Pheochromocytomas tend to occur as a principle manifestation in some families with VHL and not at all in others. Thus, only about 7-18% of all patients with VHL have pheochromocytomas (4,12,18,50). However among selected families the prevalence can be very high. For instance, 53% of members from a large family from Newfoundland and 57% of members from large family from Pennsylvania demonstrated pheochromocytomas (10,82). These families have a lower frequency of cerebellar Hb than other families and a decreased tendency for renal cancers resulting in a milder form of VHL (82). Patients from families in whom pheochromocytoma is prevalent often present at a young age with a mean of 20.2 years and as young as eight years of age (4, personal communication).
The number of patients with pheochromocytoma who also have the VHL gene may be underestimated. Neumann et al found that 19.5% of unselected patients with apparently sporadic pheochromocytomas actually had VHL; 4% had MEN-2 (83). Neurofibromatosis is another hereditary but more infrequent cause of pheochromocytomas (84). Pheochromocytomas should always be excluded before a VHL patient undergoes surgery to avoid an anesthesia induced hypertensive crisis.
An association may exist between islet cell tumors of the pancreas and pheochromocytomas since approximately 20% of VHL families with a high prevalence of pheochromocytoma will also develop islet cell tumors whereas this tumor is rare in other VHL families (Figure 14).
Figure 14. A symptomatic patient with pheochromocytoma and islet cell tumor of the
pancreas. A small right pheochromocytoma with a necrotic center (P) is seen.
In addition, an intensely enhancing mass is present in the neck of the pancreas
(I). Two small pancreatic cysts are also seen but the bulk of the pancreas
is spared. Pancreatic islet cell tumors are associated with pheochromocytomas
and are generally not accompanied by cystic pancreatic disease.
Figure 15. Ectopic functional paraganglioma (glomus jugulare) in a patient with
VHL. T2 weighted MRI at the same location demonstrates a high signal mass
consistent with a paraganglioma. Extra adrenal paragangliomas can be found
in VHL (arrow).There are, however, small numbers of families who exhibit all the visceral manifestations of VHL including pheochromocytoma and islet cell tumors, renal cancers and pancreatic cysts (VHL Type IIB).
Pheochromocytomas arise from neural crest tissue and produce elevated levels of norepinephrine which is converted to epinephrine and is stored in neurosecretory vesicles (18). Histologically, the cells are arranged in rounded clusters separated by endothelial lined spaces. Like the pheochromocytomas associated with MEN2, those associated with VHL are often multiple and ectopic; approximately 50-80% are bilateral (23). Although generally considered benign, VHL associated pheochromocytomas can metastasize both locally to nodes and to distant organs. Ectopic paragangliomas, with pathology identical to pheochromocytoma, occur in VHL. Known sites include the organ of Zuckerkandl, glomus jugulare (Figure 15), carotid body, periaortic, perisplenic, and intrarenal (83). Metastatic carotid body tumors have been reported in VHL (85). Adrenal angiomas and adenomas have also been reported but have not been confirmed in later studies (10).
Many pheochromocytomas in VHL are asymptomatic and do not elevate serum catecholamine levels (17,23,86) (Figure 14,16).
Figure 16. Slowly growing asymptomatic pheochromocytoma. a.) This 20 year old female
had an incidental pheochromocytoma (arrow) which was detected on a routine
screening study for VHL. Urinary catecholamines were normal. b.) Six years
later the adrenal mass has dramatically increased in size (note that pancreatic
cysts are relatively stable) yet the patient still had only borderline abnormalities
in urinary catecholamines. The patient elected for surgery at this point
confirming the diagnosis of pheochromocytoma containing several cystic and
necrotic spaces.
When symptoms occur they can be varied and include, periodic or sustained hypertension, headaches, palpitations, episodic sweating, and anxiety attacks; such symptoms may be incorrectly attributed to anxiety or depression (18). Pheochromocytoma can cause such life threatening conditions as hypertensive crisis, myocardial infarction, cardiac failure, stroke and metastatic disease (10).
Laboratory tests for pheochromocytoma include serum and urinary norepinephrine (NE), epinephrine (E), and urinary vanillylmandelic acid (VMA). The 24-hour urine collection may also include metanephrine and dopamine but these are less sensitive markers. Urinary NE is more sensitive than urinary E and VMA (12,83). The glucagon stimulation test is less sensitive in familial pheochromocytomas perhaps due to lower functional levels (86). Atuk et al have noticed that NE and E plasma concentrations decrease with advancing age in patients with VHL who have pheochromocytomas (11).
Imaging tests include CT, MRI and the metaioodobenzylguanidine test (MIBG). CT is often performed with intravenous contrast because the kidney must also be evaluated. We have performed contrast enhanced CT in 21 VHL associated pheochromocytomas using non-ionic contrast media and have had no adverse effects and thus consider this policy safe. Pheochromocytomas typically enhance after contrast media although small portions of the tumor may remain low density (Figure 14,15,16).
CT is excellent for evaluating the adrenals and organ of Zuckerkandl but is less ideal for investigating other ectopic sites where MRI is superior. Pheochromocytomas, usually (95%) demonstrate high signal intensity on T2 weighted MRI, however, some lesions may be only slightly hyperintensive or even hypointense (83). MIBG is about 95% sensitive for pheochromocytoma and is 100% specific but may not detect very small lesions. When an adrenal lesion is discovered by CT, an MRI is usually performed. If the lesion is small, asymptomatic and catecholamines are normal, the patient is generally followed with CT at yearly intervals at a minimum. If symptoms or elevated catecholamines develop, the MIBG is performed prior to surgery to exclude additional sites.
Selective adrenal vein sampling of NE to E ratios has been advocated but is rarely needed. This test requires prior adrenergic blockage with phenoxybenzamine and propranolol (87). While this test is very sensitive for tiny lesions, it is uncertain whether such lesions need to be diagnosed at so early a stage (87).
Before surgical removal the patient should have adequate adrenergic blockade beginning two weeks before surgery. In the United States, adrenalectomy is the preferred technique although this approach requires subsequent adrenal replacement therapy for bilateral disease (18). Enucleation of the tumor, partial adrenalectomy or bench surgery with autotransplantation into the thigh or arm have been used in the United States and Europe as methods of preserving adrenal function and deserve attention.
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