A 26-year-old woman with a past medical history significant for
congenital heart disease, status-post multiple surgical interventions,
congestive heart failure, scoliosis, and diabetes was initially found to have
significant hypertension in 1997. CT scan of the abdomen and pelvis with
contrast revealed a low density mass in the retrocaval region, thought to be a
mass in the right adrenal gland, and a large, heterogeneous liver, suggestive
of passive congestion vs. diffuse metastatic disease. A Doppler ultrasound of
the renal arteries revealed no evidence of stenosis. A subsequent MRI of the
abdomen confirmed the presence of a 3 cm × 2 cm right adrenal mass with
moderate increased signal intensity on T2 and STIR images, and iso-intense on
T1. Due to her history, this was felt to represent a pheochromocytoma. The
liver was increased in size, but there was no evidence of metastatic liver
lesions. OctreoScan revealed no evidence of uptake. A 24-hour urine collection
for catecholamines was elevated.
She subsequently underwent laparoscopic right adrenalectomy, with
pathology revealing a pheochromocytoma measuring 2.5 cm. Also noted was a
smaller encapsulated nodule adjacent to the mass, measuring 6 mm, thought to
present invasion. Several additional foci of perineural invasion were seen as
well as evidence of focal invasion through the surrounding fibrous tissue. The
tumor was less than 1 mm from the margin. A postoperative skeletal survey
revealed no evidence of bony metastases and bone scan was negative for
She continued to have persistent episodic hypertension, prompting
multiple evaluations for recurrent or metastatic pheochromocytoma. Urine
catecholamines were also intermittently elevated. Imaging studies including
MRI, MIBG and octreotide scans were negative. She was maintained on
phenoxybenzamine (Dibenzyline, Wellspring).
Anterior and posterior images of the 96-hour I131 MIBG scan show foci of
increased uptake in the skeleton, including the right femur (anterior view,
left image) and a large focus in the left sacrum (posterior view, right image).
In addition, there are foci of increased uptake in the left lobe of the liver
(anterior view, left image), consistent with metastatic disease.
Source: M Ghesani
In June 2000, the patient fell down the stairs, with resultant left
upper arm pain, ultimately prompting an MRI evaluation of her left upper
extremity that revealed a 2.9 cm lesion in the left proximal humerus suspicious
for metastases. A biopsy was performed, which confirmed the presence of
metastatic pheochromocytoma. Subsequent imaging revealed pulmonary metastases,
liver metastases and bony metastasis in the iliac bone and sacrum. She received
palliative radiation to the left proximal humerus. Systemic chemotherapy was
recommended, but the patient refused. The patient was lost to follow-up and was
ultimately admitted to an inpatient hospice facility in 2005, where she
continued to have occasional headaches, intermittent sweating and elevated
She presented to the clinic in May 2009 with complaints of occasional
headaches and episodic sweating. Blood pressure was normal. She underwent
restaging imaging studies including an OctreoScan, which revealed a large focus
of tracer uptake in the left pelvis suspicious for a functional adrenergic
tumor, focal uptake in the left hepatic lobe suspicious for hepatic metastases,
and osseous metastases involving the right proximal femur. PET/CT demonstrated
an ill-defined region of increased metabolic activity, with a maximum SUV of
3.4, measuring 4 cm × 3 cm, in the lateral left lobe of the liver. There
was also note of an enhancing solid nodule to the left of the celiac axis
abutting the lesser curvature of the stomach felt to be a lymph node with a
maximum SUV of 1.8. Multiple small pulmonary nodules were also noted, but had
no associated hypermetabolic activity, likely too small to be characterized on
functional imaging. Presence of uptake on MIBG would indicate a
well-differentiated tumor. Relatively low-grade metabolic activity further
supported that notion and correlated with relatively indolent course of
metastatic disease for several years. Plasma free metanephrines were highly
elevated. Plans for treatment for I131 metaiodobenzylguanidine
(MIBG) are underway.
Tumors that arise from chromaffin tissue of the adrenal medulla are
termed pheochromocytomas, whereas chromaffin-cell tumors located at
extra-adrenal sites along the sympathetic and/or the parasympathetic chain are
called paragangliomas. Functional pheochromocytomas can synthesize
and secrete catecholamines, causing a variety of clinical symptoms including
the classic triad of headache, sweating and tachycardia. About half of patients
present with paroxysmal hypertension; most present with essential hypertension.
Other symptoms include palpitations, chest pain, dyspnea, nausea and/or
vomiting, weakness, weight loss, polyuria, polydipsia, visual disturbances,
arrhythmias and psychiatric disorders.
Figure 2: Axial CT
(left image) and PET (right image) images of the pelvis demonstrate a lytic
lesion in the left sacrum (left image) with associated low-grade metabolic
activity (right image).
Source: M Ghesani
Approximately 10% of all pheochromocytomas are malignant. Malignant
pheochromocytomas are histologically and biochemically the same as benign
tumors, but patients with the succinate dehydrogenase B (SDHB) mutation are
more likely to develop malignant disease. In addition, among patients with
malignant pheochromocytomas, those with SDHB mutations have shorter survival.
Although a small subset of these tumors initially present as metastatic disease
at presentation, a significant number will develop metastases during follow-up
after excision of the original tumor. Common sites of metastases include
regional lymph nodes, bone, liver and lung. Patients with persistent signs and
symptoms in the absence of radiological evidence of residual tumor should be
evaluated for the presence of occult metastases or recurrence. The incidence of
pheochromocytomas peaks in the fourth decade of life; they are relatively rare
in patients aged younger than 20.
In the right clinical setting (paroxysmal hypertension, headaches,
sweating, tachycardia, family history of pheochromocytoma, past history of
resected pheochromocytoma, and adrenal incidentaloma) the diagnosis of
pheochromocytoma is confirmed by measurements of urinary and fractionated
plasma metanephrines and catecholamines. Plasma chromogranin A, a protein that
is released along with catecholamines, has also been used for the diagnosis of
pheochromocytomas; levels correlate well with plasma metanephrines and tumor
burden. Neuron-specific enolase is another screening marker that can be
elevated in patients with malignant pheochromocytomas.
After biochemical confirmation of the diagnosis, radiological evaluation
to locate the tumor is performed. Imaging modalities widely used for the
detection of pheochromocytomas include CT scans, MRI and ultrasound. Functional
imaging of pheochromocytomas and paragangliomas is performed by using compounds
that resemble catecholamines that are taken up by adrenergic tissues such as
I131 or I123 MIBG. MIBG scintigraphy has been used
extensively for the diagnosis and staging of pheochromocytomas. PET-FDG may be
useful in identifying sites of metastatic disease. OctreoScan scanning has also
Figure 3: Axial CT
(left image) and PET (right image) images through the liver demonstrate subtle
increased uptake of FDG in the left lobe of the liver, corresponding to a
subtle low attenuation lesion on CT images.
Source: M Ghesani
Primary treatment for malignant pheochromocytoma is surgical removal of
the tumor. Although there are no clinical trial data to support this approach,
surgery should be considered especially when there is an associated secretory
tumor present, as this may ameliorate symptoms as well as reduce tumor bulk. As
in the case of this patient, painful osseous metastases can be treated with
external beam radiation. Radiopharmaceuticals such as I131 or
I123 MIBG have been used since 1984 to treat malignant
pheochromocytoma. The rationale for using this treatment lies in the ability of
MIBG to enter the cell membrane and be stored in cytoplasmic granules,
analogous to the use of radioactive iodine for thyroid cancer.
In a published review of 116 patients who received I131 MIBG,
an objective tumor response was seen in 30% of patients, stable disease in 57%,
and disease progression in 13%. It should be noted that treatment with
I131 MIBG is not curative in most cases. Although there are few data
addressing the benefit of chemotherapy in these patients, it may be considered
when the tumor is inoperable and/or aggressive, there is extensive residual
disease, or if quality of life is affected. A combination of cyclophosphamide,
vincristine, and dacarbazine (CVD) was reported to be successful based on early
trial data that showed high response rates and symptomatic improvement. Other
chemotherapy combinations such as cisplatin and etoposide, and anthracycline
plus CVD have been used in the past with some success. Novel
therapies have also been studied in patients with malignant pheochromocytomas,
most notably the tyrosine kinase inhibitor sunitinib (Sutent, Pfizer), in which
one patient achieved a near complete response and two patients had partial
Eric Gamboa, MD, is an Oncology Fellow at St Lukes-Roosevelt
Munir Ghesani, MD, is Associate Clinical Professor of Radiology at
Columbia University College of Physicians and Surgeons and Attending
Radiologist at St.Lukes-Roosevelt Medical Center.
Seth Cohen, MD, is an Attending Oncologist at St
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