Download Paraganglioma and Phaeochromocytoma: An Overview

Paraganglioma:
An Overview
Matrix Fung
QMH
Ms Lam, F/71
Admitted for right upper quadrant pain
Hypertensive
Frequent headache and palpitations for 3 years
MRI abdomen 1997 in mainland China:
Bilateral adrenal tumour
Resection done in China
No follow up afterwards
 CT
24 Hour Urine
Norepinephrine
Times of Upper Limit of
normal (x)
1.5
Normetanephrine
3.8
Epinephrine
1.4
Metanephrine
2.9
Dopamine
1.3
Laparotomy findings:
Previous right adrenalectomy
Recurrent tumour at the previous excision site
Tumour excised
Pathology:
Phaeochromocytoma
Paragangliomas
Paraganglias
neuroendocrine organs developed from neural crests cells
Homeostasis
Eg. Adrenal medulla, carotid body, vagal and aortic paraganglia
Paraganglioma
Highly vascular tumours
“ The only true indicator of malignant behavior is metastatic spread”
IARC WHO Classification of Tumours 2004
(Pheochromocytoma)
M. Lefebvre et al. Curr Oncol 2014
• Hereditary predisposition
•
Pheochromocytomas: 57%
vs
Paraganglioma: 83%
Laird et. al Langenbecks Arch Surg. 2012
National Cancer
Institute PDQ® 2015
Epidemiology
M=F
Incidence: 0.8 per 100,000 person per year
Presents in the third to fifth decades of life
Hereditary cases present ~10 years earlier than
sporadic cases
Erikson et.al Clin Endocrinol Metab. 2001
Phaeochromocytoma
0.1% to 1% of patients with hypertension
Kulke et.al J Clin Oncol 2006
The 10% Rule?
Bilateral/Multiple
Usual Sayings
10%
Current Evidence
26%
Familial
10%
33% - 50%
Extra-adrenal
10%
15-20%
Malignant
10%
20% (extra-adrenal)
10% (pheo)
Elder et.al J Surg Oncol 2005
Favier et.al J Med Sci 2012
Parenti et.al J Surg Oncol 2012
Presentation
Paroxysms of:
Hypertension, headache, perspiration, forceful palpitations,
tremor, facial pallor
Triggering events: physical stress, foods high in tyramine eg. Red
wine, chocolate, cheese
A mass
Carotid body tumour
Abdominal mass
Incidental, on imaging
Hereditary syndromes / Genetic predisposition
Risk factors
Genetics:
25% of apparently sporadic cases a component of an
inherited syndrome
Neumann et al. NEJM 2002
Eg. SDHx paraganglioma syndromes, VHL, NF1, MEN 2A and 2B
Chronic hypoxia
Living at high altitudes / Chronic obstructive lung disease
Prevalence up to 1 in 10 in humans in high altitude areas
Almost 1 in 2 in bovines
Rodríguez et al. Head Neck 1998
Diagnosis
Biochemical
Plasma-free fractionated metanephrines (sensitivity 97-99%)
24hr urine catecholamines and metanephrines (specificity 98%)
Radiological
Anatomical: USG, CT, MRI
Functional: I-MIBG, FDG PET
Biopsy
CONTRAINDICATED!
Case courtesy of Dr Frank Gaillard, Radiopaedia.org, rID: 4627
Turker et al. J Clin Imaging Sci 2015
Functional Imaging
To look for synchronous tumours and metastases
Surveillance in genetically predisposed patients
MIBG:
Resembles norepinephrine, taken up by paraganglioma
Labelled with Iodine radio-isotope
Can be used for radioablation as well
FDG PET
Overall sensitivity 74 – 100%
Fonte et al. Endocr Relat Cancer 2012
Management
Adrenergic blockade and adequate pre/intra-operative
volume expansion
Loco-regional disease:
Surgery eg. Laparoscopic adrenalectomy
Radiotherapy (Head & Neck)
Radiofrequency ablation
Transarterial chemoembolization for liver metastases
Management
Distant metastases
Surgery
Radionuclide therapy with Iodine 131-MIBG
Chemotherapy: Cyclophosphamide, Vincristine,
Dacarbazine
Targeted therapy: Sunitinib
Genetic testing and counselling
Alexandra et al. Endocrine-Related Cancer 2007
Genetics
“Genetic testing should be considered in each patient”
Endocrine Society Clinical Practice Guideline 2014
 Reasons:
1. Germ-line mutations common
2. SDHB mutations  40% metastatic disease
Young, multiple, bilateral, family history, malignant
disease
Lefebvre et al. Curr Oncol 2014
Succinate dehydrogenase (SDH)
A mitochondrial enzyme with 4 subunits coded by 4 genes:
SDHA,SDHB,SDHC,SDHD
SDHAF gene – for flavination of the SDHA subunit
Mutation Paraganglioma syndromes (PGL)
SDHD mutation  PGL1
SDHB mutation  PGL4
The two most common genetic mutations
Mutation
SDHD / PGL1
Characteristic Phenotype
Dutch, skull base/neck
SDHB / PGL4
Abdomen/pelvis/thorax, metastases,
renal cell carcinoma
Medullary thyroid cancer,
parathyroid hyperplasia
Neurofibromas,
café au lait spots etc.
Cerebellar/spinal haemangioblastoma,
retinal angiomas, clear cell RCC,
pancreatic neuroendocrine tumours
RET/ MEN2
NF1 /
Neurofibromatosis 1
VHL /
von Hipplel-Lindau
disease
Laruen et.al Ann Surg Oncol. 2013
M. Lefebvre et al. Current Oncol 2014
Prognosis
Local (Benign) Disease
Life expectancy not compromised if excised
5 year recurrence 14-33%
Amar et al. J Clin Endocrinol Metab 2005
Metastatic (Malignant) Disease
Highly variable
Reported 5 year survival 12 – 84%
Ayala-Ramirez et al. Cancer 2012
Paragangliomas
Diagnostics
Alpha and beta blockade before
investigation/intervention
Surgery if possible
Systemic therapies under investigation
Genetic testing and counselling
Thank you!
References

Genetics and mechanism of pheochromocytoma–paraganglioma syndromes characterized by germline SDHB
and SDHD mutations Endocrine-Related Cancer (2015) 22, T71–T82

Beard CM, Sheps SG, Kurland LT, Carney JA, Lie J. Occurrence of pheochromocytoma in Rochester, Minnesota,
1950 through 1979. Mayo Clin Proc. 1983;58(12):802.

Erickson D, Kudva YC, Ebersold MJ, Thompson GB, Grant CS, van Heerden JA, Young WF Jr. Benign
paragangliomas: clinical presentation and treatment outcomes in 236 patients. J Clin Endocrinol Metab.
2001;86(11):5210.

Laird AM, Gauger PG, Doherty GM, Miller BS. Paraganglioma: not just an extra-adrenal pheochromocytoma.
Langenbecks Arch Surg. 2012 Feb;397(2):247-53. Epub 2011 Nov 17.

Timmers HJ, Kozupa A, Chen CC, et al. Superiority of fluorodeoxyglucose positron emission tomography to other
functional imaging techniques in the evaluation of metastatic SDHB-associated pheochromocytoma and
paraganglioma. J Clin Oncol 2007; 25:2262.

Timmers HJ, Chen CC, Carrasquillo JA, et al. Staging and functional characterization of pheochromocytoma
and paraganglioma by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography. J Natl Cancer Inst 2012;
104:700.

Parenti G, Zampetti B, Rapizzi E, et al. Updated and new perspectives on diagnosis, prognosis, and therapy of
malignant pheochromocytoma/paraganglioma. J Oncol 2012; 2012:872713.

Elder EE, Elder G, Larsson C. Pheochromocytoma and functional paraganglioma syndrome: no longer the 10%
tumor. J Surg Oncol 2005; 89:193.

F. Grunwald, S. Ezziddinc131I-Metaiodobenzylguanidine therapy of neuroblastoma dn other neuroendocrine
tumors Semin Nucl Med, 40 (2010), pp. 153–163

Amar L, Servais A, Gimenez-Roqueplo AP, et al. Year of diagnosis, features at presentation, and risk of recurrence
in patients with pheochromocytoma or secreting paraganglioma. J Clin Endocrinol Metab 2005; 90:2110. .
 Suárez C, Rodrigo JP, Bödeker CC, et al. Jugular and vagal paragangliomas:
Systematic study of management with surgery and radiotherapy. Head Neck 2013;
35:1195.
 Alexandra Chrisoulidou, Gregory Kaltsas, Ioannis Ilias, Ashley B Grossman The diagnosis
and management of malignant phaeochromocytoma and paraganglioma.
Endocrine-Related Cancer (2007) 14 569–585
 Ayala-Ramirez M, Feng L, Habra MA, et al. Clinical benefits of systemic chemotherapy
for patients with metastatic pheochromocytomas or sympathetic extra-adrenal
paragangliomas: insights from the largest single-institutional experience. Cancer 2012;
118:2804