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CASE REPORT
Amy Chen, MD, Section Editor
Multidisciplinary management of locally advanced and widely metastatic
paraganglioma in a patient with life-threatening compressive symptoms
Vladimir Neychev, MD, PhD,1 David Straughan, MD,2 Karel Pacak, MD, PhD, DSc,3 Electron Kebebew, MD,1*
1
Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 2Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 3Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
Accepted 13 April 2015
Published online 15 June 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.24069
ABSTRACT: Background. Patients presenting with locally advanced,
metastatic paraganglioma with life-threatening compressive symptoms
of critical anatomic structure pose a significant management challenge.
Methods. We present a case of a 15-year-old patient with enlarging right
neck mass causing dysphagia and respiratory compromise from near
complete obstruction of the oropharynx.
Results. Evaluation of the patient’s family history led to the identification
of a mutation in the succinate dehydrogenase subunit B (SDSD) gene
(G725A). Laboratory and imaging workup revealed an 8.8 3 6.6 3
4.1 cm metabolically and biochemically active right neck mass, a tumor
in the left para-aortic region, and multiple bony lesions consistent with
widely metastatic disease. Multidisciplinary management included pre-
INTRODUCTION
Paragangliomas are rare neuroendocrine tumors derived
from the neuroendocrine cells of the extra-adrenal autonomic paraganglia that can be found anywhere from the
scull base to the pelvis.1 Anatomic site, clinical presentation, and malignant potential of paragangliomas are variable and closely related to the genetic background. The
highest malignancy rate is associated with inherited mutations in the B subunit of the succinate dehydrogenase
gene (SDHB).2 Patients with SDHB mutations may have
multiple catecholamine-secreting abdominal, thoracic, and
neck paragangliomas.3,4 Although the standard treatment
of locally advanced malignant paraganglioma harboring
SDHB mutation is resection of the primary tumor and
locoregional disease, the optimal management of patients
*Corresponding author: E. Kebebew, Endocrine Oncology Branch (EOB),
Building 10-CRC, Room 4–5952, 10 Center Drive, Bethesda, MD 20892.
E-mail: [email protected]
Consent and Ethics: Written informed consent was obtained from the legal
guardian of the patient for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor
of this journal. The manuscript was written in compliance with the Helsinki
Declaration.
Contract grant sponsor: This work was supported in part by the Intramural
Research Program of the Center for Cancer Research, National Cancer
Institute.
operative clinical optimization, coil embolization, and palliative resection
of the neck mass.
Conclusion. Although the currently available treatment options for
patients with advanced metastatic paraganglioma render no survival
benefit, a multidisciplinary management approach aimed at relief of
tumor-related symptoms and catecholamine excess should be underC 2015 Wiley Periodicals, Inc. Head Neck 37: E205–E208, 2015
taken. V
KEY WORDS: paraganglioma, succinate dehydrogenase gene
(SDHB), metastatic disease, compressive symptoms, management
approach
with advanced, widely metastatic tumors remains illdefined.
In this case report, we present a challenging case of a
patient with functional multifocal paragangliomas metastatic to lymph nodes and bony skeleton with lifethreatening compressive symptoms from a tumor in the
neck.
CASE REPORT
A 15-year-old boy with a medical history of autism
was in his usual state of health until a right neck mass
was appreciated by his mother. This was initially attributed to lymphadenopathy secondary to a viral illness and
no further medical attention was sought. Over the next 2
years, his mother noticed that his neck mass was enlarging, and he gradually developed difficulties with swallowing solid foods. He was able to tolerate only soft foods
and liquids, which resulted in significant weight loss
(approximately 20%). He began complaining of unrelenting headaches during the day, and he was more restless
with sweating and worsening snoring requiring use of a
continuous positive airway pressure machine during sleep.
He was also found to have an elevated blood pressure
requiring antihypertensive medications. These worrisome
symptoms, enlarging neck mass, and a family history of
neck tumors raised concern for a possible neck paraganglioma, and he was referred to the National Institutes of
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Health Clinical Center for further workup and
management.
Physical examination revealed global developmental
delay with body weight 49.9 kg (17th percentile) and
height 152.5 cm (first percentile). His blood pressure was
105/55 mm Hg with a heart rate of 64 beats per minute.
Examination of the neck revealed marked asymmetry
with a prominent, firm, mildly tender, right neck mass
extending behind the right ear and causing midline shift
with tracheal deviation. Examination of the oral cavity
revealed that the tumor was obscuring the posterior oropharynx and displacing the right pharyngopalatine arch
and tonsil. Cranial nerves II to XII were grossly intact.
The abdomen was unremarkable as was the remainder of
his physical examination.
Laboratory workup was significant for an elevated
chromogranin A of 796 ng/mL (normal, <96 ng/mL) and
plasma norepinephrine of 2514 pg/mL (normal, 84–794
pg/mL), elevated total urinary metanephrines 4278 mcg/
24h (normal, 120–603 mcg/24h), normetanephrine 4218
(normal, 91–456 mcg/24h), dopamine 445 mcg/24h (normal, 65–400mcg/24 h), and norepinephrine 555mcg/24h
(normal, 15–80 mcg/24h), and iron deficiency microcytic
anemia with a hemoglobin level of 8.6 g/dL (normal,
13.7–17.5 g/dL). Genetic testing of peripheral blood DNA
showed a G725A missense mutation in exon 7 of the
SDHB gene.
Anatomic imaging, including CT and MRI, revealed a
large, heterogeneously enhancing, hypervascular 8.8- 3
6.6- 3 4.1-cm right neck mass encasing the right common carotid artery proximally and the internal and external carotid branches distally (Shamblin class III) without
significant arterial narrowing (Figure 1A and 1B). There
was complete compression of the right internal jugular
vein and the mass extended medially displacing and significantly narrowing the oropharynx and proximal esophagus. There was also a 3- 3 3- 3 3.6-cm left para-aortic
mass and multiple skeletal lesions, including the proximal
femur, pelvis, and the entire vertebral column. Functional
imaging with 18F-fluorodeoxyglucose positron emission
tomography (18F-fluorodeoxyglucose-PET) and 18F-6-Lfluorodopa PET (18F-DOPA-PET) showed uptake in the
neck and retroperitoneum, and bony skeleton consistent
with metastatic disease (Figure 1C and 1D).
The management strategy was outlined after a multidisciplinary discussion of the case, including endocrinology,
endocrine surgery, cardiology, hematology, medical oncology, otolaryngology, interventional radiology, and anesthesiology. A decision was made to resect the right neck
mass for palliation of the compressive symptoms after preoperative clinical optimization was completed. One month
before the planned operation, the patient was started on an
a-blocker (phenoxybenzamine) for preoperative blood
pressure control and a blockade. The mother was given
instructions to keep the patient well hydrated, and a bblocker (atenolol) was initiated once sufficient a-blockade
and intravascular volume were insured. His calorie, protein, and vitamin intake in the perioperative period were
closely followed by a nutritionist. In addition, more than a
month before surgery, iron supplementation was implemented. Preoperative evaluation by otolaryngology and
anesthesiology deemed oral intubation with the aid of a
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FIGURE 1. Anatomic and functional imaging. (A) Large right neck
mass obstructing the oropharynx; (B) postoperative resolution of
the oropharyngeal obstruction; (C) 18F-fluorodeoxyglucose positron emission tomography (18F-fluorodeoxyglucose-PET) showing
metabolically active right neck and retroperitoneal paragangliomas with multiple skeletal metastases; (D) 18F-6-L-fluorodopa
PET (18F-DOPA-PET) revealing FDOPA uptake by the right neck
and left para-aortic masses and the bony skeleton metastases.
glide scope was feasible; however, nasal intubation and/or
tracheostomy were also considered as there was concern
for an impending airway emergency intraoperatively.
Before the surgery, the patient was taken to interventional radiology for right carotid artery balloon occlusion
testing and coil embolization of the tumor. The 20-minute
occlusion test revealed adequate collateral flow from the
left to right cerebral circulation and elicited no neurological symptoms (Figure 2A). These findings made the loss
of the right carotid artery and its branches possible in
case the dissection of the tumor from the carotid artery
during surgery was not possible. There was a dramatic
shrinkage of the tumor immediately after embolization
(Figure 2B and 2C). He then underwent resection through
a 5-cm oblique incision 1 cm below the angle of the mandible. Because of the complete encasement and invasion
of the right common carotid artery and internal jugular
vein, both of these structures were resected en bloc with
the tumor. He was hemodynamically stable throughout
the procedure, and there was 150 mL of blood loss. By
postoperative day 1, his clinical status and compressive
symptoms had already improved significantly. He was
able to tolerate a regular diet and other symptoms, such
as headaches and anxiousness, had resolved. He was successfully taken off of all antihypertensive medication and
did not require the use of a continuous positive airway
MANAGEMENT
OF
METASTATIC PARAGANGLIOMA
FIGURE 2. Cerebral and neck angiograms. (A) Occlusion of the right common carotid artery revealing retrograde flow from the left cerebral circulation; (B) highly vascular paraganglioma at the carotid bifurcation; (C) preoperative coil embolization of the mass resulting in a significant decrease
of tumor blood supply.
pressure machine. He recovered well from his operation
and was discharged home on postoperative day 3 without
complication. However, on postoperative day 4, he collapsed in his bathroom at home with left hemiparesis. He
was taken to a local hospital and was diagnosed with an
embolic stroke. As he had just undergone surgery, tissue
plasminogen activator treatment was not administered, but
he was placed on aspirin. Twenty-four hours after onset of
this acute cerebrovascular event, he had spontaneously
recovered almost 100% of his motor function. He was discharged home on postoperative day 6 with instructions to
continue his daily aspirin. At follow-up 3 weeks after surgery, he had no evidence of local compressive symptoms or
neurological dysfunction. MRI of the neck showed resolution of the mass effect and a patent oropharynx (Figure 1B).
One year after surgery, he is doing very well at school and
continues to be free of local or systemic symptoms.
DISCUSSION
Our understanding of the pathophysiology and genetics
of paragangliomas have improved significantly; however,
their rarity and variable clinical features continue to present a considerable diagnostic and management challenge.
These tumors may occur sporadically or as part of
hereditary syndromes. Genotype-phenotype correlation
may differ considerably depending on the underlying
genetic mutation.3,4 Patients with mutations in the SDHB
gene tend to present at a younger age and are prone to
develop particularly severe phenotype with multifocal,
usually large, paragangliomas with high metastatic potential.5–7 These slow-growing tumors can originate from
both the sympathetic and parasympathetic ganglia and
can be biochemically and clinically silent until a significant tumor bulk and metastases develop resulting in
excess catecholamine secretion. Because of this indolent
growth and insidious biochemical behavior, these tumors
usually present in an advanced stage with widespread
metastatic disease. This was the case with our patient
who sought medical attention when systemic and local
compressive symptoms from advanced metastatic disease
developed. There are considerable controversy and limited
data on the optimal management of head and neck paragangliomas.8 Although surgical resection has been recommended as the treatment of choice for early-stage
localized disease, the treatment options for patients with
locally advanced and widely metastatic tumors (especially
those harboring an SDHB mutation) are limited, and the
optimal management strategy has not been established.9,10
Nevertheless, several medical and surgical approaches
have been proposed for patients with advanced disease
including cytoreductive surgery for functional tumors,
radiotherapy for local control, systemic chemotherapy
with cyclophosphamide, vincristine and doxorubicin, 131iodine-labeled meta-iodobenzylguanidine therapy, radiofrequency ablation therapy, and or tumor embolization.
However, any form of local or systemic therapy has side
effects that may exceed the potential benefit of therapy
and can carry a significant risk of massive catecholamine
secretion and hypertensive crisis.9
For patients with progressive, bulky disease in the neck
area that requires palliation of imminent life-threatening
complications from local compression, a multidisciplinary
approach addressing all aspects of advanced metastatic
disease must be undertaken and directed toward optimizing the patient’s clinical status for cytoreductive resection.
The surgical resection of advanced, highly vascular, large
tumors in a critical anatomic location, such as the neck,
is complex, technically challenging, and carries a high
risk of postoperative complications, including cranial
nerve dysfunction, tracheoesophageal injury, and stroke.
Preoperative assessment of the patency of circle of Willis
and embolization of the main arterial supply of the
carotid body tumor within 48 hours of surgery (in an
adequately blocked patient) may help to reduce tumor
size, bleeding, and other complications associated with
surgery. Our patient underwent balloon occlusion testing
with tumor embolization, which resulted in significant
tumor shrinkage, easier dissection, and less blood loss in
what could have been a much more difficult or impossible operation otherwise. As shown in our case, a patent
circle of Willis with good retrograde cerebral circulation
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on preoperative balloon occlusion testing makes the loss
of the carotid artery encased by the tumor possible, but it
does not prevent all potential complications. Physicians
should still be aware that patients may experience transient ischemic attack or stroke postoperatively. Although
there is no evidence of survival benefit for the palliative
surgical resection of metastatic paragangliomas, in the
patient described, it resulted in an immediate improvement of compressive symptoms, may reduce hormone
secretion, and can improve the response to subsequent
therapies and the ability to tolerate the side effects.9,11,12
While some may say that putting a patient through a difficult and potentially morbid palliative surgery without
survival benefit is not warranted, it is hard to argue that a
well-planned, multidisciplinary surgical approach can
result in an instant and durable improvement of the
patient’s quality of life, as shown in our case.
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