1. ADRENAL DISORDERS PCC Dr Prashant Bansal

2. Introduction Tumour of catecholamine-producing cells of adrenal medulla Incidence: ~ 1 2/1,00,000 Responsible for approximately 0.5% of cases of hypertension Amongst adrenal incidentalomas ~5% = pheochromocytoma Incidentally discovered lesions = 10% to 25% of all PCC Extra adrenal PCC (aka Paraganglioma) Upto 25% Arise from paraganglia, a network of chromaffin-producing neural crest tissue that anatomically parallels sympathetic and parasympathetic ganglia Can arise in head, neck, thorax, abdomen, and pelvis (including bladder). The chromaffin bodies that lie between the aortic bifurcation and the root of the inferior mesenteric artery are known as the organ of Zuckerkandl, and are a common site for Paraganglioma 3. Some authors reserve term Paraganglioma for tumours only in head and neck, where they tend to be non-functional Pheochromocytoma Adrenal Extra-adrenal (75%-90) (10%-25%) Introduction 4. Pathophysiology Cells of adrenal medulla are analogous to chromaffin cells of sympathetic ganglia However, unlike sympathetic ganglia cells, they possess enzyme phenylethanolamine- N-methyl transferase (PNMT), which gives them ability to synthesize epinephrine from norepinephrine Pheochromocytomas vary in Enzymatic composition and Ability to self-metabolize catecholamines within each secretory vesicles Therefore there is great variability in amount and ratio of catecholamines secreted 5. Pathophysiology Patients that secrete primarily epinephrine E.g., Adrenal PCCs or from organ of Zuckerkandl Experience syncopal or hypotensive episodes (vasodilatory action through 2 rec) Patients with predominantly norepinephrine-secreting tumours E.g., von HippelLindau syndrome present with hypertension and sweating (affinity for vasoconstricting - adrenorec) 6. Pathophysiology Hereditary PCC Familial cases ~ 1/3rd of PCCs Many cases initially appear sporadic, are later found to be hereditary on genetic testing 24% of patients who present with isolated PCC and lack any significant F/H exhibit a germ-line mutation that predisposes them to PCC At least five genes are now a/w familial PCC REarranged Transfection proto-oncogene (RET) Von HippelLindau (VHL) Neurofibromatosis type 1 (NF1) Mitochondrial Succinate Dehydrogenase subunits D and B genes (SDHD, SDHB) Probably, these abnormalities modulate neuronal apoptosis and are related through signal transduction pathways downstream from nerve growth factor (NGF) 7. VHL Is the most relevant syndrome a/w PCC, due to their propensity to develop RCC Type 1: Patients with VHL and no family history of pheochromocytoma Type 2: = VHL + F/H of PCC Type 2A: Patients have concomitant RCC Type 2B: Patients do not exhibit e/o renal malignancy Type 2C: PCC in setting of VHL mutation, but no other stigmata of the VHL syndrome VHL-associated PCC type 2 more likely to have a missense mutation of VHL gene Whereas VHL type 2C patients appear to maintain HIF regulation, pheochromocytoma pathogenesis may occur through HIF-independent pathways Pathophysiology 8. PCC in VHL (c.f. sporadic/MEN) tend to produce less epinephrine. As a result Metanephrine levels are nearly always normal Normetanephrine levels are elevated Pathophysiology 9. Malignant PCC Is an aggressive life-threatening neoplasm Currently, malignancy can only be defined by presence of clinical mets. Pathologic appearance and local invasion are of limited value in determining mets potential A number of pathologic criteria to d/d benign from malignant disease have been proposed, but there is no single Histologic criterion agreed upon Immunohistochemical strategies: Ki-67 staining: May be the best indicator of malignancy till date Not yet validated Malignant pheochromocytoma in patients with MEN-2 and VHL is exceedingly rare SDHB mutation is the single genetic abnormality most strongly associated with malignancy Pathophysiology 10. Clinical Features Classically, pheochromocytoma has been called the 10% tumour: 10% extra- adrenal, 10% familial, 10% bilateral, 10% paediatric, and 10% malignant Extra-adrenal Upto 25% Familial Upto 30% Malignancy Is rare in sporadic (upto 5%) and hereditary cases It occurs in > 1/3rd of extra-adrenal PCC Nonhereditary cases are most often diagnosed in 4th & 5th decades Familial tumours tend to occur at a younger age Paediatric PCC Despite being uncommon, paediatric PCC = MC endocrine neoplasm in children. Upto 40% = familial > 20% = bilateral 11. For reasons that are unclear, tumours arising from right adrenal are more common, tend to be larger, and recur more frequently than those that arise in the left gland Classic hallmark of PCC = triad of headache, episodic sudden perspiration, and tachycardia Paroxysmal hypertension Episodic spikes in blood pressure Classic presenting symptom Seen in only 30 to 50% Can occur in the backdrop of baseline essential hypertension. The remainder of patients demonstrate persistently elevated blood pressure Minority = entirely normotensive More than 20% of patients can be asymptomatic Clinical Features 12. Clinical Manifestations FREQUENCY Headache 60%-90% Palpitations 50%-70% Sweating 55%-75% Pallor 40%-45% Nausea 20%-40% Flushing 10%-20% Weight loss 20%-40% Tiredness 25%-40% Psychologic symptoms (anxiety, panic) 20%-40% Sustained hypertension 50%-60% Paroxysmal hypertension 30% Orthostatic hypotension 10%-50% Hyperglycemia 40% Clinical Features 13. Occur at a younger age Tend to be multifocal and/or bilateral at presentation Pheochromocytomas in patients with MEN-2 nearly always arise from adrenal VHL extra-adrenal ~ 12% Neurofibromatosis-1 (NF1) extra-adrenal ~ 6% SDHB and SDHD mutations Mostly extra-adrenal and multifocal Solitary adrenal masses may also arise Mutations in the SDHB gene a/w very high risk of malignancy Clinical Features (Hereditary PCC) 14. Mets more common in extra-adrenal lesions SDHB mutation is strongly associated with metastatic disease Classically majority of patients exhibit extra-adrenal disease However, a significant proportion have adrenal lesions at presentation More likely to exhibit elevated dopamine levels Tend to be larger (>5 cm) However, a preclinical diagnosis of malignant potential is not possible MC sites of Mets: Bone, lungs, liver, and lymph nodes Metastatic pheochromocytoma can be present at diagnosis or be detected during surveillance after excision of the primary tumour. Most metastases are discovered within 5 years of the original diagnosis, but metastatic spread more than 15 years following initial excision has been reported Clinical Features (Malignant PCC) 15. Diagnosis Clinical evaluation depends on Biochemical testing (M Imp) Radiographic imaging Biochemical testing is the first step in evaluation of suspected PCC If positive imaging to localize the source of catecholamine excess In urologic practice, diagnosis begins with evaluation of a catecholamine hyper- secreting adrenal mass Possibility of pheochromocytoma must also be considered in Patients with a known history of malignancy, Solitary adrenal mass in those whom a metastatic adrenal lesion is suspected 16. Biochemical Evaluation Catecholamines and their metabolites, including Metanephrines, are conjugated with a sulfate moiety in the bloodstream. Free not conjugated and lack sulfate group. Total amounts of catecholamine metabolites Used in the past Not able to discriminate between free and sulfonated compounds Fractionated is used when laboratory reports Amount of each compound type (e.g., Metanephrines) and also Relative concentrations of each compound (e.g., Normetanephrine and Metanephrine) 17. CATECHOLAMINE TESTING Catecholamines: Dopamine, Norepinephrine and Epinephrine Release of these compounds into the bloodstream is often paroxysmal Measurement of urinary and serum catecholamine levels In the past mainstay for evaluation Sensitivity 85% Specificity 85% Largely replaced by measurement of Metanephrine levels (Methylated metabolites of catecholamines) Measurement of urinary catecholamines is still recommended in conjunction with urinary fractionated Metanephrine testing Biochemical Evaluation 18. METANEPHRINE TESTING O-Methylation of catecholamines is catalyzed by catechol-O-methyltransferase (COMT) enzyme O-Methylation of Norepinephrine Normetanephrine O-Methylation of Epinephrine Metanephrine Normetanephrine + Metanephrine = Metanephrines Historically, formation of Metanephrines was believed to take place by COMT in liver and kidneys after catecholamines were released into peripheral circulation Now it is clear that majority of Metanephrine synthesis occurs within adrenal medulla and/or pheochromocytoma and only then it enters bloodstream Biochemical Evaluation 19. METANEPHRINE TESTING (Contd) Because this conversion of catecholamines to Metanephrines is an uninterrupted process within Pheochromocytomas, measurement of plasma concentration of Metanephrines is a much more sensitive means of tumour detection than the measurement of rises in plasma catecholamines, which may be paroxysmal Today, measurement of Metanephrine levels in plasma or urine = foundation for pheochromocytoma diagnosis Extremely sensitive Controversy exists regarding whether plasma-free Metanephrines versus urinary fractionated Metanephrines should be used as the initial test Traditionally, when fractionated urine or total Metanephrines are ordered, urine catecholamine levels are also obtained Biochemical Evaluation 20. URINE VMA TESTING VMA is the primary end metabolite of catecholamines Synthesis of VMA requires deamination of catecholamines, or their metabolites, by the monoamine oxidase (MOA) enzyme Occurs not only in adrenal medulla but also in sympathetic nervous system. Sympathetic nervous system lacks ability to produce epinephrine (due to absence of PNMT). Therefore it only contributes to Normetanephrine but not Metanephrine ????Therefore, relative rise of VMA levels in presence of pheochromocytoma is much less dramatic than rise seen in Metanephrines levels.???? Sensitivity is therefore low (below 65%) Specificity is high, especially in nonfamilial cases (99%) Biochemical Evaluation 21. CLONIDINE SUPPRESSION TESTING Clonidine, an 2 agonist, suppresses catecholamine (specifically norepinephrine) production by the sympathetic nervous system but not by pheochromocytoma Comparison of normetanephrine levels before and after Clonidine administration has been shown to yield results with favorable test characteristics This evaluation is suggested for secondary testing in patients with pheochromocytoma who exhibit mild or borderline elevations in Metanephrine levels. When embarking on Clonidine suppression testing, one must be cognizant that Clonidine administration can result in significant hypotension in certain patients Biochemical Evaluation 22. CHROMOGRANIN A TESTING Chromogranin A belongs to a group of compounds known as granins, which exist in the secretory vesicles of the neuroendocrine and the nervous systems. Elevation of serum Chromogranin A levels has been documented in patients with pheochromocytoma Although the sensitivity of the test for detecting pheochromocytoma is suboptimal (85%) has a role for confirmatory testing in patients who have mild or moderate (less than a fourfold) elevation in free-plasma Metanephrine levels Chromogranin A is renally cleared, and the specificity of the test decreases significantly in patients with glomerular filtration rates less than 80 mL/min Biochemical Evaluation 23. Biochemical Evaluation Table 5711. Test Characteristics for Diagnosis of Pheochromocytoma from a Large Multicenter Cohort Study (n = 858, 214 Patients with Pheochromocytoma and 644 Controls) Sensitivity, % Specificity, % Hereditary Sporadic Hereditary Sporadic Plasma-free metanephrines 97 (74/76) 99 (137/138) 96 (326/339) 82 (249/305) Catecholamines 69 (52/75) 99 (126/137) 89 (303/339) 72 (220/304) Urine-fractionated 96 (26/27) 97 (76/78) 82 (237/288) 45 (73/164 Metanephrines) Catecholamines 79 (54/68) 91 (97/107) 96 (312/324) 75 (159/211) Total metanephrines 60 (27/45) 88 (61/69) 97 (91/94) 89 (79/89) Vanillylmandelic acid 46 (30/65) 77 (66/86) 99 (310/312) 86 (132/153) From Lenders J, Pacak K, Walther M, et al. Biochemical diagnosis of pheochromocytoma: which test is best? J Am Med Assoc 2002;287(11):142734, Table 3. 24. Imaging CROSS-SECTIONAL IMAGING (CT Scan) Pheochromocytomas appear as well-circumscribed lesions Given their rich vascularity and low lipid content, Pheochromocytomas typically measure an attenuation > 10 HU on NCCT (mean 35 HU) This property affords ability to differentiate them from lipid-rich adenomas Can be distinguished from lipid-poor adenomas using CT contrast washout strategies Although nonspecific, Pheochromocytomas, unlike adenomas, do not exhibit rapid contrast washout on delayed imaging Rare examples of low-density Pheochromocytomas that exhibit an unenhanced attenuation of less than 10 HU and demonstrate brisk contrast washout have been reported In the past, iodinated IV contrast was believed to be a possible trigger for a hypertensive crisis. No evidence exists to support this misconception 25. Imaging of pheochromocytoma A: Axial T2-weighted MR image of a right adrenal mass that proved to be pheochromocytoma. B: MIBG scan of a different patient with a localized left pheochromocytoma. Normal uptake can be seen in liver, salivary glands, thyroid and bladder. 26. MRI Similar to CT, magnetic resonance imaging is an excellent imaging modality for characterizing adrenal lesions Again differentiation of pheochromocytoma from adenoma centers on an assessment of the lesions lipid content Unlike lipid-rich adenomas, Pheochromocytomas do not exhibit signal dropout on out-of-phase sequences light bulb sign Classically: bright signal intensity on T2W (best seen on fat suppression sequences) Was believed to be diagnostic for pheochromocytoma. It is now clear that this is neither specific nor sensitive Imaging 27. Functional Imaging METAIODOBENZYLGUANIDINE (MIBG) SCINTIGRAPHY MIBG is a small-molecule analogue of norepinephrine When tagged with 131I or 123I, MIBG Scintigraphy has been used to evaluate PCC Selective uptake of MIBG by pheochromocytoma cells occurs 123I-MIBG for identification of pheochromocytoma Sensitivity = 83% to 100% Specificity = 95% to 100% Uses: Extra-adrenal, metastatic, or recurrent PCC To localize diseases in patients with biochemical evidence but negative imaging for large (>5 cm) tumours is important to assess for presence of metastatic disease prior to surgery 28. Currently no consensus exists on role of MIBG in a solitary adrenal mass on imaging + biochemical evaluation s/o PCC MIBG in this situation can safely be omitted, because it only serves to confirm what is already known and does not alter management Rarely, MIBG scanning may also be employed in cases where metabolic workup of an adrenal mass reveals exclusive excess of norepinephrine and normetanephrine, but not epinephrine or Metanephrine. In such unusual circumstances, MIBG can demonstrate that actual functioning lesion is extra- adrenal Normal uptake can be seen in liver, salivary glands, thyroid and bladder. Functional Imaging 29. OTHER FUNCTIONAL IMAGING MODALITIES Whole-body functional imaging with MIBG has its limitations Tumours with VHL and SDHB mutations may exhibit cold MIBG scans Aggressive metastatic lesions may lose their ability to accumulate MIBG Several modalities using radiolabelled Somatostatin analogues and PET radiopharmaceuticals have been developed to serve as alternatives to MIBG Most have limited clinical utility However, PET imaging with 18F-dopamine has gained acceptance FDG-PET was recently shown as a useful clinical tool for patients with SDHB mutation Functional Imaging 30. Screening for Hereditary Pheochromocytoma More than one third of Pheochromocytomas Furthermore, nearly one quarter of patients who appear to have sporadic nonfamilial disease at diagnosis demonstrate germline mutations upon genetic testing Despite this, the consensus of The First International Symposium on Pheochromocytoma in 2005 did not endorse universal genetic testing in all patients diagnosed with pheochromocytoma Figure 5719 summarizes how clinical history and disease characteristics at presentation should guide genetic testing All patients under age 50 deserve genetic testing for the RET, VHL, SDHB, and SDHD gene mutations Routine testing for the NF1 gene is not recommended in patients who do not meet clinical criteria for neurofibromatosis Genetic Testing 31. Treatment Pheochromocytoma is a surgical disease Complete resection of tumour is advised whenever possible Laparoscopic adrenalectomy = standard of care for most tumours Open approach = for large and/or surgically difficult tumours 32. Preoperative Management Catecholamine release during intraoperative tumour manipulation can result in hazardous blood pressure elevation and cardiac arrhythmias. In 2005, the First International Symposium on Pheochromocytoma recommended that all patients with pheochromocytoma and an abnormal metabolic evaluation undergo preoperative catecholamine blockade, including patients who do not exhibit evidence of blood pressure elevation and lack classic symptomatology Now a days, mortality rates = 80 mm Hg is acceptable Final dosing of 1 mg/ kg is usually sufficient to achieve adequate blockade Preoperative Management 34. In children, recommended dose: 0.2 mg/kg QID Increase by 0.2 mg/kg Maximum dose = 10 mg Due to irreversible #, patients may require transient BP support postoperatively. Reversible 1 blockers Terazosin, Doxazosin, Prazosin Used alone/ in combination with Phenoxybenzamine May have fewer side effects than Phenoxybenzamine But, data regarding their efficacy is contradictory Preoperative Management 35. BETA BLOCKADE Should be used with caution in patients with PCC Use may be necessary due to reflex tachycardia and arrhythmias that can result upon initiation of blockade # should never be started prior to appropriate # In absence of #, #s cause a potentiation of action of epinephrine on 1 receptors (due to # of arteriolar dilation at 2 receptor) For this reason, selective 1 #s, such as atenolol and metoprolol, are generally preferred Dosing for these agents is summarized in Figure 5720 Preoperative Management 36. CATECHOLAMINE SYNTHESIS BLOCKADE. Alpha-methyltyrosine (Metyrosine) Blocks the rate-limiting step in biosynthesis of catecholamines Inhibits tyrosine hydroxylase enzyme #s the conversion of tyrosine to L- dihydroxyphenylalanine (L-DOPA) Approximately 3 days treatment to achieve full clinical effect Because blockade of catecholamine synthesis is incomplete generally coupled with Phenoxybenzamine Central nervous system side effects Sedation, Depression, and Galactorrhea Extra-pyramidal symptoms resembling parkinsonism can result and require cessation of Phenoxybenzamine Not routinely used. Reserved for refractory or metastatic patients Preoperative Management 37. CALCIUM CHANNEL BLOCKADE Lowers blood pressure by smooth muscle relaxation Use of agents such as Nicardipine has been suggested as an adjunct to traditional -blockade therapy in refractory patients. Others report that CCBs alone are sufficient. This approach avoids reflex tachycardia and postoperative hypotension that is seen with use of Phenoxybenzamine. The team from NIH suggests that this strategy be reserved for patients with only mild symptomatology at presentation Preoperative Management 38. INTRAVASCULAR VOLUME MANAGEMENT Restoration of intravascular volume is the most important component of preoperative management Intake of salt and fluid is encouraged once catecholamine blockade has been initiated Admit patients the day before surgery and initiate aggressive IV fluid resuscitation The last dose of Phenoxybenzamine and/or Metyrosine is usually given on the night prior to surgery, and the next mornings dose is held. (minimizes potentially prolonged hypotension following resection) Preoperative Management 39. Postoperative Management Immediate postoperative period Must be actively monitored If Phenoxybenzamine was employed for preop # hypotension is common Moreover, in a high catecholamine state, 2-adrenoreceptor stimulation inhibits insulin release. The withdrawal of this adrenergic stimulus following tumour resection, may result in rebound hyperinsulinemia and subsequent hypoglycaemia Follow-up Repeat metabolic testing ~ 2 weeks after adrenalectomy In patients in whom Metanephrine levels remain elevated MIBG imaging MIBG uptake by previously unseen mets may become evident following resection of primary tumour 40. Long-term vigilant postoperative follow-up is essential Lifelong screening for recurrence is recommended 10-year recurrence rates are as high as 16% Recurrence has been noted in > 15 years following resection of original tumour Annual biochemical follow-up is mandatory No consensus on follow-up protocols exists Biochemical testing at 6 months after surgery, followed by annual testing Post-operative cross-sectional imaging To document tumour resection and appropriate healing of the resection bed Need for subsequent imaging should be guided by results of biochemical testing Postoperative Management 41. Treatment of Hereditary PCC For patients with MEN-2 and VHL Risk of malignancy is low Risk of bilateral disease is significant Partial cortical-sparing adrenalectomy has been advocated Hormonal replacement may still be necessary despite a seemingly successful cortex-sparing procedure Life-threatening addisonian crisis can also occur Close long-term biochemical and radiographic follow-up is essential Recurrence rates are poorly defined but appear to be significant 42. Treatment of Malignant PCC Largely palliative Surgical metastatectomy of resectable disease is the standard of care Little evidence exists to demonstrate that it prolongs patient survival or is more effective for symptomatic relief than medical treatment Medical treatment: with / blockade and -methyl-Paratyrosine Local palliative tumour control using ablation techniques and Embolisation Radiotherapy: Systemic treatment of mets with radioactive 131I-MIBG may be instituted. Before initiation of therapy, MIBG uptake by tumour targets should be demonstrated with traditional MIBG imaging Symptomatic response is seen in up to 2/3rd patients. > 40% of patients reduction in catecholamine levels Tumour volume reduction ~ 30% But, complete responses < 5% 43. High-dose radiotherapy (Rose and colleagues (2003)) 131I-MIBG at 2 to 3.5 times its usual dose Although toxicity was not trivial, 25% of patients exhibited a lasting complete response Two of these patients had both bony and soft tissue metastatic lesions. Given significant toxicity, routine use continues to be controversial Chemotherapy Treatment of Malignant PCC 44. Combination of Cyclophosphamide, Vincristine, and Dacarbazine (CVD) Response rates can be significant > 50% radiographic tumour response ~ 75% biochemical response Generally short-lived (2 years) Primarily used in patients who have Failed MIBG therapy Tumours which do not demonstrate MIBG uptake on initial MIBG imaging Combination therapy with CVD and MIBG has been explored but its risks and benefits are poorly defined Treatment of Malignant PCC 45. Prognosis Following surgical resection generally do well Surgical mortality rates < 3% Hypertension usually resolves Despite excellent prognosis, the disease can recur many years following resection in up to 16% of patients, necessitating vigilant lifelong follow-up More likely to recur: Extra-adrenal disease (hazard ratio 11.2) Hereditary Pheochromocytomas (HR 3.4) Right adrenal tumours (HR 3.1) Bilateral tumours (HR 1.4) Larger tumours (HR 1.2 per cm of diameter) ~ 50% of recurrences are malignant 46. Some patients with metastatic disease progress rapidly, while others exhibit nonaggressive disease and can live > 20 years Bone metastases appear to carry the most benign prognosis 5-year survival ~ 50% Prognosis 47. 10 % tumour-bilateral ,malignant,extra adrenal ,familial,multiple,& in children Commonly presents in early adult life Excessive noradrenaline 20:1 Familial a component of MEN 2 syndrome 3/22/2014DR.H.VEERESH.ASSOCIATE PROFESSOR.DEPT OF SURGERY.RIMS. 51 phaeochromocytoma 48. Headache Palpitation Vomitting Sweating Dyspnoea Hypertension & hyper glycemia. arrhythmias 3/22/2014DR.H.VEERESH.ASSOCIATE PROFESSOR.DEPT OF SURGERY.RIMS. 52 Clinical features 49. VMA & metanephrines in urine collected over 24 hrs.false + ve if on MAO inhibitor drugs,contrast studies. Plasma catecholamines CT scan & MRI. MIBG scan 3/22/2014DR.H.VEERESH.ASSOCIATE PROFESSOR.DEPT OF SURGERY.RIMS. 53 investigatioons 50. Control of hypertension-alpha & beta blocker drugs. Takes 1-3 weeks Preop hydration 3/22/2014DR.H.VEERESH.ASSOCIATE PROFESSOR.DEPT OF SURGERY.RIMS. 54 Preoperative preparation 51. Minimal handling Difficult phases are induction,positioning,manipulation,removal. Adrenal vein ligated as a first step Sodium nitroprusside used intra operatively for lowering BP. 3/22/2014DR.H.VEERESH.ASSOCIATE PROFESSOR.DEPT OF SURGERY.RIMS. 55 Intra operative