Paraganglia


The Autonomic Nervous System

Diagram of autonomic nervous system

The autonomic nervous supply to most organs is laid out as in the diagram to the right. Pre-ganglionic nerve cells emerge from the spinal cord, and synapse in an autonomic ganglion; post-ganglionic fibres run to the target organ as shown in the islet cell diagram below.

Normal sympathetic ganglion

Paraganglia

The paraganglia have a different layout. Their cells are derived from neural crest, and are effectively the post-ganglionic neurones themselves (see diagram below). The pre-ganglionic neurones synapse with the post-ganglionic neurones within the target organ itself; thus, the target organ is the ganglion, hence the name "paraganglia".

Innervation of paraganglion

Anatomy of paraganglia

At birth, small patches of paraganglionic cells are located internally and centrally around major arteries, nerves, within organs and distributed from the skull base to the pelvic floor. However, progressive involution, which lasts until puberty, normally obliterates most sites. The organ of Zuckerkandl (OZ), the clusters of tissues around the origin of the inferior mesenteric artery, is the major paraganglionic organ that secretes catecholamines in the fetal and newborn period. As the OZ regresses, the carotid body (CB) and adrenal medulla take over as the major paraganglionic organs.

Paraganglia contain the following cell types:

  • Type 1 cells - glomus or chief cells, are sensitive to hypoxia and produce catecholamines
  • Type 2 cells - envelop type 1 cells and have features of Schwann cells
  • Type 3 cells - sensory nerve endings

Head & Neck Paragangliomas

Hormonally-secreting paragangliomas are known as phaeochromocytomas, most of which arise in the adrenal medulla. Paragangliomas of the head and neck are usually not hormonally active.

Main locations

  • Carotid body. Largely asymptomatic except for a mobile, non-tender, growing, lateral neck mass. Mass effect may cause hoarseness, dysphagia, vertigo and/or paresis resulting from CN compression.
  • Jugular bulb. Glomus jugulare tumours are typically under the skull base, at the external jugular bulb, but may spread into the jugular foramen, causing 9th, 10th and 11th nerve deficits.
  • Middle ear cavity. Glomus tympanicum tumours arise with the tympanic branch of the glossopharyngeal nerve. Glomus jugulare and glomus tympanicum tumours have similar clinical features. Early symptoms are pulsatile tinnitus, conduction hearing loss, aural pain, vertigo, and hoarseness. Later, 7th and 8th nerve deficits may develop.
  • Cervical vagus nerve. Typical presentation of glomus vagale tumours is slow-growing mass in the parapharyngeal space. Later, may cause CN palsies of one nerve or combination of vagus, hypoglossal, accessory, and glossopharyngeal nerves. Vagus nerve deficits are usually late because the individual fibres are splayed across the surface of the tumour.

Clinical aspects

  • Incidence peaks at 45-60 years of age.
  • Malignancy rates of 5-7% are reported.
  • Vast majority are slow growing.
  • Mortality rates 9-15%, depending on location of tumour.
  • Local invasion and compression can cause significant problems.
  • Treatment is surgical in all cases, because:
    • no way of knowing which will become malignant
    • surgical risk much lower for small tumours not encasing the carotids
    • all will eventually become symptomatic

Carotid bodies

These line the medial walls of the bifurcations of the common carotid arteries. They detect changes in arterial paO2, paCO2, pH and other factors, increasing or decreasing stimulation to the respiratory centres, affecting respiratory rate and cardiac output. Chronic hypoxaemia is a stimulus for gland hypertrophy. Non-familial paragangliomas are commoner at high altitude.

SDH mutations may affect oxygen sensing, explaining why they cause carotid body tumours. The penetrance and frequency of SDH mutations is affected by altitude: higher altitude increases phenotypic severity and decreases population prevalence.

Hypoxia-inducible pathways

The phaeochromocytomas of VHL also involve constitutive activation of hypoxia-inducible pathways. The HIF1-α protein, the master transcriptional factor inducing hypoxia tolerance genes, is normally hydroxylated by a group of prolyl hydroxylase enzymes (PHDs). The VHL protein is a recognition component of the E3 ubiquitin ligase complex. This promotes the ubiquitylation of HIF-1α which is then targeted for proteasomal degradation.

Hypoxia inducible pathways

The activation of hypoxia inducible pathways in von Hippel-Lindau disease is caused by the inability of mutant VHL protein to target hydroxylated HIF1-α protein for degradation. Succinate accumulation may also inhibit the PHDs leading to stabilisation of HIF1-α. Accumulation of fumarate and reactive oxygen species (ROS) may also inhibit PHDs, increasing levels of HIF1-α. Fumarate accumulation is seen in an inherited condition of leiomyomata and renal cell cancer (HLRCC).