Neuroendocrine tumours of the small bowel: interpretation of raised circulating chromogranin A, urinary 5 hydroxy indole acetic acid and circulating neurokinin A.

BACKGROUND: Neuroendocrine tumours (NETs) of the small bowel are difficult to diagnose as symptoms are non-specific and more often found in common gastrointestinal diseases. Chromogranin A (CGA), urinary 5 hydroxy indole acetic acid (U-5HIAA) and Neurokinin A (NKA) are used as laboratory diagnostic tests but results may be misleading or confusing. AIM: To clarify the relevance of NET biomarkers for diagnosis of small bowel NETs. DESIGN: A review of laboratory test results. METHODS: We reviewed 500 consecutive raised plasma CGA, U-5HIAA and plasma NKA, results from patients in N Ireland. The diagnosis of NET was confirmed by the Northern Ireland Cancer Registry. RESULTS: In 500 specimens recording raised CGA, 52.2% were from patients with NETs, 13.6% being small bowel tumours, 5.4% of specimens from patients with auto-immune atrophic gastritis and 15.4% from patients taking proton pump inhibitors. In 500 specimens with raised U-5HIAA, 87.8% were from patients with NETs, 68.2% being small bowel tumours. Lung NETs contributed 12.2% and NETs from other sites, 7.4%. Of 500 specimens with raised NKA (reference range (RR) > 20 ng/L), 72.6% were from patients with small bowel NETs and 6% specimens from patients with other NETs. In 20% of specimens NKA concentrations were 21-23 ng/L, within limits of assay precision. CONCLUSION: CGA remains the best general circulating marker for NETs although only half of raised test results are due to an NET. U-5HIAA is an excellent marker for small bowel and lung NETs with 80% of high test results confirming these diagnoses. NKA is the most specific biomarker for small bowel NETs.

A rapid rise in circulating pancreastatin in response to somatostatin analogue therapy is associated with poor survival in patients with neuroendocrine tumours.

AIM: To assess the value of pancreastatin as a predictive factor for identifying patients with neuroendocrine tumours (NETs) who respond poorly to somatostatin analogues. METHODS: A retrospective study of patients with NETs. Patient records from the Northern Ireland Neuroendocrine Tumour Register were interrogated. Those who had pancreastatin concentrations measured on two or more occasions, before and during somatostatin analogue therapy (within the set time-limits) were selected. Data relating to diagnosis, surgery, somatostatin analogue therapy and survival outcome were noted. Data were subjected to univariate and multivariate analysis using Cox proportional hazard model. RESULTS: Fifty-nine patients with gastroenteropancreatic NETs fulfilled the inclusion criteria. Factors associated with a poor survival outcome on univariate analysis were primary tumour site (P = 0.006) and rapid rise in pancreastatin during somatostatin analogue treatment (P < 0.001). In multivariate analysis, highly significant clinical prognostic indicators were: tumour location (P < 0.001), pre-treatment pancreastatin (P < 0.001) and pancreastatin change (P < 0.001). CONCLUSIONS: This study endorses the finding that pancreastatin is a useful prognostic indicator of neuroendocrine disease. On commencement of treatment, one-third of the subjects showed an immediate negative pancreastatin response to somatostatin analogues, which was associated with poor survival. This is the first study to document such an association. These findings have significant therapeutic consequences. In the presence of a rapidly rising pancreastatin alternative, treatment modalities should be sought.

Cyclooxygenase-2 expression correlates with phaeochromocytoma malignancy: evidence for a Bcl-2-dependent mechanism.

AIMS: Phaeochromocytomas are rare but potentially life-threatening neuroendocrine tumours of the adrenal medulla or sympathetic nervous system ganglia. There are no histological features which reliably differentiate benign from malignant phaeochromocytomas. The aim of the study was to evaluate cyclooxygenase (COX)-2 and Bcl-2 as tissue-based biomarkers of phaeochromocytoma prognosis. METHODS AND RESULTS: COX-2 and Bcl-2 expression were examined immunohistochemically in tissue from 41 sporadic phaeochromocytoma patients followed up for a minimum of 5 years after diagnosis. There was a statistically significant association between COX-2 histoscore (intensity x proportion) and the development of tumour recurrence or metastases (P = 0.006). A significant relationship was observed between coexpression of COX-2 and Bcl-2 in the primary tumour and the presence of recurrent disease (P = 0.034). A highly significant association was observed between (i) tumour-associated expression of these two oncoproteins (P = 0.001) and (ii) COX-2 histoscore and the presence of Bcl-2 expression (P = 0.002). COX regression analysis demonstrated no significant relationship between (i) the presence or absence of either COX-2 or Bcl-2 and patient survival or (ii) COX-2 histoscore and patient survival. CONCLUSIONS: COX-2 and Bcl-2 may promote phaeochromocytoma malignancy, and these oncoproteins may be valuable surrogate markers of an aggressive tumour phenotype.

Circulating markers of prognosis and response to treatment in patients with midgut carcinoid tumours.

BACKGROUND AND AIMS: Midgut carcinoid tumours are uncommon tumours with an unpredictable clinical behaviour and few useful prognostic markers. Somatostatin analogues are widely used in treatment but a survival advantage has not been proven. We analysed features associated with poor prognosis and assessed the clinical implications of the biochemical response to therapy. METHODS: Clinical and biochemical data were collected for patients with midgut carcinoid tumours attending a tertiary referral neuroendocrine clinic from 1978 to 2000. Using death as the end point, univariate and multivariate survival analyses were performed to identify prognostic indicators. The significance of altering biomarkers with therapy was also studied by including repeated measurements of the most prognostic biochemical parameter in a time dependent covariate survival analysis. RESULTS: We identified 139 patients with sufficient data for our analyses. Factors associated with a poor outcome on univariate analysis included: plasma neurokinin A (NKA), urinary 5-hydroxyindolacetic acid output, age, and >/=5 liver metastases. Plasma NKA was the strongest and only independent predictor of outcome on multivariate analysis. Patients in whom NKA continued to rise despite somatostatin analogues had a significantly worse survival than those in whom NKA stabilised or fell (one year survival rate 40% v 87%). Time dependent covariate analysis concluded that survival was better predicted by the most recent plasma NKA value rather than by the initial value. CONCLUSIONS: Plasma NKA is an accurate marker of prognosis for midgut carcinoid tumours. This is the first paper to support a survival advantage in patients in whom plasma NKA is altered by somatostatin analogues.

The importance of the measurement of circulating markers in patients with neuroendocrine tumours of the pancreas and gut.

The measurement of general and specific biochemical markers in patients with neuroendocrine tumours assists with diagnosis and gives an indication of the effectiveness of treatment and they may be used as prognostic indicators. There is much agreement that chromogranin A is the most universally helpful marker; it is found to be elevated in the circulation of about 90% of patients with metastatic neuroendocrine tumours and there are several excellent commercially available kits which give reliable estimations. Specific markers are useful for diagnosis also, and are helpful indicators of the effectiveness of treatment, particularly where tumour bulk may not change as much as tumour activity. Sporadic pancreatic neuroendocrine tumours may secrete more than one peptide and this indicates a worsening prognosis. Because of the wide variation in the progression of neuroendocrine tumours, a prognostic indicator gives a significant advantage to the clinician in order to facilitate optimum treatment at the optimum stage of disease. Both chromogranin A and neurokinin A have been used as powerful prognostic indicators for midgut carcinoid tumours.