Parathyroid hormone-related peptide-secreting pancreatic neuroendocrine tumours: case series and literature review.

BACKGROUND/AIMS: Parathyroid hormone-related peptide (PTHrP) was discovered in 1987 as the tumour product responsible for humoral hypercalcaemia of malignancy (HHM). Pancreatic neuroendocrine tumours (NETs) are uncommon malignancies with an incidence of 1:100,000 population. PTHrP-secreting NETs are rare but are being recognised as a cause of HHM in NETs. We describe the largest series to date and the management of these rare tumours. METHODS: One male and 4 female patients were seen in our unit from 1998 to 2006. The average duration of follow-up was 86 months from initial diagnosis. All patients had a histologically confirmed diagnosis of pancreatic NET, all of which were low-grade tumours. PTHrP assay was performed in 4 of 5 cases and was elevated in these patients. RESULTS: Initial management involved surgery in 2 of 5 cases, whilst 2 cases underwent chemotherapy and 1 case was commenced on interferon-alpha. We discuss the further therapies that all patients underwent and the complexities that arose in managing disease progression as well as resistant hypercalcaemia. CONCLUSION: PTHrP-secreting tumours should be considered in the differential diagnosis of patients with NETs who present with hypercalcaemia and a disproportionately low PTH. PTHrP tumours may well be underestimated as the assay is difficult to perform and may not be requested. In hypercalcaemic patients the standard management acutely includes intravenous fluids, diuretics and intravenous bisphosphonate. In the further management, somatostatin analogue therapy is the first medical option to consider and we discuss the role of other therapies.

Novel markers of cell kinetics to evaluate progression from cirrhosis to hepatocellular carcinoma.

BACKGROUND: We investigated cell cycle kinetics of nodular lesions in cirrhosis to differentiate hepatocellular carcinoma (HCC) from its precursor lesions. METHODS: Twelve small HCC, 10 regenerative (RN), six large regenerative (LRN), and five dysplastic nodules (DN), identified in explant cirrhotic livers of five consecutive patients transplanted at Royal Free Hospital in 2002. Immunoperoxidase for MCM2, geminin and Ki67 was performed and the percentage of positive cells counted. RESULTS: The proportion of cells expressing MCM2 was more than those expressing Ki67, which in turn was more than those expressing geminin (overall median=16%, 2% and 0.5%, respectively, P<0.001). There was a statistically significant trend of increasing Ki67 expression (P=0.006), from RN to HCC; this trend was not statistically significant for geminin (P=0.18) or MCM2 (P=0.51). The median percentage of cells expressing Ki67 was 1% in RN, 0.5% in LRN, 2.2% in DN and 5.4% in HCC. The combination of these markers identified four different cell kinetics patterns: 'resting' (G0 cells: MCM2 -ve, Ki67 -ve, geminin -ve); 'licensed' (MCM2 +ve, Ki67 -ve, geminin -ve); 'slowly growing' (G1 phase arrest, MCM2 +ve, Ki67 +ve, low (0.4%) geminin) and expanding (MCM2 +ve, Ki67 +ve, geminin +ve) nodules. CONCLUSIONS: The combination of MCM2, geminin and Ki67 could represent a valuable tool in the understanding of HCC progression in cirrhosis.

Large-volume liver metastases from neuroendocrine tumors: hepatic intraarterial 90Y-DOTA-lanreotide as effective palliative therapy.

PURPOSE: To prospectively evaluate the safety and effectiveness of hepatic intraarterial injection of yttrium 90 ((90)Y) tetraazacyclododecane tetraacetic acid (DOTA) lanreotide as a treatment for patients with progressive large-volume somatostatin receptor-positive liver metastases from neuroendocrine tumors. MATERIALS AND METHODS: The study was local ethics committee approved, and all patients gave informed consent. Twenty-three patients (13 men, 10 women; age range, 21-69 years; median age, 57 years) with histologically proved large-volume liver metastases from neuroendocrine cancers were treated. All patients had radiologic evidence of liver disease progression and high uptake of indium 111 ((111)In) pentetreotide at scintigraphy. Selective hepatic intraarterial injection of (90)Y-DOTA-lanreotide (total of 36 treatments; median activity per dose, 1 GBq) was administered with or without embolization. Treatment cycles were performed in 8-week intervals. Clinical, biologic, and radiologic tumor responses were assessed 8-12 weeks after each treatment cycle. Objective tumor response was classified according to World Health Organization response criteria as complete regression, partial response, stable disease, or disease progression. Kaplan-Meier survival curves were used to calculate 1-year survivals. RESULTS: Partial response to treatment was achieved in three (16%) of 19 patients, and stable disease was achieved in 12 (63%). Four (21%) of 19 patients had continued disease progression. Clinical improvement was reported by 14 (61%) of the 23 patients, and a reduction in biologic marker levels was observed in nine (60%) of 15 patients. Reversible hematologic toxicity (National Cancer Institute common toxicity criteria grade > 2) occurred in three patients. The 1-year survival rate was 63% (median survival time, 15 months). CONCLUSION: Hepatic intraarterial injection of (90)Y-DOTA-lanreotide is a safe and effective palliative treatment for patients with progressive large-volume somatostatin receptor-positive liver metastases from neuroendocrine tumors.