The Diagnosis and Clinical Significance of Paragangliomas in Unusual Locations

Abstract

Paragangliomas are neuroendocrine neoplasms, derived from paraganglia of the sympathetic and parasympathetic nervous systems. They are most commonly identified in the head and neck, being most frequent in the carotid body, followed by jugulotympanic paraganglia, vagal nerve and ganglion nodosum, as well as laryngeal paraganglia. Abdominal sites include the well-known urinary bladder tumors that originate in the Organ of Zuckerkandl. However, other unusual sites of origin include peri-adrenal, para-aortic, inter-aortocaval, and paracaval retroperitoneal sites, as well as tumors in organs where they may not be expected in the differential diagnosis of neuroendocrine neoplasms, such as thyroid, parathyroid, pituitary, gut, pancreas, liver, mesentery, lung, heart and mediastinum. The distinction of these lesions from epithelial neuroendocrine neoplasms is critical for several reasons. Firstly, the determination of clinical and biochemical features is different from that used for epithelial neuroendocrine tumors. Secondly, the genetic implications are different, since paragangliomas/pheochromocytomas have the highest rate of germline susceptibility at almost 40%. Finally, the characterization of metastatic disease is unique in these highly syndromic lesions. In this review, we summarize updated concepts by outlining the spectrum of anatomic locations of paragangliomas, the importance of morphology in establishing the correct diagnosis, the clinical implications for management, and the impact of genetics on the distinction between multifocal primary tumors compared with malignant disease.

Keywords: SDHB; catecholamines; genetic susceptibility; metastatic paraganglioma; paraganglioma; pheochromocytoma.

Figure 1

Location of paraganglia. This figure illustrates the location of normal paraganglia in the neck, thorax and abdomen. Locations in the head are not shown.

Figure 2

Localization of paragangliomas on Computed Tomography (CT) imaging. Multifocal paraganglia in patients with genetic predisposition to paraganglioma syndrome. (a) There are multiple small lesions all along the para-aortic channel (arrows), each representing a small paraganglioma in this patient with germline predisposition and multiple tumors, including multiple liver lesions. (b) In this patient with genetic predisposition to paraganglioma, there are multiple masses (arrows) that the radiology report identified as “multiple mesenteric lymph nodes, the largest one measures 5.1 × 1.9 cm, and there also sub-centimetric retroperitoneal lymph nodes”.

Figure 3

Histology and immunoprofile of a duodenal Succinate Dehydrogenase (SDH)-deficient paraganglioma. (a) This tumor is identified underlying duodenal mucosa and was classified as a small bowel neuroendocrine tumor. (b) The tumor cells are form small nests within a fibrovascular stroma. They are somewhat elongated and have moderate nuclear pleomorphism. (c) The tumor is strongly positive for chromogranin-A. (d) Sustentacular cells are highlighted by their intense reactivity for S100 protein. (e) There is nuclear staining for GATA-3 in tumor cells. (f) Strong cytoplasmic positivity for tyrosine hydroxylase confirms the diagnosis of paraganglioma. (g) This tumor is SDH-deficient as shown by lack of cytoplasmic granular reactivity for SDH subunit B (SDHB); note the positivity in stromal cells that serve as an internal control.

Figure 4

GATA-3 (GATA-binding factor 3) immunolocalization in adrenal medulla and paragangliomas. (a) In this section of normal adrenal, the medulla (left) stains for GATA-3 whereas the adrenal cortex (right) is completely negative. (b) A cardiac paraganglioma exhibits strong nuclear reactivity for GATA-3. (c,d) Lung paragangliomas have variable nuclear positivity for GATA-3.

Figure 5

Biochemical and genetic clusters of paragangliomas.