Atypical thymic carcinoid manifesting with nephrotic-range proteinuria in a 7-year-old boy.

BACKGROUND: Nephrotic-range proteinuria as a paraneoplastic syndrome (PNS) is an exceptional presentation, especially in children. It is usually associated with hematologic malignancies. Solid tumors are very rare causes of proteinuria. CASE-DIAGNOSIS/TREATMENT: We present the case of a 7-year-old boy with an extremely rare atypical thymic carcinoid accompanied by nephrotic-range proteinuria as PNS. The kidney biopsy was consistent with minimal change disease (MCD). Tests for a neuroendocrine tumor were performed due to symptoms of hypercortisolemia and an elevated concentration of chromogranin A in the serum. The chest computed tomography revealed a tumor in the anterior mediastinum, which was diagnosed as an atypical thymic carcinoid. A complete resolution of the nephrotic-range proteinuria was observed within 1 week after the first thoracoscopic surgery, with almost complete reduction of the tumor mass. CONCLUSIONS: This extremely rare case shows that MCD can occur as a PNS even in children. Nephrotic-range proteinuria can be a symptom of malignant solid tumor. This case highlights the possibility of secondary causes of MCD in children.

Serum and plasma 5-hydroxyindoleacetic acid as an alternative to 24-h urine 5-hydroxyindoleacetic acid measurement.

BACKGROUND: Neuroendocrine tumours are slow growing tumours known to secrete a variety of vasoactive peptides which give rise to symptoms of the carcinoid syndrome. The diagnosis and monitoring of patients with neuroendocrine tumours is undertaken in many centres using 24 h urinary measurement of 5-hydroxyindoleacetic acid. However, 5-hydroxyindoleacetic acid can also be quantified in plasma and serum. METHODS: We measured 5-hydroxyindoleacetic acid concentration in 134 paired EDTA plasma and urine samples from 108 patients with known neuroendocrine tumours and 26 healthy volunteers. We also compared 5-hydroxyindoleacetic acid concentrations in paired serum and plasma samples (n = 63), then analysed paired urine and serum samples (n = 97). Furthermore, we examined the impact of renal impairment on serum 5-hydroxyindoleacetic acid by analysing 5-hydroxyindoleacetic acid in patients without neuroendocrine tumours in different stages of chronic kidney disease, as indicated by the estimated glomerular filtration rate. RESULTS: Plasma and urine 5-hydroxyindoleacetic acid had very similar diagnostic sensitivities and specificities, with areas under the curve on ROC analysis of 0.917 and 0.920, respectively. Serum and plasma 5-hydroxyindoleacetic acid values showed good correlation but serum results demonstrated a positive bias, indicating the necessity for different serum and plasma reference intervals. There was an inverse correlation between estimated glomerular filtration rate and serum 5-hydroxyindoleacetic acid concentration, with 5-hydroxyindoleacetic acid increasing once the estimated glomerular filtration rate falls below 60 mL/min/1.73 m(2). CONCLUSION: The measurement of both serum and plasma 5-hydroxyindoleacetic acid can be used for the diagnosis and monitoring of patients with neuroendocrine tumours. Provided renal function is taken into consideration, either of these tests should be incorporated into standard practice as an alternative assay to urinary 5-hydroxyindoleacetic acid.

The perforated appendiceal carcinoid in children: a surgical dilemma.

The decision for aggressive reoperation after discovery of an appendiceal carcinoid is generally based upon criteria such as size, grade, degree of involvement of the mesoappendix or the appendiceal base, lymphovascular invasion, and the presence of goblet cell or adenocarcinoid features. No guidelines currently exist for the management of perforated appendiceal carcinoids. We present a case of perforated appendiceal carcinoid that was subsequently treated with right hemicolectomy, and we review the pertinent literature.

HPLC-mass spectrometry method for quantitative detection of neuroendocrine tumor markers: vanillylmandelic acid, homovanillic acid and 5-hydroxyindoleacetic acid.

BACKGROUND: The urinary excretion of vanillylmandelic acid (VMA), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) can be increased in the presence of neuroblastic and carcinoid tumors. The former is characterized by defective catecholamine metabolism which results in high urinary levels of VMA and HVA. The latter shows an altered metabolism of tryptophan and an increased synthesis of serotonin, producing high 5-HIAA urinary concentrations. METHODS: We describe an HPLC-tandem mass spectrometric method for the simultaneous quantification of VMA, HVA and 5-HIAA in human urine. The chromatographic separation is performed on a reversed-phase C18 column. Instrumental analysis is performed on a Q-Trap 2000 triple quadrupole/ion trap mass spectrometer. RESULTS: The method is fast and does not require sample pre-treatment. Multiple calibration curve exhibited consistent linearity and reproducibility. Linear responses were observed in the concentration range 0-50 mg/l for each analyte. Limits of detection were 0.001 mg/l for VMA, 0.015 mg/l for 5-HIAA and 0.050 mg/l for HVA with a signal-to-noise ratio of 3. Limits of quantification were 0.005 mg/l for VMA, 0.050 mg/l for 5-HIAA and 0.1 mg/l for HVA with a signal-to-noise ratio of 10. CONCLUSIONS: This method can be proposed as a tool for neuroendocrine tumor markers detection.

[Gastrointestinal carcinoid tumors: a multi-technique diagnostic approach]. / Tumeurs endocrines digestives: stratégie diagnostique.

Carcinoid tumors account for less than 1% of all malignancies. The majority arise in the gastrointestinal system (GI carcinoids). The diagnosis of GI carcinoids is often made late, the protean symptoms are easy to overlook. Diagnosis, prognosis and treatment options are based on biochemical markers and imaging investigations. A high concentration of urinary 5-HIAA or an elevated serotonin level in plasma help to establish the diagnosis of GI carcinoid. Plasma chromogranin A has poor specificity (68%); its level depends on disease involvement and therapeutic response. Octreoscan is the best imaging technique to detect GI carcinoids, but CT scan and MRI are superior for the detection of metastasis. 18F-DOPA or 11C-5-HTP/PET, imaging fusion as of octreoscan or PET scan with CT or MRI, improve the results of metabolic imaging. Coronal contrast-enhanced CT or MRI angiogram can evaluate mesenteric vessel spread before surgery. Upper endoscopy or colonoscopy, can be performed to detect foregut carcinoid in MEN, or hindgut carcinoid. Echoendoscopy visualizes abdominal wall and local node involvement. Enteroscopy and capsule endoscopy localize 66% of midgut carcinoids. Although there have been considerable advances in diagnostic modalities, the diagnosis of carcinoid tumors is still, all too often, late.

Persistent low urinary excretion of 5-HIAA is a marker for favourable survival during follow-up in patients with disseminated midgut carcinoid tumours.

Survival of patients with disseminated midgut carcinoid tumours varies. We investigated which factors predict survival at referral and during follow-up, with emphasis on urinary 5-hydroxyindolacetic acid (5-HIAA) levels. Between 1992 and 2003, 76 patients were studied; urine was prospectively collected over a 24 h period every 3 months in order to measure 5-HIAA levels. Uni- and multivariate analyses were performed. Median follow-up was 55 months with a median survival of 54 months. Prognostic factors for poor survival were high age, high gamma-glutamyltransferase levels and greatly increased 5-HIAA levels (>20 mmol/mol creatinine) The Hazard Ratio (HR) of a greatly increased 5-HIAA level was 3.33 (95% confidence interval (CI) 1.66-6.66, p=0.001). In a multivariate survival analysis with the 5-HIAA level as time dependent covariable, the HR for the 5-HIAA level was 1.007 (95% CI 1.004-1.010, p=0.000). In conclusion, patients with persistent moderately increased urinary 5-HIAA levels (< or =20 mmol/mol creatinine) have favourable outcome.

Biomarkers predict outcomes following cytoreductive surgery for hepatic metastases from functional carcinoid tumors.

BACKGROUND: Cytoreductive therapy for metastatic carcinoid provides symptomatic relief and improvement in overall survival. We evaluated whether CgA and 5HIAA could predict symptomatic relief and control of disease progression after cytoreductive surgery. METHODS: We retrospectively reviewed 70 patients who underwent cytoreductive surgery for neuroendocrine hepatic metastases between 1996 and 2005. Twenty-two patients had pre and post-operative CgA and/or 5HIAA levels measured. Reduction of biomarkers following cytoreduction was correlated with patient symptoms and progression of disease following surgery. RESULTS: Our study consisted of 14 males and 8 females with a mean age of 55 (+/-12 years). Median follow-up was 18 months (range 5-64 months). Six patients (26.1%) had complete (R0) cytoreduction, while 4 (17.4%) and 13 (56.5%) had microscopic (R1) and gross (R2) disease remaining. All patients reported improvements in their symptoms, with 12 (54.5%) reporting complete resolution (CR) and 10 (45.5%) reporting partial resolution (PR). Reduction of CgA of >or= 80% was highly predictive of complete resolution of symptoms (P = 0.007) and stabilization of disease (P = 0.034). Reduction of 5HIAA levels of >or= 80% (or normalization) was predictive of symptomatic relief, but not progression of disease (P = 0.026 and P = 0.725). Five of six patients who had R0 resections had CR and were free of disease at last follow-up (median 24.5 months, range: 11-48, P = 0.002). CONCLUSIONS: We conclude that >or= 80% reduction in CgA level following cytoreductive surgery for carcinoid tumors is predictive of subsequent symptom relief and disease control. Substantial reduction in CgA is associated with improved patient outcomes, even after incomplete cytoreduction.

Biochemical assessment of niacin deficiency among carcinoid cancer patients.

OBJECTIVE: Carcinoid cancer patients often have elevated levels of serotonin or its precursor 5-hydroxytryptophan. Normally, serotonin synthesis accounts for a small fraction of tryptophan catabolism, which should be directed along a pathway that allows partial conversion to niacin; hence, increased diversion of tryptophan toward serotonin could cause variable degrees of niacin deficiency in carcinoid patients. Therefore, the prevalence of niacin deficiency among carcinoid patients was investigated by clinical assessment of pellagra and biochemical assessment of whole blood niacin number, a ratio derived from two biologically active forms of niacin (NAD/NADP x 100). METHODS: Clinical and biochemical niacin status were assessed in a cohort of newly diagnosed carcinoid patients with carcinoid syndrome (CCS, n = 36), carcinoid patients without carcinoid syndrome (CWCS, n = 32) and noncarcinoid controls (n = 24) recruited at two primary care clinics. Other aspects of serotonin metabolism were measured by analyses of plasma serotonin and tryptophan and urinary excretion of 5-hydroxyindoleacetic acid. RESULTS: Biochemical niacin deficiency (niacin number < 130) was significantly more common in CCS patients (10 out of 36) compared to controls (p < 0.05, Fisher's exact test), while CWCS patients displayed an incidence that was not significantly elevated (4 out of 32). Only one CCS patient, who was also identified biochemically as niacin deficient, was clinically diagnosed with pellagra. CONCLUSION: Biochemical niacin deficiency is more prevalent among newly diagnosed CCS patients than in controls. Manifestation of pellagra is a less sensitive indicator, and dependence on this endpoint could lead to a lack of appropriate nutritional support for this group of patients.

Diagnosing, treating and managing carcinoid tumours.

Carcinoid tumours are slow-developing, rare, malignant, hormone-secreting tumours. This article discusses their diagnosis, treatment and symptom management and highlights the need for a multidisciplinary approach to patient care.

A phase II study of docetaxel in patients with metastatic carcinoid tumors.

UNLABELLED: Twenty-one patients with metastatic carcinoid tumors were treated with docetaxel. Although the treatment was well tolerated, no objective radiologic responses were observed. Novel, more effective agents are needed for this disease. BACKGROUND: Traditional combination chemotherapy regimens containing streptozocin, doxorubicin, and 5-fluorouracil have yielded disappointing results in patients with metastatic carcinoid tumors. The lack of efficacy of these combinations, together with their toxicity, has led to efforts to investigate therapeutic agents that are potentially more active and tolerable. We, therefore, assessed the efficacy of docetaxel in the treatment of patients with metastatic carcinoid tumors. METHODS: Twenty-one patients with metastatic carcinoid tumors were treated with docetaxel, administered at a dose of 75 mg/m2 every three weeks. Patients were followed for evidence of toxicity, response, and survival. RESULTS: Docetaxel was well tolerated in this patient population. However, no objective radiologic responses were noted in any of the 21 patients. Of the 13 patients who were evaluable for biochemical responses to therapy, four (31%) experienced decreases in 24-hour urinary 5-hydroxyindole acetic acid (5HIAA) excretion of greater than 50%. The clinical course of the patients enrolled in this study was marked by a high incidence of radiologically stable disease (81%), a median progression-free survival time of 10 months, and a median overall survival time of 24 months. CONCLUSION: Although treatment with docetaxel results in biochemical responses in patients with metastatic carcinoid tumors, the lack of more significant antitumor activity demonstrates the need for novel, more effective agents in this disease.

Angioedema as a single manifestation of carcinoid syndrome in a bronchial carcinoid tumor.

BACKGROUND: The association of bronchial carcinoid tumours with carcinoid syndrome is extremely rare especially in the absence of metastasic disease, and the angioedema is not a typical sign of this syndrome. METHODS AND RESULTS: We report the case of a 39 year-old woman referred to our allergy department with recurrent episodes of angioedema. The aetiological study of angioedema did not show evidence of hypersensitivity to common inhalants, food allergens and latex. C1-inhibitor, C3, C4, C1q, proteinogram and immunoglobulins (IgA, IgG, IgM) all were normal. TSH determination gave normal results, too. Faecal analyses for parasites were negative. The haemogram showed moderate leucocytosis and hypocromic mycrocitic anaemia. The thoracic radiography showed a mediastinal node image in the right paratracheal region. Histology analyses of the samples were diagnostic of a typical carcinoid tumor. Levels of 5-hydroxyindolacetic acid (5-HIIA) were slightly increased. A superior lobectomy was performed and no new episodes of angioedema appeared after surgical intervention. CONCLUSIONS: We report the first case of typical bronchial carcionid tumour, without metastasic disease, with angioedema as a single manifestation of carcinoid syndrome. In our knowledge, only one case of Quincke's edema as part of typical carcinoid syndrome has been reported, in a case of primary midgut carcinoid tumor with metastasic disease to liver. It is very important to include complementary tests, as thoracic radiography, in the routine study of angioedema to reject malignant diseases.

Hepatic artery embolization for control of symptoms, octreotide requirements, and tumor progression in metastatic carcinoid tumors.

Hepatic artery embolization (HAE) has been utilized for treatment of advanced hepatic carcinoid metastases, with promising symptom palliation and tumor control. Our institution employs transcatheter HAE using Lipiodol/Gelfoam for treatment of carcinoid hepatic metastases, and this report presents our experience with twenty-four patients, examining symptom control, quality-of-life, octreotide dependence, and tumor progression. Twenty-four (11 male, 13 female, mean age = 59.4 +/- 2.5 yr) patients with carcinoid and unresectable hepatic metastases, confirmed by urinary 5-hydroxyindole acetic acid (5-HIAA) measurement and biopsy, were treated with Lipiodol/Gelfoam HAE from 1993-2001. Median follow-up was 35.0 months. Before HAE, 14 patients (58.3%) had malignant carcinoid syndrome, with symptoms quantified using our previously reported Carcinoid Symptom Severity Score, and 13 patients (54.2%) required octreotide for symptom palliation. Following treatment, symptom severity, octreotide dose, and tumor response were measured. Asymptomatic patients did not develop symptoms or require following treatment. Hepatic metastases remained stable (n = 4) or decreased (n = 19) in 23 patients (95.8%). Mean pretreatment Symptom Severity Scores (3.8 +/- 0.2), decreased to 1.4 +/- 0.1 post-treatment (P < 0.00001), with 64.3% of patients becoming asymptomatic. Mean pretreatment octreotide dosages (679.6 +/- 73.0 microg/d), decreased to 262.9 +/- 92.7 microg/d (P = 0.0024) post-treatment, with 46.2% of patients discontinuing octreotide. There were no treatment-related serious complications or deaths. This study demonstrates that Lipiodol/Gelfoam HAE produces excellent control of malignant carcinoid syndrome, allowing patients to decrease or eliminate use of octreotide, while controlling hepatic tumor burden.

Use of octreotide and lanreotide in the treatment of symptomatic non-resectable carcinoid tumours.

BACKGROUND: Carcinoid tumours are rare neoplasms that secrete hormones and biogenic amines, most commonly serotonin. Octreotide and long acting lanreotide are found to be useful in the management of carcinoid syndrome by its interaction with somatostatin receptor, found on the carcinoid tumour. The aim of this study is to look at the efficacy of octreotide and long acting lanreotide in the treatment of symptomatic non-resectable carcinoid tumours. METHOD: The effects of octreotide and long-acting lanreotide were studied in 10 patients with symptomatic non-resectable carcinoid tumours. RESULTS: Symptom improvement occurred in nine of 10 patients. Three patients responded only to octreotide, three patients responded to both octreotide and long-acting lanreotide and three patients only responded to long-acting lanreotide. Slight reductions in 24-h urine 5-hydroxyindoleacetic acid levels occurred in three of six patients but no patients were found to have objective tumour regression on computed tomography scan. CONCLUSIONS: Octreotide and long-acting lanreotide are useful palliative treatments for the control of symptoms in patients with non-resectable carcinoid tumours but there is no evidence of tumour stasis.

Evaluation of whole blood serotonin and plasma and urine 5-hydroxyindole acetic acid in diagnosis of carcinoid disease.

BACKGROUND: Carcinoid disease is an uncommon disorder resulting from tumours of the enterochromaffin cells. Current biochemical investigation usually involves the measurement of 5-hydroxyindole-3-acetic acid (5-HIAA) in 24-h urine collections. Because of the problems associated with urine collections (i.e. inconvenience, accuracy of collection and requirement for preservatives) two alternative markers, fasting plasma 5-HIAA and whole blood serotonin (5-hydroxytryptamine), have been studied. METHODS AND RESULTS: Whole blood serotonin concentration and plasma and urine 5-HIAA concentrations were measured by high-performance liquid chromatography in 31 patients suspected of having carcinoid and 26 known carcinoid patients. Receiver operator characteristic curve analysis of the data showed no statistical difference between the three markers (P>0.01) with regard to their discriminating function. However, fasting plasma 5-HIAA assay showed greater stability than whole blood serotonin assay and is more convenient for the patient than a 24-h urine collection. At a cut-off value of 118 nmol/L plasma 5-HIAA assay showed a sensitivity of 89%, a specificity of 97% and a test efficiency of 93%. Whole blood serotonin assay was further limited by its saturation in platelets at 40 nmol/10(9) platelets which made it less suitable for monitoring the treatment of carcinoid disease. CONCLUSION: Fasting plasma 5-HIAA concentration provides a more convenient screening test for carcinoid and overcomes the problems associated with 24-h urine collections, without any loss of diagnostic precision.

Long-term palliation in metastatic carcinoid tumours with various applications of meta-iodobenzylguanidin (MIBG): pharmacological MIBG, 131I-labelled MIBG and the combination.

Carcinoid tumours are rare, but well known for their characteristic presentation with diarrhoea and flushes due to overproduction of serotonin in the case of liver metastases. Treatment is mainly based on the reduction of vasoactive peptide hypersecretion and symptomatic improvement Octreotide and interferon are widely applied and effective treatment options to induce symptomatic improvement and, to a lesser extent, biochemical response. The main drawbacks, however, are the need for frequent injections and/or the occurrence of side effects. A rather new approach is the application of meta-iodobenzylguanidine (MIBG), which resembles noradrenalin and serotonin. In carcinoid patients, MIBG is taken up in the tumour cells and stored in the neurosecretory granules. When labelled with 131 iodine, radionuclide imaging is positive in up to 70% of the patients. In these patients, two cycles of a therapeutic dose of radioactive MIBG may induce long-lasting palliation (8 months) by internal irradiation. Also, the non-radioactive MIBG compound may be effective in palliation, even in patients with a negative scan. The mode of action is based on specific tumour acidification as found in animal models, and/or based on its effect as a false neurotransmittor. Three case reports demonstrate different therapeutic possibilities of MIBG: 1) symptomatic relief with unlabelled MIBG, which is a safe and simple treatment; 2) the longterm palliation following radioactive treatment; and 3) an additional new aspect of predosing with unlabelled MIBG followed by radioactive MIBG led to improved tumour targeting and impressive clinical response.

Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome.

PURPOSE: Subcutaneous (SC) octreotide acetate effectively relieves the diarrhea and flushing associated with carcinoid syndrome but requires long-term multiple injections daily. A microencapsulated long-acting formulation (LAR) of octreotide acetate has been developed for once-monthly intramuscular dosing. PATIENTS AND METHODS: A randomized trial compared double-blinded octreotide LAR at 10, 20, and 30 mg every 4 weeks with open-label SC octreotide every 8 hours for the treatment of carcinoid syndrome. Seventy-nine patients controlled with treatment of SC octreotide 0.3 to 0.9 mg/d whose symptoms returned during a washout period and who returned for at least the week 20 evaluation constituted the efficacy-assessable population. RESULTS: Complete or partial treatment success was comparable in each of the four arms of the study (SC, 58.3%; 10 mg, 66.7%; 20 mg, 71.4%; 30 mg, 61.9%; P> or =.72 for all pairwise comparisons). Control of stool frequency was similar in all treatment groups. Flushing episodes were best controlled in the 20-mg LAR and SC groups; the 10-mg LAR treatment was least effective in the control of flushing. Treatment was well tolerated by patients in all four groups. CONCLUSION: Once octreotide steady-state concentrations are achieved, octreotide LAR controls the symptoms of carcinoid syndrome at least as well as SC octreotide. A starting dose of 20 mg of octreotide LAR is recommended. Supplemental SC octreotide is needed for approximately 2 weeks after initiation of octreotide LAR treatment. Occasional rescue SC injections may be required for possibly 2 to 3 months until steady-state octreotide levels from the LAR formulation are achieved.

Phosphorylation and O-glycosylation sites of human chromogranin A (CGA79-439) from urine of patients with carcinoid tumors.

Because of their water-soluble properties, chromogranins (CGs) and chromogranin-derived fragments are released together with catecholamines from adrenal chromaffin cells during stress situations and can be detected in the blood by radiochemical and enzyme assays. It is well known that chromogranins can serve as immunocytochemical markers for neuroendocrine tissues and as a diagnostic tool for neuroendocrine tumors. In 1993, large CGA-derived fragments have been shown to be excreted into the urine in patients with carcinoid tumors and the present study deals with the characterization of the post-translational modifications (phosphorylation and O-glycosylation) located along the largest natural CGA-derived fragment CGA79-439. Using mild proteolysis of peptidic material, high performance liquid chromatography, sequencing, and mass spectrometry analysis, six post-translational modifications were detected along the C-terminal CGA-derived fragment CGA79-439. Three O-linked glycosylation sites were located in the core of the protein on Thr163, Thr165, and Thr233, consisting in di-, tri-, and tetrasaccharides. Three phosphorylation sites were located in the middle and C-terminal domain, on serine residues Ser200, Ser252, and Ser315. These modified sites were compared with sequences of others species and discussed in relation with the post-translational modifications that we have reported previously for bovine CGA.