Pheochromocytomas and Abdominal Paragangliomas: A Practical Guidance

Abstract

Pheochromocytomas and abdominal paragangliomas (PPGLs) are rare tumors arising from the adrenal medulla or the sympathetic nervous system. This review presents a practical guidance for clinicians dealing with PPGLs. The incidence of PPGLs has risen. Most cases are detected via imaging and less present with symptoms of catecholamine excess. Most PPGLs secrete catecholamines, with diffuse symptoms. Diagnosis is made by imaging and tests of catecholamines. Localized disease can be cured by surgery. PPGLs are the most heritable of all human tumors, and germline variants are found in approximately 30-50% of cases. Such variants can give information regarding the risk of developing recurrence or metastases as well as the risk of developing other tumors and may identify relatives at risk for disease. All PPGLs harbor malignant potential, and current histological and immunohistochemical algorithms can aid in the identification of indolent vs. aggressive tumors. While most patients with metastatic PPGL have slowly progressive disease, a proportion of patients present with an aggressive course, highlighting the need for more effective therapies in these cases. We conclude that PPGLs are rare but increasing in incidence and management should be guided by a multidisciplinary team.

Keywords: genetics; histopathology; imaging; paraganglioma; pheochromocytoma; prognosis.

Figure 1

Anatomic overview of pheochromocytoma and the most commonly encountered abdominal paraganglioma. While pheochromocytomas arise in the adrenal medulla, abdominal pargangliomas derive from sympathetic paraganglia. The latter entity most commonly occurs in the retroperitoneum along the sympathetic trunk, not seldom within the organs of Zuckerkandl. Paragangliomas may also develop in paraganglia distributed along the urinary and gastrointestinal tracts. Created with BioRender.com.

Figure 2

Computed tomography displaying a 6 × 5 cm large, well-defined and heterogenous-appearing pheochromocytoma originating from the left adrenal gland. The right adrenal gland is normal.

Figure 3

All images represent staining with hematoxylin-eosin (H&E) unless otherwise specified. (A) Low-power image of a pheochromocytoma (star) arising in adrenal gland asterisk). (B) High-power view illustrating the classical nested appearance of the tumor cells with a finely granular, amphophilic cytoplasm. (C) Subsets of cases may display nuclear pleomorphism and hyperchromatic nuclei. (D) Immunohistochemistry reveals diffuse chromogranin A positivity.

Figure 4

Main molecular clustering of pheochromocytomas and paragangliomas (PPGLs). Tumors are traditionally divided into four main transcriptomal clusters depending of the mRNA profiles, of which three are detailed here with a representative set of specific genes highlighted for each sub-group. In terms of clinical importance, cluster 1 tumors exhibit the highest proportion of metastatic cases and are usually driven by somatic or constitutional mutations in genes responsible for the cellular response to hypoxia. These gene variants either aggregate in genes encoding enzymes propelling the tricarboxylic acid (TCA) cycle, or in genes regulating hypoxia-inducible factor more directly (“TCA cycle non-aberrant”). While this triaging is helpful, it should be stressed that individual genes of certain sub-groups may have a risk of dissemination that does not fit perfectly with the assigned cluster. Subsets of cases adhering to the cluster1 sub-groups may be identified by immunohistochemical (IHC) analyses targeting the SDHB and CAIX proteins. Cluster 2 is defined by PPGLs exhibiting mutations in genes regulating kinase-associated pathways, and these tumors usually have low metastatic potential. Finally, cluster 3 is represented by PPGLs driven by MAML3 gene fusions or CSDE1 mutations, causing an aberrant Wingless type (Wnt) pathway signaling. These tumors have an intermediate risk of metastatic disease. Created with BioRender.com.

Figure 5

Potential future work-up of pheochromocytomas and abdominal paragangliomas may require a combination of histology and molecular immunohistochemistry as well as screening for somatic genetic aberrations in order to facilitate the detection of cases with the potential to metastasize. Created with BioRender.com.

Figure 6

Proposed clinical flowchart for clinical management of PPGL patients. It is recommended to individualize management due to factors such as age and aggressiveness of disease, which are factors not accounted for in this scheme. When interpreting normetanephrine/metanephrine levels, any drug effect must be excluded. *Recurrences may be detected after more than 10 years, so some departments advise lifelong annual follow-up with biochemical tests. Created with BioRender.com.