New insights on the pathogenesis of paraganglioma and pheochromocytoma

Introduction

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are chromaffin cell tumors derived from adrenal (PCC) or extra-adrenal sympathetic or parasympathetic paraganglia (PGL)¹, respectively. Though once thought of as being mostly benign and biochemically active, these tumors could show a wide spectrum of cellular and biochemical de-differentiation, including aggressive metastatic course and biochemical silence. Despite being anatomically distinct, PCCs and PGLs display a common pathologic basis and frequently are referred to as pheochromocytoma/paraganglioma tumors (PPGLs), the term we will use throughout this article. The incidence and prevalence of PPGLs are based on older literature, which in part paralleled our understanding of the field and could be misleading to some degree. Overall, it is stated that the annual incidence of PCC is between two and eight cases per million, whereas in patients with hypertension, the prevalence of PPGL varies between 0.2 and 0.6%. It is important to remember that in patients with incidentally radiologically discovered adrenal masses, 5% will have PCCs (reviewed in 1,2).

Recent years have tremendously changed our understanding of each and every aspect of PPGL biology—genetics, clinical and biochemical behavior, pathogenesis, diagnosis, and treatment—which to a major degree also propelled our understanding of PPGL-related and general pathophysiology of tumorigenesis. The PPGL field has also undergone a significant transformation in recent years. In older times, pheochromocytoma was seen as a mostly sporadic and benign disease, usually seen by endocrinology and surgery. Hereditary cases were relatively rare and included MEN2, neurofibromatosis type 1, and von Hippel–Lindau syndromes. Sympathetic paragangliomas were usually managed by the anatomically related (chest, abdomen, and pelvis) surgical specialties with significantly more frequent involvement of medical oncology and endocrinology on an “as needed basis”. Parasympathetic silent head-and-neck paragangliomas were seldom seen as part of the PPGL syndrome and were managed by ear, nose, and throat (ENT) and oncology. With increasing understanding of the high heritability of PPGL and similarity in pathology of seemingly discrete conditions, the field has transformed into all-inclusive and comprehensive medicine approach-based multispecialty management. We now know that PPGLs represent the highest hereditary-driven endocrine condition—up to 40% of cases are related to mutations in 15 well-established driver genes and a growing number of disease-modifying genes and these numbers are expected to grow^3–5.

As our understanding of PPGLs deepens, it seems that current anatomic (World Health Organization, 2017) or standard staging (American Joint Commission Cancer staging, 2017) classifications fell short of providing sufficient insight into pathogenesis, clinical presentation, and (perhaps more importantly) prognostic value with respect to malignant potential, response to therapy, and possible recurrences. Functional, pathogenesis-based classification does allow a better understanding of actual tumorigenesis, expected biochemical profiles, tumor location, and malignant potential. The more recently formulated group of disease-modifying genes is expected to expand and possibly explain tumor formation in a growing number of apparently mutation-free cases (Figure 1 and Table 1).

Figure 1. Differential characteristics of hereditary pheochromocytoma/paraganglioma tumors (PPGLs).

A, degree of PPGL cell differentiation; B, risk of metastatic/malignant potential and norepinephric versus epinephric secretory profile.

This functional classification of currently established susceptibility genes consists of four major groups: the pseudohypoxia group, the kinase signaling group, the Wnt signaling group, and the disease-modifying gene group.

Pseudohypoxia group

This group can be further subdivided to the following subgroups:

Kinase signaling group

This group comprises the majority of PPGLs (50 to 60%) and is driven by either germline or somatic mutations in up to 20% of cases. It includes oncogenes—rearranged during transfection (RET) proto-oncogene and H-ras GTPase proto-oncogene (HRAS)—and several tumor suppressors: neurofibromin 1 (NF1), transmembrane protein 127 (TMEM127), and MYC-associated factor X (MAX). These mutations are associated with the activation of kinase signaling pathways: RAS-RAF-MEK and PI3K-AKT-mTOR for RET, HRAS, NF1, and TMEM127 and MYC-MAX for MAX.

Activation of RET gene is essential for development of both sympathetic and parasympathetic components of the autonomous nervous system through growth and differentiation of the neural crest precursors. Tumorigenesis occurs through activation of the tyrosine kinase, which signals through the above pathways to promote cell growth and survival. The NF1 gene is predominantly expressed in neurons, Schwan cells, oligodendrocytes, and leukocytes. Its main function as a tumor suppressor is ras GTP-ase which de-activates RAS, thus preventing activation of the oncogenic RAS-RAF-MEK signaling cascade. TMEM127 is a negative regulator of mTOR, which is a PI3K kinase, shown to be activated in many human cancers and associated with increased cell proliferation, angiogenesis, and survival. MAX is a transcription factor associated with proto-oncogene MYC.

Rat sarcoma viral oncogene (ras) genes are frequently found in human cancers and function as activators of cell growth and survival. Of multiple group members, only Harvey (H-ras) and Kirsten (K-ras) were shown to associate with PPGL formation.

A small proportion of PPGLs show additional kinase signaling pathway–associated mutations in FGFR1, KIF1B, and MET but these still need to be validated. KIF1B is a tumor suppressor gene necessary for the neuronal apoptosis.

Wnt signaling group

Tumors in this group occur in 5 to 10% of PPGLs and in most cases are related to somatic mutations in tumor suppressor cold shock domain-containing E1 (CSDE1) and oncogene mastermind-like transcriptional coactivator 3 (MAML3).

Disease-modifying gene group

Somatic mutations in five genes—ATRX, KMT2D, SETD2, TERT, and TP53—have a synergistic effect on PPGL tumorigenesis and raise the possibility of association with an excessively aggressive course of the disease.

Recent advances in our understanding of the pathogenesis of PPGL had significantly changed our approach to the condition. The change in classification moved different forms of PPGLs into pathogenesis-driven groups, which allowed a better understanding of major disease-related features: clinical presentation, biochemical approach, and predisposition to malignant course and possible differences in therapy and follow-up. It had also brought back some old concepts—like Warburg effect (tumorigenesis related to accelerated glycolysis)—that fit well into the model of pseudohypoxia-driven disease. Understanding differential pathogenetic pathways in different forms of PPGL allowed a better design of biochemical tests with a recent use of metabolomics through high-end nuclear magnetic resonance spectroscopy as a differential tool on a biochemical level^14,15. Pathogenesis-based knowledge had also allowed us to design new therapeutic approaches; the best example would be the use of specific HIF-2α antagonists (PT2399) and prolyl hydroxylase activators (R59949 and KRH102053) that promote HIF hydroxylation, thus restoring VHL-driven recognition and rapid degradation. These could switch the pseudoxypoxic signal and potentially disrupt the tumorigenesis process at the actual pathogenetic point¹⁵. The possibility of multiple additional clinical presentations and novel mutations will further boost our ability to more deeply understand and affect the pathogenesis of this fascinating condition. One example would be a recent report of PPGL associated with cardiac dysplasia¹⁶. There are still plenty of questions waiting to be answered in relation to the particular mechanisms of tumorigenesis and possible interventions early in the course of the disease to prevent possible adverse outcomes. This will definitely improve with new knowledge and experience.