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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 10 3356-3360
Copyright © 1997 by The Endocrine Society

Original Studies

Functioning Thoracic Paraganglioma: Association with Von Hippel-Lindau Syndrome1

Bernhard U. Bender, Carsten Altehöfer, Andrzej Januszewicz, Roland Gärtner, Heinrich Schmidt, Michael M. Hoffmann, Peter H. Heidemann and Hartmut P. H. Neumann

Department of Internal Medicine, Division of Nephrology and Hypertension (B.U.B., H.P.H.N.), the Department of Diagnostic Radiology (C.A.), and the Department of Clinical Chemistry (M.M.H.), Albert Ludwigs University, Freiburg, Germany; the Departments of Internal Medicine (R.G.) and Pediatrics (H.S.), Ludwig Maximilian University (R.G.), Munich, Germany; and the Department of Pediatrics I, Zentralklinikum Augsburg (P.H.H.), Augsburg, Germany; and the Department of Internal Medicine, University of Warsaw (A.J.), Warsaw, Poland

Address all correspondence and requests for reprints to: Dr. Bernhard U. Bender, Medizinische Universitätsklinik, Hugstetterstrasse 55, D 79106 Freiburg, Germany.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Functioning thoracic paraganglioma (pheochromocytoma) is unusual and therefore suggestive of a pathogenesis distinct from that of sporadic adrenal pheochromocytoma. To determine whether the pheochromocytoma-associated syndromes Von Hippel-Lindau disease (VHL) and multiple endocrine neoplasia type 2 (MEN 2) play a role in the development of thoracic functioning paragangliomas, germline DNA from five unselected patients with this rare tumor was analyzed for mutations in the genes that predispose to VHL and MEN 2. Genetic investigations and further clinical data revealed that three had VHL, with two different germline mutations of the vhl gene, but no individual was affected by MEN 2. Two of the three patients with VHL did not show any additional VHL-associated lesions. This result suggests that VHL should be considered in the differential diagnosis of thoracic pheochromocytoma, as such a diagnosis carries further important implications for the patient and family. Conversely, in patients suspected of a catecholamine-secreting tumor and known VHL, thoracic localization should be considered if an adrenal pheochromocytoma cannot be detected.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
EXTRAADRENAL paragangliomas arise in cells associated with the ganglia of the autonomic nervous system. Of these tumors, catecholamine-secreting neoplasms are termed functioning paraganglioma or extraadrenal pheochromocytoma. Accounting for fewer than 2% of functioning paragangliomas, pheochromocytomas with thoracic localization are unusual (1), and therefore, they not only represent a clinical challenge but also raise the possibility of a pathogenesis distinct from that of sporadic adrenal pheochromocytomas. One possible explanation for extraadrenal development of catecholamine-producing neoplasms is the presence of a pheochromocytoma-predisposing tumor syndrome. Pheochromocytoma as a frequent feature of inherited cancer syndromes is illustrated by Von Hippel-Lindau disease (VHL), and multiple endocrine neoplasia type 2 (MEN 2). Both syndromes have an autosomal dominant pattern of inheritance, predisposing to multiple tumors at a young age. Most common components of VHL (estimated incidence, 1 in 40,000) are retinal and cerebellar hemangioblastomas, renal cell carcinoma, and pheochromocytoma (2). In affected members of families with MEN 2, pheochromocytoma occurs in up to 50% (3). The susceptibility gene for VHL on chromosome 3p was identified in 1993 (4). The coding sequence of this tumor suppressor gene consists of 852 nucleotides (nt) in 3 exons. Germline mutations within the vhl gene have been identified in 63–75% of affected families (5, 6). MEN 2 is associated with germline mutations of the ret protooncogene, which codes for a receptor tyrosine kinase on chromosome 10q. In over 92% of families with MEN 2, germline mutations are located in 1 of the 5 exons, 10, 11, 13, 14, and 16 (7, 8, 9, 10).

To determine whether thoracic functioning paragangliomas are components of VHL and MEN 2, genetic investigations for both syndromes were performed in five consecutive patients with thoracic pheochromocytoma.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients

Searching for all cases with thoracic pheochromocytoma treated at our institutions over the last 2 decades, we found five patients aged 6–70 yr at the time of diagnosis (Table 1Go). Four patients were alive, none of whom fulfilled the minimal clinical diagnostic criteria of VHL or MEN 2 (10, 11), although one subject (case 5) also had a right adrenal pheochromocytoma. The remaining patient (case 2) was dead, but blood leukocytes of two sisters and her daughter were available. Twenty years ago, this patient developed synchronous bilateral adrenal pheochromocytomas, pancreatic islet cell tumor, and basophilic pituitary adenoma. Two decades later, retinal angiomatosis was diagnosed in her daughter, and therefore, VHL was suspected, representing the only case of this series with clinical evidence of an associated tumor syndrome.


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  		Table 1. Patients with thoracic pheochromocytoma

 
Methods

Constitutional DNA was isolated from 10 mL ethylenediamine tetraacetate-anticoagulated blood by phenol-chloroform extraction according to standard protocols (12). PCR was performed in a volume of 10 µL containing 20 ng genomic DNA, 1.5 mmol/L MgCl2, 0.1 U Taq DNA polymerase, 50 mmol/L KCl, 10 mmol/L Tris-HCl (pH 8.3), 200 mmol/L of each deoxy-NTP, 0.01% gelatin, and 20 pmol of each primer. Exons 10, 11, 13, and 16 of the ret protooncogene and the three exons of the vhl gene were amplified using primer sets previously described (13, 14). The vhl gene was first screened for mutations using the single strand conformation polymorphism analysis (SSCP) as previously described (6). After electrophoresis, gels were silver stained and dried according to established protocols (15, 16). Aberrant bands were cut out of the dried gel, and the DNA was redissolved at room temperature for 2 h in 500 µL water. One microliter of this solution served as a template for reamplification. Reamplified fragments were sequenced with fluorescence-labeled oligonucleotides and the dideoxy method on an automatic sequencer (A.L.F., Pharmacia, Piscataway, NJ). The detected base exchange at nt 505 was verified by digestion of the PCR fragments with the restriction endonuclease FokI, which cuts the mutated allele if a modified primer (5'-CGG CCC GTG CCA GGC GGC AGC GTT GGA T-3') is used for amplification. As the SSCP of the vhl gene detected no pathological alteration in cases 4 and 5, all exons of the vhl gene were subsequently sequenced in both of these individuals.

Screening analysis for the exchange nt 287 C->T within the vhl gene was performed using the restriction enzyme Sau96I, which cleaves only the wild-type allele.

Cases 4 and 5 were investigated for germline mutations within the ret protooncogene by DNA sequencing of exons 10 and 11 as previously described (13). The only known mutations within exons 13 and 16 were tested by cleavage with AluI (codon 768 GAG->GAC) and FokI (codon 918, ATG->ACG).

Haplotype analysis was performed with highly informative microsatellite repeats for the loci 1p32 (MYCL1), 1p35-p36 (D1S160), 3p13 (D3S1542), 3p14.3 (D3S1358), 3p24.3 (D3S1537), and 22q12 (D22S268) using primer sets according to sequences previously reported (17, 18, 19, 20, 21). After electrophoresis on large acrylamide gels (8% acrylamide, 8 mol/L urea, and 1 x tris-borate electrophoresis buffer), the gels were silver stained and dried on a gel dryer at 80 C for 45 min.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Of the five cases with thoracic pheochromocytoma, three patients were found to have VHL, whereas no patient had clinical or genetic evidence of MEN 2. Genetic analysis of case 1, a 30-yr-old woman (Fig. 1Go), demonstrated a germline vhl mutation at nt 505 T->C (Tyr98His). Case 3, a 6-yr-old boy, had the nt exchange nt 490 G->A (Gly93Ser; Fig. 2Go). Despite the young ages at presentation, neither subject had further signs of the tumor syndromes. Investigation of the vhl gene in the parents of case 3 showed no abnormalities, and subsequent haplotype analysis revealed that the germline alteration was a de novo mutation. The third patient with VHL in this series (case 2) had clinical evidence of VHL, and the detection of the vhl alteration nt 505 T->C in her two sisters and her daughter (Fig. 3Go) confirmed the diagnosis of VHL.



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  		Figure 1. Diagnostic magnetic resonance imaging (T2-weighted) of the thoracic pheochromocytoma in case 1 with coronal (A), sagittal (B), and transverse view (C).

 


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  		Figure 2. PCR SSCP (A) and nucleic acid sequence analysis of vhl gene exon 1 (B). SSCP with PCR products of normal control DNA (N), case 3 (+), and DNA of two negative samples (S) is shown. Note the aberrant band pattern of patient 3 in line 2. Sequence analysis of case 3 (B): identification of the nt 490 G->A (Gly93Ser) germline mutation (arrows) compared with the wild-type sequence.

 


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  		Figure 3. Fok1 restriction enzyme digestion of vhl gene exon 1 of PCR products of normal control DNA (N), case 1 (1), the daughter of patient 2 (2), and one negative sample (S). The germline mutation nt 505 T->C leads to a new restriction site within the fragment if a modified primer is used (see above). Identification of nt 505 T->C in case 1 and in the daughter of case 2 is shown.

 
In 2 subjects (cases 4 and 5), no disease-associated mutations within the vhl and ret genes were found. Interestingly, case 5 was suspicious for an associated tumor syndrome because of multifocal pheochromocytomas. Case 4, a 70-yr-old man with an isolated thoracic pheochromocytoma, showed nt 287 C->T within the vhl gene. This change causes the substitution of proline by glutamine and has been previously described as a polymorphism by Chen et al., with a heterozygote frequency of 2% (6). To reevaluate the pathogenetic relevance of the nt 287 change, we performed intensive clinical investigations of the patient, but there was no evidence of another VHL lesion. Furthermore, DNA samples from 300 unselected individuals obtained from the clinical laboratory of the University of Freiburg were tested for this nt exchange, and it was identified in 2 cases. Neither individual had evidence of VHL, thus confirming that nt 287 is a rare polymorphism (0.75% in our control population).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Functioning thoracic paraganglioma is extremely rare. Because of its rarity and unusual location we speculated that it might be associated with a tumor syndrome. This hypothesis is supported by several cases of thoracic pheochromocytoma in children and young adults (22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43), some of whom also had multifocal pheochromocytomas (26, 28, 33, 38, 40) and/or familial history of catecholamine-secreting neoplasms (26, 33, 44). In our study, we found VHL in three of five unselected patients with thoracic pheochromocytoma. These preliminary data might suggest an association between VHL and pheochromocytoma with thoracic localization. Surprisingly, there are only two documented cases of VHL and functioning thoracic pheochromocytoma in the literature (44, 45). There are several explanations for these apparently conflicting observations. The relatively high prevalence may be due to chance, as our series is small, and reported cases in the pediatric age group could be explained with the more developed paraganglioma system in children (37). On the other hand, in patients with thoracic pheochromocytoma, VHL may be underdiagnosed, as suggested by our series in which, initially, no case had any identifiable inherited tumor syndrome. In case 2, the clinical diagnosis of VHL was not possible until retinal angiomatosis was found in her daughter 20 yr after the index patient’s death. Furthermore, in two patients (cases 1 and 3), VHL was not recognized until genetic investigation was performed, which was only possible after identification of the vhl gene in 1993. The genetic data highlight the reasons for unrecognized VHL in these subjects. First, we were able to identify a true de novo mutation in case 3, thus explaining the absence of any family history suggestive of VHL. De novo mutations seem to play a greater role in VHL than previously expected (5). Second, in two patients (cases 1 and 2), the mutation nt 505 T->C was identified. Although individuals demonstrating this germline alteration have a high risk of developing pheochromocytoma, there is in view of all syndrome lesions a probably significant lower penetrance than the majority of vhl mutations, leading to an oligosymptomatic VHL (46). Affected families are predominantly found in the Black Forest in Germany and in Pennsylvania. Previously, Brauch et al. found strong evidence for a common origin of families with nt 505 T->C in the Black Forest (46). Haplotype analysis of our two patients with this mutation confirmed the evidence for a common ancestor with 3p haplotype sharing.

In two patients (cases 4 and 5), no germline mutations within the vhl or ret gene was detectable. These negative results are possibly attributable to the incomplete ascertainment of the mutation detection in VHL. As there is no genetic heterogeneity in VHL, it remains unclear why 30% of families with clinically diagnosed VHL have no structural abnormality of the vhl gene. Especially in view of the 17-yr-old patient with multiple pheochromocytomas and the absence of clinical or genetic evidence for VHL and MEN 2 (case 5), an alternative explanation would be another pheochromocytoma-predisposing gene. Possible candidates are the genes for familial nonchromaffin paragangliomas that are located on chromosome 11q23 (pgl 1) (47) and 11q13.1 (pgl 2) (48). Germline mutations within these genes might not only be associated with nonfunctional paragangliomas of the head and neck region, but they may predispose to catecholamine-secreting pheochromocytomas arising at each site of the autonomic paraganglion system. This hypothesis is supported by several reports of association between nonfunctional paraganglioma and pheochromocytoma (28, 49, 50, 51). For example, Dunn et al. described three patients with middle mediastinal pheochromocytoma and intercarotid paraganglioma (49).

Our finding that no patient was affected by MEN 2 is concordant with the literature. To our knowledge, there has been no reported case of thoracic pheochromocytoma in MEN 2.

In conclusion, we find that thoracic pheochromocytoma may be a component of VHL. In addition, we have demonstrated that two of five cases of apparently isolated thoracic functioning paraganglioma have occult or de novo germline vhl mutations. Should our findings be confirmed in a larger series, we would then recommend that all patients with thoracic pheochromocytomas undergo vhl gene testing, the results of which have implications for the further clinical management of the index patient and his family. Until then, however, we urge that clinicians who see patients with thoracic pheochromocytoma consider the diagnosis of VHL.


   Acknowledgments
 
We gratefully acknowledge Barbara Mueller (Freiburg, Germany), Charis Eng, M.D./Ph.D. (Boston, MA), Astrid Hartmann, M.D. (Munich, Germany), and Alfred Heger, M.D. (Munich, Germany), for their support.


   Footnotes
 
1 This work was supported by grants from the Forschungskommission and the Zentrum für Klinische Forschung of Albert Ludwigs University (Freiburg, Germany). Back

Received February 25, 1997.

Revised June 4, 1997.

Accepted June 26, 1997.


   References
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 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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