Paragangliomas and paraganglioma syndromes

Abstract

Paragangliomas are rare tumors of neural crest origin. They are benign in the majority of cases and are characterized by a strong vascularisation.In the head and neck region they most commonly occur as carotid body tumors. Jugulotympanic and especially vagal paragangliomas are seen less frequently. Complete surgical resection represents the only curative treatment option even though resection of locally advanced tumors regularly results in lesions of the lower cranial nerves and major vessels. Appoximately 30% of all head and neck paragangliomas (HNPs) are hereditary and associated with different tumor syndromes. The paraganglioma syndromes 1, 3 and 4 (PGL 1, 3 and 4) make up the majority of those familial cases. PGL 1 is associated with mutations of the succinate dehydrogenase subunit D (SDHD) gene, PGL 3 is caused by SDHC and PGL 4 by SDHB gene mutations. Multiple HNPs and the occurance of HNPs together with pheochromocytomas are seen in SDHD as well as SDHB mutation carriers. In patients with SDHB mutations the risk for the development of malignant paraganglial tumors is significantly higher compared to SDHC and SDHD patients as well as patients with sporadic tumors. SDHC mutation carriers almost exclusively present with benign HNP that are unifocal in the majority of cases. The role of transmission is autosomal dominant for all three symptoms. Interestingly, there is a "parent-of-origin-dependent-inheritance" in subjects with SDHD gene mutations. This means that the disease phenotype may only become present if the mutation is inherited through the paternal line. We recommend screening for mutations of the genes SDHB, SDHC and SDHD in patients with HNPs. Certain clinical parameters can help to set up the order in which the three genes should be tested.

Keywords: glomus tumor; paraganglioma; paraganglioma syndrome; pheochromocytoma; rare diseases.

Table 1. Classification of jugulotympanic paragangliomas according to Fisch & Mattox [60]

Table 2. Differential diagnosis of pulsatile tinnitus (modified according to Gehrking [50])

Table 3. Recommendations for therapy of head and neck paragangliomas

Table 4. Recommendations regarding preoperative embolisation

Table 5. Tumor syndromes associated with HNPs and pheochromocytomas

Figure 1. Figure 1a: CBT (class I): The axial T1-weighted MRI with contrast medium shows a CBT in typical location. Splaying of the left carotid bifurcation without any surrounding of the carotid vessels.

Figure 1b: CBT (class II): Axial T1-weighted MRI with contrast showing a right-sided CBT partially surrounding the internal and external carotid artery. Figure 1c: CBT (class III): A large left-sided CBT intimately surrounding the carotid vessels (axial T1 weighted MRI with contrast).

Figure 2. Dynamic contrast-enhanced magnetic resonance angiography (MRA) of a 44 year old male SDHD mutation carrier. Note bilateral CBTs and a jugular paraganglioma on the right in the early arterial phase.

Figure 3. ¹⁸F-DOPA-PET presenting a right CBT, a right jugular paraganglioma, a remnant of a left CBT as well as pheochromocytomas in the left atrium and in projection to the aortic arch. This 41 year old male SDHD patient had already undergone surgery for bilateral abdominal pheochromocytomas. Physiologic tracer uptake is seen in the gallbladder, the renal pelvis and the urinary bladder.

Figure 4. ⁶⁸Ga-DOTATATE-PET with multiple bone metastases in the spine, the rips and at the skull base (marked by arrows). Physiologic tracer uptake in the liver, the kidneys, the adrenals, the stomach, pancreas, spleen and the small bowel. This 41 year old female SDHB mutation carrier had first undergone resection of a malignant carotid body tumor with regional lymph node metastases seven years earlier.

Figure 5. Frontal fusion between computed tomography and PET affirms the spinal metastasis in the SDHB mutation carrier from Figure 4.

Figure 6. The hematoxiline-eosine staining reveals chief cells in a classical “Zellballen” pattern surrounded by ectatic blood vessels and sustentacular cells (original magnification x100).

Figure 7. On immunhistochemistry the chief cells are positive for chromogranin (original magnification x200).

Figure 8. Positive staining of the chief cells for NSE (original magnification x100).

Figure 9. S-100 positive sustentacular cells surrounding the chief cells (original magnification x100).

Figure 10. General algorithm for cost-effective mutation screening in patients with head and neck paragangliomas (HNPs) according to Neumann et al. [10].