Malignant pheochromocytoma: indolent course and matching molecular characteristics on imaging

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 osteoblastic lesions.

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).

Figure 1: 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 blood pressure.

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.

Discussion

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 been used.

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 responses.

Eric Gamboa, MD, is an Oncology Fellow at St Luke’s-Roosevelt Hospital Center.

Munir Ghesani, MD, is Associate Clinical Professor of Radiology at Columbia University College of Physicians and Surgeons and Attending Radiologist at St.Luke’s-Roosevelt Medical Center.

Seth Cohen, MD, is an Attending Oncologist at St Luke’s-Roosevelt Hospital.

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