PPGL – The 3 Ps Triad of Hypertension, Palpitations and Diaphoresis
PPGLs can be broadly classified according to biochemical secretory patterns and produce a variety of clinical manifestations. The 3 Ps triad of hypertension, palpitations and diaphoresis/flushing are the most common symptoms but a wide range of signs and symptoms also occur.
Hereditary PPGLs are more frequently extra-adrenal, multifocal and metastatic than their sporadic counterparts. This highlights the importance of somatic – as well as germline – genetic testing in patients with a hereditary predisposition to develop PPGLs.
Symptoms
PPGLs are neuroendocrine tumors that result from the proliferation of catecholamine-producing cells in the adrenal medulla (pheochromocytoma, PHEO) or in the sympathetic and parasympathetic ganglia of the adrenal glands ppgl (paraganglioma, PGL). In a minority of cases (up to 20%) PPGLs are malignant.
Most patients with ppgl have paroxysmal symptoms, which are provoked by physical or emotional stress and sometimes by certain foods, beverages or drugs (see the image below). The most common symptoms are high blood pressure (hypertension) and headache. Often the patient has heavy sweating for no apparent reason (perspiration). These episodes of signs and symptoms, called “attacks” or “spells,” can happen weekly or several times daily and last less than an hour.
In some cases, ppgls secrete androgens (male hormones). This may cause the penis in boys or the clitoris in girls to become enlarged. It can also cause menstrual periods in girls and breast growth in boys.
The diagnosis is usually made by MRI of the adrenal glands, although imaging of the abdomen, chest and pelvis should be completed because of the frequent localization of PPGL in these organs. On MRI, adrenal pheochromocytomas appear as bright lesions compared to the liver and are most clearly visible on T2-weighted images. Other diagnostic modalities include ultrasound, CT scan and MRI elastography.
Diagnosis
The clinical presentation of PPGL is very variable. In general, a diagnosis is made by recognizing the presence of catecholamine excess in the blood. The clinical symptoms include hypertension and paroxysmal, recurrent headache or sweating. The blood pressure increase is usually orthostatic and may be associated with nausea, vomiting or weight loss. Some patients with PPGL have bladder tumors, which can produce urinary incontinence and increased blood flow to the pelvic organs, producing takotsubo cardiomyopathy and causing a tachycardia (23).
While most PPGL are sporadic, about 40% occur in the context of an autosomal dominantly inherited syndrome and more than 20 susceptibility genes have been identified (SDHA, SDHB, FH, MDH2, VHL, RET, TMEM127 and MAX)5.
The diagnosis is made based on biochemical testing – plasma free metanephrines – and nuclear medicine imaging using 123I- and/or 131I-metaiodobenzylguanidine (MIBG) scintigraphy. The use of MIBG scanning is particularly useful to locate extra-adrenal PPGLs and to identify metastases. However, it should be emphasized that the sensitivity of MIBG scintigraphy is compromised by a number of factors, including hepatic and renal impairment and some medications, such as anti-hypertensive agents and tricyclic antidepressants, which affect the uptake of this radiopharmaceutical. The diagnosis is further confirmed by genetic evaluation. This includes a complete panel of chromosomes, as well as a search for germline pathogenic variants (GPVs). These mutations can cause mitochondrial dysfunction and lead to cellular dedifferentiation and proliferation leading to a pheochromocytoma-like phenotype (5,6).
Treatment
The clinical presentation of PPGL is highly variable, reflecting the hemodynamic and metabolic effects of catecholamine excess. In spite of this, a large proportion of patients with PPGL present with the 3 Ps – pain, palpitations and generalized inappropriate sweating. This triad is the main reason to raise suspicion of a PPGL. Increasingly, these tumors are discovered incidentally during radiological procedures for unrelated reasons or as a consequence of genetic screening in families with mutations that predispose to PPGL2.
Biochemical diagnosis is made by measurement of plasma free metanephrines or 24-hour urinary fractionated metanephrines. It is important to note that secretory PPGLs secrete a combination of different catecholamines and the episodic nature of their secretion means that one estimation misses the diagnosis in 30% of cases2.
Metastatic PPGLs are very unlikely to metastasize, but as only 10-25% of PPGLs have been reported to do so, it is essential to evaluate all PPGLs for evidence of malignancy. This can be accomplished with a variety of tests including CT scan, MRI and functional whole-body imaging (e.g. FDG-PET, DOTATATE-PET and [123I]MIBG scintigraphy).
Currently, all PPGLs are considered potentially malignant as 40% of them occur in the context of an autosomal inherited syndrome and more than 15 predisposing genes have been identified (SDHA, SDHB, SDHC, SDHD, RET, VHL, NF1, TMEM127 and MAX)2. However, the predictive value of various scoring systems (pheochromocytoma of adrenal gland scaled score, tyrosine hydroxylase immunohistochemistry and expression of heat shock protein 90 and pS100 and CSDE1 and MAML3 mutations) remains suboptimal1. In view of this, all patients with a PPGL should be offered genetic testing to identify first degree family members that may benefit from targeted screening and monitoring programmes.
Follow-up
PPGLs are rare tumors of catecholamine-producing neuroendocrine cells that arise from the adrenal medulla, sympathetic or parasympathetic ganglia. Symptoms are diverse and can be catastrophic and lethal if untreated. They are often misdiagnosed due to their heterogeneous clinical presentation and rare anatomy. carbon steel manufacturer They are also associated with familial syndromes which complicate diagnosis and treatment.
PGLs are categorized into functional and non-functional groups based on secretory function or lack thereof. Functional tumors secrete catecholamines, and can be grouped into three biochemical phenotypes – noradrenergic (predominantly norepinephrine), adrenergic, and dopamine secreting. A non-secretory phenotype is also seen in cluster 3 mutations involving abnormal activation of Wnt and Hedgehog signaling or methylation defects of the gene CSDE1.
Metastatic PPGL are difficult to completely resect and are frequently found by chance in patients with otherwise benign and curable localized PPGL. They also tend to recur at a higher rate than sporadic PPGL. Several molecular targeted agents can be used in combination with surgery to improve survival and reduce the risk of recurrence. Sunitinib is an example of a tyrosine kinase inhibitor that decreases angiogenesis and directly inhibits catecholamine synthesis. It has been shown to be effective in treating metastatic PPGL in a single epidemiological study.
In addition to radiotherapy, molecular targeted therapy can be useful in treating recurrences of metastatic PPGL. 68Ga-labeled somatostatin analogues that bind to subtype 2 SSTRs have been demonstrated to be highly sensitive and more specific than MIBG in detecting metastatic PPGL (44,45).