Pathology Associates Of Lexington, P.A.
Pathology Associates Of Lexington, P.A.
Pathology Associates Of Lexington, P.A.
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        Catecholamine Testing
Pheochromocytoma work up

This tumor can cause a type of episodic hypertension (high blood pressure) that can be hard to diagnose...the condition is pretty rare, being found in fewer than 1% of hypertensive cases in which the tumor is actually searched for. It is a pheo when in the adrenal and a variety of paraganglioma when of extra-adrenal origin4. But, historically, the laboratory work-up can be frustrating to patients, doctors, and laboratorians. The tumor releases "bursts" of catecholamines which cause the high BP. Various tests for catecholamines, VMA, and metanephrines have been used. See an algorithm HERE.

As below, the plasma free metanephrine test is the screen of choice.

The search for a "pheo" is almost never a medical emergency. In the zeal to quickly rule in or rule out a "pheo", unnecessary efforts & costs are often incurred by inattention to the rigors of required elimination of pretest sources of false positive results: sources are (1) diet, (2) drugs, and (3) stressors.

Our modern times of body imaging for the sources of aches & pains, we will incidentally find this as a small tumor by CT [L09-616 2cm & had adrenal vein invasion & PASS score of 1] or MRI. Deliberate searches for location of an extra-adrenal pheo (paraganglioma) include octreotide scintigraphy.

Patient Preparation for old classical urine tests:

  1. diet: coffee of any type contains the interferer caffeic acid; caffeine and nicotine increase plasma levels of catecholamines. Alcohol can interfere. Counteract this by fasting overnight prior to drawing of blood sample.

  2. drugs:  tricyclic antidepressants or phenoxybenzamine falsely increase the norepinephrine result; epinephrine and epinephrine like drugs can cause false positives; one must be free of any medication containing acetaminophen (lots of "cold" and aches and pains drugs contain this). Counteract this by stopping at least these types of drugs for at least 48 hours.

  3. stressors: emotional stress, "white coat hypertension" at the time of blood sampling, or even upright posture can release increased catecholamines into the blood. Counteract this by drawing the specimen with patient in supine position at a time of least life stress and with least phlebotomy stress.

The Interferences-Situation Solution...a blood test:

But...avoiding much of the above pretest variables, the "plasma free metanephrine" blood test (a send-out test from our lab), when results are in the normal range, is said to be the most dependable test to rule the condition out...if the results are not elevated, "pheo" is essentially 100% ruled out1. And, about 80% of cases with a definite pheo tumor have test values so elevated that the diagnosis is not in doubt (so, the hunt for the tumor should begin)1.  An EDTA specimen is used and plasma is frozen for transport. No 24 hour urine collections!!

  favor potentially aggressive (malignant) behavior favor benign behavior
gender male 3  
location extra-adrenal3  
size when larger3; only 13% <30 g or 4cm5 smaller3
confluent necrosis when present3 absent
vascular invasion when present3  
circumscription when poor circumscription3  
nodularity when coarsely nodular 3  
hyalin globules with absence of globules 3  
sustentacular cells when decreased3  
smaller tumor cells when present absent
mitotic rate >5 figures per hpf5  
Ki67 proliferation >3% (100% spec & 50% sens.)3; elevation not to categorize but to prompt pathologist to discern other concerning features leading to increased PASS score 7 3% or less 3, 4; even >2%4
tenascin by IHC when increased, pheos only5 when hardly evident
p53 over-expression not, pheos only5; p53 status not reliable6, 7, 8  
PASS score , below >/=6 (>/4 just follow closely)7; >/=44 <4

SUMMARY: Every malignant tumor5 had at least one histologically suspicious feature (over 5 mitoses per 10 hpfs, confluent necrosis, vascular invasion, or capsular in vasion). However, these tumor collections accrued prior to the days of widespread deliberate or coincidental discovery of quite small tumors (markedly down-staged situations).

PASS Score...sum of your case's points, below:
parameters: points when present:
vascular invasion 1
capsular invasion 1
peri-adrenal fat invasion 2
large cell nests or diffuse growth 2
focal or confluent necrosis 2
high cellularity 2
tumor cell spindling 2
tumor cellular monotony 2
mitosis rate >3 per 10 hpfs 2
presence of atypical mitoses 2
profound nuclear pleomorphism 1
nuclear hyperchromasia 1



  1. Lenders JWM, et. al., Toward Optimal Laboratory Use: Biochemical Diagnosis of Pheochromocytoma; Which Test is Best?, JAMA 287(11): 1427-1434, 20 March 2002.
  2. Ronald A. DeLellis , MD, Pathologist-in-Chief @ Lifespan Academic Med. Ctr in Providence, Rhode Island. He has served on key committees, including the WHO Project on Classification of Endocrine Tumoprs. He was a speaker at The Second International Course in Applied Immunohistochemistry and Molecular Pathology (Santa Barbara, Calif. 1/28/08-2/1/08).
  3. Clarke MR, et. al., [Pittsburgh, n=33,1953-1993] "Prognostic markers in pheochromocytoma", Human Pathology, 29(5):522-526, May 1998.
  4. Nagura S, et al. [Japan, n=42 1985-1997] "Immunohistochemical estimations of growth activity to predict biological behavior of pheochromocytomas", Mod Pathol, Dec 1999 12(12):1107-11.
  5. Salmenkivi K, et. al., [Finland, n=65] "Increased expression of tenascin in pheochromocytomas correlates with malignancy.", Am J Surg Pathol., Nov 2001, 25(11):1419-23.
  6. Salmenkivi K, et. al., [Finland, n=105...?malig...lots of detail in this paper 1976-2001] "Lack of histologically suspicious features, proliferative activity, and p53 expression suggests benign diagnosis in phaeochromocytomas.", Histopathology, July 2003, 43(1):62-71.
  7. Strong VE, et. al., [USA MSKCC, n=51, 1987-2006] "Prognostic indicators of malignancy in adrenal pheochromocytomas: clinical, histopathologic, and cell cycle/apoptosis gene expression analysis [PASS score, too] ", Surgery, June 2008, 143(6):759-68.
  8. Thompson LD, [from USA AFIP, n=100, mean size 7.2cm & 222g] "Pheochromocytoma of the Adrenal gland Scaled Score (PASS) to separate benign from malignant neoplasms: a clinicopathologic and immunophenotypic study of 100 cases.", Am J Surg Pathol, May 2002, 26(5):551-66.

(posted 28 September 2003; latest addition 20 September 2010)

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