Cognitive impairment associated with carcinoid syndrome.

OBJECTIVES: To evaluate the cognitive performance of patients with carcinoid syndrome (CS) compared with population norms and cancer patients with non-neuroendocrine (non-NET) liver metastases. BACKGROUND: The release of serotonin into the systemic circulation from metastatic small bowel neuroendocrine tumors (SB NET) causes CS. Many patients with CS followed in a multidisciplinary NET clinic seemed to exhibit a unique cognitive impairment. Because serotonin is known to influence a range of cognitive function, the question arouse as to whether cognitive impairment is another manifestation of CS. METHODS: Patients were recruited from the multidisciplinary NET and the hepatobilary cancer clinics at the cancer center. The CS group consisted of patients with proven SB NETs metastatic to liver; the cancer comparison group consisted of patients with liver metastases from non-NET cancer. All completed a self-reported cognitive questionnaire and a battery of 6 standardized neurocognitive tests. Both groups were compared to age/sex/educational-matched norms. RESULTS: Thirty-six patients with CS and 20 with non-NET metastases were enrolled. Patients with CS reported greater cognitive dysfunction in all cognitive domains than both norms and the comparison cancer group. On cognitive testing, patients with CS demonstrated weakness in initiation, processing speed, visual memory, cognitive efficiency, and delayed verbal recall compared with norms. Although the patients with non-NET cancer also demonstrated some cognitive dysfunction compared with norms, the patients with CS did significantly worse on delayed recall (P = 0.03) and marginally slower on speeded mental flexibility (P = 0.097) compared with patients with non-NET cancer. CONCLUSION: This study confirmed our clinical observation that patients with CS suffer from cognitive impairment that is different from the non-NET cancer group and population norms.

Role of imaging in the preoperative staging of small bowel neuroendocrine tumors.

BACKGROUND: Imaging studies are important in the preoperative staging of patients with small bowel neuroendocrine tumors (NET) and when selecting patients for cytoreduction procedures for metastatic disease. The purpose of this study was to assess the accuracy of preoperative imaging compared with operative findings in the staging of small bowel NET. STUDY DESIGN: Sixty-four patients with small bowel NET undergoing laparotomy and who had preoperative imaging with combinations of CT, MR, and radionuclide scintigraphy were reviewed. Results of imaging studies were compared with operative findings to assess the ability of these investigations to detect mesenteric, peritoneal, and hepatic metastases. RESULTS: Mesenteric nodal metastases were seen on imaging in 47 (73%) patients and were present at laparotomy in 56 (88%) patients. Peritoneal metastases were seen on preoperative imaging in 4 (6%) patients and found at laparotomy in 16 (25%) patients. Hepatic metastases were seen on imaging in 42 patients (66%) and found at laparotomy in 49 (77%). Sensitivity and specificity for detection of hepatic metastases were 77% and 100% for CT, 82% and 100% for MR, 63% and 100% for (123)I-meta-iodobenzylguanadine scintigraphy, and 63% and 100% for (111)In-octreotide. Imaging studies failed to detect hepatic metastases in 7 patients and underestimated the extent of hepatic metastatic disease in 17 patients. CONCLUSIONS: Imaging of small bowel NET, even with combinations of CT, MR, and radionuclide studies, underestimates the extent of peritoneal, mesenteric, and hepatic metastatic disease. Accurate staging of small bowel NET might be best performed at the time of laparotomy.

Impairment of cognitive function reported by patients suffering from carcinoid syndrome.

BACKGROUND: Carcinoid syndrome (CS) is characterized by symptoms of diarrhea, flushing, bronchospasm, and valvular heart disease. It has been our impression that patients with CS also exhibit features of cognitive impairment. The purpose of this pilot study was to evaluate if symptoms of cognitive impairment were reported by patients with CS. METHODS: Patients with proven CS completed a 38-question multiple-ability self-report questionnaire (MASQ) to assess symptoms in five cognitive domains: language skills, attention/concentration (A/C), visual-perceptual function, visual memory, and verbal memory. Patients subsequently underwent neurocognitive assessment using a battery of six standardized tests. Results of the MASQ and the cognitive test were compared to published results for healthy individuals. RESULTS: Twenty-one patients with CS were studied. MASQ symptom scores were higher than published norms in all five cognitive domains. Patients reported greatest difficulty with verbal memory (mean +/- SD = 2.74 +/- 0.5), followed by A/C (2.41 +/- 0.65), language (2.31 +/- 0.55), visual memory (2.30 +/- 0.65), and visual-perceptual function (2.17 +/- 0.59). In contrast, neurocognitive tests for verbal memory immediate recall, visual memory, language, and executive function were within the normal range. CS patients, however, scored lower than expected in tests of verbal memory delayed recall and visual-perceptual function. CONCLUSIONS: Patients with CS report high levels of symptoms of impairment in all cognitive domains; however, on formal neurocognitive testing, patients scored lower than expected only in tests of verbal memory delayed recall and visual-perceptual function. These findings appear to confirm our clinical impression that cognitive impairment may be an additional feature of CS. Further studies are needed to confirm and elucidate the cause of this cognitive impairment.

The palliative benefit of aggressive surgical intervention for both hepatic and mesenteric metastases from neuroendocrine tumors.

BACKGROUND: Metastatic neuroendocrine tumors (NETs) can present with complications of gastrointestinal tract obstruction or ischemia and carcinoid syndrome (CS). The purpose of this study was to assess whether aggressive surgical intervention of metastatic NETs provides effective palliation from these symptoms. METHODS: Sixty-six patients with metastatic gastrointestinal tract NETs that presented with either CS and/or obstructive symptoms were retrospectively reviewed. All patients were managed according to a standardized protocol that involved initial surgical resection of regional and/or hepatic disease followed by appropriate medical therapy. RESULTS: Symptoms of obstruction or ischemia were present in 24 patients (36%) and CS in 56 (85%). All patients with obstructive symptoms undergoing operative therapy had complete symptomatic relief. Hepatic cytoreduction was performed in 30 (45%). Overall symptoms of CS improved in 42 patients (75%); 86% of patients that underwent hepatic cytoreduction and 64% of those receiving medical therapy alone (P = .064). Postoperative morbidity was 22% with no mortality. Mean follow-up was 47 months (range, 6-156). Overall 5-year survival rate was 74%. CONCLUSIONS: Surgical resection is highly effective in relieving symptoms of intestinal obstruction and ischemia. Hepatic cytoreduction seems to enhance the ability to control the symptoms of carcinoid syndrome. A surgically aggressive approach in patients with metastatic NETs provides effective palliation in carefully selected patients.

Differential expression of the five somatostatin receptor subtypes in human benign and malignant insulinomas - predominance of receptor subtype 4.

Insulinomas constitute a subgroup of pancreatic endocrine tumors showing B cell differentiation and clinical symptoms related to inappropriate insulin secretion (WHO). Many endocrine tumors express somatostatin receptors (sstrs), which can be visualized by octreotide scintigraphy; however, about half of all insulinomas are reported to be negative. Previous immunohistochemical investigations with antibodies to sstr subtypes 1, 2, 3, and 5 have revealed differences in expression between various neuroendocrine tumors. In the present study, the immunoreactivity to all five human sstr was studied in ten benign and six malignant human insulinomas. Sstr4 was the receptor subtype most frequently expressed in both benign and malignant tumors. A difference in the immunohistochemical sstr5 expression pattern was seen between benign and malignant tumors: Three of the six malignant tumors, but none of the benign tumors, expressed sstr5. The other receptor subtypes were expressed in low numbers with no difference between benign and malignant tumors. The finding of a strong expression of sstr4 in both benign and malignant insulinomas suggests that this receptor subtype could be of importance for diagnostic and therapeutic use.

Prognostic indicators for carcinoid neuroendocrine tumors of the gastrointestinal tract.

Factors that determine the clinical course and outcome of patients with gastrointestinal (GI) carcinoid tumors are complex and multifaceted. These include the site of origin within the GI tract, the size of the primary tumor, and the anatomical extent of disease, whether localized, regional, or metastatic to distant sites. The new World Health Organization (WHO) histological classification of endocrine tumors, including carcinoids, represents a significant advance in terms of providing a consistent framework for histopathological interpretation that should facilitate multicenter research on treatment outcomes. Histochemical indicators of a poorer prognosis are the degree of expression of the proliferation protein Ki-67 and the p53 tumor suppressor protein. Adverse clinical indicators are the malignant carcinoid syndrome, carcinoid heart disease, and high concentrations of the tumor markers, urinary 5-HIAA and plasma chromogranin A.

131I-meta-iodobenzylguanidine in the management of metastatic midgut carcinoid tumors.

The management of metastatic neuroendocrine tumors incorporates multimodal therapy with surgery, biotherapy, and chemotherapy. Tumor-targeted therapies using radiolabeled octreotide and metaiodobenzylguanidine (mIBG) represent a novel treatment approach. The aim of this study was to evaluate the effectiveness of 131I-mIBG in the treatment of metastatic midgut carcinoid tumors. survival outcomes were assessed for patients treated at two regional cancer centers and then compared. One center used 131I-mIBG routinely in the management of metastatic carcinoid tumors (center A), and the other did not use this modality (center B). Only patients with histologically proven metastatic carcinoid tumor shown, or thought most likely, to be of midgut origin were included in the study. During the period 1980 to 2002, a series of 58 patients from center A with metastatic carcinoid tumor arising from the midgut underwent multimodality therapy with the addition of 131I-mIBG. Their median age was 64 years. The median dose of 131I-mIBG administered was 6751 MBq, and there was an average of 2.8 treatments per patient. During the same period, 58 patients with metastatic carcinoid were treated at center B with similar multimodality therapy without the use of 131I-mIBG therapy. Their median age was 65 years. Survivals at 3 and 5 years were 77% and 63%, respectively (95% CI 47-75), for group A. The 3- and 5-year survivals for group B were 56% and 47% (95% CI 34-59), respectively. The mean follow-up was 6.6 years for group A and 5.0 years for group B. Although retrospective in nature, this study suggests that the addition of 131I-mIBG therapy to the treatment protocol of patients with metastatic midgut carcinoid tumors prolongs survival.

The palliative role of 131I-MIBG and 111In-octreotide therapy in patients with metastatic progressive neuroendocrine neoplasms.

BACKGROUND: Radiolabeled octreotide and metaiodobenzylguanidine (MIBG) have demonstrated limited antitumor effect on neuroendocrine neoplasms (NENs). The purpose of this study was to assess the palliative benefit of radionuclide therapy (RNT) in NENs. METHODS: Since April 2001, RNT for progressive, nonsurgically resectable NENs was utilized. NENs that were MIBG positive received 131 I-MIBG therapy, whereas octreotide-only-positive neoplasms received 111 In-octreotide therapy. Symptomatic, quality of life (QoL), biochemical, and radiographic responses to RNT were evaluated. RESULTS: Twenty-four patients had either MIBG or octreotide avid NENs. A mean (range) of 4 (1-7) 131 I-MIBG treatments were given to 13 patients over a duration of 18 months (6-42). The group consisted of 2 medullary thyroid cancer (MTC), and 2 foregut and 9 small-bowel carcinoids; 12 patients (92%) had symptomatic improvement. Stability of tumor size was confirmed in 6, regression in 2, and progression in 5. Biochemical responses were demonstrated in 2. Five (2-16) treatments of 111 In-octreotide was given to 11 patients over 17 months (6-40). There were 1 MTC, 1 insulinoma, 2 gastrinomas, and 3 small-bowel and 4 foregut carcinoids. Symptomatic benefit was seen in 6 (55%), biochemical response in 3. Tumor regression was seen in 1, stability in 5, and progression in 5. CONCLUSIONS: Radionuclide therapy appears to offer good palliation to patients with progressive NENs.

Bone mineral density in well-differentiated thyroid cancer patients treated with suppressive thyroxine: a systematic overview of the literature.

BACKGROUND: The effects of subclinical hyperthyroidism on bone mineral density (BMD) induced by suppressive thyroxine therapy in patients with well-differentiated thyroid cancer (WDTC) remains unclear. An overview of the current literature was undertaken to evaluate studies to date. METHODS: A systematic medline search yielded a total of 11 studies appropriate for review which included premenopausal women, postmenopausal women, and men on suppressive thyroxine post thyroidectomy for WDTC. Main outcome measures were bone mineral density and bone turnover markers. CONCLUSIONS: Although studies were limited by small numbers and varying degrees of control for confounding variables, results suggested no significant change in bone mineral density for premenopausal women or men. Findings for postmenopausal women remain unclear with two of the best controlled studies reporting opposing results. Further studies for this population are recommended to help guide clinical practice.