Pheochromocytomas are derivatives of the neural crest and arise from adrenal chromaffin cells. Extra-adrenal (chromaffin) paragangliomas may be referred to as extra-adrenal pheochromocytomas. Medical textbooks have traditionally suggested that approximately 10 % of pheochromocytomas are heritable, 10 % are extra-adrenal, and 10 % are malignant. However, the frequency of heritable pheochromocytoma has been underestimated, and in one population-based study, 25 % of unrelated, apparently sporadic presentations of pheochromocytomas, without syndromic features or family history, were found to harbor germline mutations in one of four genes, VHL, RET, SDHD, or SDHB (Neumann et al. 2002). This frequency has been confirmed in referral series as well (Benn et al. 2006). Due to these and related findings, all presentations of pheochromocytomas, regardless of age, syndromic features, or family history, should considered for mutation analysis in the setting of cancer genetic consultation which includes genetic counseling. The genetic differential diagnosis of pheochromocytoma includes MEN 2 caused by germline mutations in the RET gene; von Hippel–Lindau (VHL) disease caused by VHL mutations; the pheochromocytoma–paraganglioma syndrome caused by germline mutations in the SDHB, SDHC, and SDHD genes; and, very rarely, NF 1 (Maher and Eng 2002; Eng et al. 2003; Neumann et al. 2004; Schiavi et al. 2005). Familial site-specific pheochromocytomas are mainly attributable to germline mutations in VHL, SDHD, or SDHB (Woodward et al. 1997; Astuti et al. 2001a, b). Such families with pheochromocytomas as well as chemodectomas or glomus Tumours are almost always due to germline mutations in SDHB, SDHC, or SDHD (Maher and Eng 2002; Neumann et al. 2004). Recently, germline mutations in TMEM127 were described in rare familial adrenal pheochromocytoma cases (Yao et al. 2010). These cases were characterized by unilateral Tumours diagnosed in the 40s. However, a subsequent registry-based study demonstrated that germline TMEM127 mutations could also be associated with extra-adrenal disease, occurring in about 5 % of 48 individuals with paraganglioma but without mutations in the other predisposition genes (Neumann et al. 2011). Even more recently, germline MAX mutations were described in ~10 % of hereditary pheochromocytoma cases characterized by very early-onset and malignant disease (Comino- Mendez et al. 2011).
In general, like virtually all inherited neoplasias, the mean age at diagnosis for heritable pheochromocytoma is lower, and there will be a higher incidence of bilateral Tumours and multifocal disease when compared to sporadic pheochromocytoma. Nonetheless, these clinical features, the clinical hallmarks of heredity, are syndrome dependent (and hence, dependent on susceptibility gene involved) (Neumann et al. 2004). For example, in the population-based study on non-syndromic pheochromocytomas, while the mean age at presentation in individuals without germline mutations (sporadic) was 44 years, the mean age was 36 years for those shown to carry a RET mutation (MEN 2), 18.3 years for VHL, and approximately 27 years for those found to have germline SDHD/SDHB mutations (Neumann et al. 2002). NF 1-related pheochromocytomas are usually diagnosed relatively older, around 40 years. Further, of those found to carry germline mutations, about one-third presented with multifocal disease compared to two-thirds with a solitary lesion (Neumann et al. 2002). Therefore, two algorithms were computed to help clinicians determine whether to offer germline gene testing in pheochromocytoma and paraganglioma presentations, and if so, then which genes to prioritize [Fig. 1 of Erlic and Fig. 2 of Neumann] (Erlic et al. 2009; Neumann et al. 2009).
Fig. 2 Clinical algorithm to priorities whether genetic testing is warranted (first step predictors), and if so which gene(s) to prioritize (second step predictors) for pheochromocytoma presentations
There has been scant information regarding somatic mutations in sporadic pheochromocytoma except for relatively low frequencies of somatic VHL mutations, somatic RET mutations, and somatic SDHD mutations (Eng et al. 1995a, b; Gimm et al. 2000; Astuti et al. 2001a, b). Interestingly, differential distributions of frequencies of LOH at 1p, 3p, and 22q exist between VHL- related pheochromocytomas and those of sporadic Tumours (Bender et al. 2000). In VHL-related pheochromocytomas, almost all showed LOH of markers around VHL at 3p with LOH of markers at 1p and 22q being 15 and 21 %, respectively. In contrast, sporadic Tumours showed LOH at 3p in only 21 % of samples but relatively high frequencies of 1p and 22q marker LOH (Bender et al. 2000). In MEN 2-related pheochromocytoma, it is believed that amplification of the mutant REt allele could contribute to carcinogenesis in an unknown proportion of Tumours (Huang et al. 2000). Despite genome-wide approaches, mainly of the transcriptome, clarity in regard to somatic alterations did not go beyond what was already known for 10 years. Recently, integrative genomic approaches utilizing 202 sporadic and 75 hereditary pheochromocytoma and paraganglioma Tumours revealed that ~45 % carried some form of germline or somatic alteration, with 14 % harboring VHL or RET mutations (Burnichon et al. 2011). As found previously, transcriptome signatures were consistent with germline status and clearly distinguished VHL-related from SDHx-related Tumours (Burnichon et al. 2011).
Individuals at risk for pheochromocytoma should be offered annual surveillance. The precise measures for clinical surveillance are dependent on the specific syndrome at risk for and the institution. In general, annual physical examination paying particular attention to the retinal examination and blood pressure measurements, especially with orthostatic maneuvers, and 24-h urinary catecholamines and vanyllylmandelic acid measurements are performed. Some centers advocate serum catecholamine, vanyllylmandelic acid, and chromogranin-A measurements as well. Further investigation may include MIBG and computerized tomography (CT) or magnetic resonance imaging (MRI) scans and selective venous sampling as appropriate. Recently, positron emission tomography (PET) scanning is performed for surveillance in certain centers. Full details of screening protocols in VHL disease, NF1, and MEN 2, and a sample screening protocol for SDHB and SDHD gene carriers is suggested in Table (1).