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- 1. Adrenal physiology and adrenal tumours Lim Ee Jean Whip : Henry Ho
- 2. Outline • Anatomy, Physiology and Pathology of adrenal glands • Approaches to adrenal masses 1) Is the mass metabolically active? - Hyper/Hypofunctinonal disorders 2) Is the mass malignant? - Adenoma - ACC - Mets 3) Is there any indication for surgical intervention? - Open/ Lap
- 5. Embryology • Paired retroperitoneal organs composed of cortex and medulla embryologically and functionally distinct units. • The cortex is derived from the mesoderm - endocrine • The medulla is derived from neural crest cells - neurocrine
- 6. Arterial Supply • Several sources • Superior adrenal arteries • Branches from inferior phrenic arteries • Middle adrenal arteries • Direct from aorta • Inferior adrenal arteries • Branches from the ipsilateral renal artery
- 7. Venous Drainage • Right adrenal vein > inferior vena cava • Left adrenal vein > Left renal vein / Inferior phrenic vein
- 9. Innervation • Cortex • Postganglionic fibres from splanchnic ganglia • Medulla • Preganglionic sympathetic fibres off sympathetic trunk
- 10. Approach 1) Is the mass metabolically active? 2) Is the mass malignant? 3) 3) Is there any indication for surgical intervention?
- 11. Approach 1)Is the mass metabolically active? 2) Is the mass malignant? 3) 3) Is there any indication for surgical intervention?
- 12. Physiology
- 16. Zona Glomerulosa - Aldosterone Action Effect Site of Action Renal Na reabsorption Increased blood volume Increased BP Decrease urine Na Distal Tubule Connecting segment collecting system Renal Cl reabsorption Increase in serum Cl Decrease in urine Cl Distal Tubule Connecting segment collecting system Renal K secretion Decrease serum K Increase urine K Distal Tubule Connecting segment collecting system Renal H+ secretion Increased urine NH4 Collecting system
- 17. Renin- angiotensin- aldosterone (RAA)
- 19. Approach
- 20. Classification of Adrenal Tumours • Adrenal Cortical Tumours • Benign • Adenoma/ Nodular Hyperplasia • Malignant • Adrenocortical Crcinoma • Myelolipoma • Metastasis • Adrenal Medullary Tumours • Benign • Ganglioneuroma, • Pheochromocytoma • Malignant • Neuroblastoma
- 21. Classification of pathology of adrenal gland
- 22. AdrenoCortical Adenoma • Non functioning/ Non hormone producing tumours • With advent of better CT/MRI imaging -> increasing pickup of incidentaloma • Functional/ Hormone producing • Hypersecretion of Cortisol => CUSHING’s syndrome • Hypersecretion of Aldosterone = CONN’s syndrome
- 23. Regulation of cortisol (HPA axis )
- 24. Regulation of Aldosterone (RAS)
- 25. Cortisol Regulation • Hypothalamus – Pituitary Adrenal Axis Feedback loop (HPA)
- 26. Cushing’s syndrome • Signs and symptoms due to Hypercortisolism • Cushing’s disease = pituitary tumour secreting inappropriate ACTH
- 27. Causes of Cushing’s syndrome
- 28. Evaluation of Cushing’s Syndrome 1. 24hr- urinary free cortisol evaluation • Most accurate in GFR > 60ml/min • Cut off 50-100mcg/24hrs 2. Low-dose dexamethasone suppression test • 1mg dexa at 11pm-12mn, serum cortisol at 8-9am • Cortisol level should be suppressed below 5mcg/dl • Not affected by GFR; 50% false positive with oral contraceptives 3. Late night salivary cortisol • False +ve with depression, altered sleep, chronic illness • Tobacco affects salivary cortisol
- 30. Treatment of Cushing’s syndrome • Exogenous Cushing syndrome • Cessation of glucocorticoids gradually • ACTH secreting pituitary adenoma (Cushing disease) • Transsphenoidal resection • Bilateral adrenalectomy • Ectopic ACTH • Resection of primary ACTH producing tumor • Bilateral adrenalectomy • ACTH independent macronodular adrenal hyperplasia (AIMAH) / Primary pigmented nodular adrenocortical disease (PPNAD) • Bilateral adrenalectomy is done when hypercortisolism is lifethreatening and swift definitive treatment is mandatory or in patients with unresectable primary tumors or whose primary ACTH-producing tissue cannot be identified. • Medical treatment • Medications that block enzymes of steroid synthesis • Metyrapone. Aminoglutehimidine, trilostan, ketoconazole, etomidate
- 31. Peri-operative management • Pre-operative management • Treat comorbidities DM/HTN, and osteoporosis • Postoperative management • No steroid coverage postoperatively, measure morning cortisol on POD1 and start hydrocortisone until cortisol level available • Cover with glucocorticoids and evaluate HPA axis later on Martha AZ et al. Medical and surgical evaluation and treatment of adrenal incidentalomas. J Clin Endocrinol metab Jul 2011, 96(7): 2004-15
- 32. Primary Aldosteronism • Pathophysiology • Increased aldosterone secretion independent of the RAAS. • Clinical features • Hypertension, hypokalemia, hypernatremia, metabolic alkalosis • Causes • 2/3 of cases are due to Adrenal adenoma – surgical treatment (adrenalectomy) • 1/3 Idiopathic Adrenal Hyperplasia – medical treatment (Spironolactone, antihypertensives)
- 35. Evaluation of Primary Aldosteronism • Screening of PHA • Morning (8-10am) plasma aldosterone concentration and plasma renin activity • Aldosterone: renin ratio > 30 (NIH Consensus) • & PAC > 20ng/dl • Confirmatory testing • Fludrocortisone suppression test • Oral sodium loading test • IV saline infusion • Captopril suppression test
- 36. Lateralization of aldosterone secretion • Adrenal CTs • Disadvantages • Small size producing adenoma (False Neg) • Non functional incidentaloma (False positive)
- 38. Peri-operative mxn of PA • K supplementation and spironolactone should be stopped on POD1 • Close monitoring of serum K • Temporary state of hypoaldosteronism • Increase salt intake • Fludrocortisone 0.1mg/d x few weeks Martha AZ et al. Medical and surgical evaluation and treatment of adrenal incidentalomas. J Clin Endocrinol metab Jul 2011, 96(7): 2004-15
- 39. Medical Management of PA • Aldosterone receptor antagonist • Spironolactone / eplerenone • 25 – 400mg /day • Gynecomastia, impotence, menstrual disturbance • Other antihypertensives • Weight loss, low sodium diet • FM type 1 • Can be treated with corticosteroids decrease ACTH
- 40. Phaechromocytoma • Adrenal Medulla tumour • Catecholamine-producing cells • 5% of incidentalomas • 10% tumor • 10% extraadrenal - paragangliomas • 10% familial • 10% bilateral • 10% paediatric • 10% malignant (+ metastases)
- 44. Localization of pheochromocytoma • Radiological cross sectional • CT • Attenuation >10HU on Unenhanced scan • NO Rapid contrast washout • MRI • Does NOT exhibit signal dropout on out of phase sequences ( Unlike lipid rich adenoma)
- 45. Localization of pheochromocytoma •Functional imaging •Metaiodobenzylguanidine (MIBG) scintigraphy • 131I or 123I MIBG • High sensitivity (83-100%) and specificity (95-100%) • W/u of extraadrenal, metastatic, recurrent pheo • For > 5cm pheo to rule out metastasis •PET • 18F-Dopa • Galium-68 DOTATATE PET/CT ( Known MEN )
- 46. Pre-operative management • CONTROL BP • Alpha blockade 1st! • INTRA VASCULAR VOLUME • In absence of alpha blockade, beta blockade may potentiate the action of EPINEPHRINE on Alpha 1 receptors, due to blockage of arteriolar dilatation at Beta 2 receptors • Intraoperatively • HYPERTENSIVE CRISIS – Nitroprusside / Esmolol
- 47. Post-operative management • BLOOD PRESSURE • Hypotension => Long term effects of phenoxybenzamine • GLYCEMIC CONTROL • Hypoglycemia • A2-adrenoreceptor stimulation inhibits insulin release • Withdrawal of stimulus leads to rebound hyperinsulinemia and hypoglycemia
- 48. Follow up • Repeat metabolic testing at 2 weeks to document normalization • Lifelong follow up with pheochromocytoma is essential • Annual biochemical follow up • Post operative cross sectional imaging • * 10 year recurrence rates are as high as 16%
- 50. Hyposecretion / Adrenal Insufficiency
- 51. Acute adrenal insufficiency Crisis • Hypotension unresponsive to fluid resuscitation • Abdominal pain • Nausea • Vomiting • Fever
- 53. Diagnosis and treatment • Diagnosis • Screening • Morning cortisol and ACTH • Abnormal aldosterone / renin • Synacthen stimulation tests • Treatment – adrenal hormonal repletion • Hydrocortisone 15-25mg / day • Fludrocortisone (only in primary adrenal insufficiency)
- 55. Approach 1) Is the mass metabolically active? 2) Is the mass malignant? 3) 3) Is there any indication for surgical intervention?
- 56. Adrenocortical carcinoma (ACC) • Incidence 0.5-2 per million • Bimodal age distribution • 1st decade of life, 4-5th decade of life • F : M 1.5 :2.1 • Majority are sporadic and unilateral • 2% bilateral disease => associated with hereditary disorder ( Li- Fraumeni, Beckwith-Wiedman) • Symptoms at diagnosis (2/3) • Hormonal hypersecretion • Cortisol (30%), androgen (20%), estrogen (10%), aldosterone (1%), multiple (35%) • Pain from voluminous or locally invasive tumor
- 58. Diagnosis • CT / MRI • Heterogeneous texture • Irregular contour • Foci of hemorrhage or necrosis • Almost all > 5cm • Detect local invasion, peritumoral lymphadenopathy, mets to lungs, liver, bone, peritoneal surface • FDG-PET enhances • Percutaneous biopsy • not performed prior to surgical excision due to unacceptable risk of needle- tract seeding Germain et al. Surgical management of adrenal tumors. Journal of Visceral Surgery 2011; 148: e250-61
- 61. Staging • UICC, Union Internationale Contre Le Cancer; WHO • T1, <5 cm • T2, >5 cm • T3, infiltration of surrounding adipose tissue • T4, invasion into adjacent organs.
- 62. Principles of Surgical Management • Complete R0 resection without capsular rupture or tumor dissemination • Enblock resection with removal of locally involved organs is recommended • Eg tumour thrombus in vena cava • Tumor debulking -> control hormone excess in functioning tumors • European Network for the Study of Adrenal Tumors (ENSAT) • Stage I – III , open surgery by expert surgeon is treatment of choice. • In patients without distant mets • Predictors for tumor-free survivor • Absence of nodal involvement • Venous Thrombosis • Invasion of peri-adrenal fat
- 63. Principles of Surgical Management • Laparoscopic adrenalectomy for ACC is possible with equivalent local recurrence, peritoneal, distant metastasis rate (26-32%) • Reserved for small tumors < 8cm • Follow up CT chest/abdo/pelvis Rare malignancy requiring multispecialty care! Germain et al. Surgical management of adrenal tumors. Journal of Visceral Surgery 2011; 148: e250-61
- 64. Medical management • Patients not amenable to surgery • Mitotane (a drug specifically killing cells of adrenocortical origin) • Requires constant monitoring • Advanced disease • Phase 3 trial • Etoposide, doxorubicin, cisplatin plus mitotane and streptozotocin plus mitotane)
- 65. European Network for the Study of Adrenal Tumors (ENSAT)
- 66. Adrenal Metastasis • Primary • Melanoma, Lung, • RCC, Breast, Medullary thyroid, contralateral adrenocortical ca, GI, prostate ca, cervical ca, basal cell, pancreatic, cholangioca, urothelial, SCC, seminoma, thymoma, CML • In pt with previous malignancy, 50% of new adrenal lesions are metastatic • Few pt with met to adrenals exhibit adrenal insufficiency
- 67. Adrenal Adenoma • Most common neoplasms arising from adrenal gland, associated with cortex • > 85% of adrenal neoplasms discovered on imaging are adenomas • Incidence rises with age • Abdundant lipid; histologically difficult to distinguish from adenoca – use Weiss criteria • 7.1% of adenomas metabolically active • 6% glucocorticoids • 1.1% aldosterone
- 68. Imaging characteristics of adrenal adenoma Germain et al. Surgical management of adrenal tumors. Journal of Visceral Surgery 2011; 148: e250-61
- 69. • Surgery • All secretory tumors • Those with imaging characteristics suggestive of malignancy • Tumors > 4cm (risk of malignancy substantial) • Tumors that cause pain / other symptoms • Follow up (Surveillance) • BMI, hypertension, glycemia, lipid levels 6mth initially then 2-5yrs • 1mg DST, measurement of metanephrines 6mth then every 2-5yrs • Reimaging at 6, 12 and 24mths to document indolent growth Adrenal Adenoma
- 70. Adrenal Oncocytoma • Rare (50 cases in literature so far) • Mitochondria-rich, large, eosinophilic cells with abdunant granulations • F : M 2.5 :1 • L :R 3.5 :1 • Metabolic INACTIVE • Usually made on surgical resection Macroscopic appearance of the oncocytoma with compressed residual adrenal (arrow).
- 71. Adrenal Myelolipoma • Incidence 0.1% in autopsy series • Stem cell proliferation – mixture of mature adipose tissue and hematopoietic elements • Asymptomatic, spontaneous rupture rare, metabolically nonfunctional • CT • well circumscribed, varying amt of mature adipose tissue 30HU interdigitated with higher density myeloid components • Presence of macroscopic fat diagnostic • Classically treated conservative, surgery for symptomatic lesions
- 72. Other adrenal masses • Ganglioneuroma • Rare, benign neuroectodermal neoplasm • Occur in the young • Can grow to encase critical structures • Diagnosis is pathologic and clinical course benign • Adrenal cysts • Rare, 0.064% -0.18% in autopsy series, 1-5% of incidentalomas • Pseudocysts, endothelial, epithelial, parasitic • 7% associated with malignancy • Active surveillance done with caution; surgical resection remains standard of care
- 73. Adrenal Incidentalomas • >1cm identified on cross sectional imaging performed for UNRELATED CAUSES • NEW disease due to improvements in imaging • Incidence increases with age, • <0.5% in 20yrs , to 7% > 70yrs • INCIDENTAL does NOT mean NOT SIGNIFICANT • Up to 20% are potentially surgical lesions
- 75. • Imaging • Size • Functional testing
- 76. Size? • Retroperitoneal space – can allow up to 20cm before symptomatic • Increase in size = Increase in adverse pathological features • < 4cm, follow up (baseline malignancy risk =2%) • 4-6 cm, not well established (baseline malignancy risk = 6%) • >/=6cm resected (baseline malignancy risk = 25%) ACR Appropriateness Criteria on incidentally discovered adrenal mass 2012
- 77. Rate of growth • Unusual for malignancy to be stable over 6mths • If stable on prior imaging for 2 years no further follow up • If < 2yrs, follow up till 2 yrs • No threshold guidelines • New lesion/ Rapid growth >1cm/ year suggestive of malignancy • Stablility or slow growth rate (0.5cm to 1cm/yr) suggests a benign process The Incidentally Discovered Adrenal Mass. William F Young Jr MD. N Engl J Med 2007; 356: 601-10
- 78. Adrenal Biopsy? • Utility is limited • Modern imaging superb diagnostic capability • Histologically adenomas cannot be reliably differentiated from adrenal carcinomas • Adrenal biopsy risks • Bleeding • Pneumo/hemothorax • Needle tract seeding • Hemorrhage that complicate future resection • Always exclude pheo • Differentiate benign from metastatic disease
- 80. Approach 1) Is the mass metabolically active? 2) Is the mass malignant? 3)Is there any indication for surgical intervention?
- 83. Contraindications to Laparoscopic Approach? • Absolute • Severe coagulopathy • Poor cardiopulmonary status • Relative contraindications to laparoscopy • Previous open surgery • Tumor size • Obesity • Adrenal cortical carcinoma
- 84. Open adrenalectomy ? • Adrenal cortical carcinoma with radiographic evidence of extra- adrenal tumor invasion of adjacent organs • Extension of adrenal vein tumor thrombus into inferior vena cava • Approaches • Transperitoneal • Better exposure for large tumors • Prolonged ileus; difficult exposure in obese patients • Midline • Subcostal • Thoracoabdominal • Retroperitoneal • Less ileus shorter hospital stay • Smaller operative field, access to large tumors and surrounding involved organs difficult • Flank • Posterior lumbodorsal
- 88. Disorders of HYPERfunction • Hypercortisolism (Cushing’s syndrome) • Hyperaldosteronism (Conn’s syndrome) • Virulism tumors
- 92. Zona Glomerulosa - Aldosterone
- 93. Principles of Endocrine Surgery • Confirm diagnoiss • Render the patient safe • E.g. HTN , steroid supplementation • Localization • Is surgery indicated?
- 94. Histology
Editor's Notes
- Retroperitoneal Mustard yellow cortex 4 – 5g 4-6cm length, 2-3cm width Right triangular, left crescent shaped
- Above each adrenal lies the diaphragm; medially are the aorta or the vena cava; laterally is the abdominal wall; inferiorly is the kidney to which the adrenal is so firmly attached that pulling down the kidney is a useful way of bringing the adrenal into a surgical incision. In front are the duodenum and colon: behind the diaphragm, 12th rib, and the pleural recess. The right gland has a pyramidal shape and lies between the inferior vena cava and the right crus of the diaphragm. Its upper part lies in contact with the bare area of the liver, whilst its lower half has a peritoneal covering. The left gland is more crescentic in shape and lies on the medial border of the left kidney above the hilum, sandwiched between tail of pancreas and left crus of diaphragm.
- The adrenal cortex comprises three zones: Zona glomerulosa – mineralocorticoids predominantly aldosterone Zona fasciculata – glucocorticoids Zona reticularis – sex steroids estrogens and androgens The adrenal medulla comprises less than 10% of total adrenal mass. Lies at the center of the gland and is an integral part of the autonomic nervous system. secretes epinephrine (80%), norepinephrine (19%), and dopamine (1%).
- Zona Glomerulosa - Aldosterone
- Primary Pigmented Nodular Adrenocortical Disease. Like AIMAH, primary pigmented nodular adrenocortical disease (PPNAD) is exceedingly rare, accounting for less than 1% of cases of Cushing syndrome. Unlike AIMAH, however, the adrenal glands in this condition remain normal in size and exhibit black or brown cortical nodules (Young et al, 1989). The cortical tissue surrounding the nodules is atrophic, and the adrenal medulla is free of disease (Lacroix and Bourdeau, 2005). Approximately half of PPNAD is found in patients with the autosomal dominant Carney complex, which is also responsible for spotty skin and mucous membrane lesions, and a variety of neoplasms that include Sertoli cell tumors. The other half of cases of PPNAD are nonhereditary with no known cause (Lacroix and Bourdeau, 2005). ACTH secreting pit adenoma Primary tumour resection , however it might not possible ( only 10%) resectable Bilateral adrenealectomy with lifelong replacement therapy Medical treatment For bridging a patient to surgery or when surgery not possible Block enzmes of steroid synthesis Left to endocrinologist
- In primary aldosteronism, aldosterone secretion is independent of the RAAS, and plasma renin levels will be suppressed. This finding is in contrast to patients with secondary hyperaldosteronism, in whom elevated renin levels are the cause of elevations in aldosterone secretion. This distinction between plasma renin levels in primary and secondary hyperaldosteronism is a critical concept used when screening for primary aldosteronism
- Before screening is initiated, hypokalemia should be corrected and all contraindicated medications discontinued. Although patients can continue the majority of antihypertensive agents during screening, mineralocorticoid receptor antagonists are contraindicated and should be stopped at least 6 weeks before testing (Seifarth et al, 2002; Young, 2007a). Patients requiring these agents for control of severe hypertension should be transitioned to agents, such as α1-receptor blockers or long-acting calcium channel blockers, with minimal effects on screening test results (Rossi et al, 2008a). Other antihypertensive agents can alter screening values, but not to the extent that mandates their discontinuation (see Fig. 65-32, later). Screening for primary aldosteronism begins by obtaining a morning (between 8 and 10 AM) plasma aldosterone concentration (PAC) and PRA (Funder et al, 2008). From these tests, the PAC and aldosterone-to-renin ratio (ARR) are used to screen for autonomous aldosterone secretion. Whereas the ARR is dependent on PRA, it is recommended that the lowest PRA value be set at 0.2 ng/mL/hr to avoid falsely elevated ratios (Rossi et al, 2006a). The PACs and ARRs that define a positive screen and suggest the diagnosis of primary aldosteronism are subject to laboratory variability; thus, standard thresholds have not been established. Reported sensitivities and specificities for use of ARRs in screening for primary aldosteronism range from 66% to 100% and 61% to 96%, respectively (Jansen et al, 2014).The National Institutes of Health (NIH) Consensus Statement (2002) on the management of the clinically inapparent adrenal mass suggests cutoffs of greater than 30 for the ARR and greater than 20 ng/dL for the PAC. However, other institutions have recommended lowering the cutoffs to greater than 20 and greater than 15 ng/dL, respectively (Young, 2007a; Rossi et al, 2008a). Although lowering the thresholds for a positive screening test result may increase the rate of false positives, all positive test results must be confirmed with further testing before the diagnosis of primary aldosteronism is made. Measurement of PRA can be time-consuming and varies among different laboratories. For this reason, plasma renin concentration has been evaluated as a possible replacement for PRA in screening for primary aldosteronism (Ferrari et al, 2004; Perschel et al, 2004). Although initial series evaluating the usefulness of plasma renin concentration in primary aldosteronism screening have demonstrated promise, these findings require further standardization and validation before widespread use (Young, 2007a; Rossi et al, 2008b). Confirmatory Testing. After a positive screening test result, a confirmatory test must be performed before the diagnosis of primary aldosteronism is secured, owing to the known variability of aldosterone and PRA levels secondary to day-to-day oscillation, posture, diet, and antihypertensives (Salva et al, 2012). Of patients with positive screening test results, only 50% to 87% will be diagnosed with primary aldosteronism on confirmatory testing (Mosso et al, 2003; Seiler et al, 2004; Giacchetti et al, 2006; Nanba et al, 2012). As with screening for primary aldosteronism, proper patient preparation is required, with the correction of hypokalemia and discontinuation of mineralocorticoid receptor antagonists. Of the confirmatory tests available, the majority evaluate the suppression of aldosterone after sodium loading. The underlying theory behind the sodium loading tests is that loading will decrease plasma renin and aldosterone production in patients without autonomous aldosterone secretion (Mattsson and Young, 2006). Additional confirmatory tests, including captopril suppression test, furosemide-upright test, and the ACTH stimulation test, have been described but are not widely accepted or used (Hirohara et al, 2001; Sonoyama et al, 2011). The selection of the confirmatory test used depends on individual patient characteristics and physician preferences. Blood pressure should be monitored closely in all patients during confirmatory testing. The fludrocortisone suppression test requires the administration of the synthetic mineralocorticoid fludrocortisone (0.1 mg every 6 hours) and sodium chloride (2 g every 8 hours) for 4 days. After 4 days of fludrocortisone and sodium loading, PAC is measured in the upright position. Failure to suppress PAC to less than 6 ng/dL is diagnostic of primary aldosteronism. Once considered
- 5 year survival is poor 20-47% Advanced stage at diagnosis High rate of recurrent disease Limited efficacy of current systemic treatment
- In patients not amenable to surgery, mitotane (a drug specifically killing cells of adrenocortical origin) remains the treatment of choice. Monitoring of drug levels (therapeutic range 14 - 20 mg/l) is mandatory for optimum results. In advanced disease, the most promising therapeutic options (etoposide, doxorubicin, cisplatin plus mitotane and streptozotocin plus mitotane) are currently compared in an international phase III trial. Adjuvant treatment options after complete tumour removal (e.g. mitotane, radiotherapy) are urgently needed, as postoperative disease free survival at five years is below 50%.
- Masses that exceed 6 cm should be considered malignant until proven benign, which usually requires definitive resection. Management of incidentalomas between 4 cm and 6 cm is more controversial. In this intermediate size range, the rate of malignancy is estimated to be only 6% (
- Transperitoneal Better exposure for large tumors Prolonged ileus; difficult exposure in obese patients Midline Subcostal Thoracoabdominal Retroperitoneal Less ileus shorter hospital stay Smaller operative field, access to large tumors and surrounding involved organs difficult Flank Posterior lumbodorsal
- The adrenal cortex comprises three zones: Zona glomerulosa – mineralocorticoids predominantly aldosterone Zona fasciculata – glucocorticoids Zona reticularis – sex steroids estrogens and androgens The adrenal medulla comprises less than 10% of total adrenal mass. Lies at the center of the gland and is an integral part of the autonomic nervous system. secretes epinephrine (80%), norepinephrine (19%), and dopamine (1%).