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Familial Malignant Catecholamine-Secreting Paraganglioma with Prolonged Survival Associated with Mutation in the Succinate Dehydrogenase B Gene

Genetic Counseling Program (A.L.Y.), University of Minnesota, Minneapolis, Minnesota 55455; Departments of Psychiatry, Otolaryngology, and Human Genetics (B.E.B.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; and Division of Endocrinology, Metabolism, and Nutrition (W.F.Y.) and Department of Internal Medicine (A.D.), Mayo Clinic, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: William F. Young, Jr., M.D., Mayo Clinic, 200 First Street S.W., Rochester, Minnesota 55905. E-mail: . young.william{at}mayo.edu

Abstract

Approximately 10% of catecholamine-secreting tumors are malignant, and 10% are familial. These tumors have been associated with several hereditary syndromes, including multiple endocrine neoplasia type 2, von Hippel-Lindau syndrome, neurofibromatosis type 1, and familial paraganglioma. Mutations in succinate dehydrogenase (SDH) subunit genes have been identified in some kindreds with catecholamine-secreting tumors.

In 1972 at the Mayo Clinic, a metastatic catecholamine-secreting paraganglioma was diagnosed in a 32-yr-old man. In 1979, 7 yr after the initial surgical treatment, a lytic metastasis to the left femur was found and was treated with local external radiotherapy. Locally metastatic abdominal catecholamine-secreting paragangliomas were diagnosed in the patient’s 27-yr-old son.

Analyses of the VHL, RET, SDHD, and SDHC genes revealed no mutations. However, a missense point mutation was detected in the SDHB gene: c.725GA in exon 7, which alters a conserved arginine at amino acid position 242 to a histidine (R242H). Sequencing of the SDHB gene in the tumors did not reveal any somatic mutations or loss of heterozygosity of the remaining allele.

Thirty years after the initial diagnosis, the father is one of the longest living survivors of malignant catecholamine-secreting paraganglioma. Our findings indicate that mutations in SDHB may be associated with metastatic, yet clinically indolent, abdominal paraganglioma in some families.

CATECHOLAMINE-SECRETING tumors are located in either the adrenal medulla (pheochromocytoma) or extraadrenal paraganglion tissue (catecholamine-secreting paraganglioma). Several forms of familial catecholamine-secreting tumors have been characterized. Pheochromocytomas may be associated with multiple endocrine neoplasia types 2A and 2B, von Hippel-Lindau syndrome, neurofibromatosis type 1, familial pheochromocytoma, and familial paraganglioma. Catecholamine-secreting paragangliomas may be associated with familial paraganglioma and neurofibromatosis type 1.

Succinate dehydrogenase (SDH; succinate:ubiquinone oxidoreductase) subunit genes SDHB, SDHC, and SDHD, which compose portions of mitochondrial complex II, are associated with some cases of familial paraganglioma (1, 2, 3, 4). Germline mutations (inherited mutations present in all cells of the body) in SDHD have been identified in multigenerational families with head and neck paragangliomas (1). SDHC mutations have been associated with familial paraganglioma (2), and mutations in SDHB have been shown to cause susceptibility to familial pheochromocytoma and familial paraganglioma (3). Among the three mitochondrial complex II genes, mutations in SDHD are the predominant causes of head and neck paragangliomas (5, 6). The prevalence and distribution of SDH gene mutations in patients with pheochromocytoma and/or paraganglioma have not been well characterized.

Ten percent of catecholamine-secreting tumors are malignant (7), and approximately 10% are familial (8). Catecholamine-secreting tumors that are both familial and malignant are rare. Herein, we report on a family with malignant catecholamine-secreting paraganglioma and the results of genetic analyses.

Case Reports

Patient 1

In 1972, a 32-yr-old man was evaluated at the Mayo Clinic (Rochester, MN) and was diagnosed with a metastatic catecholamine-secreting paraganglioma. He presented with recurrent spells of throbbing headache, palpitations, diaphoresis, and anxiety. He was hypertensive and had increased 24-h urinary excretion of catecholamines and total metanephrines. At laparotomy, three paragangliomas were resected. Although the right adrenal gland was not involved directly, it was removed along with an immediately adjacent paraganglioma (2.5 x 2.2 cm). The other two periaortic paragangliomas had maximal dimensions of 1.9 and 1.5 cm. The 24-h urinary excretion of catecholamines and total metanephrines did not normalize postoperatively. At a second exploration 5 months later, a paraganglioma behind the head of the pancreas (3.5 x 2.5 x 1.5 cm) and a 1.9-cm nodule of metastatic paraganglioma in the region of the vena cava just beneath the diaphragm were found. A third lesion located deep within the substance of the liver and firmly attached to the wall of the vena cava could not be resected. After the second operation, the 24-h urinary excretion of catecholamines and total metanephrines again failed to normalize (Fig. 1). In 1979, 7 yr after the initial resection, the patient presented with low back and hip pain. A bone scan and plain radiographs showed increased uptake in the proximal left femur, corresponding to a 3.5 x 2.0-cm well defined lytic lesion arising within the medullary cavity. This was treated with local external radiotherapy (4400 cGy). Over the next decade, complete occlusion of the inferior vena cava and prominent collateral veins over the anterior abdominal wall slowly developed. The patient’s lower leg edema was treated with compression stockings. The metastatic lesion in the femur remained unchanged. In 1999, [¹²³I]metaiodobenzylguanidine ([¹²³I]MIBG) scintigraphy showed uptake in the liver, left femur, and posterior mediastinum near the aortic arch. Magnetic resonance imaging (MRI) scan of the chest showed a 2-cm nodule inferior to the right pulmonary artery, consistent with the finding on the [¹²³I]MIBG scan.

View larger version (23K): [in this window] [in a new window]   Figure 1. The 24-h urinary excretion of total metanephrines (A) and catecholamines (B) over 29 yr of follow-up are shown. Dashed lines indicate the upper limit of normal. Urinary total metanephrines can be converted from micromoles per day to milligrams per 24 h by dividing by 5.07. Urinary norepinephrine can be converted from nanomoles per day to micrograms per 24 h by dividing by 5.911.

Genetic testing of the RET oncogene and the von Hippel-Lindau tumor suppressor gene was negative for mutations. Next, we analyzed the SDHB, SDHC, and SDHD genes for mutations. No mutations could be identified in the SDHD and SDHC genes. However, a missense point mutation (c.725GA in exon 7) was detected in the SDHB gene (Fig. 2). This point mutation alters an arginine residue at amino acid position 242 to a histidine residue (R242H). This arginine residue is conserved in other organisms, including the mouse, rat, fly (Drosophila melanogaster), yeast (Saccharomyces cerevisiae), plant (Arabidopsis thaliana), and several microorganisms such as Escherichia coli and Vibrio cholerae. PCR amplification of SDHB exon 7 and restriction enzyme digestion with MspA1 I, which discriminates the mutant allele, did not demonstrate the presence of this variant in 300 normal control chromosomes. These studies indicate that R242H is not a polymorphism but a pathogenic mutation.

View larger version (35K): [in this window] [in a new window]   Figure 2. The pedigree and the haplotypes around the SDHB gene are shown. Affected individuals are shown with blackened symbols. The alleles in parentheses are deduced from the remaining genotypic data. Cosegregation of the mutant allele with informative marker alleles from father to son enabled us to determine the alleles on the disease chromosome. The solid bars indicate the disease haplotype. The intermarker distances are given on the left in centromeres. D1S170 and SDHB are located within an approximately 50-kb interval in the genomic sequence (GenBank accession no. AL049569). The boxed alleles on the nonmutant haplotypes were lost in the tumors. Mu, Mutant allele; Wt, normal nonmutant allele.

In 1997, the 27-yr-old son of patient 1 presented with hypertension. He had a 2-yr history of exercise-precipitated episodes of forceful palpitations. He is an ultrasonographer, who incidentally discovered that he had a nodule anterior to the inferior vena cava. Because of his recent onset of hypertension, the abdominal nodule found with ultrasonography, and the family history of malignant catecholamine-secreting paraganglioma in his father, a 24-h urine test for total metanephrines and catecholamines was performed with the following results: total metanephrines, 9.1 µmol (normal, <6.6); norepinephrine, 4622 nmol (normal, <473); epinephrine, 24 nmol (normal, <109); and dopamine, 2808 nmol (normal, <2612). Computed tomography (CT) of the abdomen showed two masses (1.7 and 1.5 cm) at the level of the right renal vein: one mass between the inferior vena cava and aorta and one mass lateral to the inferior vena cava. [¹²³I]MIBG scintigraphy showed two areas of increased uptake that corresponded to the two masses seen on abdominal CT. Blood pressure was well controlled with phenoxybenzamine (30 mg/d) and propranolol (40 mg/d). At abdominal exploration two paragangliomas (3.0 x 1.9 x 1.7 cm and 3.7 x 1.2 x 0.8 cm) were removed from the region of the right renal vein and inferior vena cava. A third paraganglioma (1.3 x 1.2 x 0.8 cm) and a lymph node were excised from the region just inferior to the left renal vein. The lymph node contained metastatic chromaffin tissue. DNA flow cytometric analysis showed that the tumor was predominantly aneuploid. Postoperatively, 24-h urinary excretion of catecholamines and total metanephrines normalized. Blood pressure was normal, and treatment with antihypertensive medications was discontinued. A CT scan performed 1 yr postoperatively showed no evidence of recurrent or metastatic disease. The 24-h urinary excretion of catecholamines and total metanephrines remained normal when checked every 6 months through April 2002. All three of the patient’s siblings had undergone biochemical screening for catecholamine-secreting paragangliomas, and the results were normal. Analysis of the patient’s peripheral blood DNA by sequencing, PCR amplification of SDHB exon 7, and restriction enzyme digestion confirmed inheritance of the R242H missense mutation from his father (Fig. 2).

Analysis of somatic alterations in the tumors

To determine somatic alterations in the vicinity of the SDHB gene, we extracted DNA from paraffin-treated tissue slices and performed SDHB gene sequencing and loss of heterozygosity (LOH) analyses with several flanking polymorphic markers on chromosome 1p35. We sequenced each of the eight exons of the SDHB gene in the tumor tissues extracted from both subjects, but failed to identify any somatic mutation. Sequencing of exon 7 further indicated the absence of LOH targeting the normal nonmutant alleles in both subjects (Fig. 3). However, genotyping of flanking markers uncovered LOH targeting the normal alleles at two telomeric markers: D1S170 was lost in the father’s tumor, and D1S507 was lost in the son’s tumor. No LOH was evident in the other heterozygous markers (Fig. 2).

View larger version (45K): [in this window] [in a new window]   Figure 3. A, Sequencing of the blood and tumor DNAs from both affected subjects showed the presence of the mutation formed by the alteration of a guanine residue to an adenine residue (noted by arrow). Sequencing of exon 7 further indicated the absence of LOH targeting the normal nonmutant alleles (noted by tall black peak) in both subjects. B, However, genotyping of flanking markers uncovered LOH targeting the normal alleles at two telomeric markers: D1S107 was lost in the father’s tumor, and D1S507 was lost in the son’s tumor. The arrows indicate the position of the lost allele. The small circles indicate the positions of the two alleles in the constitutional blood DNA.

After xylene treatment of the paraffin-embedded tumor samples and purification of white blood cells from blood samples, DNAs were extracted by standard sodium dodecyl sulfate/proteinase K/phenol-chloroform extraction. Genotyping of the polymorphic STRP markers was performed by standard radioactive ³²P amplification and was analyzed on 6% denaturing polyacrylamide gel. The marker information is available at http://gdbwww.gdb.org/, the web site of The Genome Database. The mutation analysis of the SDHB gene was performed by PCR amplification of the gene exons using previously described primers (6) and direct DNA sequencing. The conservation of the mutated amino acid residue was assessed online by standard protein-protein BLAST (blastp) analysis at http://www.ncbi.nlm.nih.gov/BLAST/.

The institutional review boards of the Mayo Foundation and University of Pittsburgh approved the study. Informed written consent was obtained before genetic testing. There was no sponsor involvement or funding for the study.

Discussion

Catecholamine-secreting paragangliomas account for approximately 10% of all catecholamine-secreting tumors and have traditionally been thought to be associated with a higher rate of malignancy than pheochromocytomas. However, several more recent studies have suggested that the prevalence of malignancy in pheochromocytomas and catecholamine-secreting paragangliomas is equivalent (9, 10). The frequency of malignant disease has been estimated to range from 13–26% of all pheochromocytomas (11). The diagnosis of malignant catecholamine-secreting paraganglioma is established by demonstrating local tumor invasion into surrounding tissues or the presence of metastatic tumor at sites not known to contain chromaffin tissue (e.g. lymph nodes, bone, lung, and liver).

The clinical behavior of malignant catecholamine-secreting tumors is highly variable. In a large series reported from the Mayo Clinic, the 5-yr survival rate was 36% (12). According to more recent data, the 5-yr survival rate for patients with malignant pheochromocytoma is 57% and 74% for patients with malignant catecholamine-secreting paragangliomas (9).

The unpredictable nature of malignant catecholamine-secreting tumors is illustrated by the case of patient 1. Even though metastatic disease was diagnosed within 1 yr after our patient’s initial presentation, he was well 30 yr later, with little antitumor-specific therapy. Patients who have locally invasive malignant pheochromocytomas have been reported to survive for more than 28 yr from the time of diagnosis (13). However, patients with tumors that have distant metastasis, as in the case of patient 1, usually have a much poorer prognosis. To our knowledge, patient 1 is one of the longest living survivors of a malignant catecholamine-secreting tumor that metastasized. His case is even more unique because of the familial nature of his disorder.

There is a familial association in at least 10% of patients with pheochromocytoma and up to 50% of patients with head and neck paragangliomas (4, 8, 14). Pheochromocytoma occurs in several hereditary syndromes and affects approximately 30–50% of subjects with multiple endocrine neoplasia type 2 (15, 16, 17), 15–20% of those with von Hippel-Lindau syndrome (18), and 1–5% of those with neurofibromatosis type 1 (19). The occurrence of catecholamine secretion in familial paraganglioma depends on tumor location; approximately 5% of head and neck paragangliomas and 50% of abdominal paragangliomas are hormone producing (20).

The genetic cause of catecholamine-secreting tumors is heterogeneous. Mutations in the RET proto-oncogene, the von Hippel-Lindau tumor suppressor gene, and the neurofibromatosis 1 gene have been associated with pheochromocytoma. Catecholamine-secreting paragangliomas have been associated with mutations in the genes encoding SDH proteins (1, 2, 3, 4). The SDH proteins SDHD, SDHB, and SDHC are subunits of mitochondrial complex II, or succinate-ubiquinone oxidoreductase, in the electron transport chain (21).

The first SDH mutations were identified in the SDHD gene on chromosome 11q23 in kindreds with familial paraganglioma that had a high prevalence of carotid body tumors (1, 5, 22). Carotid body tumors are not often associated with catecholamine hypersecretion. Germline SDHD and SDHB mutations were subsequently documented in sporadic and familial pheochromocytomas and abdominal paragangliomas (4, 23, 24). There is one report of a germline mutation in SDHC, which was associated with familial nonfunctioning head and neck paragangliomas (2). It is currently not known whether certain SDH mutations are more frequently associated with specific tumor location or biological behavior. A compilation of all SDHB mutations described is shown in Table 1. The R242H mutation, identified in our family, has also been recently described in a patient with a sporadic catecholamine-secreting tumor; it was not noted whether the tumor was malignant (4). As more patients with familial paraganglioma are genetically characterized, it will be important to correlate SDHB mutations with clinical parameters, such as tumor location, malignant behavior, sites of metastatic disease, catecholamine secretory status, and age at diagnosis.

Fifteen distinct mutations observed in SDHB (3, 4, 6) to date provide no evidence for a common origin (i.e. founder effect). Although certain mutations have been detected in unrelated individuals, it would be premature to assume a common origin without demonstrating haplotype sharing. It is possible that R242H may be a recurrent mutation induced by a common mutational mechanism that involves deamination of CpG to TpG on the noncoding strand of the SDHB sequence. In contrast, the SDHD mutations are associated with a strong founder effect (5, 27).

The inheritance pattern exhibited by SDHB, SDHC, and SDHD is autosomal dominant. In families with SDHD mutations, penetrance is dependent on the parent of origin; that is, the disease is not manifest when the mutation is inherited from the mother, but is highly penetrant when inherited from the father (1). Although this observation is suggestive of genomic imprinting, no evidence of this phenomenon has been documented at the molecular level (1). Interestingly, in the abdominal paraganglioma families with SDHB mutations, only maternal transmission has been observed (3), whereas both maternal and paternal transmissions were detected in head and neck paraganglioma families (6). The observation of paternal transmission of abdominal paraganglioma in our family confirms the absence of parent of origin effects at the SDHB locus.

Although mutation detection rates are currently unknown, it may be reasonable to consider genetic analysis for individuals presenting with familial disease because SDH gene mutations have been documented to predispose to familial paraganglioma and/or pheochromocytoma. Although the presence of familial disease increases the likelihood of identifying a mutation, affected individuals with negative family histories may also be candidates for genetic testing because of the masking effect of imprinting on pedigree analysis in families with SDHD mutations. The index of suspicion should be raised if the individual presents at a young age and/or has multiple tumors. However, the chance that a SDH mutation will be detected in a sporadic case of paraganglioma is probably no greater than 10% (4, 6). Therefore, patients pursuing genetic analysis should be thoroughly counseled regarding the uncertain detection rates and the implications of a negative result.

Acknowledgments

We thank Joan Willett-Brozick and Elizabeth Lawrence for their excellent technical assistance.

Footnotes

A.L.Y. and B.E.B. are co-first authors.

Abbreviations: CT, Computed tomography; LOH, loss of heterozygosity; MIBG, metaiodobenzylguanidine; MRI, magnetic resonance imaging; SDH, succinate dehydrogenase.

Received February 27, 2002.

Accepted June 14, 2002.

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