Increased production and release of catecholamines (epinephrine, norepinephrine and dopamine) by the tomors to circulation result in the clinico-pathological manifestations of PCCs and PGLs. Catecholamines cause intense vasospasm and hypertension through α-adrenergic effect, and vasodilatation, diaphoresis and tachycardia from the β-adrenergic effect (Pappachan et al. 2014). Severe orthostatic hypotension with syncopal episodes can occasionally result from unbalanced effects of α- and β-adrenergic receptors in different vasculature in the body (Pappachan et al. 2014; Desai et al. 2009).

The paroxysmal nature of the catecholamine release may explain the episodic nature of symptoms in PCCs/PGLs. Recurrent surge of these hormones may cause a (reversible) form of cardiomyopathy called catecholaminergic cardiomyopathy (Pappachan et al. 2014; Desai et al. 2009). 10–15 % of PCCs and 20–50 % of PGLs can be malignant, and as there is no clear-cut histological criteria to determine malignancy in resected tumors, life-long follow up for recurrence in an appropriate clinical scenario is recommended by many authorities (Parenti et al. 2012; Tsirlin et al. 2014; Lenders et al. 2014). Several genetic mutations have been recently described in PCCs/PGLs (Pappachan et al. 2014) that may be associated with malignant potential and inheritance to successive generations, and the recent endocrine society guidelines in 2014 recommend appropriate testing and follow up algorithm of the disease (Lenders et al. 2014).

Although the classical clinical presentation is with headaches, palpitations and sweating with hypertension, many of these tumours present with protean manifestations including prolonged periods of clinical silence. <1 % of resistant hypertension cases are related to PCCs/PGLs (Rimoldi et al. 2014). With the increasing use of cross sectional abdominal imaging for medical diagnostics, many cases of PCCs/PGLs are diagnosed in the recent years while evaluating adrenal incidentalomas. About 4 % of adrenal incidentalomas are reported to be PCCs (Kasperlik-Zaluska et al. 2006). Few multi-organ endocrine neoplastic syndromes such as Multiple Endocrine Neoplasia (MEN) 2A and 2B, Von Hippel-Lindau (VHL) disease and neurofibromatosis type 1 can have PCCs/PGLs as disease manifestations (Pappachan et al. 2014; Desai et al. 2009). Hypertensive crisis during emergency surgery, general anaesthesia or contrast radiography, unexplained heart failure, drug-induced hypertensive crisis (with beta-blockers or monoamine oxidase inhibitors), and new-onset diabetes in an young lean hypertensive are some of the atypical clinical presentations of the disease (Pappachan et al. 2014).

As in any other endocrine disease biochemical confirmation of the diagnosis is the first-line approach to the diagnosis of PCCs/PGLs. Plasma free metanephrines or urinary fractionated metanephrines is the screening investigation of choice for suspected cases with very high sensitivity and good specificity (Pappachan et al. 2014; Lenders et al. 2014). Intake of multiple medications and other chemicals before testing can interfere with the results reducing the positive predictive value of this screening assay. A detailed list of these medications can be found in the relevant literature (Pappachan et al. 2014; Lenders et al. 2014). Therefore, raised levels ≤ 3–4 times the laboratory reference range should be interpreted with caution to avoid un-necessary work up because of a false positive test. A clonidine suppression test may be useful in such situations (Lenders et al. 2014; Eisenhofer et al. 2003).

Imaging studies for localisation should only be undertaken after the biochemical diagnosis is proven. CT scan and Magnetic Resonance Imaging (MRI) have excellent sensitivity and reasonable specificity for anatomical localisation of these tumours. Non-ionic contrast is preferred for CT scan because of the risk of hypertensive crisis (Lenders et al. 2014). MRI is preferred over CT in patients in whom where radiation needs to be avoided and in patients suspected to have metastatic disease (Pappachan et al. 2014; Lenders et al. 2014).

Once the anatomical diagnosis is established with an initial imaging modality, functional imaging is usually recommended to prove the diagnosis, and to exclude the possibility of metastasis and multi-site disease in cases of PGLs. ¹²³I-metaiodobenzylguanidine (MIBG) scitigraphy is the usual functional imaging modality utilized in most centers. The sensitivity and specificity of ¹²³I-MIBG scintigraphy is around 85 % in PCCs. A variety of different radio-pharmaceutical agents can be used for functional imaging in cases with a negative ¹²³I-MIBG scintigraphy (Pappachan et al. 2014; Lenders et al. 2014).

The recommendations for genetic testing and the testing algorithm can be found in the 2014 Endocrine society guidelines (Lenders et al. 2014).

Surgery is the preferred definitive management option for all cases of PCCs/PGLs unless contraindicated. Complete resection of the tumor often results in cure of the disease although improvement in hypertension depends on other factors too.

Prompt control of hypertension and appropriate preoperative preparation is a must as manipulation of the tumour during surgery results in hypertensive crisis because of the massive release of catecholamines to circulation. Adequate control of hypertension with non-selective α-adrenergic blockers such as phenoxybenzamine (10 mg BD to a maximum of 1 mg/kg/day) or α-1 selective agent doxazosin (2–32 mg/day) 10–14 days prior to the surgery along with liberal intake of fluids and salt to replenish volume depletion is recommended in all cases (Pappachan et al. 2014; Lenders et al. 2014). Addition of a β-adrenergic blocker such as propranolol or atenolol to counteract the reflex tachycardia and postural hypotension associated with α-blockers may be necessary after few days of starting α-blockers. Other antihypertensive medications such as calcium channel antagonists and metyrosine may be necessary for optimal control of BP in some cases (Pappachan et al. 2014; Tsirlin et al. 2014; Lenders et al. 2014). The target BP control should be < 130/80 mm Hg while seated and > 90 mm systolic while standing and a heart rate 70–80 per minute (Pappachan et al. 2014; Tsirlin et al. 2014; Lenders et al. 2014). Appropriate modifications in these targets may be made in the presence of cardiovascular disease.

Surgeon and anaesthetist with sufficient experience with the management of these rare tumors should perform the surgery to optimise safe outcomes. Laparoscopic adrenalectomy is the preferred surgery in most cases of PCCs. Large tumors, PGLs and suspected metastatic disease are indications for an open surgery (Pappachan et al. 2014; Tsirlin et al. 2014; Lenders et al. 2014). Intra-operative BP changes should be closely monitored with administration of intravenous α-adrenergic blockers (phentolamine or phenoxybenzamine) for hypertensive episodes during surgery, and intravenous crystalloids and vasopressors to manage the postoperative hypotension in an intensive care unit may be necessary to manage cases (Pappachan et al. 2014; Tsirlin et al. 2014).

Withdrawal of the antihypertensive medications and hypoglycemic agents (if secondary diabetes was present pre-operatively) may be possible in some cases. Testing plasma (or urinary) metanephrines 10 days after the surgery to ensure complete removal of the tumor is recommended in all cases (Pappachan et al. 2014; Tsirlin et al. 2014; Lenders et al. 2014). Regular endocrine follow up of the patients with appropriate long-term care plan is also mandatory.

The follow up care of patients with PCCs and PGLs is detailed in the 2014 guidelines of the Endocrine Society (Lenders et al. 2014).

A majority of cases of CS results from an ACTH producing pituitary adenoma that is otherwise known as Cushing’s disease. Ectopic production of ACTH accounts for a significant proportion of cases other than pituitary Cushing’s, followed by cortisol-secreting adrenal adenomas and carcinomas, and adrenal nodular hyperplasia. Exogenous steroid administration for therapeutic purposes results in iatrogenic CS in many patients. Carney complex, a rare genetic disorder (autosomal dominant), characterized by pigmented skin and mucosal lesions, cardiac and cutaneous myxomas, and multiple endocrine and non-endocrine neoplasms is an uncommon cause of CS (Correa et al. 2015). Another rare cause for CS is ectopic CRH (corticotropin releasing hormone) producing tumors. Subclinical CS, results from alterations in the hypothalamus–pituitary–adrenal (HPA) axis without overt signs or symptoms of hypercortisolism (Di Dalmazi et al. 2015).

Hypertension in CS may be multi-factorial, and the exact mechanisms still remain elusive. Several putative mechanisms have been identified including imbalance between vasodilatory and vasoconstrictor chemicals such as prostacyclin, nitric oxide and endothelins, the mineralocorticoid receptor activation (Di Dalmazi et al. 2015; Anagnostis et al. 2009; Mihailidou et al. 2009; De Leo et al. 2010; Rizzoni et al. 2009), endothelial abnormalities (Di Dalmazi et al. 2015; Anagnostis et al. 2009), and development of metabolic syndrome (Di Dalmazi et al. 2015; Anagnostis et al. 2009; Ferraù and Korbonits 2015).

A wide variety of clinical manifestation may be seen in a classical case of overt CS (Nieman 2015). These include facial plethora, fragility of skin, acne, hirsutism, thinning of scalp hair, weight gain with truncal obesity, buffalo hump and supraclavicular fatty pad (due to ectopic fat distribution), labile mood and sometimes frank psychosis, menstrual irregularities, proximal myopathy, growth failure in children, sexual dysfunction (and even impotence), hypertension, hypokalaemia, glucose intolerance or frank diabetes, osteoporosis, metabolic syndrome, and susceptibility to infections due to suppressed immunity. However, these classical manifestations are less frequently observed these days because of wide availability of investigations and awareness of the disease among physicians. In up to 15 % of adults with CS, the clinical manifestations may occur only periodically, a condition known as cyclical Cushing’s syndrome (Alexandraki et al. 2009).

Although the American Endocrine Society Guidelines on diagnostic evaluation of CS is slightly old (Nieman et al. 2008), most of the recommendations are still valid for work up of suspected cases. An exclusive meeting to discuss about CS, held in Germany in October 2014 with wide participation from global experts, compiled further evidence on the diagnostic and management algorithms of the disease (Reincke 2015). A detailed discussion of the diagnostic approach to CS can be found in these published literature and only a brief account is given here.

A thorough history of extraneous steroid administration should be obtained in all cases of clinically suspected CS before biochemical testing. The Endocrine society recommends testing for CS in patients with multiple clinical features described above, children with growth retardation with abnormal weight gain, illnesses uncommon in younger age-groups such as hypertension and osteoporosis, and adrenal adenomas (Nieman et al. 2008).

In suspected cases of CS, one of the following screening investigations should be performed initially: 24-hour urinary free cortisol (at least 2 samples), late night salivary cortisol, 1-mg overnight dexamethasone suppression test (DST) or low-dose DST (0.5 mg QDS for 48 h) (Nieman et al. 2008). Further evaluation by an endocrinologist is recommended in cases with at least one positive test and in those with negative screening tests and clinically suspected cyclical CS. Random plasma cortisol measurement has no value for screening cases of CS because of the marked variability of levels depending of many factors.

Confirmation of CS in suspected cases needs detailed endocrine work up. Measurement of corticotrophin (ACTH) levels is the next step in diagnosis. Suppressed level of ACTH indicate an adrenal/iatrogenic source of hypercortisolism. If adrenal source is suspected a contrast CT scan of the adrenal glands should be done. If ACTH levels are high or high normal, an MRI of pituitary should be done. A pituitary mass ≥ 1 cm may be an indication of Cushing’s disease and pituitary surgery although controversy still remains among endocrinologists on size criteria (Florez et al. 2013). A high-dose DST (using 2 mg QDS for 48 h) and/or CRH stimulation tests is recommended by some centers if the pituitary mass is smaller or absent, in presence of raised ACTH levels. A suppressible cortisol with high-dose DST or 20 % rise in cortisol following CRH administration indicates pituitary-driven corticotrophin excess although overlap with ectopic source is well recognised. Bilateral inferior petrosal sinus sampling (BIPSS) with baseline and CRH-stimulated ACTH measurements is the next step. If BIPSS is negative, imaging of thorax and/or abdomen and pelvis should be performed to identify an ectopic source of ACTH. Finally, an octreotide scan may be necessary if all other confirmatory tests are negative. A useful algorithm for diagnostic work up of CS can be found in the full-test article (freely available) by Florez et al. (2013).

Management of CS can be complex in many cases, and the mortality related to the disease is reported to be higher than in normal age-matched controls even in treated cases (Clayton et al. 2011; Graversen et al. 2012). Complete cure of the disease may not be always possible, and management of disease manifestations shall be the only options in such cases. Whenever feasible, surgical removal of the cause of excess cortisol/ACTH is the most appropriate and potentially curable management option.

Even in curable cases, medical management should bridge the definitive surgery for adequate preparation of the patient. First-line agent widely used is metyrapone, a 11-β-hydroxylase enzyme inhibitor (dose range 1–4 g/day in divided doses). The drug has been found to be very effective for short- and long-term control of endogenous steroid excess in a recent multicenter study (Daniel et al. 2015). However, the drug can increase the adrenal synthesis of steroids with mineralocorticoid activity that worsens hypertension (Ferraù and Korbonits 2015). Other cortisol-lowering medications such as ketoconazole (Nieman 2002), mitotane (Donadille et al. 2010) and mifepristone (Fleseriu et al. 2012) also have beneficial effects on hypertension in CS, although careful monitoring for side effects of these agents is necessary. Recent guidelines from the Endocrine Society and recommendation from the European Medicines Agency suggest ketoconazole as highly effective option for medical management of CS when used judiciously (European Medicines Agency 2016; Nieman et al. 2015). Combination therapy with ketoconazole and metyrapone may be necessary to obtain rapid control hypercortisolism in some cases (Nieman et al. 2015). Pasireotide alone (Colao et al. 2012), or in combination with cabergoline and ketoconazole (Feelders et al. 2010) also have been reported to benefit treatment of hypertension in CS. Recently, retinoic acid (Pecori Giraldi et al. 2012) and LCI699 have been shown to be effective in treatment of CS and disease-related hypertension (Bertagna et al. 2014; Daniel and Newell-Price 2015). Along with medical measures to manage hypercortisolism, conventional antihypertensive treatment also needs to be administered for control of BP in patients with CS.

Transphenoidal hypophysectomy is the preferred surgical treatment in Cushing’s disease although cure is not guaranteed in all cases owing to the difficulty in removal of the entire tumour tissue in some cases, especially small adenomas. Pituitary radiotherapy may be necessary in selected cases with residual tumour although associated with higher long-term complication rates including pan-hypopituitarism. Functional imaging of the pituitary with (11)C-methionine positron emission tomography-computed tomography (PET-CT) scan is recently reported to be an excellent tool to localise residual disease after previous hypophysectomy for targeted therapy (Koulouri et al. 2015).

In over 95 % of cases, acromegaly results from a GH-secreting somatotroph adenoma of pituitary causing GH and IGF-1 overproduction (Melmed 2009; Katznelson et al. 2014). Majority of these are macroadenomas (size > 1 cm). Less than 5 % of cases results from a hypothalamic tumour or a neuroendocrine tumour secreting Growth Hormone Releasing Hormone (GHRH) or rarely GH overproduction from a hemopoeitic or abdominal tumor (Katznelson et al. 2014). GH-producing tumours may be a consequence of the genetic MEN-1 syndrome.

Overstimulation from the excess GH in circulation results in raised plasma levels of IGF-1 produced from liver that causes overgrowth of somatic tissues culminating in the clinical manifestations of acromegaly. Disfigurement of the facial skeleton and enlargement of limbs result from prolonged hyper-stimulation of IGF-1. The clinical manifestations of the disease are related to overgrowth of tissues and the metabolic abnormalities related to excess circulating IGF-1 levels.

The disease affects most body organs and the common manifestations are headache, coarse facial features (frontal bossing and prognathism), enlargement of hands and feet, hypertension and diabetes, osteoarthritis, entrapment neuropathies, sleep apnoea, visual field defects and heart failure. A detailed account of the disease and its clinical features can be found in the recent article (available free in the web) by Capatina et al. (2015).

All patients with clinically suspected acromegaly and typical features should undergo testing for IGF-1 levels. Those with some of the features without a definite clinical picture may also need IGF-1 testing when some of disease-associated features such as sleep apnoea, type 2 diabetes, hypertension, carpel tunnel syndrome, debilitating arthritis or hyperhidrosis are present (Katznelson et al. 2014). IGF-1 levels also should be measured in patients with a pituitary mass to exclude the disease. Biochemical confirmation of acromegaly in patients with elevated or equivocal IGF-1 levels is by a glucose tolerance test to show lack of suppression of GH levels during hyperglycemia (Capatina and Wass 2015; Katznelson et al. 2014).

In biochemically confirmed cases, disease localisation should be done by an appropriate imaging study. An MRI of the pituitary detects a macroadenoma in about 77 % cases (Katznelson et al. 2014; Mestron et al. 2004), and a hyper-intense T2-weighted MRI signal may have prognostic significance (enhanced response to somatostatin receptor ligand [SRL] therapy) (Katznelson et al. 2014; Puig-Domingo et al. 2010). Visual field testing is recommended in all cases with a pituitary macroadenoma in the MRI. If pituitary imaging is negative, GHRH levels should be measured to exclude rare location of the disease in hypothalamus or other tissues with appropriate imaging when necessary (Capatina and Wass 2015).

All resectable tumors in the pituitary should be removed through a transphenoidal hypophysectomy if possible. Some large tumors may need a trans-cranial or combined approach. Sometimes surgical de-bulking improves the medical treatment outcome later if complete removal of the tumor is impossible (Katznelson et al. 2014; Katznelson 2010). Repeated surgery may be necessary if initial procedure did not clear the entire tumor. Postoperative measurement of GH and IGF-1 levels give evidence for clearance of tumor during surgery and pituitary imaging is necessary for anatomical assessment. These are usually done after 12 weeks of surgery (Katznelson et al. 2014).

Medical management becomes necessary when tumors are inoperable or when surgery is incomplete with residual disease. SRLs and pegvisomant are the two classes of drugs with good activity against acromegaly. 2 forms of SRLs are commercially available widely (Octreotide LAR [long acting release] and lanreotide depot/autogel). Pasereotide is a novel SRL with enhanced activity and confers better tumoral response to treatment (Capatina and Wass 2015; Katznelson et al. 2014; Colao et al. 2014). Pegvisomant possess better treatment response than SRLs in patients with acromegaly (Katznelson et al. 2014; van der Lely et al. 2012). Monitoring of response to treatment and dose adjustments are done with serial measurements of IGF-1 and pituitary imaging. Mild disease may respond to dopamine agonists such as cabergoline. Combinations of different drug classes in different multi-drug regimes may be necessary in some cases for enhanced response to treatment (Capatina and Wass 2015; Katznelson et al. 2014). Pituitary radiotherapy may also be necessary in cases with residual disease when medical therapy fails to control the disease.