A Mini Review of Paragangliomas with Presentation of Two Cases

REVIE\N ARTICLE

turnours. MRI surpasses metaiodobenzylgua nid ine (MIBG) scanning in A mini review of detecting adrenal disease and non- functional paragangliornas. paragangliomas MISG has greater sensitivity and specificity than MRI in the with presentation detection of extra- adrenal tumours, although both are of two cases superior to CT. MRI is currently the 1. Paragangliomas E Kader investigation of choice, arising from the adrenal vvith MISG being used MBChB (UCT) medulla in cases of disease Department of Radiology, 2. Aortico-sympathetic University of Cape Town recurrence, metastases paragangliomas or equivocal MRI. 3. Parasympathetic and Surgical cure is possible Abstract visceroautonomic in up to 85°/() of cas s. paragangl iomas The recurrence rate is Paragangliomas are rare 4. Paragangliomas not betvveen 5 and 10 oir>, tu rnou rs of the othervvise specified. vvith a 5 year survival paragangl ion system, They occur sporadically rate of 80 lo 95%. vvhich may, in or in families, and have approximately 80<1<) of recognised associations cases, be hormonally vvith other diseases. The Introduction active vvith potentially majority are benign. Paragangliomas are rare tumours lethal consequences. In Ninety percent of arising from the paraganglion system. this mini revievv, the tumours are adrenal and The incidence inthe general population classification, pathology, 1OCYo are extra-adrenal. is 0.001-0.002 %, and 0.1 to 0.5 % in pathophysiology and Patients commonly those with hypertension.V Affected clinical management are present vvith individuals may be asymptomatic if described. An atternpt is hypertension or the tumour is non-functional, or can also made to evaluate p.arcrxvsrria.l crises and present with a broad spectrum of the relative advantages the laboratory diagnosis and disadvantages of the hinges on the symptoms in the case of functional most commonly used demonstration of tumours. These tumours carry a high diagnostic irriagi ng elevated catecholamine morbidity and mortality if discovered modalities, viz. levels. Initial incidentally. Diagnosis relies on a high Magnetic Resonance management involves clinical index of suspicion and appro- Imaging (MRI), stabilisation vvith alpha- priate biochemical evaluation. Subse- Computed Tornography blockade follovved by quent management includes (CT) and radionuclide preoperative tumour stabilisation of the patient and scintigraphy. localisation. preoperative evaluation prior to sur- Paragangl iomas are MRI has similar gical excision. Surgical cure rates of divided into four accuracy to CT in 66-85 % have been reported, given anatomical classes: diagnosis of adrenal early intervention. 2,3 to page 12

11 SA JOURNAL OF RADIOLOGY. November 1998 A mini revievv of paragangliomas vvith presentation of tvvo cases

from page 11 This review attempts to address the radiograph confirmed pul- recommended nomenclature and clas- monary oedema. The ab- sification of these tumours, as well as dominal x-ray was normal. their basic pathological and pathophysi- The plasma noradrenaline ological features. Numerous biochemi- level was 16 500 (normal cal tests are currently employed in di- range 80-2 200) and urine agnosis, and their relative merits and NMA was 90.9 (normal demerits are compared. MRI, CT and range 0-5).A large,para-aor- nuclear medicine (NM) scanning have tic softtissuemass inthe left largely replaced more invasive tech- infrarenalareawasnoted on niques in preoperative tumour localisa- Figure 2: MIBG scan showing an area of increased uptake in the region ultrasound (US) (Figure 3) of the aortic bifurcation (arrows). tion. The relative advantages, disadvan- and CT (Figure 4). The tages and recommended application of The lesion was excised and was mass was surgically excised and histol- these three modalities are considered. histologically confirmed to be a para- ogy confirmed a paraganglioma. Case 1 ganglioma. A 20-year-old man presented with Case2 a brief history of lower abdominal pain A 19-year-old man presented with accompanied by nausea and vomiting. a history of progressive dyspnoea, loss He had been entirely well prior to this of weight and palpitations. He was ad- presentation and had no significant fam- mitted to hospital in pulmonary ily history. On examination the patient oedema secondary to malignant hyper- was apyrexial, normotensive and not tension. He had been investigated ayear tachycardie.Tenderness was noted in the earlier for lethargy, episodic headache, left lower abdominal quadrant. The palpitations and epigastric pain with chest radiograph was normal. The ab- nausea and vomiting. On examination dominal x-ray revealed a soft tissue den- he was tachycardie and hypertensive sity to the left of the umbilicus. This was (blood pressure was ]83/139 mmHg) confirmed on ultrasound. Catecho- with clinical evidence of cardiac fail- lamine assays were normal. The CT ure. Fundoscopy revealed grade 3 scan demonstrated a 5 em lesion with hypertensive retinopathy. A chest a central low density at the aortic bifurcation (Fig- ure 1). On the basis of the incon- clusive findings above, an 1123 metaicdobenzyl- guanidine (MIBG) scan was performed and revealed an area

óf increased up- Figure 3a-c: Longitudinal (3aand b) and transverse(3c) take in the region ultrasound scans demonstrating an infra-renaI6.S by 2.9 cm Figure 1: Computed tomogram with intravenous contrast medium demonstrat- inhomogeneous lesion in the left para-aortic area. Therelationship of the aortic bifur- ing a rounded soft-tissue mass with central low density (arrow) anterior to the of the lesion (thick arrows) to the left kidney (curved arrows),aorta cation (Figure 2). lumbar spine. (thin arrows), and psoas muscle (arrowhead)can be appreciated.

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12 SA JOURNAL OF RADIOLOGY- November 1998 A mini rev ievv of parngrmgf iorrias vvitl t presentation of tvvo cases

from page 12 classes of paragan- and adrenaline in ratios greater than glia usually occur is physiologically normal, while extra- in the head and adrenal tumours tend to excrete neck and generally noradrenaline exclusively. Isolated stain negative for adrenaline secretion is rare. A wide chromaffin, while variety of secreted peptides have been tumours of the lat- documented including endogenous ter two groups oc- opioids, neuropeptide Y, chromogranin cur along the aorta, A, dopamine, somatostatin and in association with calcitonin. Their functional signifi- blood vessels or cance is dubious.v' visceral organs, and are usually chro- Pathology Figure 4: Computed tomogram (without intravenous contrast agent) of the lower maffin positive. The incidence of paragangliomas abdomen demonstrating an inhomogeneous, soft-tissue mass in the left para-aortic region (arrow). This classification in the general population is 0.001- is very similar to 0.002 % and 0.1 - 0.5 % in the hyper- the more recent WHO classification tensive population. 1·3 The commonly Anatomy of 1980, which defines four classes of affected age group is 25-35 years with The paraganglion system is part of paraganglia on an anatomical basis: I a median age of 37 -40 years." Ther the Amine Precursor Uptake and 1. Paragangliomas arising from the is a known familial predisposition in Decarboxylation (APUD) system (or adrenal medulla. Only these are re- l G % of cases. In these situations the "diffuse neuroendocrine system") ferred to as phaeochromocytomas. incidence of multiplicity is 35%,while which modulates the function of the 2. Aortico-sympathetic paraganglio- bilateral phaeochromocytomas may nervous and endocrine systems. Para- mas associated with the sympathetic occur in up to 50 % of individuals, com- ganglion cells are derived from neuro- chain. pared to la % in sporadic cases.I-3,5,9 ectoderm and are topographically and 3. Parasympathetic paragangliomas There is a well recognised association physiologically integrated with the (including chemodectomas) and with other diseases, notably multiple autonomic nervous system.I,3,4 visceroautonomic paragangliomas endocrine neoplasia type 2a & b Aggregations of cells associated with (found in association with small blood (MEN 2a & 2b), Von Hippel-Lindau the sympathetic nervous system vessels in organs). disease, neurofibromatosis, Cushing's (chromaffin cells) constitute the chro- 4.Paragangliomas not otherwise speci- disease and Carney's triad (extra-ad- maffin system and can conveniently fied. renal paraganglioma, gastric leiomy- osarcoma and pulmonary chon- be conceptualised as being adrenal Pathophysiology medullary or extra-adrenal. The ex- droma). tra-adrenal cell groups are called para- All paraganglion cells store Eighty to ninety percent of paraganglia and occur in or near the sym- catecholamines and may therefore be gangliomas are adrenal and 10-20 % pathetic chain, near major blood ves- hormonally active. The hormones are are extra-adrenal. In the extra-adre- sels, or in various organs. In addition, not released secondary to neurologi- nal group, 80 % (8-16% of all para- paraganglion cells are also encoun- cal impulses, as the tumours are not gangliomas) are abdominal, occurring tered in association with innervated. Ninety percent of adrenal most commonly in the organ of parasympathetic tissue.!" tumours are active, while approxi- Zuckerkandl (para-aortic body) and Glenner and Grimley, in 1974, mately 50 % of extra-adrenal tumours renal hila. One to two percent occur classified paraganglia, and tumours and 1 % of parasympathetic tumours in the thorax, usually the posterior arising from them, into four classes, are hormonally active." mediastinum. Less than 1 % are found viz. branchiomeric, intravagal, aortico- Most paragangliomas secrete no- in the head and neck, commonly in sympathetic, and visceroautonomic.' radrenaline and/or adrenaline. Adre- the glomus caroticum (carotid body) Tumours arising from the first two nal types usually secrete noradrenaline

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13 SA JOURNAL OF RADIOLOGY. November 1998 A mini review of paragangliomas with presentation of two cases

(rom page 13 and glomus jugulare, followed by the hypertension which may be paroxys- elevated. In general, therefore, plasma glomus vagale and glomus mal or constant. Less than 5 % of pa- assays are reserved for cases with tympanicum. The larynx and orbits tients present with hypotension due equivocal urine results. Less com- may be involved. Approximately 1 % to excessive adrenaline release. Pa- monly performed tests include plate- occur in the bladder. The filum tients may also present with charac- let catecholamine levels, plasma terminale is the commonest site of teristic paroxysms or crises, consist- chromograninA and pharmacological CNS involvernent.l+!'' ing of one or more of a variety of tests (phentolamine based adrenolysis Paragangliomas are typically soft, symptoms including headaches, pal- assessment, tyramine or glucagon in- rounded vascular tumours, less than pitations, tachycardia, apprehension, duced pressor reactions, or clonidine 5 cm in size when extra-adrenal and nausea and vomiting, syncope and suppression tests). less then 10 cm when adrenal. They chest pain. Additional features include The differential diagnosis includes are usually solid with areas of necro- a raised metabolic rate, carbohydrate drug-related hypertensive crises, in- sis,haemorrhage or cystic change. On intolerance and, in a small group of tracranial lesions (posterior fossa le- microscopy polyhedral cells are ar- patients, adverse drug reactions, par- sions,subarachnoid haemorrhage) and ranged in clusters ("zelballen") within ticularly to tricyclic antidepressants, diencephalic epilepsy (a rare condi- a fibrovascular stoma. The immuno- opioids and monoamine oxidase in- tion that presents with aura, an ab- histochemical classification into chro- hibitors. 2,7,8, 10 normal EEG and favourable response maffin and non-chromaffin tumours to anti-convulsantsj.i-' is based on their reaction with chro- Diagnosis mium salts-" on histological staining. The diagnosis of paragangliomas is Management Paragangliomas are usually benign based on the demonstration of raised In the acute stage the management and reported malignancy rates vary catecholamine levels. Radiology only is resuscitative and based on control only slightly. Adrenal tumours are has a place in the evaluation of estab- of hypertension and arrhythmias. malignant in less than 10 % of cases, lished cases. Several laboratory tests Most paragangliomas are benign and while extra-adrenal types have a exist, of which a few are commonly complete surgical excision is usually higher malignancy rate: 40 % of para- used in clinical practice. Twenty- four possible. The preoperative manage- aortic body tumours and 18 % of va- hour urinary catecholamine assays ment principles are: gal body tumours have metastases at remain the cornerstone of diagnosis, • Induction of stable alpha-block- presentation. It must be noted that the with a sensitivity of over 96 % pro- ade, usually with phenoxybenzamine. histological criteria for malignancy are vided specific collection criteria are This decreases the risk of pressor re- unreliable and no significant correla- adhered to. In particular, no recent actions and facilitates expansion of tion has been demonstrated between radiographic contrast media should intravascular volume malignancy, functional status, location have been administered to the patient. • Beta-blockade for tachycardia, and histology. This diagnosis is based Serum catecholamine levels are gen- only after stable alpha-blockade has on local invasion and the presence of erally regarded as unreliable in isola- been achieved since unopposed beta- distant metastases (commonly to tion, because of their tendency to be blockade may precipitate a crisis by bone, lung, liver and lymph normal between crises. Urine assays, antagonising beta-modulated periph- nodes ).1,2,8,9,11.13 in contrast, provide an integrated cat- eral vasodilation echolamine value as a function of time • Metyrosine (a tyrosine hydroxy- Clinical and are less likely to render a false lase inhibitor) may be used to inhibit manifestations negative result. A further difficulty catecholamine production Cervical paragangliomas present with serum assays lies in the defini- • Tumour localisation predominantly with local effects, tion of a reliable normal range. The Currently, tumour localisation is whereas thorace-abdominal tumours stress of specimen collection may raise dominated by non-invasive imaging tend to present by means of humoral basal catacholamine levels. During modalities, with infrequent use of in- symptoms, The single commonest anxiety or seizure attacks plasma cat- vasive procedures. The main presenting symptom is recalcitrant echolamine levels may also be to page 15

14 SA JOURNAL OF RADIOLOGY- November 1998 A rrrirri review of paragangliomas with presenlal ion of two cases

(rom page 14 modalities include, in the former metabolic/synthetic pathway as no- fl31MIBG therapy, or where the diag- group, MRI, nuclear medicine and CT, radrenaline, resulting in concentration nosis is in doubt (familial syndromes while arteriography and venous sam- within the tumour by amine uptake, may have paragangliomas with nor- pling are included in the latter. Nu- but is not metabolised to any signifi- mal catecholamine levels). In the case merous studies exist comparing the cant extent (Figure 5). of non-functioning tumours, MRI is relative advantages and disadvantages an acceptable alterna- of the various modalities and an at- tive. Some authors ad- H H NH tempt is made to provide an overview c-c-c/ vocate routine MIBG of the prevailing opinions. HO@e~;-N~ H H 'NH, scanning to exclude CT can detect lesions as small as multicentric disease, 0.5 cm with 75-87 % sensitivity. How- HO ©JI but no data exist to ever, it may miss small adrenal lesions. Noradrenaline MIBG support this. Furthermore, in extra-adrenal para- Inlll DTPA- gangliomas, whole body scanning de- Figure 5: Mo/ecu/ar structure of M/BG and noradrenaline. octreotide is a new livers a high radiation dose to the pa- agent that is a tient and is time consuming. In addi- J123is preferred to II31because of somatostatin analogue which binds to tion, intravenous iodinated contrast the former's lack of beta emission, receptors on neuroendocrine cells. may precipitate a hypertensive reac- resulting in lower radiation dose to the Studies have shown sensitivities as tien." On CT scanning,55 % of tu- patient and superior images. Many high as 94 % and superior perform- mours are homogeneous, 40 % have a drugs can interfere with MIBG uptake ance when compared to MIBG.5,lJ,IO,17 central low density and 15 % demon- including cocaine, reserpine and Its routine use is limited by lack of strate punctate calcification. The tu- tricyclic antidepressants. long-term experience and cost. mours are very vascular and enhance MRI and MIBG have comparable Angiography and venous sampling intensely with contrast administra- sensitivity for functioning tumours, but have a limited role in thoraco-abdomi- tion.I.8,13,ls MRI is able to demonstrate non func- nal disease. Their use is rather indi- MR imaging has been used for tioning tumours missed by scintigraphy. cated in equivocal cases when at- many years and in larger centres has MIBG and MRI have sensitivities rang- tempting to define suspicious areas for superseded CT completely. It has ing from 83-93 % and are superior to re-investigation by axial scanning been proven to be comparable in sen- CT with sensitivities of 75-87 %. The methods. sitivity to CT for adrenal lesions and specificity of MIBG is 100 % and is superior to it for extra-adrenal disease. superior to CT or MRL1,13,ISIn a study Definitive On MRI these tumours are T2 by Van Gils et al, MRI was compared treatment hyperintense relative to the liver. Sev- to MIBG scanning, finding relative sen- In adequately experienced surgi- eral studies have confirmed the abil- sitivitiesof91 % and 80 % respectively. cal and anaesthetic hands operative ity to differentiate adrenal paragang- MRI performed better in the detection mortality is less than 2 %.2Irresectable liomas from adenomas based on the of adrenal lesions (100 % vs 75 %), or malignant tumours, however, re- tumour to liver signal ratio. Ratios while MIBG was superior in the quire medical therapy with adrener- greater than 2.5 suggest paragang- detection of extra-adrenal disease and gic blockers and metyrosin .Although lioma and less than 2, adenoma.':" recurrence (88 vs 75 %). The overall they are relatively radio-resistant, Radionuclide studies are a particu- specificities were 100 % for MIBG malignant paragangliomas show a par- larly valuable tool in the preoperative and 82 % for MRI. I tial response to chemotherapeutic assessment of the patient with para- The currently accepted ideal ap- agents including streptozocin or com- ganglioma. The two commonly used proach therefore is that MRI be used bined regimens such cyclophospha- 123 tests are MIGB (labelled with 1 or as the initial investigation and MIBG mide, vincristine and dacarbazin ,3 1131)and DTPA-octreotide (labelled is reserved for cases of equivocal MR! with In!"]. MIBG is an analogue of results, recurrent disease, suspected guanethedine and follows the same metastases, multicentricity, prior to topage24

15 SA JOURNAL OF RADIOLOGY. November 1998