Pheochromocytoma

1. Pheochromocytoma Dr. Karoly Racz 2nd Department of Medicine Semmelweis University

2. Epidemiology of pheochromocytoma Prevalence: • 0.01 – 0.3 % of the hypertensive population • autopsy: • 1 pheo/2031 cases (Australia, 1991-1997) • 1 pheo/2140 cases (Hong Kong, 1981-1998) Incidence: • 2.1/million/year (1958-1993, Sweden) • 2.06/million/year (1980-1992, Spain) Clinically unrecognized: • 74-17% of all cases (1950 – 1998)

3. Pheochromocytoma – Key features Catecholamine overproduction - potentially lethal if undetected (compliactions may precede diagnosis cerebrovascular accident circulatory shock     left ventricular failure     pulmonary edema     paralytic ileus - associated with long-term morbidity -possible long-term cure if diagnosed and treated surgically

4. Pathophysiology of catecholamines

5. Catecholamine and catecholamine metabolite production of pheochromocytomas Catecholamines - norepinephrine (NE): typical in extraadrenal pheo - epinephrine (E): typical in adrenal pheo - dopamine (DA): rare Catecholamine metabolites: - metanephrine (MN) and normetanephrine (NM): mainly produced by membrane-bound COMT present within the tumor - VMA: metabolite of both NE and E - sulfoconjugated catecholamines (NE-sulfate, E- sulfate, DA-sulfate): may be produced by the tumor

6. Pheochromocytoma – main symptoms Hypertension - stable: 40% of pts -paroxysmal: 50% of pts -normotensive: 10% of pts Headache Palpitation Perspiration Pale skin

7. Frequency of symptoms in 100 patients with pheochromocytoma Symptom % Symptom % __________________________________________________________ Headache 80 Anxiety 22 Diaphoresis 71 Epigastric abdominal pain 22 Palpitation 64 Chest pain 19 Pallor 42 Dyspnoe 19 Nausea 42 Flushing 18 Tremor 31 Paresthesias or numbness 11 Generalized weakness 28 Blurring of vision 11 From JE Thomas et al., JAMA 1966, 197:754-758.

8. Biologically active non-catecholamine substances reportedly secreted by pheochromocytomas Substance Symptom __________________________________________________________________ Histamine hypotension Neuropeptide Y pallor, vasoconstricion Endothelin vasoconstriction Calcitonin-gene-related peptide flushing, hypotension Vasoactive intestinal peptide (VIP) flushing Substance P hypotension, perspiration Insulin hypoglycemia ACTH Cushing’s syndrome Interleukin 6 fever, inflammation markers PTHrP Hypercalcemia Chromogranin A, dopamine -hydroxylase?

9. Indications for screening Pheochromocytoma should be considered in patients with - paroxismal or resistant hypertension - severe hypertension or unexplainedhypotension during anesthesia, surgery or angiography - family history of pheochromocytoma or suspicion for syndromic (hereditary) pheochromocytoma - incidentally discovered adrenal masses - idiopathic dilated cardiomyopathy

10. Diagnostic approach - Biochemical tests catecholamine and/or catecholamine metabolite measurements - Localization radiologic visualization methods - Search forunderlying genetic disease - Predict malignancy

11. Biochemical tests

12. Biochemical tests to detect pheochromocytoma Blood - Free (unconjugated) E, NE and DA - Metanephrines (total and unconjugated NM, MN) - Chromogranin A, B, C - Neuropeptide Y - Pancreastatin Urine - Metanephrines (NM, MN) - Free (unconjugated) catecholamines (E, NE, DA) - VMA - HMMA, Iso-VMA - HVA (homovanillic acid) - DHPG (3,4-dihydroxyphenylglycol) - DOPAC (3,4 dihydroxyphenylacetic acid)

13. Landers et al., JAMA 2002, 287: 1427-1434.

14. Landers et al., JAMA 2002, 287: 1427-1434.

15. Biochemical tests Recommended for routine evaluation: - Plasma and urine metanephrines (HPLC) - Urine catecholamines (HPLC) Not recommended for routine evaluation: - Chromogranin A - Provocative tests

16. Clonidine test Blood pressure mmHg Plasma NE+E (pg/ml)

17. Localization methods

18. Localization MIBG-scintigraphy CT MRI DOPA-PET

19. Localization – practical approach • 90% of pheochromocytomas are found in the adrenals • most adrenal pheochromocytomas are visible by ultrasound • in addition to CT (or MRI), radionuclid scanning methods (123I-MIBG, octreoscan or PET scan) should be performed to detect multiple or metastatic pheochromocytomas

20. Search for underlying cause

21. Freiburg pheochromocytoma registry • 271 cases with negative family history • RET, VHL, SDHD, SDHB gene mutation present in 24% of cases • Mean age at diagnosis 24.8 yrs (vs 43.9 yrs in sporadic cases) • 461 cases with negative or positive family history • Age at the time of diagnosis • under 10 yrs of age 70% of cases are hereditary • under 18 yrs of age 59% of cases are hereditary • above 60 yrs of age 0% of cases are hereditary • multifocal (bilateral adrenal) pheochromocytomas • 89% of cases are hereditary

22. Hereditary phaeochromocytomas MEN2A, MEN2B von Hippel-Lindau Neurofibromatosis type 1 Familial paraganglioma syndromes

23. Prediction of malignancy

24. Prediction of malignancy Clinical: • presence of metastases • limited usefulness: extraadrenal location, large tumor size, presence of necrosis within the tumor, serum chromogranin A Histopathological: • classical histologic features of malignancy are highly unreliable (nuclear hyperchromasia, pleomorphism, vascular invasion, etc.)

25. PASS score(Phaeochromocytoma of the Adrenal gland Scaled Score) (Thomson LD, J Surg Pathol 26: 551; 2002) Diffuse cellular growth 2 Central or confluent tumor necrosis 2 High cellularity 2 Cell monotony 2 Narrowed tumor cells 2 Mitosis >3/10HPF 2 Atypic mitosis 2 Invasion to fat tissue 2 Invasion to vessels 1 Invasion to tumro capsule 1 Nuclear pleomorphism 1 Nuclear hyperchromasia >4 high metastatic potential <4 low metastatic potential

26. Wu D et al.: Observer variation on the application of the pheochromocytoma of the adrenal gland scaled score. J Surg Pathol 33: 599, 2009

27. Wu D et al.: Observer variation on the application of the pheochromocytoma of the adrenal gland scaled score. J Surg Pathol 33: 599, 2009

28. Preoperative and surgical treatment

29. Preoperative treatment goals - to inhibit the end-organ actions of NE and E until tumor removal - to correct hypovolemia, typically present in patients with pheochromocytoma - to maintain efficacious control of blood pressure and blood volume before and during surgery - to minimize the risk of hypertensive crisis during anesthesia and surgical exploration

30. Preoperative treatment Drug treatment - -adrenoceptor antagonist - -adrenoceptor antagonist + -adrenoceptor antagonist (to decrease tachycardia or arrythmia caused by E-release) - calcium-channel blockers - correction of hypovolemia (high-sodium diet) Clinical notes: - start therapy with -adrenoceptor antagonist - never use -adrenoceptor antagonist without-adrenoceptor antagonist - nonselective -adrenoceptor antagonist without - adrenoceptor antagonistmay precipitate crisisin patients with E-producing pheochromocytoma

31. Phenoxybenzamine - noncompetive nonselective inhibitor of -adrenoceptors - used traditionally for preoperative treatment - half-life: 24 hours - starting dose: 10 mg, titrated upward every 2 days until normal/low blood pressure (usually 80-100 mg daily in divided doses) - 2 weeks needed to reach maximum effect - side-effects: hypotension, tachycardia, head- ache, somnolence, fatigue, nasal congestion

32. Selective 1-adrenerg receptor antagonists Prazosin: - less clinical experience Doxazosin: - longer half-life (once-a-day dosing) - starting dose: 1 or 2 mg, increasing to a dose of 2 to 16 mg/day until normal normal/low blood pressure - patients are typically treated for 2 weeks before surgery - side-effects: hypotension, tiredness

33. Additional treatment -adrenergic antagonists: - used to treat arrythmias and tachycardia associated with E-secreting tumors Calcium channel blockers: - nicardipine is used most commonly - may diminish catecholamine-induced vasoconstriction - few side-effects Metyrosine: - competitive inhibitor of tyrosine hydroxylase - inhibits catecholamine synthesis - decreases tumoral tissue catecholamine content - starting dose: 250 mg every 6 hours, increasingto a dose of 2 to 3 g/day - patients are treated for at least 2 weeks before surgery

34. Case story - 45-yr-old woman with a 4-years history of throbbing bitemporal headache, general weakness, palpitation and perspiration. - few months before admission raised BP noted (treatment with ACE inhibitors and calcium blockers). - one day before admission, the pt. awakened from sleep with midepiagstric pain, strong pulsations in her head and vomiting. next morning BP 210/120 mmHg - ECG, blood chemistry and an abdominal ultrasound were performed. ECG and the results of laboratory tests normal abdominal ultrasonography: left adrenal mass 3 cm in size

35. Case story Examination - on admission physical examination was normal except a mild increase of blood pressure(150/90 mmHg) - shortly after admission the patient experienced a typical paroxysmal spell with sudden headache, visual changes, headache, epigastric pain and palpitation. - during the spell heart rate was 128 bpm and the blood pressure was 240/140 mmHg.

36. Case story Laboratory tests - Routine chemistry normal(blood cell count, glucose, electrolytes, calcium, phosphorous, creatinine, liver function, urinalysis) - 24 h urine (at the time of spell) • Norepinephrine:6580 nmol/24 h(normal:  500) • Epinephrine: 98 nmol/24 h(normal:  100) • Normetanephrine:13000 nmol/24h(normal:3000) • Metanephrine: 1100 nmol/24 h (normal:  1200) • VMA:165 mol/24 h(normal:  49)

37. Case story: Adrenal CT Unenhanced CT: hypointensive (10 HU) left adrenal mass

38. Case story Additional localization methods 123I-MIBG scintigraphy • no uptake in the adrenal region • isotope accumulation in the mediastinum Thoracal computed tomography • paraaortic tumor (4 x 4 cm) Diagnosis - extraadrenal pheo (paraaortic paraganglioma) - left adrenal incidentaloma

39. Case story: Lessons to learn • Extraadrenal pheochromocytomas secrete NE. Adrenal pheochromocytomas usually secrete both E and NE (epinephrine secretion may be explained by the induction of PNMT by high intraadrenal glucocorticoid concentration). • On unenhanced CT scan an attenuation of 10 HU of an adrenal mass is typical for lipid-rich benign adrenocortical adenomas rather than for pheochromocytomas.