The Pheochromocytoma/Paraganglioma syndrome: an overview on mechanisms, diagnosis and management

Lima Junior, José Viana; Kater, Claudio Elias

doi:10.1590/S1677-5538.IBJU.2023.0038

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REVIEW ARTICLE • Int. braz j urol 49 (3) • May-Jun 2023 • https://doi.org/10.1590/S1677-5538.IBJU.2023.0038 copy

The Pheochromocytoma/Paraganglioma syndrome: an overview on mechanisms, diagnosis and management

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Pheochromocytomas/paragangliomas (PPGL) are rare, metastatic, and potentially fatal neuroendocrine tumors, often neglected because they present symptoms similar to other prevailing clinical conditions such panic syndrome, thyrotoxicosis, anxiety, hypoglycemia, etc., delaying diagnosis and treatment. The rate of diagnosis of PPGL has been increasing with the improvement in the measurement of catecholamine metabolites and the expanding availability of imaging procedures. Its essential genetic nature has been extensively investigated, comprising more than 20 genes currently related to PPGL and more new genes will probably be revealed. This overview will shed some light on the clinical, laboratory, topographical, genetic diagnosis, and management of PPGL.

Pheochromocytoma; Paraganglioma; Metanephrine

Transcriptional signature
Cluster 1 group (10-15%)	Cluster 2 group (50-60%)	Cluster 3 group (5-10%)
Cellular response to hypoxia	Proteins that activate kinase signaling	Via Wnt
Extra-adrenal syndrome + von Hippel-Lindau	Adrenal	Adrenal + Extra-adrenal
Germline / Somatic	Germline / Somatic	Somatic
Normetanephrine / 3-Methoxytyramine (3-MT)	Normetanephrine + metanephrine or metanephrine only	Normetanephrine metanephrine / Chromogranin A
SDHD, SDHC, SDHB, SDHA, SDHA2F, VHL, HIF, FH, EGLN1 (PHD2), EGLN2 (PHD1), KIF 1β, EPAS1/2 (HIF2A), MDH2	RET, NF1, MAX, TMEM127, HRAS	CSDE1, MAML3

Gene	Syndrome	Tumor location	Rate of PPGL metastases	Association with other tumors
NF1	Neurofibromatosis type 1	Mostly adrenal (bilateral)	12%	Neurofibromas, malignant tumors of the peripheral nerve sheath, optic gliomas and leukemias
RET	Multiple endocrine neoplasia type 2	Adrenal (bilateral)	<5%	Medullary thyroid carcinoma, parathyroid adenomas/ hyperplasia
VHL	von Hippel Lindau	Mostly adrenal (bilateral)	5-8 %	Renal clear cell (RCC) carcinoma, neuroendocrine tumors of the pancreas (mostly non-functioning), CNS hemangioblastomas, endolymphatic sac tumors, pituitary adenomas
SDHA	Hereditary PGL syndrome	Any	30-60%	RCC carcinoma, gastro-intestinal stromal tumors (GIST) and pituitary adenomas
SDHB	Hereditary PGL syndrome	Any, mostly extra-adrenal	35-75%	RCC carcinoma, GIST and pituitary adenomas
SDHC	Hereditary PGL syndrome	Head and neck, can be thoracic	Low	RCC carcinoma, GIST and pituitary adenomas
SDHD	Hereditary PGL syndrome	Any, mostly head and neck	15-29%	RCC carcinoma, GIST and pituitary adenomas
SDHAF 2 (SDH5)	Hereditary PGL syndrome	Head and neck (multifocal)	Not Known	RCC carcinoma, GIST and pituitary adenoma
TMEM 127	Familial PGL syndrome	Any, mostly adrenal	Low	RCC carcinoma
MAX	Familial PGL syndrome	Mostly adrenal (bilateral)	Intermediate to high	Pituitary adenomas
EPAS1	Familial PGL syndrome, polycythemia	Any	Unknown	Somatostatinoma
FH	Hereditary leiomatosis, RCC carcinoma	Any	Possibly high	Cutaneous and uterine leiomyomas, renal papillary carcinoma
MDH2		Any	Unknown

ITEMS CONSIDERED	PASS Score
Diffuse growth pattern or in "large nests"	2
Focal or diffuse necrosis	2
High cellularity	2
Cellular monotony	2
Tumor with spiculated cells	2
Mitotic index >3/10 large increase field	2
Atypical mitoses	2
Vascular invasion	1
Capsular invasion	1
Extension to adjacent adipose tissue	1
Intense nuclear pleomorphism	1
Nuclear hypercromasia	1

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[1] Correspondence address: José Viana Lima Junior, MD Divisão de Endocrinologia e Metabolismo, Faculdade de Medicina da Santa Casa de São Paulo Rua Dr. Cesario Mota Junior, 112 - Vila Buarque São Paulo, SP, 01221-010, Brasil E-mail: jose.viana@grupofleury.com.br