The presentation of phaeochromocytomas can have a wide clinical spectrum from asymptomatic disease to non-specific symptoms leading all the way up to resistant hypertension and hypertensive crises. The clinical literature describes a classic clinical triad seen in phaeochromocytoma including headache, sweating and tachycardia. Although typical when present, this clinical triad is not commonly encountered in most patients with phaeochromocytomas.

Paroxysmal clinical features or ‘spells’ are a well-recognised consequence of episodic secretion and release of catecholamines. A spell can start with a sense of shortness of breath followed by palpitations and a throbbing headache. Peripheral vasoconstriction associated with such an episode leads to cold peripheries and facial pallor. Towards the end of the episode the patient may feel a sense of warmth and sweating. These can be either spontaneous or precipitated by postural change, medications (Table 2), exercise, or manoeuvres such as lifting and straining. The presentation of spells can be highly variable; however, they tend to be stereotypical for each patient. The frequency of episodes can vary as well, where some patients experience spells several times a day, while others only develop them very infrequently (Young 2011). It is important to bear in mind that these episodes are common and can be due to many other causes apart from phaeochromocytoma. Facial flushing is described in many textbooks, but in our view is rarely seen. Concomitant swelling of the thyroid has been described (Nakamura et al. 2011).

Hypertension is one of the most common presenting features of catecholamine-secreting tumours. Several large retrospective case series have elaborated the prevalence of hypertension in patients with phaeochromocytomas to be between 51 % and 90 % (Baguet et al. 2004; Guerrero et al. 2009). The presentation of hypertension can be quite variable in phaeochromocytoma. It is usually stable and permanent; however, it can be paroxysmal with wide fluctuations, and resistant to treatment. Although uncommon, phaeochromocytoma can also present with postural symptoms with episodic hypotension due to extreme blood pressure fluctuations. This has been reported in patients with predominantly adrenaline-producing tumors, where the presentation can be with hypotension or even shock (Streeten and Anderson 1996; Bergland 1989). Hypotension in these patients could be due to the catecholamine-induced intravascular volume depletion, an abrupt decline of catecholamine levels due to tumour necrosis, hypercalcaemia, desensitisation of adrenoceptors, or acute cardiovascular events such as acute myocardial infarction, tachyarrhythmia or aortic/coronary artery dissection.

Several case series have elaborated the association between phaeochromocytoma and hypertension. In one series, approximately 50 % of the patients were discovered due to hypertension of which half of these had hypertension that was paroxysmal in nature. The series further elaborates that, when the reason for the discovery of phaeochromocytoma was permanent hypertension, it was symptomatic, severe, and treatment resistant (Baguet et al. 2004). Moreover, approximately 10 % of patients in the series presented with normal blood pressure, which was commonly seen in patients with adrenal incidentalomas or in those undergoing screening for familial phaeochromocytoma. However, it is important to bear in mind that, in phaeochromocytoma, patients with normal blood pressure can still have life-threatening paroxysms of hypertension. There appears to be a more pathological effect on cardiac function than the hypertension per se would impose (Stolk et al. 2013).

Therefore, hypertension is the initial presentation in most patients with catecholamine excess, and one should be alerted to the possibility of a phaeochromocytoma in patients with hypertension, especially if the hypertension is:

With the widespread availability of imaging techniques, the detection of adrenal incidentalomas has increased over the last few decades. Approximately 5 % of all incidentally-detected adrenal tumours are found to be phaeochromocytomas, and some 25 % of all phaeochromocytomas are now being incidentally discovered during imaging studies for unrelated disorders (Young 2011; Lenders et al. 2005; Mantero et al. 2000).

Apart from hypertension and incidental discovery, phaeochromocytoma can present with a wide variety of clinical features (Table 3).

Cardiovascular complications are another well-recognised presentation in phaeochromocytoma. Apart from the cardiac emergencies such as myocardial infarction, cardiac arrhythmias and aneurysms, it can present with more long-standing cardiac complications such as dilated or hypertrophic cardiomyopathy and congestive heart failure (Liao et al. 2000).

Excess catecholamines can also affect the gastrointestinal system including inhibition of peristalsis causing constipation or even pseudo-obstruction or ileus. Moreover, vasoconstriction of the mesenteric artery can lead to ischaemic enterocolitis and intestinal necrosis.

In summary, patients with excess catecholamines can show a wide spectrum of clinical features and it is recommended that one considers the possibility of a phaeochromocytoma especially when patients exhibit certain clinical features (Lenders et al. 2014):

In contrast to the conventional teaching of a 10 % familial tendency, recent studies have identified multiple genes in association with phaeochromocytoma, with up to 30 % or possibly more exhibiting a disease-causing germ-line mutation. Along with the well-recognised genetic disorders such as multiple endocrine neoplasia-2 (MEN-2), neurofibromatosis type 1 and Von-Hippel Lindau syndrome, nearly 21 genes have been identified in association with phaeochromocytoma. Most phaeochromocytomas due to syndromic causes present at a younger age than their sporadic counterparts, although part of this earlier identification my relate to genetic or biochemical screening.

Multiple endocrine neoplasia-2 is the one of the earliest syndromes to have been associated with phaeochromocytoma. Interestingly, only half of the patients with phaeochromocytoma with MEN2 exhibit clinical feature and fewer patients have hypertension (Pomares et al. 1998). This might relate to early diagnosis due to other syndromic associations or screening. MEN 2A (now known as MEN2) is characterised by medullary thyroid cancer in all patients, phaeochromocytoma in 40–50 % and primary hyperparathyroidism in 20 %. MEN2B (now known as MEN3) accounts for approximately 5 % of MEN syndromes and has a similar percentage of medullary carcinoma and phaeochromocytoma along with mucocutaneous neuromas; however, it is not associated with hyperparathyroidism. The genetic defect in MEN2 and MEN3 is in the RET proto-oncogene on chromosome 10, which is inherited in an autosomal dominant pattern with high penetrance. Several codon mutations in the RET gene have been associated with MEN2/3 and these are gain-of-function mutations: the great majority of MEN2 are associated with a mutation at codon 634 which codes for the extra-cellular domain of RET, while for MEN3 the dominant mutation at 918 codes for part of the intra-cellular domain. It has been hypothesised that the subtle changes in the clinical presentation is due to these genetic variations in the mutation (Mulligan and Ponder 1995). It is vital to identify phaeochromocytomas in these patients to avoid perioperative hypertensive crisis during thyroidectomy for medullary thyroid carcinoma. Phaeochromocytomas seen in MEN2 are frequently bilateral and almost invariably benign.

Neurofibromatosis type 1 (NF1) is another autosomal dominant disorder, characterized by neurofibromas, café-au-lait spots, freckling, Lisch nodules, phaeochromocytoma and paraganglioma: 2 % of patients with the NF1 gene present with solitary and benign pheochromocytoma. However, they can occasionally be bilateral or extra-adrenal (Walther et al. 1999). Insulinomas and somatostatinomas are also seen in this syndrome.

In von Hippel-Lindau (VHL) syndrome, phaeochromocytomas are more frequently bilateral with mediastinal, abdominal or pelvic paragangliomas. Other syndromic features of VHL include CNS hemangioblastoma, retinal angioma, clear cell renal cell carcinoma, pancreatic neuroendocrine tumours and middle ear tumours. As in MEN-2, VHL too has considerable genetic variability among kindreds with certain mutations causing a higher frequency (up to 20 %) of phaeochromocytoma, (Dluhy 2002). Interestingly, patients habouring the VHL mutation have a lower incidence of hypertension and have elevated normetanephrine, in contrast to patients with MEN-2, who show elevated metanephrine levels (Eisenhofer et al. 2001). Malignancy is rare but does occur.

Another important cause for familial catecholamine-hypersecreting tumours is succinate dehydrogenase (SDH) gene mutation. Several mutations in the SDH gene have been identified including SDHB, SDHC, SDHD, SDHAF2, and (very rarely) SDHA. Similar to the previously mentioned mutations, SDH mutations are also inherited in an autosomal dominant pattern. However, interestingly, SDHD and SDHAF2 have a paternal inheritance pattern due to maternal imprinting. In patients with SDH mutations causing paragangliomas/phaeochromocytomas, the type of catecholamine produced depends on its location. An SDH-induced paraganglioma is different from phaeochromocytoma in general in the fact that tissue expression of PMNT in these tumors is minimal, which means that the preferential catecholamine production is norepinephrine or dopamine and they produce normetanephrine, or normetanephrine and methoxytyramine, or rarely only methoxytyramine (Timmers et al. 2007). Interestingly, tumours only producing methoxytyramine are usually SDH tumors. Of abdominal paragangliomas, most secrete noradrenaline, often both noradrenaline and dopamine and rarely only dopamine. The rate of noradrenaline production is much lower in head-and-neck paragangliomas. Most mutations in the SDHD, SDHAF2 and SDHC are associated with non-catecholamine secreting, head-and-neck paragangliomas (Kantorovich et al. 2010). Although SDHB mutation commonly presents with extra-adrenal abdominal or thoracic disease, a primary presentation with an adrenal phaeochromocytoma is still evident in some patients. Approximately 1/3 of patients with SDHB mutations present with multifocal disease (Kantorovich et al. 2010). Moreover, carriers of SDHB mutations can develop early onset abdominal, pelvic, and thoracic catecholamine-secreting paragangliomas that are more likely to be malignant, possibly in up to 50 % of patients. SDHB carriers who develop malignant paragangliomas are more likely to develop other neoplasms including papillary thyroid tumours, renal cell carcinoma, neuroblastoma, or gastrointestinal stromal tumours (GIST) (Neumann et al. 2004). A link has also been shown between SDH mutation status and pituitary tumours (Galan and Kann 2013).

Apart from these more commonly known mutations, several new mutations have been identified in association with pheochromocytoma. TMEM127 is a recently identified germ-line mutation, inherited autosomal dominantly, commonly associated with benign unilateral adrenal phaeochromocytoma. However, there are few case studies of bilateral, malignant and extra-adrenal disease. Interestingly, the presentation of these patients is in the fifth decade, more in keeping with the onset of sporadic phaeochromocytoma rather than the familial form.

The MAX (Myc-associated factor X) gene is another more recently reported susceptibility gene, which is inherited as autosomal dominant and, similar to SDHD and SDHAF2, has a paternal inheritance pattern. The majority of patients with MAX mutations present at a younger age and tend to have bilateral or unilateral phaeochromocytoma with an increased potential to develop malignant disease and predominantly produce noradrenaline (Dénes et al. 2015; Comino-Mendez et al. 2011).

Several other mutations such as HIF2α, KIF1β, fumarate hydratase and PHD2 have been reported recently, although detailed studies have yet to be performed on their syndromic associations and characteristics of phaeochromocytoma. (eg. Carney–Stratakis syndrome- familial paraganglioma and Gastrointestinal Stromal Tumours (GIST),). Finally, the recently-described Pacak-Zhuang syndrome, which shows an association between paragangliomas, polycythaemia and retinal angiomas with somatic mutation of HIF-2α, most likely occurs as a mosaicism similar to the McCune-Albright syndrome (Zhuang et al. 2012).

Genetic screening plays a vital role in the management of phaeochromocytoma, not only to detect other associated life-threatening conditions in the index patient but also for the diagnosis and treatment family members with certain mutations (eg, medullary carcinoma of the thyroid with RET mutations). Moreover, genetics can alert the physician to the malignant potential of phaeochromocytomas, especially in patients harbouring certain mutations (eg, SDHB), and to actively seek for the presence of metastases. Similar to the genetic mutation offering clues regarding character of the tumour, certain characteristics such as tumour location, the presence of metastases and the type of catecholamine synthesised can give clues to the possible causative mutation. Therefore, genetic analysis has become an important tool in the investigatory armamentarium for the evaluation and management of this rare syndrome. Accordingly, recently-published major guidelines recommend that all patients diagnosed with phaeochromocytoma/paraganglioma should be engaged in shared decision making for genetic testing for a possible somatic or germ line mutation (Lenders et al. 2014). Due to cost factors, the Endocrine Society recommends prioritising certain genetic screening based on the clinical and biochemical features (Fig. 1). Nevertheless, in Oxford we screen routinely for a panel of 10 genes in almost all patients. It has been shown that even in older patients with single benign phaeochromocytomas and no family history or syndromic featues, nearly 10 % will still harbour a germline mutation (Brito et al. 2015).

The measurement of catecholamines and/or their by-products is the key in diagnosing pheochromocytoma. Although in the past the direct measurement of catecholamines was commonly used in the diagnosis, it is now considered a poor screening tool due to its relatively low sensitivity.

All catecholamines have a similar chemical structure with a catechol ring (ortho-dihydroxybenzene) and an amine group (Fig. 2).

Tyrosine is the initial substrate in the formation of catecholamines and is either derived from food or is synthesised in the liver from phenylalanine (Fig. 3). It subsequently enters chromaffin cells by active transportation and undergoes hydroxylation and decarboxylation to form various types of catecholamines. The rate-limiting step in catecholamine synthesis is the conversion of tyrosine to DOPA, which is regulated by the enzyme tyrosine hydroxylase. In managing patients with catecholamine-secreting neoplasms, inhibition of this rate-limiting step by tyrosine hydroxylase inhibitors (e.g. metyrosine) can inhibit the synthesis of catecholamines.

Subsequent to this rate-limiting step, dopamine is synthesised by further decarboxylation of DOPA by the enzyme, aromatic L-amino acid decarboxylase. It is then hydroxylated to form noradrenaline and stored as granules within the chromafin cells. It is subsequently released it to the cytoplasm of the chromaffin cells in the adrenal medulla, where phenylethanolamine N-methyltransferase (PNMT) converts it to adrenaline. Interestingly, PNMT is regulated by glucocorticoids and, due to the corticomedullary portal system in the adrenal gland, medullary PNMT-producing cells are exposed to high concentrations of cortisol, making the adrenal medulla the prime location for adrenaline-secreting adrenal tumours.

Once formed, these catecholamines are stored in electron-dense granules. Transport of substances into these granules is regulated by vesicular monoamine transporters (VMAT). Iodine-labelled MIBG (¹²³I or ¹³¹I) is transported by VMAT into these storage granules and is a useful tool in localising (and treating) catecholamine-secreting pheochromocytoma/paraganglioma.

Catecholamines have a short half-life, of approximately 10–100 s, in the plasma. The nerve terminals reuptake the catecholamines they produce themselves, while extra-neuronal catecholamines are metabolised by catechol-O-methyl-transferase (COMT) to form metanephrine and normetanephrine. Sympathetic nerves contain MAO, but not catechol-O-methyltransferase (COMT). Intraneuronal metabolism of norepinephrine leads to production of the deaminated metabolite, DHPG, but not the O-methylated metabolite, normetanephrine. Consequently, almost all of the DHPG in plasma has a neuronal source, whereas normetanephrine and metanephrine are derived exclusively from non-neuronal sources including chromaffin cells in the adrenal medulla (Eisenhofer et al. 2004). Normally the O-methylation pathway represents a minor route of catecholamine metabolism while deamination of noradrenaline within sympathetic nerves is the major pathway (Fig. 3). However, in patients with pheochromocytoma, intratumoral O-methylation pathway dominates catecholamine metabolism, leading to relatively large increases in production of the O-methylated metabolites compared with minor increases of the deaminated metabolites (Eisenhofer et al. 2004; Eisenhofer 2012).

Unfortunately, the short half-life of catecholamines makes it difficult to discriminate pathological overproduction from normal transient bursts of secretion during stress. Therefore, due to the short plasma half-life and intermittent nature of secretion, measurement of catecholamines can give a high rate of false positive results, while sampling between bouts of paroxysmal release will cause false negatives. Most authorities, including major guidelines, recommend that either free plasma metanephrines or fractionated urinary metanephrines as the investigations of choice for the diagnosis of phaeochromocytoma. The recommended laboratory techniques are liquid chromatography with mass spectrometric or an electrochemical detection method (Lenders et al. 2014) Although plasma free metanephrine and normetanephrine are nearly as rapidly cleared from the circulation as their catecholamine precursors, they are superior to catecholamines for diagnosis as these metabolites are produced continuously from catecholamines leaking from storage vesicles into the cytoplasm where COMT then leads to conversion to metanephrine and normetanephrine. This process is not only continuous, but also independent of exocytotic catecholamine secretion, which in phaeochromocytomas can be intermittent or only active with low rates of secretion.

Plasma fractionated metanephrines have a high sensitivity, 96–100 %, with a specificity of 85–89 %, and is especially useful in diagnosing patients who carry a higher risk for habouring a phaeochromocytoma. High-risk patients, who would benefit from initial plasma metanephrine measurment, are patients with resistant hypertension, typical spells, a past history of phaeochromocytoma, genetic syndromes or a family history of a genetic syndrome, or an adrenal incidentaloma suggestive of a phaeochromocytoma. Apart from these, plasma measurements can be useful in children where 24-h urine collection is difficult. Due to its high sensitivity, a normal plasma metanephrine result will exclude the presence of a phaeochromocytoma in the above-mentioned high-risk patients. The only exceptions are seen in preclinical early disease or tumours with selective dopamine hypersecretion (Sawka et al. 2003). The plasma sample should ideally be drawn from a supine patient (fully recumbent for at least 20–30 min) and appropriate supine cut-offs should be used in the interpretation. In fact, it has been recently indicated that with a ‘seated sampling’ the diagnostic accuracy of the plasma test is no better, if not worse, than the urinary test (Lenders et al. 2014; Därr et al. 2014).

Twenty-hour fractionated urinary metanephrines are another investigation frequently used by clinicians. Perry et al. demonstrated that 24-h urine fractionated metanephrines using mass spectrometry provide excellent sensitivity (97 %) and specificity (91 %) for the diagnosis of a phaeochromocytoma. Therefore, it can be used in patients with a lower index of clinical suspicion as it has a higher specificity than the plasma measurement (Perry et al. 2007). Urinary metanephrines should include a urinary creatinine measurement to verify adequacy of urine collection, and assessments of the utility of random urine samples are in process. However, it should be emphasised that in practice there is probably little difference in the utility of plasma or urinary collections, with appropriate cut-offs, and the assay employed will often depend on local resources and experience.

Although metanephrine and normetanephrine are the preferred biochemical substances for diagnosis in comparison to catecholamines, their levels can be altered by several medications due to their effect on the metabolising enzymes, COMT and MAO, and uptake pathways. Tricyclic antidepressants (TCA) are well recognised to interfere with the assessment of metanephrines, and it is recommended to taper off and withhold TCAs and other anti-psychotics (except highly selective serotonin reuptake inhibitors) for at least 2 weeks prior to metanephrine analysis (Neary et al. 2011) (Table 4).

Once catecholamine excess is biochemically confirmed, tumor localisation can be initiated by way of imaging. While imaging is almost always followed by biochemical confirmation, in patients with high risk factors such as a past history or genetic predisposition to phaeochromocytoma (eg. SDH mutation) there might be justification to proceed with imaging in the absence of compelling biochemical evidence. Some paragangliomas, especially in the head and neck region, can be biochemically silent and imaging with negative biochemistry is warranted in these instances as well.

As discussed previously, 90 % of phaeochromocytomas are adrenal in origin, while 10 % are extra-adrenal. Of these extra-adrenal phaeochromocytomas or paragangliomas, 80–95 % are within the abdomen and pelvis (superior and inferior para-aortic areas in the abdomen −75 %, urinary bladder- 10 %, thorax −10 %, head, neck, and pelvis –5 %) (Whalen et al. 1992). Therefore, CT scanning of the abdomen and pelvis following an adrenal protocol is the recommended initial imaging modality (Mantero et al. 2000). CT provides high tomographic resolution with a localisation sensitivity between 88 % and 100 %. On CT imaging, phaeochromocytomas can be homogeneous or heterogeneous, solid or cystic and with or without calcification. Phaeochromocytomas are notorious in being able to mimic the radiological features of adrenal carcinoma. Most (if not all) phaeochromocytomas have an attenuation greater than 10HU due to their lower fat content, while some can demonstrate very high attenuation due to haemorrhage (Sane et al. 2012; Blake et al. 2004).

The use of contrast agents during CT scanning has been an area of controversy for many years with concerns on risk of precipitating a hypertensive crisis; however, low-osmolar non-ionic contrast agents have been used safely in patients with phaeochromocytoma (Mukherjee et al. 1997), and this has more recently been confirmed (Baid et al. 2009). Phaeochromocytomas typically enhance avidly, indicating the rich capillary framework in the tumour, but nevertheless they can be heterogeneous with regions of absent enhancement due to cystic changes and necrosis. Contrast washout is useful in the evaluation of adrenal lesions, with an absolute contrast wash out of >60 % or a relative washout of >40 % at 15 min indicating a lipid-rich adenoma. Phaeochromocytoma, in its typical inconsistent nature, can have variable washout patterns, although the majority of phaeochromocytomas have a delayed contrast washout (Blake et al. 2004) (Fig. 4).

MRI is another useful tool in localising phaeochromocytomas. The most common MR imaging appearance of a phaeochromocytoma is of low signal intensity on T1 imaging and high signal intensity on T2-weighted imaging. They usually enhance avidly on T1-weighted imaging after gadolinium-enhancement. Although MRI lacks the superior spatial resolution of CT, it is useful to detect skull base and neck paragangliomas, for patients who cannot undergo CT scanning (metal clips, allergy to contrast, etc.), and for patients in whom exposure to radiation should be minimised (children, pregnant women, patients with known germline mutations undergoing regular screening) (Lenders et al. 2014; Jalil et al. 1998).

Functional imaging is another widely used imaging modality for phaeochromocytomas. Meta-iodobenzylguanidine (MIBG) is a radiopharmaceutical agent that accumulates preferentially in catecholamine-producing cells and is transported into the electron-dense catecholamine storing granules via the transporter molecule VMAT. Radiolabelled MIBG is taken up by normal tissue innervated by the sympathetic system, such as heart, salivary glands, and tumours that express the neurohormonal transporters. ¹²³I-labelled MIBG has a sensitivity between 85 % and 88 % for phaeochromocytomas and between 56 % and 75 % for paragangliomas. Its specificity ranges from 70–100 % to 84–100 %, respectively (Berglund et al. 2001; Bhatia et al. 2008; Jacobson et al. 2010; Mozley et al. 1994). ¹²³I-MIBG allows better imaging when compared to ^13II-MIBG as its photon energy allows SPECT scanning which can greatly improve the sensitivity of the image. Therefore, ¹²³I MIBG remains the recommended agent for functional imaging in patients with phaeochromocytoma. Due to the fact that up to 50 % of normal adrenals take up MIBG asymmetrically, one should be aware of false positive results, especially when performed on a patient with normal biochemistry or after unilateral adrenalectomy (Jacobson et al. 2010). The major uses of MIBG imaging are confirmation that an adrenal lesion is a phaeochromocytoma, the identification of metastases, and for assessing suitability for ¹³¹I-MIBG therapy. ¹²³I-MIBG imaging gives a valuable hint on the response to ¹³¹I MIBG treatment in patients with metastatic pheochromocytoma or paraganglioma. Apart from this, ¹²³I MIBG can be used to detect occult metastasis in patients with increased risk for metastatic phaeochromocytoma or paraganglioma (eg, a large primary tumour, recurrent disease, and extra-adrenal or multifocal disease) (Lenders et al. 2014).