Catecholamines in neuroblastoma: Driver of hypertension, or solely a marker of disease?

Abstract Background Neuroblastoma is a common solid tumor of childhood and is often associated with hypertension. Potential etiologies contributing to hypertension include renal compression, pain, volume overload, and catecholamine secretion. Cases We completed a single center retrospective review of children with neuroblastoma and ≥stage II hypertension (per Hypertension Canada guidelines) over a 2‐year period. All patients (n = 10) had elevated urine normetanephrine levels and eight had intra‐abdominal tumors. Four patients had refractory hypertension requiring > three agents, of which three required alpha/beta blockade. Conclusion Although multifactorial, hypertension in neuroblastoma often has a neuroendocrine component. Excess normetanephrine production in neuroblastoma may be a more common hypertensive mechanism than previously appreciated. Urinary normetanephrine elevation could suggest potential neuroendocrine‐mediated hypertension.


| INTRODUCTION
Neuroblastoma is the most common extracranial solid tumor of infancy. 1 Tumors arise from the post-ganglionic sympathetic nervous system and often present with a suprarenal mass. Patients with high-risk disease often present with irritability, pain, cytopenias, and fever. 2,3 A number of reports describe severe hypertension associated with neuroblastoma. 2,[4][5][6][7][8][9][10][11] Patients may have transient hypertension, which can be exacerbated by induction of anesthesia or intraoperative tumor manipulation. [6][7][8][9][10][11] Others may develop refractory hypertension around the time of administration of chemotherapy. Therapeutic 131 I-metaiodobenzylguanidine (MIBG) can also precipitate hypertension. 10 Hypertension is often attributed to renin-mediated effect when renal artery or parenchymal compression is present. [11][12][13] Obstruction of urinary flow may also result in hypertension. Marrow involvement can cause pain and chemotherapy treatment protocols often include hyperhydration, both of which may exacerbate hypertension. 14,15 Excess catecholamine production in neuroblastoma can directly elevate blood pressure (BP). 16 Urinary vanillylmandelic acid (VMA) and homovanillic acid (HVA) levels are routinely assessed at the diagnosis of neuroblastoma and are elevated in 90%-95% of patients. 17,18 However, baseline normetanephrine levels are not consistently assessed in standard protocols, despite being excreted by neuroblastoma and being associated with hypertension. 16,19 We review the etiology, management and outcome of neuroblastoma-associated hypertension in a cohort of pediatric patients.

| METHODS
Following research ethics board approval, we identified all children (<18 years) diagnosed with neuroblastoma and stage II hypertension (per Hypertension Canada guidelines) treated at a tertiary care pediatric center over 2 years (2015-17). 20 Cases were reviewed retrospectively. No explicit exclusion criteria were used. Collected data included demographics, tumor location/INRG stage, evidence for renal compression and Children's Oncology Group (COG) risk group, as well as hypertension severity, sequelae and duration. Maximal systolic blood pressure (n = 9; SBP) or maximal mean arterial pressure in a neonate (n = 1; MAP) was reported as Z-score for height, sex, and age. 21,22 Patients were reported as hypertensive with BP >95th centile on ≥ two occasions in each 24-h period. Estimated glomerular filtration rate (eGFR) was calculated via Schwartz formula. 23 Spot urine VMA, HVA, and normetanephrines were collected at baseline for all patients, and reported referenced to the upper limit of reference range (ULRR). The majority (70%) had urine metanephrines collected concurrently. Thereafter, catecholamine surveillance was variable; some patients had no further monitoring.  (Table S1). Urinary metanephrine and epinephrine levels were normal, when measured. Renin was measured in four patients (40%) and was normal in all cases.
One of eight patients (12.5%) who received chemotherapy had >10 mmHg SBP increase in the 48 h following initiation of therapy. This patient was one of six who had hyperhydration for cyclophosphamide in cycle one. Three of nine patients who underwent tumor manipulation (33%) had >10 mmHg SBP increase in the 48 h following intervention; one post-biopsy and two post-tumor resection. No SBP increase was noted in the other six. One patient developed hypertension following anesthesia induction for imaging. One patient who was normotensive during tumor manipulation had prior alpha/beta blockade.
Seven patients required anti-hypertensive treatment. (Table 2) Five required therapy for > 1 week, and four required > three medica-   In patients with refractory hypertension (>3 agents required for control), the majority (80%) required alpha/beta blockade to achieve normotension. Alpha/beta blockade is employed in other catecholamine secreting tumors and in neuroblastoma in the peri-operative context. 25 This treatment approach mitigates alpha agonism on vascular smooth muscle and prevents "catecholamine storm" with tumor manipulation or anesthetic induction. Catecholamine-induced hypertension has been previously described as rare in neuroblastoma, with hypertension attributed more commonly to renin-mediated mechanisms in some case series. 11,13 In contrast, alpha/beta blockade was essential for hypertensive control of refractory hypertension in our series, suggesting that catecholamines play an important role in this patient subset.
There are several clinical implications to these data. Excess normetanephrine production in neuroblastoma may be a more common hypertensive mechanism than previously appreciated.
Urinary normetanephrine elevation should suggest potential neuroendocrine-mediated hypertension. This has important implications for secondary hypertension risk stratification and management.

CONFLICT OF INTEREST
The authors have stated explicitly that there are no conflicts of interest in connection with this article.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on reasonable request to the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

ETHICS STATEMENT
This project received institutional ethics approval from the University

CONSENT STATEMENT
Prior informed consent was not obtained as the research ethics board determined this project met criteria for a minimal risk study and approved a waiver for informed consent.