debate, numerous studies have confirmed that lying supine at rest for 20 minutes prior to blood collection prevents false-positive results due to postural-related stimulus of norepinephrine secretion.[28,46,47] Interference is also seen with tricyclic antidepressants; phenoxybenzamine; cigarette smoking; caffeine intake; and consumption of catecholamine-rich foods such as fruits, nuts, cheese, and alcohol.[3,48,49] Discontinuing the above medications and substances 24 hours prior to blood draw will help increase the diagnostic sensitivity and limit inappropriate disease exclusion due to false-negative test results.

Eisenhofer et al recently revealed that an optimized curvilinear model with age-adjusted cut-offs for the upper reference limit of NMN improved diagnostic performance with a significant increase in specificity (93.4%) and a nonsignificant loss in sensitivity (93.7%), compared to the 97.5 percentiles of the reference population, 88.3% and 93.9%, respectively.[47] While positive correlations between MN concentration and age were likewise discovered, the upper reference limits only deviated 30% across various age groups. However, with a single adjustment of the upper reference limit of MN from 0.325 to 0.446 nmol/L, the diagnostic specificity increased from 88.3% to 96.0%.[47]

The latest reports suggest that age is not the only significant factor requiring reference range adjustment for early and accurate tumor identification. After a uni- or bilateral adrenalectomy, epinephrine is expected to decrease, which will in turn decrease the MN plasma concentration.[50] Osinga et al discovered that epinephrine does decrease following adrenalectomies, but norepinephrine increases. Thus, an upward adjustment is required for the reference value of norepinephrine, while a downward adjustment is necessary for the MN reference intervals to properly detect recurrent disease and prevent unnecessary exposure to radiation with anatomical or functional imaging.[50]

In addition to plasma and urinary catecholamines and MNs, 3-methoxytyramine, the O-methylated dopamine metabolite, can aid in the identification of exclusively dopamine-secreting tumors, which often occur with an asymptomatic clinical presentation.[51] Seventy-two percent of patients with SDHB mutations and 67% of patients with an SDHD mutation had elevated 3-methoxytyramine compared to 39% for NFI and MEN2, and just 17% for VHL-associated tumors.[52] Furthermore, in 2012, Eisenhofer et al reported that 3-methoxytyramine was also significantly elevated in patients with metastases even in the absence of an SDHB mutation, and also in patients with metastatic disease secondary to adrenal tumors.[37] Therefore, along with previously identified metastatic risk factors such as the presence of an SDHB mutation, a tumor diameter greater than 5 cm, and extra-adrenal lesion locations, 3-methoxytyramine is considered a novel biomarker indicating the likelihood of malignancy.[37]

In most countries, laboratories may be unable to measure plasma and urinary catecholamines, MNs, and 3-methoxtyramine. Specialized research centers may be required to perform the most complete and accurate biochemical testing until widespread availability is achieved. Institutional differences in biochemical reference rages and techniques are important to note, indicating that direct laboratory comparisons from various centers should be avoided.