Pheochromocytoma, paraganglioma, neuroblastoma


Pheochromocytoma, paraganglioma, neuroblastoma


Pheochromocytoma, paraganglioma, neuroblastoma


Pheochromocytoma, paraganglioma, neuroblastoma

  32 Pheochromocytoma, paraganglioma, neuroblastoma

Lothar Thomas

Pheochromocytoma and paraganglioma are neuroendocrine tumors with differentiation of chromaffine cells originated from neural crests. Pheochromocytomas are located in adrenal glands. Paragangliomas, extra adrenal counterparts of pheochromocytomas, arise from ganglia along the sympathetic and parasympathetic chain. Due to the close relationship with neural tissue, composite lesions are known both in the adrenal and extra adrenal locations /1/.

Pheochromocytoma and paraganglioma can cause severe morbidity and/or lethal complications (e.g., cerebrovascular and cardiovascular) from effects of excess circulating catecholamines and hypertension /2/. Tumors usually secrete norepinephrine and epinephrine.

Neuroblastoma are neoplasms derived from post ganglionic neurons of the sympathetic system which produces catecholamines such as norepinephrine, epinephrine and dopamine. The great majority of neuroblastoma produces high levels of vanillylmandelic acid (MA) and homovanillic acid (HVA) /3/.

32.1 Metanephrines

Catecholamines (e.g., epinephrine, norepinephrine and dopamine) are metabolized within chromaffin cells to metanephrines, the respective O-methylated metabolites (e.g., norepinephrine to normetanephrine, epinephrine to metanephrine and dopamine to methoxytyramine, respectively). Because pheochromocytoma and paragangliomas (PGLs) do not always secrete catecholamines continuously, measurements of these analytes in plasma and urine often fail to reveal the presence of the tumor. In contrast pheochromocytoma (Pheo) and PGL continuously metabolize catecholamines to the O-methylated metabolites by a process that is independent of variations in catecholamine release /4/.

The measurement of plasma free normetanephrine and free metanephrine, represent the most sensitive tests to diagnose catecholamine production of Pheo and PGL. Measurements of fractionated metanephrines (i.e., normetanephrine and metanephrine measured separately) in plasma or urine provide superior diagnostic sensitivity and specificity in comparison to the measurement of catecholamines /5/.

32.1.1 Indication

Symptomatic patients /6/:

  • Hypertension (sustained hypertension in 50–60% of cases)
  • Parxoxysmal hypertension (30%), orthostatic hypertension (10–50%)
  • Headache (60–90%), palpitations (50–70%), sweating (55–75%), pallor (40–45%), hyperglycemia (40%).

Patients with adrenal incidentaloma

Individuals who have an hereditary risk for developing a Pheo or PGL.

32.1.2 Method of determination

Plasma free normetanephrine and free metanephrine are quantified by liquid chromatography with electrochemical detection, isotope dilution liquid chromatography/tandem mass spectrometry (ID-LC-MS/MS) or immunoassay. In plasma free normetanephrine and free metanephrine are predominantly present.

For discrimination of different hereditary forms of Pheo the determination of methoxytyramine is used besides the measurement of free normetanephrine and free metanephrine /7/.

Chromogranin A is a marker with high diagnostic sensitivity but low specificity for the detection of Pheo. Refer to Section 14.5.2 – Chromogranin A.

The determination of urinary metanephrine and normetanephrine differs from plasma determination in that the mainly conjugated metanephrines and normetanephrines are deconjugated prior to determination and subsequently measured as free metanephrine and normetanephrine.

Liquid chromatography with electrochemical detection

Principle: a column with cation exchange resign and ammoniacal methanol elution are used to extract metanephrines from the plasma. The eluate is dried, dissolved in the mobile phase of the reversed phase column, and then injected into the liquid chromatography column for separation. Normetanephrine and metanephrine are detected using an electrochemical detector /8/.


Principle: at first, interfering plasma proteins are removed from the sample using isopropanol precipitation, cation exchange cartridges, or other commercially available extraction agents. In the next step, the metanephrines are separated using liquid chromatography and detected and quantified using mass spectrometry /89/.


For the determination of plasma free metanephrines, interfering proteins are first removed using acid precipitation and metanephrines and normetanephrines are then acylated to their acyl derivatives. The acylated metanephrines and normetanephrines compete with a fixed number of solid phase bound antibody-binding sites (rabbit anti-metanephrine or rabbit anti-normetanephrine). When the system has reached equilibrium, free antigen antibody complexes are removed by washing. The acylated metanephrine and normetanephrine that are bound to solid-phase as immune complexes are detected using tetramethylbenzidine labeled antibodies directed against rabbit IgG. The amount of antibody bound to the solid phase metanephrine and normetanephrine is inversely proportional to the concentration of metanephrine and normetanephrine in the sample /10/.

32.1.3 Specimen

Heparin plasma: 2 mL

24-hour collection of urine in adults or random specimen in children. Refer to Section 32.1.6 – Comments and problems.

32.1.4 Reference interval

Refer to:

32.1.5 Clinical assessment

Serious morbidity and mortality rates are associated with Pheo and PGL which are related to the effects of catecholamines on various organs, especially those of the cardiovascular system. Incidence, signs and symptoms of pheochromocytoma and paraganglioma

Pheo are tumors that arise from the chromaffine cells of the adrenal glands. Adrenal Pheo account for 80–85% of these tumors. About 5–7% of Pheo are adrenal incidentalomas and about 10% of Pheo are malignant.

PGLs, the extra-adrenal counterparts of Pheo, arise from ganglia along the sympathetic and parasympathetic chain. PGLs have a prevalence of about 15% that of the adrenal tumors. Approximately 30% of these tumors are known to be hereditary. Malignancy occurs in 30–40% of PGLs. The most common lesion in PGL syndrome is gastrointestinal stromal tumor.

The prevalence of Pheo and PGL is about 1 in 2,500 to 6,500 individuals and the incidence in hypertensive patients is about 0.3–0.5%. The mean age at diagnosis is 43 years. Approximately 10–20% of Pheo or PGL are diagnosed in children /11/.

Catecholamine secretion from Pheo and PGL is often episodic, causing headache, perspiration, palpitations, and hypertension. If not recognized and treated Pheo and PGL can lead to stroke, arrhythmia, myocardial infarction, and death.

PGLs have a prevalence of approximately 15% that of the adrenal tumors and can occur in different parts of the body. Populations at increased risk for Pheo and PGL are those with germ line mutations. More than 20 genetic (mostly germ line, but some are sporadic) mutations are associated with the pathogenesis of 35% of Pheo and PGL. An additional 15% of tumors are associated with somatic mutations in these same genes. In children this rate is even higher /12/, with 69% of pediatric Pheo and PGL cases and 87.5% of metastatic Pheo and PGL patients who developed their first tumor in childhood linked to underlying germ line mutations /13/. The major genetic mutations in PGL are listed to the year of discovery are /14/: NF1, RET, VHL, SDHC, SDHD, SDHB, EGLN1, KIF1B, SDHAF2, IDH, SDHA, TMEM 127, MAX, BAP1, EPAS1, FH, MDH2 und ATRX.

The presence and characteristics of tumors in hereditary syndromes associated with Pheo and PGL are shown in: Biochemical investigation

Pheo and PGL almost all produce, store, metabolize, and secrete catecholamines or their metabolites. Epinephrine and the breakdown product metanephrine are secreted from tissue of the adrenal medulla and normetanephrine the break down product of norepinephrine is primarily secreted by PGLs. Diagnostic biochemical results

Plasma free metanephrine and free normetanephrine are the catecholamines with the highest diagnostic sensitivity for diagnosing Phe and PGL. Concentrations of one or both of these that are greater than 4 times the upper reference interval value [greater than 2.19 nmol/L (400 ng/L) for normetanephrine and greater than 1.20 nmol/L (236 ng/L) for metanephrine] have a diagnostic sensitivity of 100% for the presence of a Pheo and PGL. These tumors can be excluded on the basis of normal values and further investigations are only necessary if indicated by clinical or imaging findings /5/. Plasma is preferred over urine as a specimen because free metanephrines in plasma have a higher diagnostic specificity than fractionated metanephrines in urine Conjugated metanephrines in urine are also produced in other organs.

Refer to: Threshold biochemical results

Approximately 20–30% of patients with Pheo and PGL, in particular those who have hereditary syndromes or incidentalomas of the adrenal medulla, present values that are equivocal for plasma metanephrines below 4 times above the upper reference limit. These patients are usually normotensive and asymptomatic /15/. In such cases, it must be possible to distinguish between a false positive and a true positive result. Isolated cases of sporadic Pheo and PGL also occur in which clinical symptoms are present but metanephrines are normal. These are usually small tumors measuring less than 1 cm in diameter that are detected only because the patient has a known hereditary predisposition.

Due to the low prevalence of Pheo and PGL combined with the large number of investigations requested, the number of false positive results significantly exceeds the number of true positives. As a consequence, borderline results are often not pursued further. Studies /16/ have shown that, in up to 72% of cases where initial investigation shows borderline increases in free normetanephrines, the results are not followed up with repeat testing. For example, out of 10 patients with an adrenal mass and borderline biomarkers, only three underwent repeat testing.

Borderline increases in plasma free metanephrine and free normetanephrine are commonly caused by medications such as tricyclic antidepressants, phenoxybenzamine, and β-receptor blockers. In one study /15/, these drugs were responsible for 41% of the false positive results for plasma normetanephrine and 45% of the false positive results for urinary norepinephrine. Sympathoadrenal activation (e.g., before blood sampling) is another cause of false positive results.

Refer to Tab. 32.1-7 – Diagnostic sensitivity and specificity of laboratory tests for diagnosis of pheochromocytoma and paraganglioma. Clonidine suppression test

The clonidine suppression test is recommended in the event of borderline increases in free normetanephrine and free metanephrine.

Clonidine suppresses the release of norepinephrine at sympathetic nerve terminals by activating α2-adrenoceptors in the brain /15/. Suppression of the plasma normetanephrine concentration 3 h after oral administration of clonidine indicates increased sympathetic activity while a steady concentration indicates autonomic secretion. The clonidine test cannot be used for tumors secreting only metanephrine, because almost 99% of metanephrine is derived from the adrenal gland.

Criteria /15/:

  • Normal response to clonidine is a decline in plasma normetanephrine to within the reference interval or a decline to less than 50% of baseline values considered normal
  • Lack of decrease or a small decrease of elevated plasma levels of normetanephrine confirm Pheo and PGL with high specificity.

In one study /15/ the following normetanephrine concentrations were determined:

  • In patients with a questionable result, 2.98 ± 1.69 nmol/L before clonidine and 1.03 ± 0.79 nmol/L after clonidine
  • In patients with Pheo 11.14 ± 9.85 nmol/L before clonidine and 10.71 ± 11.29 nmol/L after clonidine.

The clonidine test has a diagnostic sensitivity of 97% and a specificity of 100% /17/. The procedure for performing the clonidine test is outlined in Tab. 32.1.8 – Clonidine test. Diagnosis of hereditary catecholamine secreting tumors

Underlying mutations in susceptibility genes are associated with approximately 35% of Pheo and PGL. Besides biochemical investigations genetic testing is important to differentiate underlying similarities in various forms of hereditary Pheo and PGL. Biochemical investigations

Different patterns have been shown to be associated with different mutations. In a study /7/:

  • Patients with MEN 2 and neurofibromatosis type 1 (NF1) could be discriminated from those with VHL, SDHB, and SDHD mutations on the basis of increased concentrations of metanephrines (indicating increased epinephrine production)
  • Patients with VHL mutations invariably showed increases in normetanephrine (indicating increased norepinephrine production). Additional increases in 3-methoxytyramine (indicating increased dopamine production) characterized 70% of patients with mutations in SDHB and SDHD
  • Patients with NF1 and MEN 2 could be discriminated from those with VHL, SDHB, and SDHD gene mutations in 99% of cases by the combination of normetanephrine and metanephrine
  • Elevated 3-methoxytyramine discriminated patients with SDHB and SDHD mutations from those with VHL mutations in an additional 78% of cases.

The determination normetanephrine, metanephrine, and 3-methoxytyramine in plasma and urine is helpful for classifying patients in the absence of clear clinical signs of hereditary Pheo and PGL and can serve as a basis for further differentiation based on molecular genetics. For example, differentiation based on the RET oncogene is only necessary for tumors that predominantly secrete metanephrine. The pattern of free metanephrine, free normetanephrine, and 3-methoxytyramine elevation indicates mutations in the VHL, SDHS, and SDHB genes

In patients with malignant disease secondary to a Pheo and PGL, almost 50% have SDHB mutations and two-thirds of patients with SDHB related PGL or Pheo will develop metastatic disease. Approximately 70–80% of patients respond to chemotherapy with vincristine, cyclophosphamide, and dacarbazine /18/.

Association with other diseases

Patients with MEN 2B have an approximately 50% risk of developing Pheo and a 100% risk of developing medullary thyroid cancer (MTC). Refer to Section 28.12 – Calcitonin. Pheo can develop in patients with familial MTC, generally at a later stage than the MTC. Patients with MEN 2A develop multi focal, bilateral MTC and have an approximately 50% risk of developing Pheo. Patients with MEN 2A also have a 20–35% risk of developing hyperparathyroidism. Molecular genetic investigations

Around 30% of catecholamine producing tumors have a genetic basis and are mainly caused by germ line mutations.

Genetic testing should be considered if a patient has one of the following /17/:

  • PGL
  • Bilateral Pheo
  • Unilateral Pheo and family history of Pheo and PGL
  • Unilateral Pheo onset at young age (< 45 years)
  • Other clinical findings suggestive of one of the associated syndromic disorders.

An asymptomatic person known to be at risk for disease on the basis of family history of Pheo and PGL should have genetic testing only if an affected family member has a known mutation.

To chose a proper genetic test, the biochemical profile of catecholamine secretion, age of the patient, localization of the primary tumor, and previous family history must be carefully evaluated and included in the genetic algorithm /19/.

Family members with a known mutation must be investigated periodically for the presence of Pheo and PGL. Because not all genetic causes of these tumors are known, all first degree relatives of patients with Pheo and PGL should undergo biochemical screening (e.g., determination of metanephrines in plasma). Asymptomatic individuals at known risk of Pheo and PGL should undergo genetic testing only if the family member with Pheo and PGL has a known mutation /19/.

32.1.6 Comments and problems


The most common cause of false positive results is inappropriate blood sampling conditions associated with sympatho-adrenal activation, particularly sampling performed with the patient in the seated rather than supine position /9/. For 12–14 hours before blood sampling, patients must abstain from coffee and other sources of caffeine and refrain from smoking or engaging in strenuous physical activity. Drugs such as tricyclic antidepressants, acetaminophen, phenoxybenzamine, β-receptor blockers, and diuretics should be discontinued 5 days prior to blood sampling.

Blood sampling

Blood samples should be obtained with the patient resting in a supine position, 30 minutes after the insertion of an intravenous catheter. Collect 5–10 mL of blood using a heparin containing collection tube. The sample must be transported immediately to the laboratory and centrifuged without delay. Alternatively, blood can be stored at 4 °C for up to 6 hours prior to centrifugation /20/.

Urine collection or spot urine samples

Fractionated metanephrines: samples do not need to be acidified to prevent degradation if they are analyzed within one week /20/.

Method of determination

HPLC with electrochemical detection and LC-MS/MS yield comparable results for free normetanephrine and metanephrine in plasma. Immunoassays also yield comparable normetanephrine concentrations but lower metanephrine values. Immunoassays are not recommended as a first choice for measurements of plasma free metanephrines /21/.

Conversion factors

To convert nmol/L into ng/L, multiply by:

  • 183 for normetanephrine
  • 169 for norepinephrine
  • 197 for metanephrine
  • 183 for epinephrine.


Urinary catecholamines: acidified to a pH of 2–3 and at 4–8 °C stable for up to 2 weeks.

Urinary fractionated metanephrines: preservation of samples is not necessary if samples are assayed or frozen within 1 week /20/.

Plasma free normetanephrines and free metanephrines: using HPLC and electrochemical detection, the samples can be stored for 3 days at 4 °C or for longer periods at –20 °C /21/. For the determination using LC-MS/MS samples can be stored 24 h at room temperature and up to 7 days at 10 °C or 4 °C /22/.

32.1.7 Biochemistry and physiology

Functional Pheo and PGL produce catecholamines, which include the following biogenic amines:

  • Dopamine, norepinephrine, and epinephrine
  • Their metabolic products 3-methoxytyramine, normetanephrine, metanephrine, homovanillic acid, and vanillylmandelic acid.

Catecholamine production

Catecholamines are synthesized in the adrenal medulla, the brain, and the sympathetic nerve terminals. Epinephrine is produced mainly in the adrenal medulla and norepinephrine is produced mainly by sympathetic nerve terminals /1523/. However, up to 91% of the metanephrine and 23% of the normetanephrine released into the plasma as a result of the metabolism of norepinephrine to normetanephrine and of epinephrine to metanephrine originates in the adrenal medulla /23/.

Catecholamine metabolism

Dopamine, epinephrine, and norepinephrine are metabolized via the following pathways (Fig. 32.1- 2 – Catecholamine metabolism):

  • Catechol-O-methyltransferase (COMT) catalyzes the methylation of the OH group in position C3 of the benzene ring to produce 3-methoxytyramine from dopamine, normetanephrine from norepinephrine, and metanephrine from epinephrine.
  • Deamination by mitochondrial monoamine oxidase. This results in the production of homovanillic acid from 3-methoxytyramine and vanillylmandelic acid from normetaphrine and metanephrine.

Following their release into the circulation, normetanephrine, metanephrine, and 3-methoxytyramine are converted into sulfate esters and glucuronides, with the result that both free and conjugated forms are present in the blood and urine. Only about 3% of the normetanephrine and metanephrine in the urine exists in free form; the remainder is conjugated. In the case of Pheo and PGL, however, there is a higher proportion of free epinephrine and norepinephrine and a disproportionate increase in normetanephrine.

Catecholamines and clinical assessment

In the biochemical diagnosis of Pheo and PGL false positive results remain a problem /10/:

  • Patients with Pheo and PGL usually have larger relative increases in metanephrine and normetanephrine than of epinephrine and norepinephrine, whereas patients with false positive results due to sympathoadrenal activation usually have larger increases in epinephrines and norepinephrines. The differences are partly due to the amounts of free metanephrine and free normetanephrine formed continuously within the Pheo and PGL and released into the circulation.
  • Another factor is the large contribution of the adrenal medulla to normal circulating levels of metanephrine and normetanephrine, a contribution that is again independent of epinephrine and norepinephrine release. Thus, during sympathoadrenal activation, increase in plasma free metanephrine is negligible and increase in normetanephrine is smaller than those of the respective parent amines. This explains why a patient with elevated plasma normetanephrine or metanephrine, but normal or slightly elevated norepinephrine and epinephrine is more likely to have Pheo and PGL than a patient with highly elevated norepinephrine or epinephrine and slightly elevated normetanephrine and metanephrine.

Most of the norepinephrine released is taken up into the nerve terminals and granules in native form before it reaches the effector cells. The high rate of false positive findings when measuring free normetanephrine in the context of chronic tricyclic antidepressant use is thought to be due to inhibition of norepinephrine re uptake /15/.

Phenoxybenzamine is a nonspecific α-adrenoceptor blocker commonly used to treat patients with Pheo. It presumably increases catecholamine release by attenuating the feedback inhibition of norepinephrine and epinephrine release /15/.

The main catecholamines produced by Pheo and PGL are epinephrine and norepinephrine, although some tumors also produce large quantities of dopamine. Epinephrine and norepinephrine are released intermittently and have a short half life. Therefore, the concentration of these catecholamines in plasma or in a random specimen of urine fluctuates significantly.

The diagnostic superiority of free normetanephrine and metanephrine in plasma over other tests include /24/:

  • Tumor cells of Pheo and PGL have a high level of catechol-O-methyltransferase (COMT) which leads to immediate metabolism. Therefore, continuously normetaphrine, metanephrine, and 3-methoxytyramine are released in the circulation. This is not the case for norepinephrine and epinephrine, which are released intermittently from vesicles.
  • The half life of normetanephrine, metanephrine, and 3-methoxytyramine is longer than that of norepinephrine and epinephrine.


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32.2 Vanillylmandelic acid and homovanillic acid

Neuroblastoma is an embryonal tumor of the nervous system, meaning that the cell of origin is thought to be a developed and incompletely committed precursor derived from neural crest tissues. Neuroblastomas generally occur in very young children. The tumor arises in tissues of the sympathetic nervous system, typically in the adrenal medulla or para spinal ganglia, and thus can present as mass lesions in the neck, chest, abdomen, or pelvis /1/.

The great majority of neuroblastoma produce higher than normal catecholamines. High levels of 3-methoxy-4-hydroxymandelic acid (vanillylmandelic acid, VMA) and 3-methoxy-4-hydroxyphenylglycol (homovanyllic acid, HVA) the most important metabolites of norepinephrine and epinephrine are measured. HVA predominates in the central nervous system. HVA and VMA are commonly assessed in the diagnosis of neuroblastoma.

32.2.1 Indication

In infants highly clinical variable symptoms ranging from a mass that causes no symptoms to a primary tumor that causes critical illness as a result of local invasion.

32.2.2 Method of determination

High performance liquid chromatography with electrochemical detection /2/. This method represents the gold method for the determination of VMA and HVA.

Ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) /3/.

32.2.3 Specimen

24 hours urine. The sample is preserved in a bottle containing 6 N HCl (5 mL) /4/.

Random urine adjusted to pH 1–3 with HCl /5/ (with or without determination of creatinine in urine /6/).

32.2.4 Reference interval

Refer to Tab. 32.2-1 – Reference intervals for VMA, HVA and dopamine.

32.2.5 Clinical assessment

Neuroblastomas are embryonal tumors of the autonomic nervous system that arise from partially uncommitted precursor cells of the neural crest. Incidence, signs and symptoms of neuroblastoma

Neuroblastomas occur in young children (median age 17 months) and less than 10% of cases are over the age of 10 years. Neuroblastoma accounts for about 7% of malignant tumors in childhood. Most children present with a palpable abdominal mass but a wide range of other symptoms may be present, such as fatigue, loss of appetite, weakness, and fever /7/. Because these tumors originate from tissues of the sympathetic nervous system, typically the adrenal medulla and paraspinal ganglia, they produce catecholamines and their metabolites. The detection of catecholamines and their metabolites is the biochemical basis for a diagnosis of neuroblastoma /8/.

Neuroblastomas may be sporadic or hereditary. In the hereditary form, two important mutations are recognized /1/:

  • An activating mutation in the tyrosine kinase domain of the anaplastic lymphoma kinase (ALK) oncogene, which is responsible for most hereditary forms of the disease
  • Loss-of-function mutations in the Homeobox gene (PHOX2B), which are associated with Hirschsprung disease, congenital central hypo ventilation syndrome, or both.

For the prognostic significance of vanillylmandelic acid in neuroblastoma refer to Ref. /9/.

Genetic testing for mutations in ALK and PHOX2B should be considered whenever a patient has a family history of neurobastoma or has an other clinical conditions that are strongly suggestive of highly penetrant transmissible mutation, such as bilateral tumors of the adrenal glands /10/. Biochemical investigation

The diagnostic evaluation of neuroblastoma includes the determination of urinary VMA, HVA, and dopamine, and less frequently, of norepinephrine, epinephrine, normetanephrine, and metanephrine. It is recommended that the cutoff for increased levels of serum or urine catecholamines or their metabolites be retained at 3.0 standard deviation above the mean per milligram creatinine for age when making a diagnosis of neuroblastoma in a patient. The rate of neuroblastoma patients with positive VMA and/or HVA at diagnosis varies with the stage of disease. Serum ferritin and LD may be useful prognostic markers for neuroblastoma at diagnosis, but they lack sensitivity and specificity to monitor disease activity. Serum NSE and chromogranin A are more specific, but they are not as sensitive /7/.

The diagnostic sensitivity of tests for measuring VMA and HVA excretion depends on the disease stage.

VMA and HVA are only sensitive enough to detect tumors from stage III on; as a result, earlier stages of disease and small tumors may be missed. The renal excretion of VMA and HVA is increased only when tumors weighing more than 5 g are present.

Measurement of VMA excretion is better than of dopamine secretion for diagnosing neuroblastoma. In a study /11/ of 249 children, 20 of whom were confirmed cases of neuroblastoma, the ratios of VMA to creatinine and dopamine to creatinine were calculated. From receiver operator characteristic curves (ROC curves), the VMA/creatinine ratio was found to have an area under the curve of 0.96 (with a diagnostic sensitivity of 95% and a specificity of 86%) compared with only 0.72 for the dopamine/creatinine ratio.

Not only the disease stage but also the age of the patient must be considered. For instance, the number of children with stage I/II neuroblastoma and high biomarker secretion is higher if the screening examinations are performed at a younger age. The diagnostic sensitivities shown in Tab. 32.2-2 – MA, HVA, ferritin, and NSE in the diagnosis of neuroblastoma have a corresponding specificity of 99% /12/. The number of elevated values requiring further testing has been found to be 2.36% /13/.

A small percentage of patients with neuroblastoma do not secrete VMA or HVA or secrete elevated HVA in isolation. However, the VMA and HVA level is only one piece of information to rule in or rule out neuroblastoma, and may be used in the context with clinical findings, symptoms and abdominal mass /3/.

Neuroblastomas are heterogeneous with regard to both their genotype and their clinical presentation /11/. The main genetic alterations found in certain neuroblastomas are:

  • Hyperdiploidy or near triploidy; the majority of neuroblastomas show a modal diploid karyotype
  • Loss of heterozygosity (LOH) of the distal end of the short arm of chromosome 1 (from 1p36.1 to 1p36.3) and of the long arm of chromosome 14 (14q)
  • Amplification of the MYCN proto oncogene
  • Expression of the receptor tyrosine kinases (RTKs).

On the basis of cytogenetic and molecular findings (karyotype, MYCN amplification, RTK expression) as well as the DNA content of the neuroblastoma cells, three genetically different neuroblastoma subtypes, each with a different prognosis, are presumed to exist. Classification of neuroblastoma

According to genetic and histopathological analysis neuroblastomas are classified into 3 stages based on the three most common and prognostically important genetic alterations (MYCN amplification, 1p deletion, and 17q gain) /14/:

  • Type 1; these tumors show none of the three significant genetic alterations and have a good prognosis
  • Type 2; these tumors show 17q gain only or 17q gain together with 1p deletion. These are progressive tumors with a poor prognosis.
  • Type 3; these tumors show all three significant genetic alterations, progress rapidly and, compared to type 2, occur in younger children and are associated with shorter survival times /15/.

The classification in Tab. 32.2-3 – Biologic and clinical subtypes of neuroblastoma classifies neuroblastomas according to their differing responses to therapy and their prognosis. Patients with neuroblastomas type 2 and 3 are usually older than 1 year. Tumors type 2 initially respond well to treatment. In around half of patients, however, rapid disease progression occurs within 6–12 months, accounting for a 5 year survival rate of only 40–50%. Patients with neuroblastoma type 3 (MYCN proto oncogene amplification, stage 3/4, age 1–5 years) have the poorest prognosis.

Other prognostic indicators for neuroblastoma include tumor cell factors and results of laboratory investigations (Tab. 32.2-4 – Neuroblastoma: prognostic factors/16/.

32.2.6 Comments and problems

24 h urine collections are difficult to obtain in pediatrics and are often incomplete. For these reasons spot urine is routinely used since their interchangeability with 24 h collections is possible /17/.

HVA and VMA daily excretion increases linearly with age with no difference between the two sexes while creatinine excretion increases in proportion with growing muscle mass. For these reasons age-related reference intervals and decision limits for VMA and HVA have to take into account for these variations.

3-methoxy-4-hydroxy phenyl glycol and homogentisinic acid (2,5-dihydroxy phenyl acetic acid) are expected to interfere in the chromatography and at the electrochemical detector /2/.


1. Maris JM. Recent advances in Neuroblastoma. N Engl J Med 2010; 362: 2202–11.

2. Moleman P, Borstrok JJM. Determination of urinary vanillylmandelic acid by liquid chromatography with electrochemical detection. Clin Chem 1983; 29: 878–81.

3. Sadlikova K, Dugaw K, Benjamin D, Jack RM. Analysis of vanillylmandelic acid and homovanillic acid acid by UPLC-MS/MS in serum for diagnostic testing for neuroblastoma Clin Chim Acta 2013; 424: 253–7.

4. Regianin LJ, McGill AC, Pinheiro CM, Brunetto AL. Vanillylmandelic acid and homovanillic acid levels in patients with neural crest tumor: 24-hour urine collection versus randon sample. Pediatric hematology and Oncology 1997; 14: 259–65.

5. Pussard E, Neveux M, Guigueno N. Reference intervals for urinary catecholamines and metabolites from birth to adulthood. Clin Biochem 2009, 42. 536–9.

6. Barco S, Gennai J, Reggiardo G, Galleni B, Barbagallo L, Maffia A, et al. Urinary homovanillic acid and vanillylmandelic acid in the diagnosis of neuroblastoma: report from the Italian cooperative group for neuroblastoma. Clin Biochem 2014; 47: 848–52.

7. Brodeur G, Pritchard J, Berthold F, Carlsen NLT, Castel V, Castleberry RP, et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 1993; 11: 1466–77.

8. Griffin A, O’Shea P, FitzGerald R, O’Connor G, Tormey W. Establishment of a paedriatric reference interval for the measurement of urinary total fractionated metanephrines. Ann Clin Biochem 2011; 48: 41–4.

9. Aydin GB, Kutluk MT, Yalcin B, Varan A, Akyuz C, Buyukpamukcu M. The prognostic significance of vanillylmandelic acid in neuroblastoma. Pediatr Hematology Oncology 2010; 27: 435–48.

10. Brodeur GM, Seeger RC, Barrett A, Berthold F, Castleberry RB, D’Angio G, et al. International criteria for diagnosis, staging response to treatment in patients with neuroblastoma. J Clin Oncol 1988; 6: 1874–81.

11. Sies CW, Florkowski CM, Sullivan M, Mackay R, George PM. Urinary VMA, dopamine and the likelihood of neuroblastoma: a preferred way of reporting laboratory results? Ann Clin Biochem 2006; 43: 300–5.

12. Carlsen NLT. Neuroblastoma: epidemiology and pattern of regression. Am J Pediatr Hematol Oncol 1992; 14: 103–10.

13. Berthold F, Brandeis WE, Lampert F. Neuroblastoma: diagnostic advances and therapeutic results in 370 patients. Monogr Paediat 1986; 18: 206–23.

14. Brodeur GM. Molecular basis for heterogeneity in human neuroblastomas. Eur J Cancer 1995; 31A: 505–10.

15. Lastowska M, Cullinane C, Variend S, O’Neill SS, Mazzocco K, Roberts P, Nicholson J, et al. Comprehensive genetic and histopathologic study reveals three types of neuroblastoma tumors. J Clin Oncol 2001; 19: 3080–90.

16. Kushner BH. Neuroblastoma: a disease requiring a multitude of imaging studies. J Nuclear Med 2004; 45: 1172–88.

17. Gregianin LJ, McGill AC, Pinheiro CM, Brunetto AL. Vanilmandelic acid and homovanillic acid levels in patients with neural crest tumor: 24-hour urine collection versus random sample. Pediatr Hematology and Oncology 1997; 14: 259–65.

18. De Jong WHA, Graham KS, van der Molen JC, Links TP, Morris MR, Ross HA, et al. Plasma free metanephrine measurement using automated online solid-phase extraction HPLC-tandem mass spectrometry. Clin Chem 2007; 53: 1684–93.

19. Eisenhofer G, Rundqvist B, Aneman A, Friberg P, Dakak N, Kopin IJ, et al. Regional release and removal of catecholamines and extraneural metabolism to metanephrines. J Clin Endocrinol Metab 1995; 80: 3009–17.

20. Peaston RT, Weinkove C. Measurement of catecholamines and their metabolites. Ann Clin Biochem 2004; 41: 17–38.

Table 32.1-1 Reference intervals for plasma catecholamines /25/


Reference interval

Free metanephrine


Free normetanephrine


Free methoxytyramine


Free epinephrine


Free norepinephrine


Free dopamine


Values are 2.5th and 97.5th percentiles. Quantification by liquid chromatography with electrochemical detection

Table 32.1-2 Reference intervals for catecholamines in urine /25/


Reference interval
(μmol/24 h)

Total metanephrine


Total normetanephrine


Free epinephrine


Free norepinephrine


Free dopamine


Values are 2.5th and 97.5th percentiles. Quantification by liquid chromatography with electrochemical detection or HPLC and tandem mass spectrometry.

Table 32.1-3 Reference intervals for excretion of metanephrines* /26/

Total normetanephrines

Total metanephrines





≤ 3 months


≤ 6 months


4–6 months


7–9 months


7–12 months


10–12 months


1–3 yrs


1–3 yrs


3–5 yrs


3–5 yrs


5–11 yrs

≤ 0.330

5–8 yrs

≤ 0.300

> 11 yrs


≥ 8 yrs

≤ 0.190

* Random urine samples. Values expressed in mmol/mol creatinine. Values are 2.5th and 97.5th percentiles

Table 32.1-4 Hereditary syndromes associated with pheochromocytoma (Pheo) and paraganglioma (PGL) /111/

Clinical and laboratory findings

Classical lesions of Pheo and PGL

Classical lesions associated with Pheo and PGL in the hereditary syndromes are multiple neuroendocrine neoplasia (MEN), neurofibromatosis and von Hippel-Lindau syndrome.

In Pheo and PGL syndromes adrenal metanephrine increase is the main biochemical indicator of disease, the secretion of norepinephrine is the indicator of the extra-adrenal PG and Pheo syndrome.

Multiple endocrine neoplasia type 2 (MEN2)

MEN2 is associated with underlying mutations in the rearranged transfection (RET) protooncogene. Pheo and PGL could be found with medullary thyroid carcinoma and parathyroid hyperplasia. Patients present with tumors in the adrenal gland, half of the patients present with bilateral tumors. The majority of patients have a strong family history. About 50% of patients present with de novo mutations.

Laboratory findings: increase in plasma epinephrine/metanephrine.

Neurofibromatosis type 1 (NF1)

The gene VHL causes VHL syndrome. The VHL protein regulates the activity of hypoxia-inducible factor alpha and regulates cellular processes, including angiogenesis. Two types of VHL are differentiated: type 1 develops retinal angiomas, central nervous system hemangioblastomas and renal cell carcinomas; patients with type 2 are at risk of Pheo and PGL.

NF1 has multiple manifestations that can include Pheo and PGL. Diagnosis is usually based on clinical criteria, often at a young age due to the frequent presence of cafe au lait spots from birth.

Laboratory findings: increase in plasma epinehrine/metanephrine.

Succinate dehydrogenase (SDH) related syndromes

Mutations in the gene SDH contribute to the hereditary PGL and Pheo syndromes and consist of pheochromocytoma and of head and neck paraganglioma. PGL1, PGL2, PGL3, PGL4, and PGL5 are associated with the genes PGL4, SDHAF2, SDHC, SDHB, SDHA, respectively.

Laboratory findings: Mutation analysis is the recommended procedure for diagnosing SDH mutations.

Rare gene mutations

Rare gene mutations associated with Pheo and PGL are:

  • The gene of mxc-associated factor X (MAX), which encodes a transcription factor that is part of the MYC/MAX/MXD1 network in regulating the myc oncoprotein.
  • The gene TMEM127 of the transmembrane protein 127.
  • The gene HIF2A of the hypoxia inducible factor 2-alpha.

Table 32.1-5 Proportion of pheochromocytoma associated syndromes, modified according to Ref. /28/













Refer to 1


> 50

< 1


> 50





Refer to 2


> 50

< 1







Refer to 3


> 50

< 1

< 1

> 50

< 1




Refer to 4










Refer to 4










Refer to 4



> 50

< 1






Refer to 4



> 50


> 50





Refer to 4



> 50


> 50


> 50



Refer to 5


> 50

< 1


> 50





Refer to 5


> 50


< 1




Non chromaffine tumors:

(1) VHL, retinal and CNS hemangioblastoma

(2) NF1, cutaneous neurofibromatosis, peripheral nerve sheath tumors

(3) MEN-2, medullary thyroid carcinoma, hyperparathyroidism

(4) PGLs, pituitary adenoma, gastrointestinal stromal tumors

(5) renal cell carcinoma; No, no data; NN, no name

Explanation of symbols: AD, autosomal dominant; AD* autosomal dominant maternal

Table 32.1-6 Diagnostics of pheochromocytoma and associated syndromes, modified according to Ref. /28/


Laboratory tests


Hypertension resistant or paroxysms, Head aches, Perspiration, Palpitations

Metanephrines, Normetanephrines

(Contrast enhanced CT or MRI, if abdominal imaging is negative consider skull base, neck, pelvis)

Postoperatively metanephrines, and than annually. Document normal glucocorticoid function with cosyntropin stimulation test


If levels of metanephrines are clearly elevated imaging is recommended

(Contrast enhanced CT or MRI, if mass is over 10 cm in diameter or extra adrenal, search for additional paragangliomas or metastatic disease with 125J MIBG scintigraphy or 68Ga-Dotatate-PET-CT)

If a pheochromocytoma or paraganglioma was resected, measure metanephrines postoperatively and then annually

Patient with mutation

RET mutation

Metanephrines and calcitonin

(Contrast enhanced CT or MRI of abdomen; seek endocrine consultation if thyroid gland is not previously resected)

Metanephrines and calcitonin postoperatively



(MRI of skull base and neck, throrax, retroperitoneum and pelvis, alternatively 68Ga-Dotatate-PET-CT)

Metanephrines yearly, if a pheochromocytoma or paraganglioma was removed; perform MRI of the surgical region annually for 1–3 years, for body areas that had no tumors perform MRI every 3 years



(MRI of the brain, spinal cord and abdomen,

Metanephrines yearly, MRI of the brain, spinal cord and abdomen, if no tumor found; monitor every 2 or 3 years



(MRI of skull base and neck or 68Ga-Dotatate-PET-CT)

If a pheochromocytoma or paraganglioma was removed; perform MRI of the surgical region annually for 1–3 years, for body areas that had no tumors perform MRI every 3–5 years

MAX or THEM 27


(MRI of the abdomen or 68Ga-Dotatate-PET-CT)

Metanephrines yearly.

If a pheochromocytoma or paraganglioma was removed perform MRI of the surgical region annually for 1–3 years, for body areas that had no tumors perform MRI every 3 years

  • Neurofibro-
    matosis type 1


If hypertension or clinical symptoms develop, measure metanephrines

Table 32.1-7 Diagnostic sensitivity and specificity of laboratory tests for diagnosis of pheochromocytoma and paraganglioma /127/

Laboratory test

Sensitivity (%)

Specificity (%)





Plasma free normetanephrine and free metanephrine





Plasma noradrenaline and adrenaline





Urinary free normetanephrine and free metanephrine





Urinary noradrenaline and adrenaline





Plasma total normetanephrine and metanephrine



Urinary vanilyl mandelic acid



Table 32.1-8 Clonidine test /15/

Test protocol: the test is performed in the morning following an overnight fast; an intravenous catheter is inserted and 10 mL of heparin blood is withdrawn after the patient has been resting in the supine position for 20 minutes.

Clonidine is administered orally (0.3 mg for a 60–80 kg patient).

Patient remains resting in the supine position for 3 hours following clonidine administration; a repeat blood sample is taken from the intravenous catheter.

Interpretation: a normal response is indicated by the suppression of normetanephrine into the reference interval or a decline of ≤ 50% of the baseline value.

Table 32.2-1 Reference intervals for VMA, HVA and dopamine in urine samples

Children aged 7 months – 16 years. Values of 24 h urine /3/:

VMA: 2.9–20.3 ug/L (95% central interval), cutoff > 20 ug/L

HVA: 2.6–29.7 ug/L (95% central interval), cutoff > 30 ug/L





0–3 months




> 3–6 months




> 6–12 months




> 1–2 yrs




> 2–5 yrs




> 5–10 yrs




> 10–15 yrs




> 15–20 yrs




> 20–25 yrs




VMA, vanillyl mandelic acid; HVA, homovanillic acid. Values expressed in mmol/mol creatinine (mg/g creatinine). Values are 95th percentiles; *ug/g creatinine

Reference intervals for urinary catecholamines expressed as analyte-to-creatinine ratio /5/.

Data are expressed as the 2.5th and 97.5th percentiles

Table 32.2-2 VMA, HVA, ferritin, and neuron-specific enolase (NSE) in the diagnosis of neuroblastoma


Diagnostic sensitivity (%)


VMA+HVA /18/

ferritin /19/

NSE /20/





















Results obtained during screening examinations in children.

Table 32.2-3 Biologic and clinical subtypes of neuroblastoma /14/


Type 1

Type 2

Type 3

MYCN oncogene



(> 10 copies)

DNA ploidy

near triploid

Near diploid or near tetra-ploid

Near diploid or near tetra-ploid

Chromosome 17q gain




Chromosome 1p LOH


± Present


Chromosome 11q LOH




trkA expression


Low or absent

Low or absent

trkB expression


Low or absent

High (full length)

trkC expression


Low or absent

Low or absent

Age (years)

Usually < 1

Usually ≥ 1

Usually 1–5


Usually 1, 2, 4S

Usually 3, 4

Usually 3, 4

5 year survival rate




LOH, loss of heterozygosity; trk, tyrosine kinase receptor

Table 32.2-4 Neuroblastoma: prognostic factors /16/


Poor prognosis

Tumor cell features

MYCN oncogene

More than 10 copies

Chromosome 17q

Gain (increased number
of DNA copies)

Chromosome 1p36

Loss of heterozygosity

Chromosome 11q14-22

Loss of heterozygosity


Absent or low expression


High expression


Absent or low expression


Increased activity or
high expression


Low expression

Shimada histology

Unfavorable by Shimada criteria

Biochemical markers

Serum LD

> 1,500 U/L

Serum NSE

> 100 μg/L

Serum ferritin

> 142 μg/L

Urinary VMA/HVA ratio

< 1.0

Figure 32.1-1 Biochemical diagnosis of pheochromocytoma and extra adrenal paraganglioma, modified from Ref. /15/. 1) Plasma normetanephrine (NMN) less than 0.61 nmol/L (112 ng/L) and plasma metanephrine (MN) less than 0.31 nmol/L (61 ng/L). 2) Plasma NMN greater than 2.19 nmol/L (400 ng/L) and plasma MN greater than 1.20 nmol/L (236 ng/L). 3) Plasma NMN and plasma MN between 1 and 2 (borderline). 4) Repeat determination of NMN and MN in plasma and/or urine. CT, computed tomography; MRI, magnetic resonance imaging; MIBG, 131I-labeled meta-iodobenzylguanidine scintigraphy.

Suspicion of pheochromocytomaFree normetanephrine (NMN) and metanephrine (MN) in plasma NMN and MN normal (1 tumour highly unlikely NMN, MN or both increased NMN, MN normaltumor unlikely High ratio meta- nephrine/katechol- amines in plasmatumorhighly likely When suspicion remains, test repetitionat a later date Suppression of NMN, MNTumor unlikely No suppression of NMN, MNTumor highly likely Strongly increased (2 tumor very likely Localize of tumor(CT, MRI, MIBG) Slightly increased (3 tumour possible Eliminate medicines or other causes for false positive results Further examinations (4 NMN, MN remain positive tumour possible Clonidin test

Figure 32.1-2 Catecholamine metabolism. COMT, catechol-O-methyl transferase; MAO, monoamine oxidase; THL, tyrosine hydroxylase; DOPA, DOPA carboxylase; DBH, dopamine β-hydroxylase; PNMT, phenyl ethanolamine N-methy transferase. Modified from Ref. /15/.

HO CH 2 CH CO 2 H NH 2 CH 2 CH CO 2 H CH 2 CH 2 NH 2 NH 2 HO HO HO HO HO HO CH(OH) –CH 2 –NHCH 3 CH(OH) –CH 2 –NH 2 3 HO HO HO H 3 CO CH 2 –CH 2 –NH 2 HO HO CH 2 –CO 2 H CH(OH)–CH 2 –NHCH 3 HO H 2 CO CH(O–CO 2 H) HO HO HO H 3 CO CH(OH)–CH 2 –NH 2 CH 2 –CO 2 H HO H 3 CO HO H 3 CO CH(OH)–CO 2 H MAO COMT MAO MAO COMT COMT COMT COMT MAO MAO Tyrosine DOPA Dopamine Noradrenalin Adrenalin Vanillylmandelic acid Homovanillinic acid 3-methoxytyramine 3.4 dihydroxyphenylacetic acid Normetanephrine 3.4 dihydroxymandelic acid Metanephrine THL L-ADC
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