Comparison of plasma metanephrines measured by a commercial immunoassay and urinary catecholamines in the diagnosis of pheochromocytoma.

BACKGROUND: The diagnosis of pheochromocytomas requires consideration among patients suffering from hypertension, unexplained spells, incidental adrenal masses, or a family history of pheochromocytoma. Accordingly, the diagnosis requires a biochemical test with high sensitivity and specificity. AIM: To compare plasma free metanephrines as measured by a commercial immunoassay and the 24-hour urinary excretion of catecholamines. METHOD: Plasma free metanephrines were measured in 185 patients suspected of pheochromocytoma. Concomitant measurements of urinary catecholamines were performed in 115 patients. Based on clinical findings, imaging and biochemistry 11 cases were found; 9 were diagnosed with pheochromocytoma, one patient with paraganglioma and one patient with ganglioneuroma. RESULTS: All patients with pheochromocytoma/paraganglioma had abnormally elevated concentrations of either plasma metanephrine or normetanephrine. The patient with ganglioneuroma had normal plasma metanephrine levels, corresponding to a sensitivity of 91%. In two patients where pheochromocytoma was excluded, plasma metanephrin or normetanephrine was above the reference level, corresponding to a specificity of 99%. Urinary catecholamines were determined in 10 of 11 patients with a positive diagnosis, and all 10 showed elevated levels of either urinary epinephrine or norepinephrine, including the patient with ganglioneuroma (equivalent to a sensitivity of 100%). Seven patients, in whom pheochromocytoma was excluded, had elevated urinary catecholamines (equivalent to a specificity of 94%). CONCLUSION: Measurement of plasma free metanephrines by immunoassay appears to be a useful diagnostic test in patients suspected of pheochromocytoma, with a high specificity as compared with urinary catecholamines. The latter may result in fewer false-positive findings, an outcome which may be particularly troublesome.

Urinary dopamine/noradrenaline and dopamine/vanillylmandelic acid ratios as a reflection of different biology of adrenergic clones in children's neuroblastic tumors.

The results of calculations of urinary dopamine/noradrenaline (DA/NAd) and dopamine/vanillylmandelic acid (DA/VMA) ratios in 54 untreated children with neuroblastic tumors are reported. Thirteen patients were in the prognostically favorable group (stages I, II, and IV-S and ganglioneuroma [GN]), and 41 had advanced neuroblastoma (stage III and IV). Among patients with ganglioneuroma and favorable neuroblastoma (n = 13), of whom all were survivors, the urinary DA/NAd and DA/VMA ratios exceeded 1.8 in only 2 cases of stage IV-S and stage I, respectively. In the advanced neuroblastoma group, the DA/NAd and DA/VMA ratios exhibited a wide range of values, but among the stage III and IV survivors (n = 10), DA/NAd ratios greater than 1.8 were noted in only 3 patients. The DA/VMA ratio was not greater than 1.8 in those 3 patients. The mean DA/NAd and DA/VMA proportions in the population comprising all survivors were 1.8 +/- 2.7 (mean +/- SD) and 1.1 +/- 0.4, respectively. The same computations carried out in patients who died showed higher values, ie, the mean DA/NAd and DA/VMA ratios were 5.2 +/- 6.3 and 5.6 +/- 10.5, respectively, showing the difference in DA/NAd and DA/VMA ratios between prognostically favorable and unfavorable groups. Of 23 survivors, only 4 had DA/NAd ratios greater than 1.8 (17%), while 24 of 31 children who died (77%) had DA/NAd ratios was greater than 1.8. The reported results suggest dissimilarity in the catecholamine metabolism of adrenergic clones with respect to the stage of advancement of neoplastic disease.

Pheochromocytoma with histologic transformation to composite type, complicated by watery diarrhea, hypokalemia, and achlorhydria syndrome.

OBJECTIVE: To describe the rare occurrence of histologic transformation of a pheochromocytoma to a composite type of tumor during a long-term follow-up, which was complicated by watery diarrhea, hypokalemia, and achlorhydria syndrome. METHODS: We report the case of a 12-year-old girl who presented with headache, hypertension, and elevated catecholamine levels in the blood and urine. A tumor was found in the right adrenal gland and resected. When she was 15 years of age, multiple metastatic nodules were found in the lung and liver. Intensive chemotherapy was ineffective, and she underwent follow-up with conservative therapy. At 25 years of age, she complained of diarrhea. Laboratory studies revealed hypokalemia and an increase in the level of serum vasoactive intestinal polypeptide (VIP). A year later, she died of extensive metastatic disease. The primary and recurrent tumors at autopsy were histologically examined. RESULTS: The primary tumor was pure pheochromocytoma, and the tumors at autopsy were a composite type of pheochromocytoma and ganglioneuroma. Only a few VIP-positive cells were found in the primary tumor, whereas both pheochromocytoma and ganglioneuroma cells of composite tumors were frequently positive for VIP. CONCLUSION: Our case showed histologic transformation from pheochromocytoma to a composite type of tumor during a 14-year clinical course, which was associated with additional hormone production and a change in symptoms. Careful attention should be paid to the alteration of endocrine symptoms and hormone levels during prolonged follow-up of pheochromocytoma in young patients.

Prognostic significance of biochemical heterogeneity of catecholaminergic clones in neuroblastoma.

BACKGROUND/PURPOSE: Genetic heterogeneity of neuroblastic tumors leads to biochemical changes that manifest themselves in different symptoms and clinical courses, which may vary from spontaneous regression and remission to progression with fatal outcome. METHODS: To test the hypothesis that ratios of dopamine (DA) to noradrenaline and of DA to vanillylmandelic acid reflect the composition of adrenergic clones and tumor heterogeneity, we determined urinary DA/noradrenaline and DA/vanillylmandelic acid ratios that presumably reflect DA-beta-hydroxylase (DBH) activity and the prognostic values thereof. RESULTS: Based on catecholamine metabolism, 4 model situations were defined: (a) complete block of DBH in all cells; (b) block of DBH in some cells; (c) a different enzymatic block; and (d) normal DBH activity in the population of tumor-forming cells. Normal DBH activity was encountered most frequently in children younger than 2 years and in tumors representing favorable prognostic stages (I, II, and IVS). Surviving children with stage IV neuroblastoma presented with tumors composed primarily of cells without the DBH block. Further stratification of 2 prognostically poor groups (stages IV and III + IV) was possible with respect to DBH activity. CONCLUSIONS: Differential production of neurotransmitters in a population of tumor cells may be explained in terms of tumor heterogeneity.

The value of catecholamine metabolite determination on untimed urine collections in the diagnosis of neural crest tumours in children.

There is still controversy regarding the relative merits of catecholamine metabolite estimations on 24 h versus untimed urine collections. The former has the advantage of taking into account diurnal variation in the rate of metabolite excretion but has the disadvantages of delaying results and of being affected by errors in collection. In this study percentile values were established for a reference population of 181 children for urinary 4-hydroxy-3-methoxyphenylacetic acid (HVA)/creatinine and 163 children for 4-hydroxy-3-methoxymandelic acid (VMA)/creatinine, using untimed urine collections. Results of similar determinations performed as part of the diagnostic work up of 23 consecutive children subsequently proven to have neural crest tumours showed that all patients had the value of at least one metabolite concentration at or above the highest reference value. In neuroblastoma all patients' VMA/creatinine exceeded the highest reference value and in neural crest tumours overall, this ratio was greater than the highest reference value in 96% of patients. These results are as good as, or better than, previously published results and demonstrate the practical value of using catecholamine metabolite determinations expressed as 'creatinine equivalents' on untimed urine specimens in the diagnosis of neuroblastoma and related tumours in children.

Ultrastructural studies on neuroblastoma: evaluation of cytodifferentiation and correlation of morphology and biochemical and survival data.

Fifteen cases of neuroblastoma, ganglioneuroblastoma and ganglioneuroma were studied by electron microscopy. Ultrastructural features of cytodifferentiation, including numbers of dense core neurosecretory granules (NSG) and neuritic processes, were used to evaluate variation within the neuroblastoma group to determine whether differences in cytodifferentiation exist where light microscopic variations are not evident. These studies revealed that undifferentiated neuroblastomas do show ultrastructural variations not evident by light microscopy. The ultrastructural findings for each case were compared with initial urinary catecholamine excretory patterns, the latter having recently been shown to have valuable prognostic significance. There was a positive correlation, in the undifferentiated neuroblastomas, between increased numbers of NSG and prognostically favorable biochemical excretory patterns. Conversely, low numbers of NSG were associated with an unfavorable biochemical pattern and fatal clinical course. These correlations between ultrastructural differentiation and the biochemical secretory pattern indicate that ultrastructural evaluation of undifferentiated neuroblastomas would appear to have prognostic value, particularly in cases lacking initial biochemical data or as an adjunct to biochemical studies.

Liquid-chromatographic evaluation of age-related changes in the urinary excretion of free catecholamines in pediatric patients.

Pediatric patients (to age 18) without neuroblastoma show an age-related decrease in urinary excretion of each of the catecholamines--epinephrine, norepinephrine, and dopamine--in relation to creatinine excretion. From these data, I have developed reference intervals for pediatric age groups. Application of these ranges to seven patients with neuroblastoma and ganglioneuroblastoma indicated a high clinical sensitivity for the urinary dopamine determination but significant false-negative results for epinephrine and norepinephrine.