Fig. 15.1
Oxidative phosphorylation and the electron transport chain. Succinate dehydrogenase (SDH) comprises complex II. Various mutations in SDH subunits have been implicated in hereditary paraganglioma syndromes
These five enzyme complexes transfer electrons from donors to recipients, and oxygen is ultimately reduced to form water. As this is occurring, protons are pumped across the inner mitochondrial membrane into the intermembrane space creating an electrical potential across the inner membrane. The protons flow back across the membrane and down the electrical gradient which supplies the energy that is used to form ATP.
In addition to its contribution to the electron transport chain, SDH participates in the Krebs cycle. In this process, it catalyzes the conversion of succinate to fumarate. The consequence of SDH deactivation is therefore an accumulation of succinate and reactive oxygen species, which has been postulated to contribute to build up of HIF and potentially tumor development as discussed previously.
Mutations in the genes that encode succinate dehydrogenase proteins are generally inactivating and can occur either somatically or in the germ line (hereditary form ensues). While mutations in all four subunits can lead to development of paraganglioma, the clinical presentation and inheritance pattern vary depending on which gene is mutated.
Paraganglioma Syndromes
Paraganglioma syndrome is a clinical term that describes a group of inherited diseases characterized by the presence of paragangliomas and/or pheochromocytomas. Patients demonstrate variable risk of developing gastrointestinal stromal tumors (GISTs), renal cancers, or pituitary tumors [17]. Paraganglioma syndromes have been classified into five entities as follows: PGL1, PGL2, PGL3, PGL4, and PGL5. Each of these has been associated with a germline mutation in a gene encoding a component of SDH . Generally speaking, the PGL syndromes are inherited in autosomal dominant fashion, with maternal imprinting implicated in PGL1 and PGL2 subtypes. Patients with hereditary PGL syndromes are more likely to present at an earlier age and have multiple tumors when compared to non-PGL individuals with sporadic tumors [19]. The penetrance of tumor development is highly variable among the different syndromes. Data for each syndrome are detailed below and summarized in Table 15.1.
Table 15.1
Hereditary head and neck paraganglioma syndromes
PGL1 | PGL2 | PGL3 | PGL4 | PGL5 | |
|---|---|---|---|---|---|
Gene | SDHD | SDHAF2/SDH5 | SDHC | SDHB | SDHA |
Inheritance | Maternal imprinting | Maternal imprinting | Autosomal dominant | Autosomal dominant | Autosomal dominant |
Chromosomal locus | 11q23 | 11q13.1 | 1q21 | 1p35–36 | Unknown |
Pheochromocytoma risk | Intermediate | Low | Low | Intermediate | Low |
Multifocality risk | High | High | Low | Intermediate | Low |
Malignancy risk | Low | Low | Low | Intermediate | Low |
PGL1 Syndrome
PGL1 syndrome is associated with mutations in SDHD, which is located on chromosome 11q23 [3]. The D subunit of SDH encodes an anchor protein in complex II. Mutations in SDHD predispose to the development of multifocal head and neck paragangliomas. Mutations in SDHD have been reported in 52% of hereditary head and neck paragangliomas [7]. Abdominal paragangliomas and pheochromocytomas have been reported but are less common than head and neck tumors [20]. Renal cancers and pituitary tumors have occasionally been reported in association with PGL1 [21, 22].
Paragangliomas in patients with PGL1 exhibit a low rate of malignancy and are nonsecretory. They typically present around the third decade of life [23]. Benn et al. reported a high lifetime penetrance, with 75% of patients manifesting disease by the fourth decade of life [24]. SDHD mutations exhibit maternal imprinting [25–27]. In this pattern of inheritance, the maternally derived allele for SDHD is imprinted (silenced), and the expressed allele is entirely dependent on its paternal origin. For this reason, phenotypic expression of PGL1 can skip generations.
PGL2 Syndrome
PGL2 is rare and is associated with SDHAF2 germline mutations [28]. The SDAF2 gene, also referred to as SDH5 in some studies, encodes a protein that is necessary for the assembly of the A subunit of SDH. These mutations have only been reported in a few families [14, 29, 30]. Patients with PGL2 tend to develop multifocal head and neck paragangliomas [30]. Like PGL1, the inheritance pattern is maternal imprinting, and the penetrance is high. Although data are limited, neither paragangliomas outside the head and neck nor pheochromocytomas have previously been reported [17].
PGL3 Syndrome
The SDHC gene, encoding the SDHC anchor protein in complex II, is mutated in PGL3 [15]. This mutation occurs less frequently than SDHB and SDHD mutations. Germline mutations in SDHC have been reported to account for 14% of hereditary head and neck paragangliomas [7]. This condition is inherited in autosomal dominant (AD) fashion. Head and neck paragangliomas are the predominant tumor in PGL3 syndrome. These tumors are almost exclusively benign, rarely multifocal, and typically nonsecretory [31, 32]. Mutations in SDHC are rarely identified in patients with thoracic/abdominal paragangliomas and pheochromocytomas [17, 31]. The typical age of presentation is in the fourth decade of life [28, 31].
PGL4 Syndrome
The SDHB gene encodes the catalytic subunit of complex II and is located on chromosome 1p35–36. Initially described in association with paragangliomas in 2001 by Astuti et al., mutations in SDHB have since been implicated in PGL4 syndrome [16]. Mutations in SDHB are estimated to account for 22–38% of hereditary tumors [33, 34]. Patients with this condition most commonly develop paragangliomas in extra-adrenal abdominal locations, but head and neck paragangliomas are often present as well. That being said, PGL4 is marked by significant heterogeneity in presentation, even within families that carry the same mutation [35]. Multifocal tumors have been reported in 28% of patients with PGL4 [23].
Mutations of SDHB are associated with a higher rate of malignancy than other SDHx mutations, particularly as it pertains to extra-adrenal abdominal paragangliomas [23, 36]. Malignant disease occurs in around one third of patients [37]. In addition, SDHB-related mutations are associated with an increased risk of secondary neoplasms such as renal cell cancer and GISTs. Renal cell cancer has been reported in roughly 14% of patients with PGL4 [17]. The reason for the apparently more aggressive nature of tumors in SDHB mutations remains unclear.
The inheritance pattern for SDHB mutations is AD. Compared to SDHD mutation carriers, the age-related penetrance of tumor manifestation is considerably lower, with roughly 40–50% of patients manifesting disease by the age of 40 [23, 38]. This contrasts with the aforementioned 75% disease penetrance of SDHB-associated mutations. If head and neck paragangliomas are examined separately, earlier onset is again observed in SDHD mutation carriers compared to SDHB mutation carriers [23]. In a series of 348 patients with SDHB and SDHD mutations, SDHD induced head and neck paragangliomas about 20 years earlier than SDHB mutations [21].
PGL5 Syndrome
SDHA is part of the catalytic subunit of the SDH complex. Mutations in SDHA have traditionally been described to cause ataxia, optic atrophy, and Leigh syndrome [4]. There is emerging data, albeit limited to case reports and small case series, to suggest that SDHA mutations should be considered a paraganglioma susceptibility gene [13]. Currently, only two patients with SDHA mutations and head and neck paragangliomas have been reported, while a few others with non-head and neck tumors have been described [13, 39]. The exact phenotype and chromosomal location for SDHA-related tumors remains unclear.
Genetic Testing and Clinical Surveillance
With the discovery of paraganglioma susceptibility genes, genetic testing is now possible. Genetic testing is performed on DNA extracted from peripheral blood. Currently, no consensus exists as to the role of genetic testing in patients with head and neck paragangliomas. In all cases, a thorough discussion should occur between clinician and patient to determine the most appropriate strategy individualized to that patient’s situation. This notion is supported by recent clinical practice guidelines, which recommend that all patients with paragangliomas be engaged in shared decision making for genetic testing [40].
There are a number of potential advantages to molecular genetic testing. If germline mutations are present, testing (1) identifies individuals at risk for development of other tumors, (2) identifies carriers that can pass along disease to their offspring, and (3) prompts evaluation of family members that may have occult tumors. If germline mutations are not found, testing is also beneficial as it identifies those not at risk for development of metachronous tumors, thus avoiding unnecessary lifelong surveillance. The disadvantages of testing include the associated cost, the need for lifelong screening in cases in which germline mutations are identified, and the psychological burden that patients may bear from not knowing if and when a tumor will develop. Financial cost of genetic testing is an important consideration and will hopefully decrease with the adoption of next-generation sequencing methods in the future.
As mentioned above, genetic counseling should be performed in all patients. A referral to medical genetics should also be offered to patients. Genetic testing for germline mutations should be considered based on clinical presentation, medical history, and family history. Predictors of hereditary tumors include a family history, syndromic features, concomitant pheochromocytoma and extra-adrenal paraganglioma, multiple head and neck paragangliomas, malignant paragangliomas, and young age at presentation [2, 40, 41]. If any of these features are present, strong consideration should be given to genetic testing. It should be emphasized that a negative family history does not preclude an inherited tumor, given the variable penetrance and inheritance patterns (maternal imprinting) associated with different germline mutations. That being said, the role of genetic testing in patients with solitary, benign disease, and a negative family history is less clear [42].
Currently, the selection of genes to be tested should be prioritized to an individual’s clinical presentation [40]. For patients with nonmetastatic head and neck paragangliomas, most authors recommend testing initially for SDHD, SDHB, and SDHC mutations [40, 42]. If metastatic disease is present, priority should be given to SDHB sequencing. The other SDHx mutations can be tested if these are negative. If testing reveals a germline mutation in an SDHx index case, posttest counseling should be performed to ensure the patient understands the implications of the diagnosis (prognosis, treatment options, recurrence risk, testing of relatives) [43]. Testing should also be offered to all first-degree relatives. Immunohistochemical information, as discussed below, may also be helpful in determining sequential genetic testing in index cases.
Immunohistochemical Staining
For patients who undergo surgical removal of their tumor, immunohistochemical staining is possible. Tumors that demonstrate loss of staining with anti-SDHB antibodies have been associated with germline mutations in not only SDHB genes but also SDHC and SDHD genes [44, 45]. The reason for this is that a mutation in any of the SDHx genes disrupts the overall SDH protein complex and alters immunohistochemical staining with anti-SDHB antibodies. There is emerging data that suggests SDHA staining is also possible and loss of staining is noted in patients with germline mutations in the SDHA gene [39].
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