PPGL: Discovering the Curable Hypertension — Pheochromocytoma and Paraganglioma Explained

In endocrinology, one disease is half-jokingly called the "great mimic," the "impostor" and the "silent killer." It is rare but extraordinarily varied: the neuroendocrine tumour group known as pheochromocytoma and paraganglioma, or PPGL.

1. The Discovery of Pheochromocytoma

The history of pheochromocytoma reaches back to the late nineteenth century. In 1886, Felix Fränkel described what may have been the world's first reported case of an adrenal pheochromocytoma — an 18-year-old woman with typical symptoms and bilateral adrenal masses. In 1896 the pathologist Manasse observed that chromium salts stain the tumour cells of the adrenal medulla a deep brown.

In 1912, the pathologist Pick coined the term "pheochromocytoma" by combining the Greek words "phaios" (dark), "chroma" (colour) and "kytos" (cell) — a name that has endured ever since.

In 1939, Peking Union Medical College confirmed the first case of pheochromocytoma in China. As research deepened, academic interest in pheochromocytoma broadened from clinical phenotype to genotype.

2. Classification of Pheochromocytoma and Paraganglioma

Pheochromocytoma (PCC) arises from the adrenal medulla, while paraganglioma (PGL) arises from the extra-adrenal sympathetic chain; both are hormone-secreting neuroendocrine tumours, and together they are called PPGL [1].

In the 2022 WHO fifth-edition classification of endocrine and neuroendocrine tumours, pheochromocytoma is defined as a neuroendocrine tumour derived from the chromaffin cells of the adrenal medulla — that is, an intra-adrenal paraganglioma [2]. Paraganglioma also includes sympathetic (abdominal), sympathetic (head and neck) and parasympathetic (such as the carotid body) subtypes.

In the past, PPGL was divided into benign and malignant forms. However, in the 2017 WHO fourth-edition classification of neuroendocrine tumours, "malignant PPGL" was replaced by "metastatic PPGL," on the view that all PPGLs carry metastatic potential.

3. Epidemiology and Causes

PPGL is a rare neuroendocrine tumour that causes endocrine (secondary) hypertension. Reported overseas incidence of PCC is roughly 2 to 8 cases per million people per year, and the prevalence of PPGL in general hypertension clinics is 0.2% to 0.6% [1]. Since the 1990s, a growing body of research has found that a series of gene mutations — such as RET, VHL, NF1, SDHB, SDHC, SDHA, SDHAF2, TMEM127 and MAX — are associated with the development of PPGL. More than one third of PPGLs are linked to hereditary tumour-susceptibility syndromes [3], such as multiple endocrine neoplasia type 2A (MEN 2A) and type 2B (MEN 2B), von Hippel-Lindau (VHL) syndrome, and neurofibromatosis type 1 (NF1).

As a result, the development of human PPGL is now considered to be closely tied to genetic susceptibility, and its mechanisms are described by several theories, including the "pseudohypoxia" mechanism, kinase signalling pathways and the Wnt signalling pathway.

4. Clinical Presentation and Diagnosis

PPGL can occur at any age, but peaks between 30 and 50 years, with no clear difference in incidence between men and women. Its clinical manifestations are highly variable — shaped not only by tumour location and size but also by age and sex. The core presentation stems from the inappropriate release of catecholamines (CAs), which drives hypertension together with cardiovascular, cerebrovascular and renal complications and metabolic changes. Catecholamines include epinephrine (E), norepinephrine (NE) and dopamine (DA) — key neurotransmitters that maintain normal physiological function.

Hypertension is the most common symptom. It may be paroxysmal, persistent, or paroxysmally aggravated on top of persistent hypertension, and in a few patients blood pressure remains normal. Long-standing hypertension can cause severe cardiac, cerebral and renal damage, and sudden severe hypertension can be life-threatening. In addition, PPGL can cause a range of physiological abnormalities including hyperglycaemia, lipid-metabolism disorders and electrolyte disturbances.

Because PPGL symptoms lack specificity, routine tests such as electrocardiography and ultrasound often fail to reveal obvious abnormalities, and patients are easily misdiagnosed or missed — sometimes treated simply as essential hypertension. If PPGL is diagnosed and treated early, it is a form of endocrine hypertension that can be expected to be cured. A triad of headache, palpitations and sweating during a hypertensive episode is of great significance for diagnosis, but fewer than 25% of patients present with the classic triad [4].

Qualitative Diagnosis: The First-Choice Biochemical Test

Qualitative diagnosis is therefore very important. The Chinese Society of Endocrinology's Adrenal Group, in its 2020 Expert Consensus on the Diagnosis and Treatment of Pheochromocytoma and Paraganglioma, recommends measuring plasma free or urinary metanephrine (MN) and normetanephrine (NMN) concentrations as the first-choice biochemical test for diagnosing PPGL. Blood or urine norepinephrine, epinephrine, dopamine and other metabolite concentrations can be measured at the same time to support the diagnosis. Measurement of 3-methoxytyramine (3-MT) can improve the sensitivity and screening positivity of head-and-neck PGL detection, and markedly elevated plasma DA and 3-MT levels often point to metastatic PPGL.

Methodology: Why LC-MS/MS

On methodology, liquid chromatography-tandem mass spectrometry (LC-MS/MS) is recommended for measuring metanephrines. Multiple authoritative reports show that LC-MS/MS more precisely quantifies low-concentration (pg-level) analytes such as 3-methoxytyramine (3-MT) in plasma.

Localization and Genetic Diagnosis

Localization diagnosis usually relies on ultrasound, CT and MRI, while molecular-functional imaging may also be needed to screen for and localize metastatic PGL lesions. Molecular genetic diagnosis is likewise essential to the treatment and management of PPGL, particularly for patients with hereditary susceptibility.

5. Treatment and Follow-Up

Today the only curative treatment for PPGL remains surgery, and laparoscopic adrenal surgery is regarded as the "gold standard" for treating adrenal tumours. Once the qualitative and localization diagnoses of PPGL are clear, the tumour should be resected as early as possible. For certain special situations — such as very large or invasive PPGL — open surgery may be required. For patients who cannot be cured by resection, treatment options include radionuclide therapy, combination chemotherapy and external radiotherapy. Genotyping can offer patients more individualised treatment choices and has even opened a new era of targeted therapy.

Although most patients with PPGL can be cured by surgery, a small proportion (about 5%) may still experience recurrence, metastasis or a new tumour during five-year post-operative follow-up. Regular follow-up is therefore essential for all patients, including review of symptoms, signs and blood pressure, testing of blood or urine metanephrines and catecholamines, and imaging as needed.

6. VirtueDx Precision Catecholamine Testing for PPGL Diagnosis

As research deepens, PPGL — once a mysterious disease — is gradually becoming understood, and new testing technologies are enabling earlier diagnosis and more comprehensive treatment, with the prospect of an eventual cure.

VirtueDx has developed a catecholamine and metabolite detection kit based on its proprietary liquid chromatography-tandem mass spectrometry platform, QSight 420MD. Using a non-derivatisation approach, it quantifies six plasma analytes in a single injection, and its lower limit of detection for 3-MT reaches below 5 pg/mL — fully meeting clinical needs.

References

[1] Expert Consensus on the Diagnosis and Treatment of Pheochromocytoma and Paraganglioma (2022 edition). Chinese Journal of Endocrinology and Metabolism, 2020, 36:737-750.

[2] Overview of the 2022 WHO classification of paragangliomas and pheochromocytomas. Endocr Pathol, 2022, 33:90-114.

[3] Phaeochromocytomas and paragangliomas: an update on genetics and management. Clin Exp Pharmacol Physiol, 2008, 35(11):1311-9.

[4] Clinical presentation and management of pheochromocytoma: a practical guide for internists. Eur J Intern Med, 2015, 26(3):188-93.