Mediastinal paragangliomas: association
with mutations in the succinate
dehydrogenase genes and aggressive
Stephen R Hammes, Zahid Ahmad, Alexander Tessnow, Ivica Lazu ´rova ´4,
Karen T Adams1, Antonio T Fojo5, Karel Pacak1and Richard J Auchus
Division of Endocrinology, Department of Internal Medicine, Southwesterm Medical Center, University of Texas, 5323 Harry Hines
Boulevard, Suite Y-5.318, Dallas, Texas 75390-8857, USA
1Reproductive Biology and Medicine Program, National Institute of Child Health and Human Development, National Institutes of
Health, Bethesda, Maryland, USA
2Department of Endocrinology and Metabolism, Leiden University Medical Center, Leiden, The Netherlands
3Institute of Clinical Chemistry & Laboratory Medicine and Department of Medicine, University Hospital, Dresden, Germany
4Department of Medicine, Faculty of Medicine, P.J. Sˇafa ´rik University, Kos ˇice, Slovak Republic
5Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
(Correspondence should be addressed to R J Auchus; Email: firstname.lastname@example.org)
*H K Ghayee and B Havekes contributed equally to this work
Extra-adrenal pheochromocytomas, otherwise known as paragangliomas (PGLs), account for
about 20% of catecholamine-producing tumors. Catecholamine excess and mutations in the
genes encoding succinate dehydrogenase subunits (SDHx) are frequently found in patients with
PGLs. Only 2% of PGLs are found in the mediastinum, and little is known about genetic alterations
in patients with mediastinal PGLs, catecholamine production by these tumors, or their clinical
behavior. We hypothesized that most mediastinal PGLs are associated with germ line SDHx
mutations, norepinephrine and/or dopamine excess, and aggressive behavior. The objective of
this study was to characterize genetic, biochemical, and clinical data in a series of ten patients with
mediastinal PGLs. All ten primary mediastinal PGL patients had germ line SDHx mutations, six in
SDHB, and four in SDHD genes. Chest or back pain were the most common presenting symptoms
(five patients), and catecholamines and/or their metabolites were elevated in seven patients.
Additional tumors included head and neck PGLs in four patients, pheochromocytoma in one
patient, and bladder PGL in another. Metastatic disease was documented in six patients (60%),
and a concurrent abdominal mass was found in one patient. We conclude that mediastinal PGLs
are strongly associated with SDHB and SDHD gene mutations, noradrenergic phenotype, and
aggressive behavior. The present data suggest that all patients with mediastinal PGLs should be
screened for SDHx gene mutations, regardless of age.
Endocrine-Related Cancer (2009) 16 291–299
About 20% of catecholamine-producing tumors are
derived from extra-adrenal chromaffin tissues and are
termed paragangliomas (PGLs; Lenders et al. 2005).
PGLs arise from chromaffin cells associated with
sympathetic tissues. PGLs are found mostly in the
abdomen, less commonly in the pelvic sympathetic
plexus of the urinary bladder, and rarely in the
mediastinum (Pacak et al. 2006).
syndrome. Multiple endocrine neoplasia type 2, neurofi-
bromatosis type 1, and von Hippel–Lindau syndrome
Endocrine-Related Cancer (2009) 16 291–299
Endocrine-Related Cancer (2009) 16 291–299
1351–0088/09/016–291 q 2009 Society for Endocrinology Printed in Great Britain
Online version via http://www.endocrinology-journals.org
are familial syndromes that predominantly predispose
to adrenal pheochromocytomas. By contrast, mutations
in the genes encoding succinate dehydrogenase (SDH)
subunits B, C, and D cause extra-adrenal PGLs
associated with familial PGL syndromes PGL4, PGL3,
and PGL1 respectively (Baysal et al. 2000, Niemann &
Muller 2000, Astuti et al. 2001). Germ line SDHB
mutations are mainly associated with abdominal PGLs
having aggressive and malignant behavior (Gimenez-
Roqueplo et al. 2003, Neumann et al. 2004, Benn et al.
SDHD mutation carriers are frequently diagnosed with
benign and often non-functional head and neck PGLs
and/or pheochromocytomas. SDHD-associated malig-
nant disease is considered rare (Benn et al. 2006,
Havekes et al. 2007, Timmers etal. 2007). PGLs caused
by germ line SDHB mutations show hypersecretion of
both norepinephrine and dopamine in 46% and nor-
whereas hypersecretion of norepinephrine appears to be
most prevalent in SDHD-associated disease (van
Houtum et al. 2005; unpublished data Havekes).
Approximately, 100 cases of mediastinal PGLs have
been reported in the literature to date (Lamy et al.
1994, Bouhouch et al. 2007, Leshnower et al. 2007,
Paul et al. 2007, Ramos et al. 2007, Kim et al. 2008),
and 30% are associated with elevated catecholamines
or metanephrines (Dunn et al. 1986, Pacak et al. 2006).
About 5–20% of mediastinal PGLs are malignant, but
this estimate derives from a small series with divergent
data (Mader et al. 1997, Sandur et al. 1999, Kim et al.
2008). Based on the data for PGLs in other sites, we
hypothesized that most mediastinal PGLs are associ-
ated with germ line SDHx mutations, norepinephrine
and/or dopamine excess, and aggressive behavior. We
prospectively and retrospectively identified ten
patients with mediastinal PGLs, screened them for
mutations in SDHB and SDHD genes, characterized
their biochemical features, and determined the preva-
lence of malignant disease in this cohort. These data
allow us to define the biology of mediastinal PGLs and
to formulate recommendations for clinicians about the
approach to these patients.
Patients and methods
Patients in this PGL series derive from Parkland
Memorial Hospital, Dallas, Texas; the National
Institutes of Health (NIH), Bethesda, Maryland; the
Leiden University Medical Center, Leiden, The
Netherlands; and the Department of Medicine in
Kos ˇice, Slovak Republic. All patients gave written
and informed consent for genetic testing as approved
by the institutional review board of each respective
institution. Records of all patients enrolled in the NIH
pheochromocytoma protocol were considered for
inclusion. All of the patients with radiological and/or
histopathological evidence of mediastinal PGLs, who
could be studied by the investigators at these centers,
were included in this survey.
Cases 1 and 2 were retrospectively and prospec-
tively studied respectively, at Parkland Memorial
Hospital. A total of six unrelated patients with a
history of PGL were identified at the NIH and included
in this retrospective study (patients 3–8). All of these
patients were referred to the NIH for an outline of an
optimal plan for (suspected) PGL. Patient 9 was
retrospectively identified with a history of mediastinal
PGL at the Leiden University Medical Center in
Leiden, the Netherlands. Patient 10 was prospectively
identified at the Department of Medicine in Kos ˇice,
Slovak Republic. Patient characteristics are sum-
marized in Table 1.
A 27-year-old African–American woman with a
history of mediastinal PGL resected at the age of 21
presented with severe hypertension and palpitations.
She developed recurrent non-radiating chest pain
followed by gait abnormalities several months later.
Computed tomography (CT) scan of the abdomen and
lumbar spine revealed a 2.5 cm enhancing mass in the
retroperitoneum, adjacent to the left psoas at the level
of the aortic bifurcation. An [111In]pentetreotide scan
showed a recurrence of the T4 vertebral body lesion
but no uptake in the psoas mass. Chest CT showed a
2 cm heterogeneous mass at the T4 vertebral body with
extension into the spinal canal as well as extensive
bony destruction of T4. Plasma normetanephrine levels
were elevated and metanephrine levels were normal.
After adequate a- and b-adrenergic blockade, the
patient underwent a preoperative embolization of the
tumor, followed by a lateral extracavitary resection of
her recurrent mediastinal and spinal PGLs. Resection
of the psoas lesion demonstrated another PGL. Six and
twelve months post-surgery, her plasma normetanephr-
ine level was normal, and she was no longer
hypertensive. Genetic testing revealed an SDHB
mutation (c.725GOA, p.Arg242His) and radiation
therapy was started. Her mother was found to be an
asymptomatic carrier of this mutation. One year after
the diagnosis of recurrent PGL, her plasma normeta-
nephrine level is still normal.
H K Ghayee, B Havekes et al.: Mediastinal paragangliomas and SDHx mutations
Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC,
Myssiorek D, Bosch A, van der Mey A, Taschner PE,
Rubinstein WS, Myers EN et al. 2000 Mutations in
SDHD, a mitochondrial complex II gene, in hereditary
paraganglioma. Science 287 848–851.
Benn DE, Gimenez-Roqueplo AP, Reilly JR, Bertherat J,
O et al. 2006 Clinical presentation and penetrance of
Clinical Endocrinology and Metabolism 91 827–836.
Bouhouch A, Hendriks JM, Lauwers PR, De Raeve HR &
Van Schil PE 2007 Asymptomatic pheochromocytoma in
the posterior mediastinum. Acta Chirurgica Belgica 107
Brown ML, Zayas GE, Abel MD, Young WF Jr & Schaff HV
2008 Mediastinal paragangliomas: the Mayo Clinic
experience. Annals of Thoracic Surgery 86 946–951.
Drucker EA, McLoud TC, Dedrick CG, Hilgenberg AD,
Geller SC & Shepard JA 1987 Mediastinal paragan-
glioma: radiologic evaluation of an unusual vascular
tumor. American Journal of Roentgenology 148 521–522.
Dunn GD, Brown MJ, Sapsford RN, Mansfield AO,
Hemingway AP, Sever PS &Allison DJ 1986 Functioning
middle mediastinal paraganglioma (phaeochromocytoma)
associated with intercarotid paragangliomas. Lancet 1
Eisenhofer G, Goldstein DS, Sullivan P, Csako G, Brouwers
clinical manifestations of dopamine-producing paragan-
gliomas: utility of plasma methoxytyramine. Journal of
Clinical Endocrinology and Metabolism 90 2068–2075.
Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C,
Crespin M, Nau V, Khau Van Kien P, Corvol P, Plouin PF
& Jeunemaitre X 2003 Mutations in the SDHB gene are
associated with extra-adrenal and/or malignant phaeo-
chromocytomas. Cancer Research 63 5615–5621.
Havekes B, Corssmit EP, Jansen JC, van der Mey AG,
Vriends AH & Romijn JA 2007 Malignant paraganglio-
mas associated with mutations in the succinate dehydro-
genase D gene. Journal of Clinical Endocrinology and
Metabolism 92 1245–1248.
van Houtum WH, Corssmit EP, Douwes Dekker PB, Jansen
JC, van der Mey AG, Brocker-Vriends AH, Taschner PE,
Losekoot M, Frolich M, Stokkel MP et al. 2005 Increased
prevalence of catecholamine excess
and phaeochromocytomas in a well-defined Dutch
population with SDHD-linked head and neck paragan-
gliomas. European Journal of Endocrinology 152 87–94.
Kim KN, Lee KN, Roh MS, Choi PJ & Yang DK 2008
Pulmonary paraganglioma manifesting as an endobron-
chial mass. Korean Journal of Radiology 9 87–90.
Lamy AL, Fradet GJ, Luoma A & Nelems B 1994 Anterior
and middle mediastinum paraganglioma: complete
resection is the treatment of choice. Annals of Thoracic
Surgery 57 249–252.
Lenders JW, Eisenhofer G, Mannelli M & Pacak K 2005
Phaeochromocytoma. Lancet 366 665–675.
Leshnower BG, Morris RJ & Pechet TT 2007 Management of
an anterior mediastinal pheochromocytoma causing
tracheomalacia. Annals of Thoracic Surgery 84 2088–
Mader MT, Poulton TB & White RD 1997 Malignant tumors
of the heart and great vessels: MR imaging appearance.
Radiographics 17 145–153.
Neumann HP, Pawlu C, Peczkowska M, Bausch B,
Bley TA et al. 2004 Distinct clinical features of
paraganglioma syndromes associated with SDHB and
SDHD gene mutations. Journal of the American Medical
Association 292 943–951.
Niemann S & Muller U 2000 Mutations in SDHC cause
autosomal dominant paraganglioma, type 3. Nature
Genetics 26 268–270.
O’Riordain DS, Young WF Jr, Grant CS, Carney JA & van
Heerden JA 1996 Clinical spectrum and outcome of
functional extraadrenal paraganglioma. World Journal of
Surgery 20 916–922.
Pacak K 2007 Preoperative management of the pheochro-
mocytoma patient. Journal of Clinical Endocrinology and
Metabolism 92 4069–4079.
Pacak K, Keiser HR & Eisenhofer G 2006 Pheochromocy-
toma. In Endocrinology, pp 2501–2534. Eds LJ deGroot
& JL Jameson., 5 Philadelphia: Elsevier.
Paul S, Jain SH, Gallegos RP, Aranki SF & Bueno R 2007
Functional paraganglioma of the middle mediastinum.
Annals of Thoracic Surgery 83 e14–e16.
Ramos R, Moya J, Villalonga R, Morera R & Ferrer G 2007
Mediastinal aortosympathetic paraganglioma: report of
two cases. Asian Cardiovascular & Thoracic Annals 15
Sandur S, Dasgupta A, Shapiro JL, Arroliga AC & Mehta AC
1999 Thoracic involvement with pheochromocytoma: a
review. Chest 115 511–521.
Scholz T, Eisenhofer G, Pacak K, Dralle H & Lehnert H 2007
Clinical review: current treatment of malignant pheo-
chromocytoma. Journal of Clinical Endocrinology and
Metabolism 92 1217–1225.
Thines L, Lejeune JP, Ruchoux MM & Assaker R 2006
Management of delayed intracranial and intraspinal
metastases of intradural spinal paragangliomas. Acta
Neurochirurgica 143 63–66 (discussion 66).
Timmers HJ, Kozupa A, Eisenhofer G, Raygada M, Adams
KT, Solis D, Lenders JW & Pacak K 2007 Clinical
presentations, biochemical phenotypes, and genotype–
phenotype correlations in patients with succinate
dehydrogenase subunit B-associated pheochromocytomas
and paragangliomas. Journal of Clinical Endocrinology
and Metabolism 92 779–786.
Timmers HJ, Pacak K, Bertherat J, Lenders JW, Duet M,
Eisenhofer G, Stratakis CA, Niccoli-Sire P, Tran BH,
Burnichon N et al. 2008 Mutations associated
with succinate dehydrogenase D-related
malignant paragangliomas. Clinical Endocrinology
Endocrine-Related Cancer (2009) 16 291–299