General
- Use to be under glioneural and neuronal tumours but now here because
- Involve specialized neuroendocrine cells of the sympathetic and parasympathetic nervous system, these tumors are now included with nerve tumors
- Do not Call chemodectoma
- These tumors arise from paraganglion cells (not chemoreceptor cells as previously thought; therefore the term chemodectoma is rarely used).
Definition
- A unique neuroendocrine neoplasm,
- Usually encapsulated and benign,
- Arising in specialized neural crest cells associated with collateral autonomic ganglia (aka prevertebral ganglia, or paraganglia);
- Consisting of uniform chief cells exhibiting neuronal differentiation forming compact nests (Zellballen) surrounded by sustentacular cells and a delicate capillary network
Numbers
- Commonest Middle Ear Tumour
- Incidence 1 in 1.3 million
- 2nd commonest tumour to invade temporal bone after VS
- F:M 4:1
- Chronic
- Slow growth
- Significant size to become symptomatic
Origin
- Neuroendocrine cells of the autonomic nervous system
- A) Paraganglia develop from neural crest cell precursor cells that migrate to various body sites. Different subpopulations are recognized that differ in their spatial predominance and capability of giving rise to functional or non-functional paragangliomas.
- B) Distribution and frequency of paragangliomas in the human body: cauda equina paragangliomas are exceptionally rare.
- C) Common sites of paraganglioma origin in detail with type of precursor neural crest cell population indicated by colour.
Anatomical classification
Head and neck: Parasympathetic (NonChromaffin) paragangliomas
- Arise within paraganglia of the head and neck
- In association with the branches of the glossopharyngeal and vagus nerve
- They are generally non-secretory.
Carotid bifurcation | Carotid body paraganglioma (carotid body tumour) |
Auricular branch of Vagus nerve (middle ear) | Juglotympanic paraganglioma (Glomus tympanicum) |
Superior Vagal ganglion (Jugular foramen) | Glomus Jugulare |
Inferior Vagal ganglion (nasopharynx at skull base) | Glomus Intravagle (glomus Vagale), laryngeal paraganglioma |
Below head and neck: Sympathetic (Chromaffin) paragangliomas
- Arise in paraganglia below the level of the neck.
- Chief cells from neural crest
- Secrete catecholamines
- Epinephrine
- Nor epinephrine
- Extra-adrenal: arise outside the adrenal gland along the length of the sympathetic chain
- Abdomen
- Organ of Zuckerkandl
- Bladder base
- Thorax (see mediastinal paraganglioma)
- Paravertebral (Aortosympathetic paraganglia)
- Great vessels of the chest (aortopulmonary paraganglia)
- Cardiac (extremely rare; may be located along the epicardium, in the atrial cavity, the interatrial septum or the ventricles)
- Adrenal (Pheochromocytomas)
- May be sporadic, or as part of familial syndrome (von Hippel-Lindau disease, MEN 2A & 2B, & neurofibromatosis).
- Consider genetic testing if age at diagnosis is < 50 years for mutations of VHL and other genetic abnormalities (RET, SDHS, SDHB, SDHC51
- Laboratory studies
- Fractionated plasma metanephrines:
- 96% sensitivity, 85% specificity.
- More sensitive than serum catecholamines with sporadic elevations.
- Pheochromocytoma is ruled out if plasma nor metanephrine (NMN) < 112 pg/ml and metanephrine (MN) < 61 pg/ml.
- Highly suspicious if NMN> 400 pg/ml or MN> 236 pg/ml
- 24 hr urine collection for:
- Total catecholamines (epinephrine and norepinephrine) and metanephrines (88% sensitivity, 99.7% specificity).
- Note: testing for vanillylmandelic acid (VMA) is no longer done as it does not measure fractionated metanephrines.
- Where elevation is found, a clonidine suppression test can be done.
- Normal response consists of a fall in plasma catecholamines to ≤ 50% of baseline and below 500 pg/ml
- There will be a reduction in essential hypertension
- No change with pheochromocytoma or other tumor production
- Imaging
- Indicated when laboratory tests confirm pheochromocytoma.
- MRI+ C
- Best investigation
- CT
- Used when MRI is contraindicated,
- Less sensitive
- Especially for lesions < 1cm diameter.
- 123I-MIBG (iodine-123-meta-iodobenzylguanidine) scintigraphy
- Detects extra-adrenal pheochromocytomas
- With 83–100% sensitivity, 95–100% specificity.
- If not available, 131I-MIBG may be used
- 77–90% sensitivity
- 95–100% specificity.
Other ways of classifying
- Adrenal: Pheochromocytoma
- Extra-adrenal: Paragangliomas
CNS WHO grading
- Grade I
- Malignancy
- Only metastasis is diagnostic as mitosis and necrosis are not reliable
Histopathology
Macroscopic
- Highly vascular masses
- Majority (75%) are encapsulated
- Attached to the filum terminale or less commonly a nerve root
Microscopic
- All paragangliomas consist of two types of cells
- Type 1: The main components are lobules or nests of chief cells, (Zellballen)
- Type 2: They are surrounded by a single layer of sustentacular cells
Immunophenotype
- Chief cells (type I) 5:
- Chromogranin-A: positive
- Synaptophysin: positive
- Neuropeptides: can be positive
- 5-HT
- Somatostatin
- Met-enkephalin
- Sustentacular cells (type II):
- S100: usually positive
- GFAP: usually positive
Genetic profile
- Strong hereditary group
- > 80% of these tumours in children are inherited
- >10 genes associated with all paragangliomas
- VHL (associated with von Hippel- Lindau disease)
- RET (associated with multiple endocrine neoplasia type 2)
- NF1 (associated with neurofibromatosis type 1)
- Genes coding for the subunits of the succinate dehydrogenase enzyme
- SDHD (associated with inherited paraganglioma- 1)
- TSG on HIF-1A reducing VEGF and EPO
- SDHA and SDHAF2 (associated with paraganglioma-2)
- SDHC (associated with paraganglioma-3)
- SDHB (associated with paraganglioma- 4)
- Which forms part of mitochondrial complex II
- Tumour suppressors TMEM127
- MAX
- Associated with
- Von Hippel-Lindau syndrome
- Multiple endocrine neoplasia types 2A and 2B
- Neurofibromatosis type 1
- Carney-Stratakis syndrome
- Three methylation subclusters (M1–M3) which are strongly associated with molecular subtypes: (The Cancer Genome Atlas -TGCA)
- (TCGA- M1 cluster)
- Pseudohypoxic PGLs with genetic alterations in tricarboxylic acid cycle genes show DNA hypermethylation
- Head and neck paragangliomas
- (TCGA M2 cluster)
- Pseudohypoxic VHL- and EPAS1-related PGL show intermediate DNA methylation
- (TCGA M3 cluster)
- Wnt and kinase signalling alterations exhibit DNA hypomethylation
- Spinal paragangliomas
- Biochemical and genetic clusters of paragangliomas.
Management
General
- Difficult to treat because
- Tumours are vascular
- Locally aggressive
- Involve important neurovascular structures,
- ICA
- Jugular Bulb
- Facial nerve (FN)
- Lower cranial nerves (LCNs, CN IX, X, XI, XII)
- Small tumours (confined to the middle ear)
- Surgical resection is usually simple and effective
- Larger tumours
- Invade and destroy bone, the relative role of surgery and/or radiation is not fully determined.
- With large tumours, surgery carries the risk of significant cranial nerve palsies.
- Algorithm
- Radiotherapy as a first-line treatment
- Indicated for
- Tumour without neurological deficit
- Radiotherapy > surgery (better results)
- Regardless of the tumor volume with local tumour control rates 95-100% up to 10 years, stabilization or even improvement of neurological deficit, fewer iatrogenic effects, and usually preserved hearing and facial nerve function.
- Subtotal resection (function sparing) → early (planned) or delayed (evidence of tumor progression) radiotherapy
- Preoperative embolization → surgical resection
- Treatment of choice for globus jugulare paragangliomas
Medical management
- General information
- Most tumour are benign and slow growing
- For tumors that actively secrete catecholamines, medical therapy is useful for palliation or as adjunctive treatment before embolization or surgery.
- Alpha and beta blockers given before embolization or surgery blocks possibly lethal blood pressure lability and arrhythmias.
- Adequate blockade takes ≈ 2–3 weeks of alpha blocker and at least 24 hours of beta blocker therapy;
- In emergency, 3 days of treatment may suffice.
- Alpha blockers
- Reduce BP by preventing peripheral vasoconstriction.
- Phenoxybenzamine (Dibenzyline®):
- Long acting; peak effect 1–2 hrs.
- Start with 10mg PO BID and gradually increase to 40–100mg per day divided BID
- Phentolamine (Regitine®):
- Short acting. Usually used IV for hypertensive crisis during surgery or embolization.
- ℞: 5mg IV/IM (peds: 1mg) 1–2 hrs pre-op, repeat PRN before and during surgery
- Beta blockers
- Reduces catecholamine-induced tachycardia and arrhythmias
- May also prevent hypotension that might occur if only alpha blockade is used
- These drugs are not always needed, but when used:
- Beta blockers
- Must not be started before starting alpha-blockers
- If used before alpha blocker: beta blocker → reduce inotropic effects → reduce BP → With already significant vasoconstriction in the presence of catecholamines in blood → reflex tachycardia → reflex HTN (hypertensive crisis and myocardial ischemia).
- Propranolol (Inderal®):
- ℞: oral dose is 5–10mg q 6 hrs. IV dose for use during surgery is 0.5–2mg slow IVP
- Labetalol (Normodyne®):
- May have some efficacy in blocking α1 selective and β nonselective (potency < propranolol)
- Serotonin, bradykinin, histamine release blockers
- These agents may provoke bronchoconstriction that does not respond to steroids, but may respond
- To inhaled β-agonists or inhaled anticholinergics. Somatostatin may be used to inhibit release of serotonin,
- Bradykinin, or histamines. Since this drug has a short half-life, it is preferable to give octreotide
- (p.763) 100 mcg sub-Q q 8 hrs.
Radiation therapy
- Radiotherapy indication
- Inoperable tumours due to tumour size
- XRT may relieve symptoms and stop growth in spite of persistence of tumor mass.
- ICA invasion with poorly tolerated clamping test or exclusively ipsilateral venous return or deficient contralateral venous return, other surgical contraindications, or
- Bilateral tumors.
- As an adjunct to incomplete surgery.
- Salvage therapy after failure of surgery or relapse.
- Some surgeons pretreat 4–6 mos preoperatively with XRT to decrease vascularity (controversial).
- Dose
- 40–45 Gy in fractions of 2 Gy has been recommended.
- Lower doses of ≈ 35 Gy in 15 fractions of 2.35 Gy appear as effective and have fewer side effects.
Embolisation
- Indication
- Large tumours with favourable blood supply (i.e. vessels that can be selectively embolized with no danger of particles passing through to normal brain)
- Used as primary treatment (± radiation) in patients who are not surgical candidates.
- In this case, XRT is only palliative, as tumor will develop new blood supply
- May be used preoperatively to reduce vascularity.
- Performed 24–48 hours pre-op (not used prior to that, because of post-embolization edema)
- Caution
- Post-embolisation tumour swelling may compress brainstem or cerebellum
- Actively secreting tumours that may release vasoactive substances (e.g. epinephrine) upon infarction from the embolization
- Absorbable (Gelfoam®) and non-absorbable (Ivalon®) materials have been used
Surgical treatment
General information
- The tumor is primarily extradural, with extremely vascular surrounding dura.
- Suboccipital approach may cause dangerous bleeding and usually results in incomplete resection.
- Team approach by a neurosurgeon in conjunction with a neuro-otologist (and possibly head and neck surgeon) has been advocated.62 This approach utilizes an approach to the skull base through the neck.
- ECA feeders are ligated early, followed rapidly by draining veins (to prevent systemic release of catecholamines).
- Sacrifice of the jugular vein (JV) is tolerated if the contralateral JV is patent (often, the ipsilateral JV will already be occluded).
Indication
- Young patients
- Preoperative facial nerve or glossopharyngeal, vagus, and accessory nerve paralysis;
- Low probability of surgical complications;
- Intracranial extension;
- Recurrence after irradiation;
- Major petroclival extension with ICA invasion and well tolerated clamping test.
- Another argument justifying first-line surgery can be that resection of surrounding bone reduces the risk of late osteoradionecrosis in the event of subsequent radiotherapy.
Surgical complications and outcome
- Complications are
- CSF fistula,
- Facial nerve palsy,
- Varying degrees of dysphagia (from dysfunction of lower cranial nerves).
- Dysfunction of any of the cranial nerves VII thru XII can occur, and a tracheostomy should be performed if there is any doubt of lower nerve function, and a gastrostomy feeding tube may be needed temporarily or permanently.
- Lower cranial nerve dysfunction also predisposes to aspiration, the risk of which is also increased by impaired gastric emptying and ileus that may occur due to reduced cholecystokinin (CCK) levels post-op.
- Excessive blood loss can also occur.
- Even after gross total tumor removal, recurrence rate may be as high as 1/3
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