Pheochromocytomas are tumors composed of chromaffin cells and usually are located in the adrenal medulla. They are rare tumors and account for <1% of patients with systemic hypertension. Extraadrenal pheochromocytomas are called paragangliomas and may be divided into those that arise from parasympathetic tissues along the cranial or vagus nerves and those that arise from sympathetic chromaffin tissue. Thus, they may lie anywhere between the base of the brain and the epididymis but usually lie along the sympathetic chain in the retroperitoneum. Eighty-five percent of pheochromocytomas arise from chromaffin tissue in the adrenal medulla. Sporadic pheochromocytomas average 4 cm in diameter at presentation, while those associated with syndromes are often smaller.
Patients may complain of episodes of headaches associated with palpitation and diaphoresis. If the pheochromocytoma is located in the bladder wall, micturition may induce a symptomatic episode.
Hypertension is the most common finding and is present in >90% of patients. Hypertension from a pheochromocytoma may be difficult to distinguish from renovascular or essential hypertension; however, patients with a pheochromocytoma are more likely to have labile hypertension with discrete paroxysmal attacks. These patients are also prone to hypertensive attacks during anesthesia induction. Manipulation of the gland during surgery, percutaneous adrenal biopsy, or even selective adrenal angiography may also induce a hypertensive crisis.
Pheochromocytomas are associated with other endocrine tumors. The multiple endocrine neoplasia syndrome 2A (MEN2A) includes medullary carcinoma of the thyroid and parathyroid hyperplasia as well as pheochromocytoma. The MEN2B syndrome is rare and is composed of pheochromocytoma; medullary carcinoma of the thyroid; and the mucocutaneous manifestations of mucosal neuromas, intestinal ganglioneuromatosis, and a marfanoid habitus. The majority of patients with the MEN2A or the MEN2B syndrome have pheochromocytomas that are bilateral and usually intra-adrenal. However, all manifestations of the syndrome may not occur at the same time. Thus, a careful history of a previous endocrine abnormality should be obtained in evaluating patients who may fall into these categories. These syndromes are inherited in an autosomal dominant fashion.
Pheochromocytoma is also associated with neurofibromatosis (type I) and von Hippel-Lindau syndrome (type II). Paragangliomas are also associated with tuberous sclerosis and Sturge-Weber syndrome.
A syndrome of familial pheochromocytomas not associated with other endocrine tumors has also been noted. Specific gene mutations have been identified involving the mitochondrial enzyme succinate dehydrogenase (SDH). The most common of these are SDHB mutations, where patients develop thoracic or abdominal paragangliomas with a propensity for malignancy. Patients with SDHD mutations develop paragangliomas in the head and neck.
In 1977, Carney et al. reported the association of a gastric leiomyosarcoma, a pulmonary chondroma, and a functioning extraadrenal pheochromocytoma. This rare combination of neoplasms often is termed Carney triad.
Although 85% of all pheochromocytomas are located in the adrenal medulla, there is a striking difference between sporadic tumors and those associated with the MEN syndromes. The sporadic pheochromocytomas are located outside the adrenal gland in as many as 25% of cases, whereas those associated with the MEN2 syndromes are almost always intra-adrenal. Pheochromocytomas found in patients with MEN2 syndrome are usually multicentric and involve both adrenal glands in >80% of cases.
The histologic appearance also differs in sporadic and MEN2-associated cases. In sporadic cases, the tumor is well encased with normal adjacent medulla. In patients with MEN2 syndrome, the medulla is hyperplastic and the tumor may be multicentric.
If a pheochromocytoma is suspected, the diagnosis can be made by measuring elevated levels of serum or urine catecholamines. Urinary metanephrine or vanillylmandelic acid (VMA) is elevated in >90% of patients when measured on 24-hour urine collections. Plasma-free metanephrine levels are elevated in 99% of patients. However, several separate determinations should be made because of the episodic hormone secretion found in these patients. Furthermore, patients taking medications such as methyldopa or methenamine may have falsely high catecholamine levels.
Approximately 15% of pheochromocytomas lie outside the adrenal gland. Those which arise from sympathetic paraganglia are called paragangliomas, whereas those which arise from the sympathetic tissue of the cranial or vagus nerves are glomus tumors, chemodectomas, or carotid body tumors. Although they may occur anywhere from the base of the skull to the epididymis, the most common locations are in the sympathetic chain in the retroperitoneum from the level of the adrenal glands to the aortic bifurcation, which includes the region of the organ of Zuckerkandl, which lies near the origin of the inferior mesenteric artery.
Pheochromocytomas usually are benign, but approximately 13% demonstrate malignant behavior. Extra-adrenal pheochromocytomas are more likely to be malignant than intra-adrenal tumors.
A small number of patients have a pheochromocytoma that does not produce sufficient catecholamine to cause clinical symptoms. These “nonfunctioning” pheochromocytomas are discovered as palpable masses or as incidental findings at surgery and at autopsy or on imaging studies such as CT or MR examinations. In a recent series by Motte-Ramirez et al., more than half of their series of pheochromocytomas were discovered incidentally. The nonfunctioning tumors tend to be larger than functioning pheochromocytomas whose hormone production brought them to attention earlier than patients with nonfunctioning pheochromocytomas.
The treatment for patients with pheochromocytoma is surgical resection. Biochemical confirmation of the diagnosis and accurate preoperative radiologic localization have made these operations much safer. Nevertheless, patients undergoing surgical resection still must receive adrenergic blockade before the induction of anesthesia as well as careful monitoring during the operation to treat any crises. Both an α-adrenergic blocker (phenoxybenzamine) as well as a β-blocker (propranolol) are advocated, whereas nitroprusside may be used to treat hypertensive episodes. This same regimen may be used in patients requiring invasive radiologic procedures.
Neuroblastoma and Ganglioneuroma
Neuroblastomas are primitive tumors that arise from sympathetic nervous system tissue. They may occur in the neck, thorax, abdomen, and pelvis, but no definite primary site can be found in a significant minority of patients. The most common location is the adrenal gland, which accounts for approximately 35% of patients.
Neuroblastomas usually occur in young children. Approximately 25% of cases occur in the first year of life, and as many as 60% occur by the age of 2 years.
Although neuroblastoma is the most common extracranial malignant tumor in childhood, its incidence is only 1 to 3 per
100,000 children per year. An increased incidence is seen in neurofibromatosis, and familial associations have been reported.
FIGURE 3.11. Pheochromocytoma. The right adrenal mass shows heterogeneous enhancement on this MR examination.
FIGURE 3.12. Pheochromocytoma. A: The posterior view of this 123-iodine MIBG scan demonstrates intense MIGB uptake in the right posterior abdomen and physiologic activity in the liver. SPECT (B) and fused SPECT/CT (C) scans demonstrate an MIBG-avid right adrenal nodule consistent with pheochromocytoma.
Some neuroblastomas spontaneously mature into benign ganglioneuromas. Histologically, neuroblastomas contain densely packed small round cells that may be difficult to differentiate from other tumors, such as Ewing sarcoma, lymphoma, or rhabdomyosarcoma. Tumors that contain more mature ganglion cells mixed with neuroblasts are classified as ganglioneuroblastomas. Ganglioneuroblastomas and ganglioneuromas are differentiated from neuroblastomas by a greater degree of cellular maturation. Ganglioneuroblastomas are malignant tumors but may be partially or totally encapsulated. Ganglioneuromas are benign tumors with an intact capsule, but careful evaluation of the entire tumor is necessary because there may be marked variation in different parts of the tumor.
Ganglioneuromas are benign, nonhyperfunctioning tumors composed of mature ganglion cells and Schwann cells in a fibrous stroma. They arise from the sympathetic nervous system and may be found in the neck, thorax, abdomen, or pelvis. In one series, 19 (41%) of 46 abdominal ganglioneuromas were found in the adrenal gland. Because they are not hormonally active, they are usually found as a large mass or as an incidental finding on CT or MRI examinations.
An adrenal ganglioma is seen as a well-defined, rounded, homogeneous mass with an attenuation slightly less than muscle on unenhanced CT images. With the administration of intravascular contrast media, mild heterogeneity may be seen, especially in larger tumors, but the attenuation still usually is less than muscle (Fig. 3.13
A homogeneous tumor of relatively low signal intensity is seen on T1-weighted MR images. A heterogeneous high signal intensity has been reported on T2-weighted images.
The most common presentations of a child with a neuroblastoma are pain, abdominal distention, or an abdominal mass discovered by a parent. Most patients have elevated urinary catecholamines when measured as catechol excretion per milligram of creatinine. More than 50% of patients excrete high levels of VMA, and up to 90% of patients have an elevation of VMA or homovanillic acid.
FIGURE 3.13. Ganglioneuroma. This retroperitoneal mass (G) was detected as an incidental finding on an enhanced CT examination.
The International Neuroblastoma Staging System (Table 3.1
) is based on clinical, radiologic, and surgical features. Stage I tumors are those that have no nonadherent positive lymph nodes or metastases and can be completely resected. Tumors that invade one side of the neural canal are stage II. Tumors that cross the midline to the opposite side of the vertebral body are stage III. Stage IV tumors are those with distant metastases, whereas stage IVs tumors are those in which the tumor cells represent fewer than 10% of all marrow cells; other metastases are limited to the liver and skin. Approximately 70% of patients have metastases at the time of presentation.