Update in Pheochromocytoma/Paraganglioma: Focus on Diagnosis and Management

Transcription

1 Update in Pheochromocytoma/Paraganglioma: Focus on Diagnosis and Management Ohk-Hyun Ryu, MD. Associate Professor, Department of Internal Medicine Division of Endocrinology and Metabolism College of Medicine, Hallym University

2 Contents Diagnosis -Case detection -Biochemical test -Imaging studies Genetic testing Management -Presurgical medical preparation -Monitoring

3 Pheochromocytoma/Paraganglioma (PPGL) Classification Origin Location Predominant catecholamines WHO Usual Pheochromocytoma Adrenal Pheochromocytoma Adrenomedullary chromaffin cells Adrenal gland Epinephrine Paraganglioma Extra-adrenal Pheochromocytoma Sympathetic ganglia Thorax, Abdomen, Pelvis Norepinephrine Pagaganglioma Parasympathetic ganglia Skull base, neck Non-secreting

4 The prevalence of PPGLs In patients with hypertension 0.2 to 0.6% Nearly 5% of patients with incidentally discovered adrenal masses on anatomical imaging

5 The clinical importance of PPGL Cardiovascular morbidity and mortality Mass-effect symptoms Detection of a tumor in the proband (index case) may result in earlier diagnosis and treatment in other family members

6 The clinical importance of PPGL Some PPGLs have malignant potential. The prevalence of malignancy varies between 10 and 17% (higher in paragangliomas) Mutations in the gene encoding Succinate dehydrogenase subunit B (SDHB) can lead to metastatic disease in 40% or more.

7 PPGLs associated syndromes NF1 (neurofibroma, multiple café-au-lait spots) MEN2 (medullary thyroid carcinoma or hyperparathyroidism) VHL (hemangioblastomas and/or renal cell carcinoma) Paraganglioma syndrome Familial pheochromocytoma

8 Diagnosis

9 Case detection Symptom Triad Asymptomatic to mild continuous symptoms to episodic pronounced symptoms or crises (variable; the great masquerader Palpitation(tachycardia), Headaches, Profuse sweating Sign Atypical Hypertension (sustained or episodic) paroxysmal elevations in BP (hypertension, tachycardia, or arrhythmia) during diagnostic procedures, induction of anesthesia, surgery, certain food or drugs (Normal BP: 5-15%) Orthostatic hypotension, visual blurring, papilledema, weight loss, polyuria, constipation, increased erythrocyte sedimentation rate, hyperglycemia, leukocytosis, psychiatric disorders, Cardiomyopathy (Takotsubo): Heart failure, Pulmonary edema Arrhythmias, Intracranial hemorrhage

10 Clinical settings for case detection J Clin Endocrinol Metab 99: , 2014

11 Prevalence of pheochromocytoma in Korean patients with adrenal incidentaloma Retrospective analysis of 282 adrenal incidentaloma patients -Non-functioning tumor: 243 (86.2%) -Functioning tumor: 39 (13.8%) SCS: 28 (9.9%), Pheochromocytoma: 6 (2.1%), PA: 5 (1.8%) Cho YY et al. KJIM 28: , 2013 Retrospective study for 348 patients with an adrenal mass discovered incidentally on computed tomography (CT) undertaken for health examination or nonadrenal disease -Non-functioning : 82.2% -Pheochromocytomas: 7.2%, Subclinical Cushing s syndrome: 6.0%, Aldosterone-producing adenomas: 4.6% Kim J et al. Endocrinol Metab 28: 20-25, 2013

12 Characterization of Incidentally Detected Adrenal Pheochromocytoma Retrospective analysis -medical records of 198 patients with adrenal incidentaloma from 2001 to Pheochromocytoma (19/198, 9.6%) - larger than 2.0 cm - Hounsfield units were 19 or higher in precontrast CT. Sensitivity and specificity of pheochromocytoma (Criteria :Size > 2.0 cm and Hounsfield unit > 19) -100% and 79.3% Kim YA et al. Endocrinol Metab 27: , 2012

13 Plasma free metanephrines Urinary fractionated metanephrines

14 Biochemical test (confirmation) Plasma free metanephrines (MN, NMN) or 24 hour urinary fractionated metanephrines (MN, NMN) Measuring methods. 1. Liquid chromatography with tandem mass spectrometry (LC-MS/MS) gold standard 2. Liquid chromatography with electrochemical detection (LC-ECD) 3. Enzyme-linked immunosorbent assay (EIA) (imprecision, underestimate plasma metanephrine and normetanephrine )

15 Comparison of diagnostic performance of plasma vs urinary fractionated metanephrines First author, year Sensitivity Specificity Plasma Urine Plasma Urine Lender, % (211/214) 97.1% (102/105) 89.3% (575/644) 68.6% (310/452) Unger, % (23/24) 93.3% (14/15) 79.4% (54/68) 75.0% (39/52) Hickman, % (14/14) 85.7% (12/14) 97.6% (40/41) 95.1% (39/41) Grouzmann, % (44/46) 95.0% (38/40) 89.5% (102/114) 86.4% (121/140) Unger, % (17/19) 92.9% (13/14) 90.0% (54/60) 77.6% (38/49) J Clin Endocrinol Metab 99: , 2014

16 Plasma metanephrines Patient preparation Sampling in supine position (at least 30 minutes) Indication (high index of suspicion) -family history of pheochromocytoma -genetic syndrome that predisposes to pheochromocytoma (eg, multiple endocrine neoplasia type 2 [MEN2]) -past history of resected pheochromocytoma -incidentally discovered adrenal mass that has imaging characteristics consistent with pheochromocytoma (high HU in CT, cystic and hemorrhagic changes, bilaterality, or larger size..)

17 Urinary fractionated metanephrines Urinary creatinine should be measured Indication -Resistant hypertension -Hyperadrenergic spells (eg, self-limited episodes of nonexertional palpitations, diaphoresis, headache, tremor, or pallor) -Incidentally discovered adrenal mass that does not have imaging characteristics consistent with pheochromocytoma

18 Recommendation for biochemical testing Patient preparation Avoid sympathomimetic agents (including ephedrine, amphetamine, nicotine) Avoid interfering medication (including labetalol, sotalol, acetaminophen, methyldopa, antidepressants) Overnight fast, no caffeinated or decaffeinated beverages Blood sampling of metanephrines Supine condition, after 30 min supine rest Collection in heparinized tubes on ice Storage of plasma in freezer at -20 C if measured within 3 months Urine sampling of metanephrines Collection in a container without additives or eventually only sodium bisulphate Storage of urine container in a cold place Acidify urine in the laboratory to ph 4 before storing van Berkel A et al. Euro J Endocrinol 170: r109-r119, 2014

19 Plasma free metanephrines in the diagnosis of pheochromocytoma: diagnostic accuracy and strategies for Japanese patients (n=84: pheo=47, non-pheo=37) PFMs and umns had an area under the curve (AUC) (non-inferiority test p<0.0001) for (SE 0.018) VS (SE 0.027) VS for sensitivity VS for specificity Tanaka Y et al. Endoc J 61: , 2014

20 Kim HJ et al. Endo J 62: : 2015

21 Biochemical test algorithm van Berkel A et al. Euro J Endocrinol 170: r109- r119, 2014

22 Imaging Studies (anatomical) Contrast CT (first choice modality) MRI (alternative option) Metastatic PPGL ( for detection of skull base and neck paragangliomas) Surgical clips causing artifacts in CT Allergy to CT contrast Radiation exposure should be limited (children, pregnant women)

23 Imaging Studies (functional) 123 I-metaiodobenzylguanidine (MIBG) scintigraphy -metastatic PPGL (radiotherapy planned using 131 I-MIBG) -increased risk for metastatic disease [large size of the primary tumor or extra-adrenal, multifocal (except skull base and neck PPGLs), or recurrent disease] 18F-FDG PET/CT -preferred imaging modalities over 123 I-MIBG in known metastatic PPGL

24 Imaging studies I-MIBG scintigraphy 123 I-MIBG over 131 I-MIBG Shorter half-life Lower radiation exposure Disadvantages Suboptimal sensitivity : skull base and neck, thoracic/bladder (extra-adrenal), or hereditary, metastatic, recurrent PPGLs Long scanning time (at least 48 hours) Thyroid protection (potassium iodide) Higher sensitivity (Combined with CT or SPECT/CT) False negative results by some drugs (adrenergic blockers, sympathomimetic drugs, calcium channel blockers, TCA, antipsychotics, CNS stimulants, alpha blockers, opioid analgesics)

25 Targets for functional imaging of PPGLs NET: norepinephrine transporter VMAT: vesicular monoamine transporter SSTR: somatostatin receptor GLUT: glucose transporter LAT: large amino acid transporter Clin Endocrinol (Oxf) 81(3):329-33, 2014

26 Should every pheochromocytoma have 123 I-MIBG scan? No -Small(<3-4cm) unilateral pheo with no known germline mutation or syndromic features of hereditary syndrome -predominant secretion of epinephrine or metanephrine Indication -Unifocal,sporadic PPGL: 123 I-MIBG, 18 F-DOPA or 18 F-FDG (pheo), 18 F- DOPA, 18 F-FDG or 111 In DTPA-pentetreotide (para) -Multifocal, sporadic PPGLs: 18 F-FDG, 18 F-FDA, 18 F-DOPA -Unifocal PPGL and positive family history or known germline mutation: mutations in the VHL, RET or NF1 gene ( 18 F-DOPA or 18 F- FDG) SDHx mutations-related primary PPGL ( 18 F-DOPA, 18 F-FDG and 111 In- DTPA-pentetreotide) -Metastatic disease ( 18 F-FDG and 111 In- DTPA-pentetreotide) Clin Endocrinol (Oxf) 81(3):329-33, 2014

27 Decisional algorithm for functional imaging in patients with proven PPGL *treatment with radiolabeled somatostatin analogs treatment with 131IMIBG

28 Genetic testing

29 Genetic Testing 1. At least 1/3 (up to 40%) of all patients with PPGLs have germline mutations. 2. Mutations of SDHB lead to metastatic disease in 40% or more 3. Establishing a hereditary syndrome in the proband (early diagnosis and treatment in relatives)

30 Frequency in germline mutation SDHB (10.3%) SDHD (8.9%) VHL(7.3%) RET (6.3%) NF1 (3.3%) Germline mutation Less than 2% MAX TMEM127 SDHA SDHC

31 PPGLs associated with hereditary cause High likelihood Positive family history Syndromic features Multifocal, bilateral, or metastatic disease Low likelihood (at least 3 of 4) Negative family history Absence of syndromic feature Absence of bilateral disease Absence of metastatic disease

32 Genetic testing in PPGL patients with suspected germline mutations Syndromic or metastatic presentation Tumor location Biochemical (catecholamine) phenotype * Considerations: young age, positive family history, multifocal or bilateral tumors

33 Decision algorithm for sequential genetic testing RET, VHL SHDx

34 Management

35 Presurgical medical preparation Goal: normalize blood pressure and heart rate, reverse blood volume contraction Drugs α-adrenergic receptor blockers (first choice) Calcium channel blockers (add on drugs) β-adrenergic receptor blockers (control tachycardia): after administration of α - adrenergic receptors blockers High sodium diet (>5000 mg daily) and fluid intake *metyrosine (Alpha-methyl-para-tyrosine)

36 Minimally invasive (laparoscopic ) adrenalectomy in adrenal pheochromocytoma (less pain, less blood loss, fewer hospital days, less surgical morbidity) Open resection -large or invasive pheochromocytoma to ensure complete tumor resection, prevent tumor rupture, avoid local recurrence -paraganglioma Surgery Adrenal cortex sparing surgery (partial adrenalectomy) -in selected patients (hereditary pheochromocytoma, small tumors already undergone contralateral complete adrenalectomy)

37 Postoperative monitoring Blood pressure, heart rate, blood glucose in immediate postoperative period Biochemical testing after recovered from surgery for documentation of successful tumor removal Biochemical testing (plasma or urine metanephrines) annually, lifelong (imaging study?)

38 Summary Case detection: suspicion Biochemical test: plasma metanephrines (supine) or urinary fractionated metanephrines (LC-MS/MS) Imaging studies -CT or MRI (metastatic PPGL) I-MIBG (radiotherapy), 18 F-FDG PET (metastatic PPGL) Genetic test considered Medical preparation and monitoring

39 Thank you for your attention!!!