Perioperative Management of Pheochromocytomas and Sympathetic Paragangliomas

Gustavo F. C. Fagundes; Madson Q. Almeida

J Endo Soc. 2022;6(2)

Abstract and Introduction

Abstract

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors arising from chromaffin cells of the adrenal medulla or extra-adrenal paraganglia, respectively. PPGLs have the highest degree of heritability among endocrine tumors. Currently, ~40% of individuals with PPGLs have a genetic germline and there are at least 12 different genetic syndromes related to these tumors. Metastatic PPGLs are defined by the presence of distant metastases at sites where chromaffin cells are physiologically absent. Approximately 10% of pheochromocytomas and ~40% of sympathetic paragangliomas are linked to metastases, explaining why complete surgical resection is the first-choice treatment for all PPGL patients. The surgical approach is a high-risk procedure requiring perioperative management by a specialized multidisciplinary team in centers with broad expertise. In this review, we summarize and discuss the most relevant aspects of perioperative management in patients with pheochromocytomas and sympathetic paragangliomas.

Introduction

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors arising from chromaffin cells of the adrenal medulla (pheochromocytomas, 80%-85%) or extra-adrenal paraganglia (paragangliomas, 15%-20%), respectively.^[1] PPGLs have the highest heritability among endocrine tumors.^[2] Currently, about 40% of individuals with PPGLs have a genetic germline mutation and at least 12 different genetic syndromes are related to these tumors.^[3,4] This genetic diversity is more relevant in guiding a personalized approach in patients with PPGLs.

Metastatic PPGLs (mPPGLs) are defined by the presence of tumor in nonchromaffin tissues.^[5] About 10% to 20% of the patients with PPGLs develop metastatic disease.^[6] Due to its high malignant potential, curative surgical resection should be offered to all patients with localized disease. However, surgery is a high-risk procedure requiring perioperative management by a specialized multidisciplinary team in centers with broad expertise.^[7,8] Improving the clinical management, surgical techniques, and anesthetic support dropped the mortality rate of functioning PPGL surgery to around 0% to 2.9%.^[7,9,10] In this review, we summarize and discuss the most relevant aspects of perioperative management in patients with pheochromocytomas and sympathetic paragangliomas.

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Table 1. Genetic, biochemical, and clinical characterization of the 3 main clusters of pheochromocytomas and paragangliomas
Molecular pathway	Genes	Mutation type	Metastatic risk	Tumor location	Biochemical profile	Other manifestations
Cluster pseudohypoxia 1A	SDHA	G, S	Moderate	TA PGL	N/D	GIST
	SDHB	G, S	High	TA PGL	N/D	GIST and RCC
	SDHC	G, M, S	Low	HN PGL	N/D	GIST
	SDHD	G, S	Moderate	HN PGL	N/D	GIST and pituitary adenomas
	SDHAF2	G	?	HN PGL	N	NR
	FH	G	High	PHEO/TA PGL	N	Uterine leiomyoma
	DLST	G	Low	TA PGL	N	NR
	MDH2	G	High	TA PGL	N	Early-onset severe encephalopathy
	SLC25A11	G	High	TA PGL	N	NR
*Cluster* Pseudohypoxia 1B	VHL	G, M, S	Low	PHEO	N	Hemangioblastoma, RCC, pancreatic neuroendocrine tumors, retinal angiomas, testicular tumors
	EPAS1	M, S	High	TA PGL	N	Polycythemia, somatostatinoma, retinal abnormalities, organ cysts (Pacak-Zhuang syndrome)
	EGLN1/2	G	?	TA PGL	N	NR
Cluster 2 Receptor kinase signaling	RET	G, S	Low	PHEO	A	Medullary thyroid carcinoma, parathyroid adenoma
	NF1	G, M, S	Moderate	PHEO	A	Cafe-au-lait spots, Lisch nodules in the eye, neurofibromas
	MAX	G, S	Low	PHEO	N/A	Renal oncocytoma; rarely RCC
	TMEM127	G	Low	PHEO	N/A	RCC
	HRAS	S	Low	PHEO	A	Congenital anomalies (Costello syndrome)
	KIF1B	G, S	?	PHEO	A	NR
	MET	S	?	PHEO	A	NR
	FGFR1	S	?	PHEO	A	NR
	ATRX	S	High	NR	?	NR
	H3F3A	M	?	PHEO	N/A	NR
Cluster 3 Wnt signaling	CSDE1	S	High	PHEO/TA PGL	N/A	NR
	MAML3	S	High	PHEO	N/A	NR

Abbreviations: A, adrenergic; D, dopaminergic; G, germline; GIST, Gastrointestinal stromal tumor; HN, head and neck; M, mosaicism; N, noradrenergic; NR, not reported; PGL, paraganglioma; PHEO, pheochromocytoma; RCC, Renal cell carcinoma; S, somatic; TA, thoracic and abdominal.

Table 2. Trigger factors of catecholaminergic crisis
Drug class	Examples of drugs
Anesthetics	Succinylcholine, pancuronium, halothane, ketamine
Antidepressants	Amitriptyline, nortriptyline bupropion, duloxetin, paroxetine, fluoxetine
Unopposed ß-blockers	Propranolol, metoprolol
Dopamine-2 antagonists	Metoclopramide, haloperidol, olanzapine, chlorpromazine
Opioid analgesics	Morphine, tramadol
Peptide hormones	Glucagon
Sympathomimetics	Ephedrine, amphetamine, sibutramine, phentermine

Table 3. Preoperative main medication dosages
Drug Class	Dosages
Alfa-blockers
Phenoxybenzamine	10–120 mg/day
Doxazosin	2–32 mg/day
Calcium channel blockers
Nicardipine	60–120 mg/day
Nifedipine	30–60 mg/day
Amlodipine	5–10 mg/day
Tyrosine hydroxylase inhibitor
Metyrosine	250–4000 mg/day
Beta-blockers
Propanolol	60–120 mg/day
Atenolol	25–100 mg/day
Metoprolol	25–100 mg/day

Table 4. Follow-up after surgical tumor resection according to genetic diagnosis
Genetic diagnosis	Biochemical screening	Imaging
Unknown/sporadic disease	Plasma free metanephrine and normetanephrine annually	Abdominal MRI and/or from initial tumor location every 1–2 years
VHL mutation	Plasma free metanephrine and normetanephrine annually	Annually abdominal MRI and optic fundus examination; CNS MRI every 2–3 years
RET mutation	Plasma free metanephrine and normetanephrine annually, calcitonin, and serum calcium annually	Annually abdominal MRI
SDHx mutation	Plasma free metanephrine and normetanephrine annually; Plasma or urinary 3-methoxytyramine, if elevated before surgery	MRI of the first tumor location annually for 1–3 years; MRI of body areas that had no tumors (eg, head and neck) every 2–3 years