vhl alliance

Pheochromocytoma, Paragangliomas

excerpts from VHL Handbook

VHL may be associated with a kind of tumor of the adrenal glands called a pheochromocytoma, (“pheo”). Pheos are usually noncancerous and most commonly occur in the adrenal glands. Pheos located outside the adrenal glands are called paragangliomas; these tumors are very rare, even in VHL patients.

The adrenal glands are approximately 3 x 2 x 2 cm (1 inch long) perched on top of each of the kidneys. The adrenal glands make hormones in the body, including:

Catecholamines:  This is predominantly epinephrine but also some norepinephrine. Epinephrine helps to regulate the “fight or flight” response to stress (also known as adrenaline and is the main catecholamine produced by the adrenal glands).

Glucocorticoids:  The most important glucocorticoid is cortisol. Cortisol helps to regulate blood sugar, blood pressure, fat and protein metabolism, and the immune system. Cortisol is known as the ‘stress hormone.’

Mineralocorticoids:  The most important mineralocorticoid is aldosterone. Aldos­terone works mainly in the kidneys by maintaining salt and water balance within the body. This is important for blood pressure regulation and proper cardiovascular function.

Adrenal androgens:  These are precursors to sex hormones (i.e. testosterone, estrogen).

Pheos occur more frequently in some families than in others. They are rarely malignant (<7%) among people with VHL. Detected early, pheos are not difficult to deal with, but they are potentially lethal if not treated. This is especially true during times of stress, such as surgery, accidents, or childbirth. It is particularly important for patients with VHL with or without symptoms to be checked for a pheo prior to any surgery, pregnancy, or childbirth. If a pheo is present, complications may be avoided by blocking off the effects of stress hormones with drugs beginning at least 7–14 days before the procedure. Pheos secrete excessive amounts of catecholamines, norepinephrine and epinephrine, also known as “stress hormones.” However, pheos in VHL only produce norepinephrine (also known as noradrenaline). The primary clinical sign is usually high blood pressure, especially spiking blood pressure, that puts strain on the heart and vascular system, which can cause a heart attack or stroke. In some patients, though, blood pressure may be normal despite the presence of a pheo. Patients may notice headaches, irregular or rapid heartbeat, or what feels like a panic attack, fear, anxiety, or, even, rage. There may be heavy sweating for no good reason. Sometimes people have hot flashes (or cold flashes). There may be abdominal pain or unexplained weight loss. It is recommended that all people with VHL be screened for pheos. New research indicates that adrenal tumors are as much as four times more common among people with VHL than previously thought. Even in families that have not previously had a pheo, it is still important to test for presence of these tumors. In one large progeny in France where there were no pheos for three generations; there are now pheos in two branches of that family.

If surgery is required, the standard of care in VHL patients is partial adrenalectomy. Studies have shown that keeping even a small amount of the cortex of the adrenal gland if surgery on both glands is required, makes it easier to manage post-surgery. It also usually avoids the need for steroid replacement. On the other hand, it must also be recognized that the remaining adrenal tissue can be associated with recurring pheos. Removal of the entire adrenal gland is rarely required to manage VHL-associated pheos.

In recent years, the “key hole” operating technique (laparoscopy) is being used to treat pheos. With this technique, there is less risk of infection and the recovery is much faster. Some surgeons have the technology to simultaneously remove pheos located on each of the two adrenal glands. Laparoscopic or robotic surgery should be discussed with your doctor.

Prior to surgery, the medical team will prescribe “blockers” (alpha blockers, sometimes followed by beta blockers) or drugs that inhibit the formation of catecholamines. These medications will calm the effects of the chemicals produced by the pheo and allow the surgery to proceed calmly, without causing a pheo crisis. While the blockers will make you tired, they are critically important. They may be prescribed for two or more weeks before the planned surgery.

Another important consideration before surgery is to make sure that the anesthesiol­o­gist working with your surgeon has experience with pheos. The anesthesiologist is responsible for managing your blood pressure during the surgery. Your endocrine surgeon should be able to let you know who will be part of your surgical team.

Testing for a Pheochromocytoma

Traditional blood or urine tests that measure only catecholamines are inadequate to find most pheos. In order to diagnose a pheo, an initial biochemical test is done to measure blood or urine metanephrines. The “plasma-free metanephrines” test involves measurement in a sample of blood of both metanephrine, the metabolite of adrenaline, and normetanephrine, the metabolite of noradrenaline. More widely available is the 24-hour urine collection, analyzed for fractionated metanephrines, normetanephrine, and metanephrine. If additional information is required or if there are symptoms of a pheo, but the blood and urine tests are negative, anatomical imaging scans may be used.

In patients with VHL, it is the measurement of normetanephrine that is most important since associated pheos do not produce adrenaline or its metabolite, meta­nephrine, in significant amounts. Methoxytyramine is a new biomarker for the diagnosis of pheos and was introduced in 2011 as a measurement tool. However, only about 17% of VHL patients with pheos produce methoxytyramine. An increase in methoxytyramine can be useful to assess malignancy.

The accuracy of the urine and blood tests for pheo activity will be determined in large part by your own cooperation in preparing for the test. Even if no instructions are provided, you should avoid tobacco, alcohol, and caffeine for at least four hours before the test. Be sure to tell your doctor and the technician if you are taking any antidepressant or mood-altering medication. You might want to prepare a list of all the medications you are taking, discuss this list with the doctor before the test, and even send it along to the lab with the blood or urine sample, to assist in interpreting the results.

Where other instructions are given, they may differ from center to center, sometimes due to different methods of analysis. Follow any instructions carefully to avoid a false reading.

2014 Testing Standards for Pheochromocytoma and Paraganglioma

New clinical guidelines were recently approved by the Endocrine Society (June 2014) for testing for the presence of pheochromocytomas and paragangliomas, together known as PPGLs.

    • Screening for PPGLs should always include measurements of plasma-free metanephrines (obtained from a blood sample) or urinary fractionated meta­nephrines (obtained from a urine sample).

      For a blood sample, it is now recommended that patients be supine (lying down) for a minimum of 20 (ideally 30) minutes between the time the needle is inserted and the time the blood is drawn.

      For blood sample analysis, upper reference intervals (the test result above which a pheo is determined to be possible) should be established from supine tests, not seated tests, to minimize the chance of a false negative result (missing a PPGL that is present).

    • The decision was made based on the finding that seated blood testing results increased false positives, meaning that these patients must be retested. The reason for this is that the release of catecholamines by peripheral nerves and the adrenal gland is stimulated by an upright posture resulting in increased blood levels of metanephrines in seated compared to supine positions of blood sampling.
    • The VHLA guidelines for pheo testing are based on the Endocrine Society clinical guidelines: Measurement of plasma free metanephrines (with blood drawn following 20–30 minutes in a supine position following needle insertion) or urinary fractionated metanephrines (with patient adherence to recommended collection and refrigerated storage). Analysis is performed using liquid chromatography with mass spectrometric or electrochemical detection and using supine norms for plasma test results. All positive test results should be followed up. Follow-up may involve repeated biochemical studies (e.g. a clonidine test) or a CT scan or MRI (if a CT scan is not appropriate).In VHL, it is only necessary to consider elevations of normetanephrine. For plasma in an adult patient with VHL, anything over 112 picograms/milliliter (0.61 nanomoles/liter, the NIH upper reference limit) should evoke suspicion. Anything over 400 pg/mL (2.2 nmol/L) for a sample that is taken with the patient lying down and relaxed (no stress) and on no antidepressants is immediately highly suspicious (close to 100% likelihood). Imaging is then warranted. Between those ranges, the likelihood of a pheo increases with increased level and follow-up tests, such as imaging, should be considered.If these chemical tests indicate the presence of a pheo, but it cannot easily be located on MRI or CT, an MIBG or PET scan may be recommended. These scans help to localize, or locate, a pheo, even if it is outside the adrenal glands. Pheos located outside the adrenal glands are called paragangliomas. These very rare tumors may occur anywhere on the sympathetic nervous system, meaning anywhere along a line drawn from your groin to your ear lobe on either side of the body. Multiple tests may be needed to find them. According to research at the US National Institutes of Health, different tests have different success rates in locating a pheochromocytoma or paraganglioma:

      18F-FDA PET scan finds 75–92%
      18F-FDOPA PET scan finds 67–93%
      123I-MIBG scan finds 67–86%
      18F-FDG PET scan finds 83–93% (adrenal: 67%)
      Octreotide scan finds fewer than 50% of these tumors. Please note that the Octreo­­tide scan will soon be replaced by 68Ga-DOTA analogs used with PET scans.

      The choice of one of these tests is often made depending on the availability of a particular technology at your center. However it is important to note that if the test chosen does not find the pheo, there is still some chance that the pheo is, in fact, there but cannot be detected by that particular test. You may need to seek a second opinion from a VHL or pheochromocytoma expert.

      Preparing for Pheochromocytoma Testing

      It is most important to test for pheochromocytomas before undergoing surgery for any reason and before going through childbirth. Undergoing either of these stressful experiences with an unknown pheo can be extremely dangerous. If the doctors are aware that the pheo is there, they can take preventive action that will ensure the safety of the patient and any unborn child.

      Testing of blood and urine are the best tests to determine whether an active pheo is present and whether additional scanning is needed to localize or find the tumor. The urine and blood tests for a pheo are most reliable when care is taken in two areas—diet prior to the testing and preservation of the urine sample from the start of the test until the lab processing is complete.

      Medications are often recommended or self-prescribed. It is important to note that all medications may interfere with the accurate analysis of tests for pheo. If at all possible, testing for pheo should be done BEFORE beginning any medication. If this is not possible, then it is critically important that you disclose ALL medications you are taking—prescription, herbal, over-the-counter, and even illegal—in order to get an accurate reading from the tests. Such medications can interfere with the results, depending on the method of measurement used by the laboratory. Please adhere to any recommen­dations about medication indicated to you by the laboratory or your physician.

      To get the best information from a 24–hour urine test, it is critically important that the patient carefully follow the pheo test instructions that go with the test. Not all hospitals provide these instructions to the patient and not all patients follow them conscientiously. Differences in instructions may reflect different methods of analysis.

      Follow the instructions provided to you by your hospital lab staff. If instructions have not been provided, ask them if the instructions that follow would be good to ensure that the sample is fresh and that the chemical levels for which they are testing are not artificially influenced by things in your diet. It is also very important that the urine be carefully refrigerated and preserved throughout the 24–hour urine collection period and delivered fresh to the lab for immediate processing. Some people carry the jug in an insulated bag or backpack, with one or more plastic cold packs alongside the jug.

      Preparation for Blood Testing

      Do not take any medications, including aspirin and acetaminophen, without the knowledge and agreement of the doctor ordering the test. In particular, be sure to discuss theophylline, anti-hypertensives (blood pressure medicines), methyldopa, L-dopa, or any diuretic, birth control pills, birth control patches, smoking cessation products, or any antidepressants or other mood-altering drugs. Theophylline is found in tea and some other herbal supplements as well as medications.

      Refrain from eating or drinking anything except water from 10 PM the evening prior to your blood test; do not take any medications the morning of the test unless specifically approved by the doctor ordering the test. If you are instructed not to take your morning medications, take them with you to the test so that you can take them right after the completion of the test.

      If you smoke, you should not smoke on the day of the test. Contact your physician if you have questions regarding your diet.

      The procedure usually takes about 45 minutes. It is important that you be quiet and calm for 20–30 minutes prior to the blood draw to ensure accurate results. Bring something with you to keep you occupied and relaxed as you will be asked to lie quietly on a table for 20 minutes after the needle is inserted before the test begins.

      Pheos in VHL-related tumors do not produce epinephrine (adrenaline) or its metabolite metanephrine. VHL-related tumors only produce norepinephrine and its metabolite, normetanephrine. Therefore, it is the value for plasma normetanephrine that one must watch carefully in patients screened because of VHL mutations. The chemical profiles for other genetic mutation types are different.

      Upper limits for reference intervals of plasma concentrations of metanephrines in children (from samples collected lying down with an indwelling i.v.) are published:

    • For boys 5 to 18 years, the upper limit for normetanephrine is 97 picograms/milliliter (0.53 nanomoles/liter) and for metanephrine 102 pg/mL (0.52 nmol/L).

      For girls 5 to 18 years, the upper limit for normetanephrine is 77 pg/mL
      (0.42 nmol/L) and for metanephrine 68 pg/mL (0.37 nmol/L).

      The reference intervals for your lab may be slightly different due to variations in processing. If there are concerns about interactions with medications, it is important that the laboratory use LC-MS/MS techniques to analyze the sample, to achieve the highest sensitivity and selectivity in checking fractionated metanephrines, especially normetanephrine.

      Preparation for 24-hour Urine Testing

      Vanillyl Mandelic Acid testing (VMA): This test should no longer be used because the diagnostic accuracy of VMA is insufficient.

    • For catecholamines, metanephrines, epinephrine, norepinephrine: On the day of the test, avoid tobacco, medications, chocolate, fruits (especially bananas), and caffeine. Be sure to tell your doctor and the technician what medications you are taking, including any antidepressants.
    • Collection instructions: Do not begin collection on Friday or Saturday. This ensures that your sample will be delivered to the lab on a working day and can be processed promptly.

    1)  Start the collection in the morning. Empty the bladder; do not save this urine specimen.
    2)  Write this date and time on the jug. (If there is a preservative added to the jug, be careful not to get it on the skin. If this happens, wash the area immediately with water.)
    3)  Save all the urine passed for the next 24 hours in the jug provided including the final specimen passed exactly 24 hours after beginning the collection.
    4)  Keep the urine refrigerated at all times. You might keep it in a paper bag in the refrigerator. If you must be out, you could carry it in a bag or backpack with plastic ice packs against the jug.
    5)  Write this date and time on the jug when the collection is finished.
    6)  Bring the collection and the paper work to the lab as soon as possible after collection. (Labs are usually open early in the morning or have a place where you can arrange to drop it off early).