Head and neck paragangliomas: clinical and molecular genetic classification

Abstract

Head and neck paragangliomas are tumors arising from specialized neural crest cells. Prominent locations are the carotid body along with the vagal, jugular, and tympanic glomus. Head and neck paragangliomas are slowly growing tumors, with some carotid body tumors being reported to exist for many years as a painless lateral mass on the neck. Symptoms depend on the specific locations. In contrast to paraganglial tumors of the adrenals, abdomen and thorax, head and neck paragangliomas seldom release catecholamines and are hence rarely vasoactive. Petrous bone, jugular, and tympanic head and neck paragangliomas may cause hearing loss. The internationally accepted clinical classifications for carotid body tumors are based on the Shamblin Class I-III stages, which correspond to postoperative permanent side effects. For petrous-bone paragangliomas in the head and neck, the Fisch classification is used. Regarding the molecular genetics, head and neck paragangliomas have been associated with nine susceptibility genes: NF1, RET, VHL, SDHA, SDHB, SDHC, SDHD, SDHAF2 (SDH5), and TMEM127. Hereditary HNPs are mostly caused by mutations of the SDHD gene, but SDHB and SDHC mutations are not uncommon in such patients. Head and neck paragangliomas are rarely associated with mutations of VHL, RET, or NF1. The research on SDHA, SDHAF2 and TMEM127 is ongoing. Multiple head and neck paragangliomas are common in patients with SDHD mutations, while malignant head and neck paraganglioma is mostly seen in patients with SDHB mutations. The treatment of choice is surgical resection. Good postoperative results can be expected in carotid body tumors of Shamblin Class I and II, whereas operations on other carotid body tumors and other head and neck paragangliomas frequently result in deficits of the cranial nerves adjacent to the tumors. Slow growth and the tendency of hereditary head and neck paragangliomas to be multifocal may justify less aggressive treatment strategies.

Figure 1

Shamblin classification. The Shamblin classification is based on involvement of the carotid arteries, which are shown by white arrows in A–C. The tumors are indicated by yellow arrows. (A) CBT (class I): the axial T2-weighted MRI shows a CBT in a typical location. Bulging of the left carotid bifurcation without any encasement of the carotid vessels. (B) CBT (class II): axial T2-weighted MRI showing a right-sided CBT with a partial encasement of the internal and external carotid artery. (C) CBT (class III): an axial slice of CT-angiography reveals a huge left-sided CBT with a complete encasement of the carotid vessels. In this case, bone destruction of the skull base, attributed to the enormous CBT, was also detected by CT (not shown).

Figure 2

Fisch classification. The tumors are indicated by yellow arrows. (A) Tympanic paraganglioma (Fisch class A): axial CT scan of a tympanic paraganglioma (bone window) on the right promontory. Note the absence of any bony erosion. (B) Tympanic paraganglioma (Fisch class B): the axial CT scan reveals a left-sided tympanic paraganglioma surrounding and partially destroying the ossicles. The malleus and stapes could not be discriminated. The tumor had also invaded the hypotympanon. There was no destruction of the bone wall to the jugular bulb. (C) Jugular paraganglioma (Fisch class C): axial CT scan showing a left-sided jugular paraganglioma. Note the bone destruction between the jugular bulb and the soft tissue tumor in the hypotympanon. (D) Tympanic paraganglioma (Fisch class D): time-resolved contrast-enhanced MR-angiography (upper row) depicts an early venous drainage attributed to arterio-venous fistulas within this tympanic paraganglioma (solid arrows). Coronal CT (lower row left) of the petrous bone shows a soft tissue tumor with encasement of the ossicles within the whole tympanon, and destruction of the tegmen tympani. Coronal T2-weighted and contrast enhanced T1-weighted images show a small, but distinct, intracranial but extradural tumor growth on the lateral skull base (dotted arrows, lower row).

Figure 3

Histology and immunostaining of head and neck paragangliomas. (A) Demonstration of sustentacular cells by S-100 protein in an HNP. The delicate net of sustentacular cells is surrounding the so-called Zellballen of chief cells (x200). (B) Complete immunohistochemical negativity for SDHB strongly suggesting a SDHB germline mutation (x200). (C) Immunohistochemical demonstration of SDHB protein in tumor cells, virtually excluding a germline mutation in SDHB (x200).