Original article. M. Cimitan 1 *, A. Buonadonna 2, R. Cannizzaro 3, V. Canzonieri 4, E. Borsatti 1, R. Ruffo 1 & L. De Apollonia 5.

Transcription

1 Original article Annals of Oncology 14: , 2003 DOI: /annonc/mdg279 Somatostatin receptor scintigraphy versus chromogranin A assay in the management of patients with neuroendocrine tumors of different types: clinical role M. Cimitan 1 *, A. Buonadonna 2, R. Cannizzaro 3, V. Canzonieri 4, E. Borsatti 1, R. Ruffo 1 & L. De Apollonia 5 1 Nuclear Medicine Unit, 2 Medical Oncology B Division, 3 Gastroenterology Unit, 4 Pathology Division, 5 Blood Transfusion, Immunohematology and Clinical Chemistry Unit, National Cancer Institute (CRO IRCCS), Aviano, Italy Received 18 February 2003; revised 27 February 2003; accepted 10 March 2003 Background: Current diagnosis and staging of neuroendocrine tumors (NETs) are significantly improved by the introduction of the chromogranin A (CgA) assay in plasma or serum as a tumor marker, and by the use of somatostatin receptor scintigraphy (SRS) for tumor localization. However, the clinical role of CgA assay compared with SRS in the management of NETs has not been well elucidated. Patients and methods: Sixty-three consecutive patients with a histological diagnosis of NET underwent plasma CgA assay and SRS for tumor staging (23 cases), evaluation of tumor response (18 cases) and evaluation of tumor recurrence on follow-up (22 cases). Twenty-one patients had well-differentiated neuroendocrine tumors (WDNETs: 18 gastroenteropancreatic tumors and three lung NETs); 22 patients had well-differentiated neuroendocrine carcinomas (WDNECs: 17 gastroenteropancreatic carcinomas, two lung neuroendocrine carcinomas and three neuroendocrine carcinomas of unknown origin) and 20 patients had poorly differentiated neuroendocrine carcinomas (PDNECs: 14 extra-pulmonary small-cell carcinomas and six Merkel cell carcinomas). Almost all (58 of 63) NETs were non-functioning. The quantitative determination of CgA was performed in plasma using an enzyme immunoassay with a cut-off value fixed at 34 U/l. Scintigraphies with indium 111-DTPA-octreotide ( 111 In-pentetreotide) included whole-body images and single photon emission computed tomography (SPECT) scans of the chest and abdomen. Results: SRS results were compared with CgA findings and final clinical data. The overall sensitivity of SRS and CgA, based on the final clinical data, was 77% and 55%, respectively, whereas the specificity of both SRS and CgA was 94%. Concerning tumor type, SRS accuracy was 95% for WDNETs, 86% for WDNECs and 60% for PDNECs; CgA accuracy was 76% for WDNETs, 68% for WDNECs and 50% for PDNECs. With regard to disease extent, SRS sensitivity was 100% for limited disease and 72% for advanced disease; CgA sensitivity was 43% for limited disease and 57% for advanced disease. Conclusions: In our NET series, SRS proved to be more sensitive than CgA, with equivalent specificity. Tumor differentiation influences the sensitivity of SRS and CgA analysis. In addition, the plasma CgA level is related to tumor secretory activity. Nevertheless both SRS and CgA should be considered useful tools in the diagnostic work-up of NET patients. Key words: chromogranin A, 111 In-pentetreotide, neuroendocrine tumors, somatostatin receptor scintigraphy Introduction *Correspondence to: Dr M. Cimitan, Nuclear Medicine Unit, National Cancer Institute (CRO IRCCS), Via Pedemontana Occidentale 12, I Aviano (PN), Italy. Tel: ; Fax: ; mcimitan@cro.it Neuroendocrine tumors (NETs) represent a heterogeneous group of neoplastic entities derived from cell populations of the diffuse neuroendocrine system; they encompass aggressive tumors such as neuroendocrine small-cell cancer, low-growing tumors such as carcinoid and tumors with intermediate aggressiveness such as malignant carcinoid [1, 2]. They are usually divided into functioning or non-functioning tumors according to their ability to produce, or not, hormones and biologically active substances responsible for clinical syndromes. Although these tumors often have a good prognosis, they are generally diagnosed late because of their versatile presentation. Current diagnosis and staging of NETs are significantly improved by the introduction of the chromogranin A (CgA) assay in plasma or serum, as a tumor marker [3 6], and by the use of somatostatin receptor scintigraphy (SRS) for tumor localization [7 11]. Human CgA is a glycoprotein belonging to the family of chromogranins, also known as secretogranins, which is present in the secretory granules storing peptide hormones and catecholamine throughout the neuroendocrine system. Elevated 2003 European Society for Medical Oncology

2 1136 plasma CgA levels have been found in a variety (80 100%) of functional and non-functional NETs and the circulating CgA levels also reflect the tumor extent [12, 13]. SRS using indium 111-DTPA-octreotide ( 111 In-pentetreotide) is widely used to localize NET since octreotide is able to bind to somatostatin receptor subtypes 2 and 5, and almost all (80%) NETs contain the somatostatin receptor subtype 2 [7, 14, 15]. In a previous study, Kalkner et al. [16] found that positive 111 Inpentetreotide scintigraphy correlates with elevated levels of plasma CgA in patients with carcinoid tumors. However, the role of CgA assay compared with SRS has not been well elucidated. CgA production seems to depend on tumor type or tumor differentiation and the sensitivity of CgA assay as a tumor marker may be low in moderately or poorly differentiated neuroendocrine carcinomas [13]. On the other hand, the sensitivity of 111 In-pentetreotide scintigraphy may be of limited value in tumors <0.5 cm and in tumors lacking somatostatin receptor subtype 2 and 5 expression [14]. The aim of our study was to investigate the impact of SRS versus plasma CgA assay in patients with different types of NETs histologically diagnosed according to the new World Health Organization (WHO) clinicopathological formulation. We specifically compared the results of SRS and those of plasma CgA with regard to tumor staging, tumor response evaluation and follow-up. Patients and methods Patients Sixty-three consecutive patients (32 men and 31 women, aged between 18 and 76 years) with a histological diagnosis of NETs underwent plasma CgA analysis and SRS for tumor staging (23 cases), evaluation of tumor response to chemotherapy and/or somatostatin analogs (18 cases) and evaluation of tumor recurrence on follow-up (22 cases). All patients gave informed consent to participation in the study. According to the WHO pathological formulation, the histological diagnosis included 21 well-differentiated neuroendocrine tumors (WDNETs: 18 gastroenteropancreatic tumors and three lung NETs), 22 welldifferentiated neuroendocrine carcinomas (WDNECs: 17 gastroenteropancreatic carcinomas, two lung neuroendocrine carcinomas and three neuroendocrine carcinomas of unknown origin), and 20 poorly differentiated neuroendocrine carcinomas (PDNECs: 14 extra-pulmonary small-cell carcinomas and six Merkel cell carcinomas). Patients with small-cell lung carcinoma, in whom spiral computed tomography (CT) is generally used as sensitive diagnostic procedure, were excluded from the study. With regard to disease extent, the disease was defined as limited disease (a tumor <2.5 cm or a tumor >2.5 cm without lymph-node metastases), locally advanced disease (a tumor with lymph-node metastases) and metastatic disease. Among the 63 patients investigated, only five (8%) were syndromic. Immunoassay The quantitative determination of CgA was performed in plasma using an enzyme immunoassay (DAKO Chromogranin A ELISA Kit; DAKO A/S Produktionsvej 42, DK-2600 Glostrup, Denmark). It is a simplified double antibody sandwich assay where samples and peroxidase-conjugated antibody to CgA are incubated simultaneously in microwells coated with antibody to CgA. After a washing step, the chromogenic substrate is added. Color development results from the oxidation of the substrate through an enzyme-catalyzed reaction. The assay uses rabbit antibodies to a 23 kda C-terminal fragment of human CgA. CgA concentrations determined with the kit are given as U/l. Total coefficients of variation (within and between assay) are 7.3% for mean levels of 30.5 U/l (n = 36), 8.6% for mean levels of U/l (n = 30) and 5.8% for mean levels of U/l (n = 30). In our laboratory, the normal CgA values obtained in healthy subjects (58 men aged years and 57 women aged years) ranged between 0 and U/l (mean value ± standard deviation = ± 7.66 U/l) with a cut-off value fixed at 34 U/l. Somatostatin receptor scintigraphy SRS was performed with 111 In-pentetreotide, a [ 111 In-DTPA-D-Phe-] conjugate of octreotide, a somatostatin analog, which binds to somatostatin receptor subtypes 2 and 5 (OctreoScan; Mallinckrodt Medical, Petten, The Netherlands). Planar or whole-body (WB) images, as well as single photon emission computed tomography (SPECT) of chest and abdomen were performed in all patients 4 6 h and 24 h after intravenous (i.v.) injection of MBq of 111 In-pentetreotide (seldom continued for h), using a rectangular large field of view gamma camera (Sophicamera DSX, Sopha; BUC, France). Planar images were acquired for min/image, using a word matrix; WB images, anterior and posterior, were acquired into a word matrix with a speed of 8 cm/min. All SPECT studies were performed using a matrix, 64 projections with a rotation of 360 and s acquisition time per projection, and SPECT row data were prefiltered using a Butterworth filter (order 8 and cut-off 0.15). The data were then reconstructed by a maximum activity projection algorithm using a ramp filter without attenuation correction. Data interpretation All patients with plasma CgA values >34 U/l were considered positive for neuroendocrine disease. Plasma CgA assays were obtained within 1 4 weeks of scintigraphy in all cases. SRS was interpreted independently of the result of any prior investigation. To define the tumor as visualized during SRS, a simple yes-or-no system was used. Any focal activity higher than the surrounding background activity was considered a positive result if it was present on the images of both early 4 6 h and delayed h studies. SRS and CgA results were rated true-positive (TP) or true-negative (TN) based on the final data of surgery (n = 39) and/or of other diagnostic procedures such as spiral CT, magnetic resonance, ultrasonography and endoscopy (n = 24). Results Clinical data, SRS results and plasma CgA values of all 63 patients are summarized in Table 1. At initial diagnosis (before SRS and plasma CgA investigations), 21 (33%) patients had limited disease, eight (13%) locally advanced disease and 34 (54%) metastatic disease. Fourteen of 21 patients with limited disease, and two of eight patients with locally advanced disease at initial diagnosis, were disease-free based on the final clinical data. Of the 63 patients examined, 37 (59%) had scintigraphic lesions and 27 (43%) had plasma CgA levels above the normal limit (>34 U/l). Concordance between SRS and CgA results For all patients, the concordance between SRS and CgA results was 75%; 24 patients had positive scan findings and elevated CgA levels, and 23 had negative scan findings and CgA levels in the normal range (Table 2). Concerning tumor type, SRS and CgA results agreed in 15 (71%) of the 21 WDNETs, in 16 (73%) of the

3 1137 Table 1. Clinical data, somatostatin receptor scintigraphy (SRS) results and chromogranin A (CgA) levels Sex Age (years) Histology (WHO) Tumor origin Syndromic Clinical course Initial diagnosis (disease extent) SRS results CgA (U/l) a Final clinical data (disease extent) F 70 PDNEC Rectum No Follow-up Limited Neg 3 Disease-free M 67 PDNEC Rectum No Staging Metastatic Neg 20 Metastatic M 59 PDNEC Abdomen No Tumor treatment Locally advanced Pos 54 Locally advanced M 63 PDNEC Abdomen No Staging Metastatic Pos 63 Metastatic F 50 PDNEC Abdomen No Staging Metastatic Pos 95 Metastatic M 73 PDNEC Stomach No Staging Metastatic Pos 336 Metastatic F 53 PDNEC Uterus No Staging Locally advanced Neg 540 Locally advanced M 50 PDNEC Diffuse No Staging Metastatic Pos 59 Metastatic M 45 PDNEC Rectum No Staging Metastatic Neg 19 Metastatic F 64 PDNEC Ovary No Follow-up Metastatic Neg 14 Metastatic F 70 PDNEC Ovary No Follow-up Metastatic Neg 21 Metastatic F 61 WDNEC GEP No Follow-up Locally advanced Pos 8 Locally advanced F 38 WDNET GEP No Staging Limited Pos 8 Limited M 48 WDNEC GEP No Tumor treatment Metastatic Pos 9 Metastatic F 18 WDNEC Lung No Staging Locally advanced Neg 11 Locally advanced F 42 WDNET GEP No Follow-up Limited Neg 11 Disease-free M 47 WDNET GEP No Staging Limited Neg 13 Disease-free M 48 WDNET GEP No Staging Limited Pos 13 Locally advanced F 65 WDNET GEP No Staging Metastatic Pos 16 Metastatic F 51 WDNET Lung No Follow-up Limited Neg 17 Disease-free M 46 WDNET Lung No Tumor treatment Metastatic Pos 18 Metastatic M 69 WDNET GEP No Follow-up Locally advanced Pos 18 Locally advanced F 49 WDNET GEP No Follow-up Limited Neg 29 Disease-free M 58 WDNET GEP No Follow-up Limited Neg 33 Disease-free M 53 WDNEC Unknown No Follow-up Metastatic Pos 36 Metastatic M 56 WDNET GEP Yes Tumor treatment Metastatic Pos 54 Metastatic F 74 WDNEC GEP No Tumor treatment Metastatic Pos 73 Metastatic M 69 WDNEC GEP No Staging Metastatic Neg 101 Metastatic F 56 WDNEC Unknown No Tumor treatment Metastatic Pos 104 Metastatic F 44 WDNET GEP No Tumor treatment Metastatic Pos 165 Metastatic F 25 WDNET GEP No Tumor treatment Metastatic Pos 255 Metastatic M 64 WDNEC GEP No Tumor treatment Metastatic Pos 230 Metastatic F 76 WDNET Lung Yes Tumor treatment Metastatic Pos 234 Metastatic M 46 WDNEC GEP Yes Staging Metastatic Pos 450 Metastatic F 36 WDNEC GEP No Tumor treatment Metastatic Pos 510 Metastatic M 60 WDNEC GEP No Follow-up Limited Neg 150 Disease-free F 35 WDNEC GEP No Tumor treatment Metastatic Pos 530 Metastatic M 48 WDNET GEP Yes Tumor treatment Metastatic Pos 1500 Metastatic F 75 WDNET GEP No Tumor treatment Metastatic Pos 234 Metastatic M 64 WDNEC GEP No Staging Metastatic Pos 8790 Metastatic M 74 WDNEC GEP No Tumor treatment Metastatic Pos 32 Metastatic M 67 WDNET GEP No Follow-up Limited Pos 46 Limited F 61 WDNEC GEP No Staging Limited Pos 50 Limited M 47 WDNEC GEP No Staging Metastatic Pos 188 Metastatic M 45 WDNEC GEP No Follow-up Limited Neg 12 Disease-free

4 1138 Table 1. Clinical data, somatostatin receptor scintigraphy (SRS) results and chromogranin A (CgA) levels Sex Age (years) Histology (WHO) Tumor origin Syndromic Clinical course Initial diagnosis (disease extent) SRS results CgA (U/l) a Final clinical data (disease extent) F 70 PDNEC Merkel No Follow-up Locally advanced Pos 10 Locally advanced M 65 PDNEC Merkel No Follow-up Limited Neg 12 Disease-free M 61 PDNEC Merkel No Follow-up Locally advanced Neg 17 Disease-free M 65 PDNEC Merkel No Follow-up Locally advanced Neg 4 Disease-free M 45 WDNEC Lung Yes Staging Limited Neg 15 Disease-free F 46 WDNEC GEP No Tumor treatment Limited Pos 2270 Limited M 54 WDNET GEP No Follow-up Limited Neg 9 Disease-free F 64 WDNET GEP No Follow-up Limited Neg 17 Disease-free F 49 WDNEC GEP No Tumor treatment Metastatic Neg 13 Metastatic M 68 PDNEC Skin No Staging Metastatic Neg 4 Metastatic M 66 PDNEC Merkel No Staging Limited Pos 14 Limited F 71 PDNEC Rectum No Staging Metastatic Neg 15 Metastatic F 64 PDNEC Merkel No Follow-up Limited Pos 9 Limited F 47 WDNEC Unknown No Staging Metastatic Pos 647 Metastatic M 67 PDNEC Abdomen No Staging Metastatic Neg 32 Metastatic F 51 WDNEC GEP No Tumor treatment Metastatic Pos 33 Metastatic F 63 WDNET GEP No Follow-up Limited Neg 24 Disease-free F 33 WDNET GEP No Follow-up Limited Pos <2 Disease-free GEP, gastroenteropancreatic tract; Neg, negative; PDNEC, poorly differentiated neuroendocrine (small-cell) carcinoma; Pos, positive; WDNEC, well-differentiated neuroendocrine carcinoma (malignant carcinoid); WDNET, well-differentiated neuroendocrine tumor (carcinoid); WHO, World Health Organization. a Normal value 0 34 U/l. Table 2. Concordance between somatostatin receptor scintigraphy (SRS) results and plasma chromogranin A (CgA) levels NET categories SRS Pos/ CgA Pos SRS Pos/ CgA Neg SRS Neg/ CgA Pos SRS Neg/ CgA Neg Overall NETs WDNETs WDNECs PDNECs Staging Tumor treatment response Follow-up Total cases Neg, negative; NET, neuroendocrine tumor; PDNECs, poorly differentiated neuroendocrine (small-cell) carcinomas; Pos, positive; WDNECs, well-differentiated neuroendocrine carcinomas (malignant carcinoid); WDNETs, well-differentiated neuroendocrine tumors (carcinoid). 22 WDNECs and in 16 (80%) of the 20 PDNECs. Discrepancies, such as positive SRS with normal CgA levels, were noted in six of 21 cases of WDNETs, in four of 22 cases of WDNECs and in three of 20 cases of PDNECs, whereas negative SRS with high CgA levels was seen in only two cases of WDNECs and in one case of PDNECs. Concordant results between SRS and CgA were seen in 74% of patients studied at staging, in 78% of patients evaluated during treatment and in 77% of patients studied on follow-up. Overall results for SRS and CgA assay based on final clinical data We found one false-positive and 11 false-negative SRS results based on the final clinical data, as well as one false-positive and 21 false-negative CgA analyses (Table 3). The overall sensitivity (TP/TP + FN) of SRS and CgA was 77% and 55%, respectively; the specificity (TN/TN + FP) of both SRS and CgA was 94%.

5 1139 Table 3. Overall results for somatostatin receptor scintigraphy (SRS) and plasma chromogranin A (CgA) assay based on the final clinical data Overall cases (n = 63) WDNETs (n = 21) WDNECs (n = 22) PDNECs (n = 20) Limited disease (n = 21) Advanced disease (n = 42) SRS CgA SRS CgA SRS CgA SRS CgA SRS CgA SRS CgA True-positive (TP) False-positive (FP) True-negative (TN) False-negative (FN) Sensitivity (TP/TP + FN) 77% 55% 100% 58% 84% 68% 50% 37% 100% 43% 72% 57% Specificity (TN/TN + FP) 94% 94% 89% 100% 100% 67% 100% 100% 93% 93% 100% 100% Accuracy (TP + TN/TP + TN + FP + FN) 81% 65% 95% 76% 86% 68% 60% 50% 95% 80% 74% 60% Advanced disease, locally advanced and metastatic disease; PDNECs, poorly differentiated neuroendocrine (small-cell) carcinomas; Pos, positive; WDNECs, well-differentiated neuroendocrine carcinomas (malignant carcinoid); WDNETs, well-differentiated neuroendocrine tumors (carcinoid). Figure 1. A man aged 48 years at post-surgical staging for carcinoid tumor in the blind gut. Chromogranin A levels were within the normal range (13 U/l). Conversely, somatostatin receptor scintigraphy showed a focal activity in the abdomen (arrow), on early (A) and delayed (B) planar images. Threedimensional single photon emission computed tomography imaging (C, D) was useful in localizing the tumor site, which was a lymph-node metastasis on surgical exploration, not seen by other imaging procedures. With regard to the histological classification, SRS sensitivity was 100% for WDNETs, 84% for WDNECs and 50% for PDNECs, whereas CgA sensitivity was 58% for WDNETs, 68% for WDNECs and 37% for PDNECs. With regard to disease extent, SRS sensitivity was 100% for limited disease and 72% for advanced disease (locally advanced disease and metastatic disease); CgA sensitivity was 43% for limited disease and 57% for advanced disease.

6 1140 On the whole, SRS accuracy (TP + TN/TP + TN + FP + FN) was 81% and CgA accuracy was 65%. SRS provided additional detection sites compared with conventional imaging in only one case. Discussion In this study, we have investigated the clinical role of SRS and circulating CgA in the management of patients with NETs with respect to stage and type of neoplasm according to the revised WHO clinicopathological classification [1, 2, 17]. We found that positive SRS correlated with elevated levels of plasma CgA, as reported by Kalkner et al. [16]; however, SRS proved to be more sensitive than CgA with equivalent specificity (Figure 1). In previous reports, the specificity of SRS (expressed on a per patient basis) for NETs of the gastroenteropancreatic tract was 81% [18], and the specificity of circulating CgA ranged between 68% and 95% depending on the upper threshold of the normal range [19, 20]. The sensitivity of SRS in any NETs varied between 78% and 100% [7, 15 18], whereas CgA levels depended on tumor type or disease extent and presence of functioning tumors [13, 19 21]. Our results showed an overall specificity of both SRS and CgA for any NETs as high as 94%. We observed only one false-positive SRS result in a patient with limited disease, studied on follow-up (Table 1). Similarly, only one false-positive CgA result was registered in a patient with WDNEC suffering from essential hypertension and arrhythmia (Table 1). False-positive SRS results could be limited by having a thorough knowledge of other diseases or circumstances that can result in a false-positive response, as suggested by Gibril et al. [22], and the accurate definition of the normal range of CgA values obtained in our healthy control group (n = 115) has increased the CgA specificity [19]. In our study, the overall sensitivity of SRS (expressed on a per patient basis) was 77%. Moreover, SRS sensitivity was higher (100%) in the WDNET subgroup than in WDNECs (84%) and PDNECs (50%). The sensitivity of SRS was also higher (100%) in patients with limited disease than in patients with advanced disease (72%). This indicates that somatostatin receptor expression is more likely present in highly differentiated and low aggressive NETs. Conversely, a low overall CgA sensitivity of 55% was found. It is interesting to note that in our patient series, almost all (58 of 63) NETs were non-functioning, and a low CgA sensitivity was observed both in patients with limited disease (43%) and in patients with advanced disease (57%). However, our data showed that the accuracy of CgA was more elevated in patients with low-growing NETs (76%) than in patients with intermediate aggressive neuroendocrine carcinomas (68%) or with poorly differentiated neuroendocrine carcinomas (50%), as reported in the literature [20, 23]. Conclusions In our NET series, which included many cases of highly aggressive (20 cases) and intermediate aggressive (22 cases) tumors, SRS showed a better sensitivity than CgA with equivalent high specificity. Our results confirm that tumor differentiation influences the sensitivity of SRS and CgA analysis. In addition, plasma CgA level is related to tumor secretory activity. Nevertheless, both SRS and CgA should be considered useful tools for the management of NET patients. References 1. Cappella C, Heitz PU, Hofler H et al. Revised classification of neuroendocrine tumors of the lung, pancreas and gut. Digestion 1994; 55 (Suppl 3): Solcia E, Kloppel G, Sobin LH. Histological typing of endocrine tumours. World Health Organization International Histological Classification of Tumours, 2nd edition. Berlin: Springer Stridsberg M, Oberg K, Li Q et al. Measurement of chromogranin A, chromogranin B (secretogranin I), chromogranin C (secretogranin II) and pancreastatin in plasma and urine from patients with carcinoid tumours and endocrine pancreatic tumours. J Endocrinol 1995; 144: Nobels FR, Kwekkeboom DJ, Coopmans W et al. Chromogranin A as serum marker for neuroendocrine neoplasia: comparison with neuronspecific enolase and the alpha-subunit of glycoproteins hormones. J Clin Endocrinol Metab 1997; 82: Nobels FR, Kwekkeboom DJ, Bouillon R, Lamberts SWJ. Chromogranin A: its clinical value as marker of neuroendocrine tumors. Eur J Clin Invest 1998; 28: Baudin E, Gigliotti A, Duxcreux M et al. Neuron-specific enolase and chromogranin A as markers of neuroendocrine tumours. Br J Cancer 1998; 78: Krenning EP, Kwekkeboom DJ, Bakker WH et al. Somatostatin receptor scintigraphy with [ 111 In-DTPA-D-Phe1]- and [ 123 I-Tyr3]octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med 1993; 20: Schillaci O, Scopinaro F, Danieli R et al. Single photon emission computerized tomography increases the sensitivity of indium-111-pentetreotide scintigraphy in detecting abdominal carcinoids. Anticancer Res 1997; 17: Seregni E, Chiti A, Bombardieri E. Radionuclide imaging of neuroendocrine tumours: biological basis and diagnostic results. Eur J Nucl Med 1998; 25: Chiti A, Fanti S, Savelli G et al. Comparison of somatostatin receptor imaging, computed tomography and ultrasound in the clinical management of neuroendocrine gastro-entero-pancreatic tumours. Eur J Nucl Med 1998; 25: Kwekkeboom DJ, Krenning EP, de Jong M. Peptide receptor imaging and therapy. J Nucl Med 2000; 41: Goebel SU, Serrano J, Yu F et al. Prospective study of the value of serum chromogranin A or serum gastrin levels in assessment of the presence, extent, or growth of gastrinomas. Cancer 1999; 85: Seregni E, Ferrari L, Stivanello M, Dogliotti L. Laboratory tests for neuroendocrine tumours. Q J Nucl Med 2000; 44: Oberg K. State of the art and future prospects in the management of neuroendocrine tumors. Q J Nucl Med 2000; 44: Boerman OC, Oyen WJG, Corstens FHM. Radio-labeled receptor-binding peptides: a new class of radiopharmaceuticals. Semin Nucl Med 2000; 30: Kalkner KM, Janson ET, Nilsson S et al. Somatostatin receptor scintigraphy in patients with carcinoid tumors: comparison between radioligand uptake and tumor markers. Cancer Res 1995; 55 (Suppl):

7 Rindi G, Capella C, Solcia E. Introduction to a revised clinicopathological classification of neuroendocrine tumors of the gastroenteropancreatic tract. Q J Nucl Med 2000; 44: Chiti A, Briganti V, Fanti S et al. Results and potential of somatostatin receptor imaging in gastroenteropancreatic tract tumours. Q J Nucl Med 2000; 44: Baduin E, Bidart JM, Bachelot A et al. Impact of chromogranin A measurement in the work-up of neuroendocrine tumors. Ann Oncol 2001; 12: Ferrari L, Seregni E, Bajetta E et al. The biological characteristics of chromogranin A and its role as circulating marker in neuroendocrine tumors. Anticancer Res 1999; 19: Bajetta E, Ferrari L, Martinetti A et al. Chromogranin A, neuron specific enolasi, carcinoembryogenic antigen and hydroxyndole acetic acid evaluation in patients with neuroendocrine tumors. Cancer 1999; 86: Gibril F, Reynolds JC, Chen CC et al. Specificity of somatostatin receptor scintigraphy: a prospective study and effects of false-positive localization on management in patients with gastrinomas. J Nucl Med 1999; 40: Stivanello M, Berruti A, Torta M et al. Circulating chromogranin A in the assessment of patients with neuroendocrine tumours. A single institution experience. Ann Oncol 2001; 12 (Suppl 2): S73 S77.