Pheochromocytomas and Paragangliomas: New Developments with Regard to Classification, Genetics, and Cell of Origin.

Karen Koopman,Jose Gaal,Ronald R De Krijger

doi:10.3390/cancers11081070

Karen Koopman, Jose Gaal + Show 1 more

Open Access

https://doi.org/10.3390/cancers11081070

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Abstract

Pheochromocytomas (PCC) and paragangliomas (PGL) are rare neuroendocrine tumors that arise in the adrenal medulla and in extra-adrenal locations, such as the head, neck, thorax, abdomen, and pelvis. Classification of these tumors into those with or without metastatic potential on the basis of gross or microscopic features is challenging. Recent insights and scoring systems have attempted to develop solutions for this, as described in the latest World Health Organization (WHO) edition on endocrine tumor pathology. PCC and PGL are amongst the tumors most frequently accompanied by germline mutations. More than 20 genes are responsible for a hereditary background in up to 40% of these tumors; somatic mutations in the same and several additional genes form the basis for another 30%. However, this does not allow for a complete understanding of the pathogenesis or targeted treatment of PCC and PGL, for which surgery is the primary treatment and for which metastasis is associated with poor outcome. This review describes recent insights into the cell of origin of these tumors, the latest developments with regard to the genetic background, and the current status of tumor classification including proposed scoring systems.

Highlights

Pheochromocytomas (PCC) are rare neuroendocrine tumors that, by definition, arise in the adrenal medulla; the term paraganglioma (PGL) is reserved for tumors that arise from sympathetic ganglia in the thorax, abdomen, and pelvis as well as from parasympathetic paraganglia in the head and neck area
Such tumors have a relationship with various other tumors, such as neuroblastomas, that originate from the adrenal medulla and extra-adrenal sympathetic tissues as well as tumors co-occurring in various hereditary tumor syndromes, for instance, medullary thyroid carcinoma in multiple endocrine neoplasia type 2 (MEN2), renal cell carcinoma in von Hippel-Lindau (VHL) disease, and gastrointestinal stromal tumors (GIST) in the context of succinate dehydrogenase subunit gene mutations
PCC and PGL are composed of chromaffin cells, deriving from the adrenal medulla and sympathetic ganglia [1]

Summary

Introduction

Pheochromocytomas (PCC) are rare neuroendocrine tumors that, by definition, arise in the adrenal medulla; the term paraganglioma (PGL) is reserved for tumors that arise from sympathetic ganglia in the thorax, abdomen, and pelvis as well as from parasympathetic paraganglia in the head and neck area These tumors are rare, with an incidence of approximately five per million, they are relevant from various perspectives, including pathophysiology and genetic background. Chromaffin cells, which form the chief component of the adrenal medulla, have been shown to derive from peripheral glial stem cells, known as Schwann cell precursors These have a limited capability for expansion and migrate along preganglionic nerves to reach their adrenal medulla destination. Two recent histopathological scoring systems, correlating with metastatic potential, hold some promise for this purpose, including the Pheochromocytoma of the Adrenal gland Scaled Score (PASS) and the Grading system for Pheochromocytoma and Paraganglioma (GAPP) [11,12], both of which will be discussed

Genetics

Cluster 1

Tricarboxylic Acid TCA Cycle-Related

Cluster 2

Findings

Histopathological Classification