Flushing, diaphoresis and palpitations in a woman with a retroperitoneal mass

A 34-year-old woman was referred for a four-year history of episodic hypertension, palpitations, flushing and diaphoresis.

The patient presented four years ago with headache, dizziness and palpitations. After an unremarkable Holter monitor, she was discharged with no further evaluation. Two years ago, the patient presented again with the same symptoms, and she was started on hydrochlorothiazide. During the past two years, her symptoms have intensified with an increased frequency and accompanied with diaphoresis.

Stephanie L. Lee

She was seen at our hospital with abdominal pain at the site of a previous open cholecystectomy. Retained sutures were removed without resolution of her symptoms and a CT scan was ordered. The CT scan (figure 1A) demonstrated a 4.5-cm × 4-cm heterogeneously enhancing retroperitoneal mass projecting to the left hemipelvis near the origin of the inferior mesenteric artery in the region of the organ of Zuckerkandl. MRI scan demonstrated a 5.2-cm 3 × 4.4-cm mass in the left paravertebral region with significantly increased intensity on T2-weighted images, suggesting an extra-adrenal pheochromocytoma (figure 2). Twenty-four urine collection showed marked elevation of norepinephrine 1,858 mcg per 24 hours (reference, 15 mcg to 100 mcg) and its metabolites, normetanephrine 6,562 mcg per 24 hours (reference, 42 mcg to 310 mcg) and vanillyl mandelic acid 24 mg per 24 hours (reference, <8 mg), with normal dopamine 407 mcg per 24 hours (reference, 52 mcg to 480 mcg), epinephrine 20 mcg per 24 hours (reference, 2 mcg to 24 mcg) and its metabolite, metanephrine 93 mcg per 24 hours (reference, 19 mcg to 140 mcg).

The elevated urinary catecholamines were consistent with a pheochromocytoma, and a functional imaging scan was ordered for preoperative tumor localization. A 123I-metaiodobenzylguanidine (MIBG) scan demonstrated isotope accumulation in the left aspect of the abdomen on planar imaging (figure 3). Single photon emission computed tomography (SPECT) images of the 123I-MIBG exam (figures 1B and 4) further localized the isotope trapping in an extra-adrenal left retroperitoneal area. Fusion of the SPECT images with the CT scan showed co-localization of the 123I-MIBG with the retroperitoneal mass near the origin of the inferior mesenteric artery (figure 1C), consistent with an extra-adrenal pheochromocytoma in the organ of Zuckerkandl.

Treatment

The patient was started on escalating doses of labetalol, with resolution of her symptoms and hypertension. The mass was surgically removed without complication. The tumor was encapsulated without capsular invasion or necrosis with ganglia and nerves at the periphery. Immunohistochemistry showed strong positive staining for chromogranin and synaptophysin, consistent with a benign sympathetic paraganglioma (sPGL) in the organ of Zuckerkandl.

Postoperatively, the antihypertensive agents were stopped and her blood pressure at discharge was normal at 120/82 mm Hg. After surgery, her symptoms of palpitation, sweats and headaches resolved and her postoperative plasma free metanephrines (0.23 nmol/L; reference, 0 nmol/L to 0.49 nmol/L) and plasma free normetanephrines (0.44 nmol/L; reference, 0 nmol/L to 0.89 nmol/L) were normal. Genetic testing showed she was positive for a succinate dehydrogenase (SDH) subunit B mutation. She was instructed to have her siblings, who had hypertension, genetically tested in Brazil.

Figure 1. Fusion of axial images of abdominal CT scan and 123I-MIBG SPECT scans. A. CT scan B. 123I-MIBG SPECT scan C. Fusion of CT and 123I-MIBG SPECT scans. Blue arrow indicates location of a heterogeneously enhancing with contrast retroperitoneal mass on CT scan. Yellow arrow indicates retroperitoneal accumulation of 123I-MIBG. Green arrow indicates the co-localization of 123I-MIBG in the retroperitoneal mass. Photos courtesy of: Stephanie L. Lee, MD, PhD

Figure 2. MRI scan. Coronal images of an MRI scan showing a hypermetabolic mass in the left retroperitoneum that projected into the left hemipelvis near the origin of the inferior mesenteric artery in the region of the organ of Zuckerkandl. Red arrow indicates the retroperitoneal mass that is hyperintense with T2 weighting.

Figure 3. 123I-MIBG scan. Planar anteroposterior image of 123I-MIBG scan. Blue arrow shows 123I uptake into the normal thyroid scan. The 123I-MIBG is metabolized allowing the free 123I uptake into the thyroid gland. The red arrow shows 123I-MIBG accumulated in the left abdomen. The yellow arrow shows isotope accumulation in the bladder.

Figure 4. 123I-MIBG SPECT images. A. Coronal B. Sagittal C. Axial images of the 123I-MIBG SPECT scan that indicates in three dimensions the location of the isotope accumulated in a retroperitoneal mass consistent with an extra-adrenal pheochromocytoma (paraganglioma).

Succinate dehydrogenase subunits

Pheochromocytomas are catecholamine-secreting tumors of neural crest cells located primarily in the adrenal medulla but also along the sPGL; sPGLs that secrete catecholamines will cause signs and symptoms identical to an adrenal pheochromocytoma. Twenty percent to 30% of sporadic pheochromocytomas/paragangliomas have a mutation in one of six known genes for SDHB, SDHD and SDHC, von Hippel-Lindau, RET (multiple endocrine neoplasia type 2) or neurofibromatosis type 1. SDHs are tumor suppressor genes, and inactivation stimulates the hypoxia- angiogenesis pathway, resulting in apoptosis resistance with strong association with malignant transformation. The SDHB mutation of this patient is strongly associated with multifocal extra-adrenal sPGLs with a very high risk for malignant disease. The sPGL with a SDHB mutation are hyperexcrete norepinephrine, as shown by our patient, or silent.

After a biochemical diagnosis of a pheochromocytoma has been established, anatomical and functional imaging studies should be performed. Conventional CT and MRI scans have good sensitivity (90%) but poor specificity — as low as 50%. MRI scans have a slightly better sensitivity for sPGL, and high-signal intensity on T2-weighted MRI imaging is highly suggestive of a pheochromocytoma (figure 2).

Confirmation with functional imaging with a MIBG should be considered, especially for multifocal and extra- adrenal disease and to exclude an incidental non-secreting adrenal adenoma (figures 1 and 4). 123I-MIBG studies have a specificity of 95% to 100% with a sensitivity of 77% to 90%. The results of these imaging studies are particularly useful if the SPECT images of the 123I-MIBG study can be fused with anatomical CT or MRI scans (figure 1). If malignant disease is expected, especially with the SDHB-related sPGL mutation, ¹⁸F-fluorodeoxyglucose PET has been shown to be superior for localization of the metastatic tumor that is hypermetabolic and growing.

Pheochromocytomas in extra-adrenal sites are called paragangliomas and are located at sites such as the organ of Zuckerkandl. An important clinical pearl is that pheochromocytomas that secrete epinephrine (detected by metanephrine) indicate an adrenal location, but excretion of norepinephrine (detected by normetanephrine) may reflect an adrenal or extra-adrenal location. Pheochromocytomas with SDHB mutations always secrete norepinephrine. Genetic testing should be considered in all patients with paraganglioma, especially in patients aged 50 years and younger because of the higher risk for genetic mutations.

Anatomic MRI scan imaging and functional imaging with MIBG are recommended because of the risk for multifocal extra-adrenal disease. After surgical cure, annual biochemical testing should be done to assess for metastatic disease, tumor recurrence or delayed appearance of multiple primary tumors, especially in this patient, because the SDHB mutation is associated with a high risk of malignancy.

Stephanie L. Lee, MD, PhD, is Director of the Thyroid Nodule and Cancer Center and Associate Professor of Medicine at Boston Medical Center.

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