vasoactive-intestinal-peptide and Carcinoma--Neuroendocrine

We present a rare high-grade, functional, neuroendocrine carcinoma of the pancreas secreting vasoactive intestinal peptide. This case is unique, given the tumor's aggressive features and high Ki-67 index while also secreting functional hormones, which is unusual in high-grade neuroendocrine tumors (NETs). Our patient initially presented with diarrhea and was found to have a 4.7 × 3.1 × 3.3 cm pancreatic mass with diffuse hepatic metastasis staining positive for vasoactive intestinal peptide, chromogranin A and synaptophysin. She was initially underscored as grade 2 NET due to low mitosis, but subsequently restaged based on Ki-67 index as a grade 3 neuroendocrine carcinoma. She unfortunately was not a candidate for chemotherapy at that time. We conclude that high-grade NETs have the potential to secrete active peptide hormones. We therefore recommend that NETs with aggressive features be biopsied and assessed for Ki-67 activity and mitosis regardless if they are functional tumors, with goal for early initiation of chemotherapy.

Topics: Carcinoma, Neuroendocrine; Fatal Outcome; Female; Humans; Ki-67 Antigen; Liver; Middle Aged; Neoplasm Grading; Neoplasm Staging; Pancreas; Pancreatic Neoplasms; Patient Selection; Tomography, X-Ray Computed; Vasoactive Intestinal Peptide

Topics: Adenocarcinoma; Carcinoma, Neuroendocrine; Cell Differentiation; Colonic Neoplasms; Fatal Outcome; Humans; Leukemia, Hairy Cell; Liver Neoplasms; Male; Middle Aged; Mutation; Proto-Oncogene Proteins B-raf; Vasoactive Intestinal Peptide; Vipoma

Pancreatic neuroendocrine tumor (pNET) secretes various peptide hormones; however, calcitonin hypersecretion is rare. Its clinicopathological significance and treatment is still controversial.. A 43 year-old Japanese man presented severe watery diarrhea and a large mass in the pancreatic tail. Blood concentration of VIP was elevated to 649 pg/mL (reference range: 0-100 pg/mL), and calcitonin to 66,700 pg/mL (reference range: 15-86 pg/mL). There was no tumor in other endocrine organs. The resected tumor was composed of 80% calcitonin-positive cells and 10% VIP-positive cells. After the operation, the levels of VIP and calcitonin were decreased to 44 and 553 pg/mL, respectively, and diarrhea was improved. The mRNA of somatostatin receptor (SSTR) subtypes 2, 3 and 5 in the tumor tissue were increased 22.8, 25.1, and 37.0-fold of those of normal pancreas, respectively. At 19 months after the operation, blood calcitonin was again raised to 3,980 pg/mL, and metastatic tumors were found in the liver. With the treatment of long-acting somatostatin analogue, calcitonin was reduced to 803 pg/mL. The patient does not present endocrine symptom, and the size of the metastatic tumors appears stable.. From the world literature to date, co-secretion of VIP and calcitonin was documented in only 10 cases of pNET including the current case. Although VIP is a primary cause of diarrhea in these cases, high level of calcitonin may also influence on the clinical symptoms. Somatostatin analogue suppresses the levels of VIP and calcitonin, and the control proliferation is also expected when tumor cells express SSTRs.

Topics: Adult; Antineoplastic Agents, Hormonal; Calcitonin; Carcinoma, Neuroendocrine; Diarrhea; Humans; Male; Octreotide; Pancreas; Pancreatic Neoplasms; Vasoactive Intestinal Peptide

Neuroendocrine tumors are uncommon, including VIPoma that produces vasoactive intestinal polypeptide. We report a 45-year-old female presenting with a history of diarrhea lasting three months. An abdominal CAT scan showed a solid tumor in the body of the pancreas. A fine needle aspiration biopsy of the tumor was compatible with a neuroendocrine tumor. The patient was subjected to a partial pancreatectomy, excising a 4 cm diameter tumor. The pathological study was compatible with a neuroendocrine carcinoma. There was no regional lymph node involvement. During the postoperative period the results of serum vasoactive intestinal polypeptide were received. These were 815.9 pg/ml before surgery and normalized after the operation.

Topics: Carcinoma, Neuroendocrine; Diagnosis, Differential; Diarrhea; Female; Humans; Middle Aged; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

Neuroendocrine (NE) differentiation in prostate cancer has been correlated with unfavorable clinical outcome. The mechanisms by which prostate cancer acquires NE properties are poorly understood, but several signaling pathways have been proposed. We have previously observed that vasoactive intestinal peptide (VIP) stimulates cAMP production mainly through VPAC(1) receptor, inducing NE differentiation in LNCaP cells. The aim of this study was to analyze the mechanisms involved in this process.. Reverse transcriptase (RT)-polymerase chain reaction (PCR), quantitative real-time RT-PCR, Western blotting, and immunocytochemistry were performed.. LNCaP cells produce VIP, as demonstrated by RT-PCR and immunocytochemistry. VIP induced NE differentiation of LNCaP cells at a time as short as 1 hr of treatment, and the same occurred with the expression and secretion of neuronal-specific enolase (NSE, a NE differentiation marker). These effects were faster than those exerted by serum-deprivation. VIP induced extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation and NE differentiation by PKA-dependent and independent pathways, since the PKA inhibitor H89 partially blocked VIP-induced NE differentiation and did not affect ERK1/2 phosphorylation. mitogen-activated protein kinase kinase (MEK) and phosphoinositide 3-kinase (PI3K) appear to be also involved since the inhibitors PD98059 and wortmannin abolished ERK1/2 phosphorylation and decreased NE differentiation induced by VIP. Moreover, VIP activated Ras suggesting the involvement of a Ras-dependent pathway.. VIP behaves as autocrine/paracrine factor in LNCaP cells by inducing NE differentiation through PKA, ERK1/2, and PI3K.

Topics: Carcinoma, Neuroendocrine; Cell Differentiation; Cell Line, Tumor; Cyclic AMP-Dependent Protein Kinases; Humans; Male; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neuroprotective Agents; Phosphatidylinositol 3-Kinases; Prostatic Neoplasms; Vasoactive Intestinal Peptide

Our goal was to define the incidence of neuroendocrine carcinomas of the colon and rectum, the patterns of neuroendocrine expression, and the cellular subtype within neuroendocrine tumors. We attempted to determine whether differences in neuroendocrine expression or specific cell type influenced survival.. Over a ten-year period, 988 patients had resections for colorectal cancer. Using immunohistochemical staining methods specific for neuroendocrine markers, 39 (3.9 percent) neuroendocrine cancers were identified retrospectively. Tumors were also stained with monoclonal antibody A-80 which is specific for exocrine differentiation. In this way we were able to determine the extent of neuroendocrine differentiation such as pure neuroendocrine, predominant neuroendocrine, and equal neuroendocrine-exocrine expression.. Average patient age was 65.5 (range, 28-89) years; there were 25 males and 14 females. Nineteen tumors were located in the right colon, 11 in the left, and 9 were in the rectum. Three histopathologic patterns were identified: pure neuroendocrine (n = 11), predominantly neuroendocrine (n = 17), and cancers with equal exocrine and neuroendocrine differentiation (n = 7). Three cellular subtypes were seen: small-cell (n = 15), intermediate-cell (n = 15), and well-differentiated neuroendocrine cancers (n = 5). There was one Dukes A cancer, 7 Dukes B, 16 Dukes C, and 15 patients had metastases to distant sites at the time of diagnosis. As a group, neuroendocrine tumors have a poor prognosis: six-month survival was 58 percent, three-year survival was 15 percent, and five-year survival was 6 percent. Survival statistically correlated with tumor stage (P = 0.01) but not with age, sex, tumor location, histopathologic pattern, or neuroendocrine subtypes. Median survival for pure neuroendocrine carcinomas was seven months and for predominantly neuroendocrine carcinomas was five months. Tumors with equal neuroendocrine and exocrine differentiation had a median survival of 22 months (P = 0.3). Small-cell neuroendocrine carcinomas had a median survival of five months, intermediate-cell had 11 months, and well-differentiated had a median survival of 22 months (P = 0.1).. Neuroendocrine differentiation is found in at least 3.9 percent of colon and rectal cancers. Many of these tumors were initially diagnosed as "carcinoids," the diagnosis was changed to "neuroendocrine carcinoma" after immunohistochemical staining. Overall survival is poor especially for small-cell and pure neuroendocrine carcinomas.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Biomarkers, Tumor; Carcinoma, Neuroendocrine; Carcinoma, Small Cell; Colonic Neoplasms; Female; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Phosphopyruvate Hydratase; Rectal Neoplasms; Serotonin; Survival Rate; Time Factors; Vasoactive Intestinal Peptide