Elevated levels of IGF-1 receptor convey invasive and metastatic capability in a mouse model of pancreatic islet tumorigenesis.

In a prototypical model of multistage tumorigenesis involving pancreatic islets in RIP1-Tag2 transgenic mice, activation of insulin-like growth factor II (IGF-II) was previously shown to serve as a survival factor that inhibited apoptosis. Now IGF-1R, the receptor tyrosine kinase for IGF-II, has been found to be variably upregulated, first uniformly in dysplastic and angiogenic progenitors and then focally at the margins and in invasive regions of carcinomas. When the levels of IGF-1R were forcibly elevated throughout islet tumorigenesis, progression was accelerated at all stages in the pathway, although apoptosis was not differentially suppressed. Notably, encapsulated tumors were absent; instead, invasive carcinomas with downregulated E-cadherin were prevalent, and the majority of mice had local lymph node metastasis.

Immunohistochemical and clinicopathological correlation of the metastasis-associated gene 1 (MTA1) expression in benign and malignant pancreatic endocrine tumors.

Pancreatic endocrine tumors are rare tumors with unpredictable clinical behavior. No histological features or immunohistochemical markers reliably predict malignant progression and the molecular basis of progression of pancreatic endocrine tumors remains unknown. The metastasis-associated gene 1 is thought to play a role in transcription repression and estrogen receptor interaction and is overexpressed in several human cancers, including endocrine neoplasms. The purpose of this study was to analyze the expression of metastasis-associated gene 1 in pancreatic endocrine tumors for its possible role in malignant progression. Twenty-seven pancreatic endocrine tumors were identified from our archive. The mean age at presentation was 57 years (range 28-86); the male/female ratio was 1.25 to 1, and the mean size was 4.5 cm (0.1-18 cm). The clinical follow-up data were examined and tumors were classified according to the 2004 World Health Organization criteria as benign behavior (WHO 1.1), uncertain behavior (WHO 1.2), well-differentiated endocrine carcinoma (WHO 2), and poorly differentiated endocrine carcinoma (WHO 3). Histopathological and immunohistochemical stains were evaluated and metastasis-associated gene 1 expression scored semiquantitatively as absent (1+), weak (2+), moderate (3+), or strong (4+). Statistical analysis was performed using Kruskal-Wallis nonparametric analysis of variance with a significance level of 0.05. Metastasis-associated gene 1 expression was significantly higher in malignant tumors (n=17) with a mean staining intensity of 3.8 compared with 2.9 in benign tumors (n=10, P=0.046). The expression levels were significantly associated with WHO class (P=0.028), as well as size of tumor (P=0.029), and mitotic rate (P=0.035). Metastasis-associated gene 1 expression was associated with local invasion with borderline significance (0.062). We show that metastasis-associated gene 1 expression is significantly associated with malignant behavior in pancreatic endocrine tumors. This may suggest a potential role for metastasis-associated gene 1 in the malignant progression and metastasis and its use as biomarker for malignant pancreatic endocrine tumors.

Functional MRI evaluation of tumor response in patients with neuroendocrine hepatic metastasis treated with transcatheter arterial chemoembolization.

OBJECTIVE: The purpose of this study was to evaluate contrast-enhanced and diffusion-weighted MRI changes in neuroendocrine tumors treated with transcatheter arterial chemoembolization (TACE). MATERIALS AND METHODS: Sixty-six targeted lesions in 26 patients (18 men, eight women; mean age, 57 years) with hepatic metastasis of neuroendocrine tumors treated with TACE were retrospectively analyzed. MRI studies were performed before and after TACE. Imaging features included tumor size, percentage of enhancement in the arterial and portal venous phases, and diffusion-weighted imaging apparent diffusion coefficients (ADCs) of the tumor, liver, and spleen. Tumor response to treatment was recorded according to World Health Organization criteria and Response Evaluation Criteria in Solid Tumors. Liver function tests were performed, and clinical performance was assessed before and after treatment. Statistical analysis included paired Student's t tests and Kaplan-Meier survival curves. RESULTS: Mean tumor size and percentage enhancement in the arterial and portal venous phases decreased significantly after treatment (p < 0.0001). The tumor ADC increased from 1.51 x 10(-3) mm2/s before treatment to 1.79 x 10(-3) mm2/s after treatment (p < 0.0001), but the ADCs for the liver and spleen remained unchanged. Despite the change in tumor size, no patient in this cohort achieved complete response according to World Health Organization criteria and Response Evaluation Criteria in Solid Tumors. Partial response was achieved in only 27% and 23% of the patients according to the respective criteria. Results of liver function tests and performance status also remained unchanged. The mean survival period for all patients was 78 months. CONCLUSION: Contrast-enhanced and diffusion-weighted imaging showed significant changes after TACE of neuroendocrine tumors and can be used to assess response of targeted tumors.

[Case of pancreatic endocrine tumor associated with Cushing's syndrome].

A 78-year-old woman was admitted complaining of edema of the bilateral lower extremities and face. Computed tomography (CT) and ultrasonography (US) of her abdomen revealed a pancreatic tumor and multiple liver metastases. After admission, hypokalemia and muscle weakness and edema of the bilateral lower extremities rapidly worsened. The diagnosis of Cushing's syndrome was established based on clinical and biochemical data and endocrine studies. We thought that the primary tumor was a pancreatic endocrine tumor based on the liver tumor biopsy findings, and that the pancreatic tumor and liver metastatic tumors were ectopic ACTH-producing tumors. A case of pancreatic endocrine tumor associated with Cushing's syndrome is relatively rare. We summarize previous reports.

Intraductal spread by metastatic islet cell tumor (well-differentiated pancreatic endocrine neoplasm) involving the breast of a child, mimicking a primary mammary carcinoma.

Metastases to the breast are rare, accounting for an estimated 1% to 2% of malignant breast neoplasms. The key histopathologic features supporting a metastasis to the breast have been stated to be the absence of elastosis, presence of a pushing border (circumscribed lesion), multiple satellite foci, lymphatic emboli, and, most importantly, the absence of an in situ carcinoma component. We report a unique case of a pancreatic islet cell tumor metastatic to the breast of an 18-year-old girl. Clinically, the patient was thought to have a mammary primary because on her initial biopsy, the metastasis grew within mammary ducts and colonized a complex sclerosing lesion, simulating an in situ component. However, review of slides from the prior pancreatic neoplasm, review of slides from the subsequent mastectomy, and use of immunohistochemistry allowed recognition of the lesion as a metastasis, which proved to be the first clinical manifestation of a systemic relapse. To our knowledge, this is the second case of islet cell tumor reported to metastasize to the breast, and the first report of a metastasis proven to have grown within existing ducts of the breast by immunohistochemistry.

The predictive value of CK19 and CD99 in pancreatic endocrine tumors.

Prediction of behavior in pancreatic endocrine tumors (PETs) is reliant on clinicopathologic features. However, there remains a cohort of PETs that behave aggressively despite showing indolent pathologic features. Recently, it has been suggested that CK19 and CD99 are sensitive ancillary markers that predict outcome in PETs. An analysis of 54 PETs and 2 resected liver metastases was undertaken to examine the relationship of CK19 and CD99 and the pathologic criteria in the WHO classification of PETs. CK19 was found to correlate with mitotic count (>5/50 high-power fields), an MIB-1 labeling index of > or =2%, lymphovascular/perineural permeation, lymph node involvement, and liver spread. Although not statistically significant, CK19-negative tumors tended to be smaller than the average tumor size in the series (2.5 vs. 3.6 cm). CD99 did not show any significant correlation with any of the WHO criteria. Tumors that are confined to the pancreas with low mitotic count and MIB-1 labeling index, tended to be CD99-positive. Both CK 19 (negative) and CD99 (positive) correlated with insulin-positive PETs. In conclusion, CK 19 may prove to be a useful ancillary diagnostic test in the routine work-up of PETs. CD99 does not appear to be as useful. There is no compelling evidence, from our study, to suggest that both these markers may be used in concert to predict the behavior of PETs.

Differences in survival for patients with resectable versus unresectable metastases from pancreatic islet cell cancer.

Well-differentiated islet cell tumors can be associated with aggressive biology, resulting in early metastases to the liver. This study was carried out to determine whether survival for patients with malignant islet cell tumors and synchronous liver metastases is affected by complete surgical resection. Thirty-one patients with synchronous liver metastases from islet cell cancer underwent surgical exploration with the intent for complete tumor resection, and all patients underwent resection of the pancreatic primary. The patients were divided into two groups, those with resectable versus unresectable liver metastases. Twenty-six of 31 (84%) patients underwent complete resection of both the primary tumor and all liver metastases, and 5 (16%) patients underwent only complete resection of the pancreatic primary without liver resection. To extirpate the primary tumor, a pancreaticoduodenectomy was performed in 11 of the 26 (42%) completely resected patients and in 4 of the 5 (80%) incompletely resected patients, P = NS. The remainder of the patients underwent distal pancreatectomy. There were no statistical differences in primary tumor size, lymph node metastases, or adjuvant treatments between patients with resected and unresected liver metastases. The median overall survival for the completely resected group was 78 months, longer than the 17 months for the group with unresectable liver metastases (P = 0.06). Complete tumor resection (or the tumor biology that allows such complete resection) affords a survival advantage to patients with metastatic islet cell tumors of the pancreas. Patterns of liver metastases from islet cell tumors, specifically multiple bilobar metastases that are not amenable to resection and/or ablation, predict a poor outcome despite resection of the primary pancreatic tumor.

Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas.

PURPOSE: The role of systemic chemotherapy in the management of pancreatic endocrine carcinoma (islet cell carcinoma; PEC) is an area of considerable controversy. Response rates ranging from 6% to 69% have been reported for streptozocin-based chemotherapy. We retrospectively studied 84 patients with locally advanced or metastatic PEC who had been treated with fluorouracil, doxorubicin, and streptozocin (FAS) to determine the objective response rate, duration of progression-free survival (PFS), and duration of overall survival (OS). PATIENTS AND METHODS: Eligible patients had histologic or cytologic confirmation of their tumor and measurable disease on computed tomography or magnetic resonance imaging scans. Response to treatment was evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors Committee. RESULTS: Sixty-one of the patients were male and 23 were female, with a median age of 54 years (range, 24 to 78 years). The response rate (RR) to FAS was 39%, with a median response duration of 9.3 months. The 2-year PFS rate was 41%, and the 2-year OS rate was 74%. The extent of liver metastatic disease correlated with a worse PFS (P = .01 by log-rank test) and a worse OS (P < .0001 by log-rank test). Analyses showed that metastatic replacement of more than 75% of the liver and prior chemotherapy were independently associated with inferior PFS. CONCLUSION: Patients with locally advanced or metastatic PEC who are treated with FAS may have a reasonable RR, and responders may experience longer PFS and OS. The volume of metastases in the liver is the most important predictor of outcome.

Pathological assessment of pancreatic endocrine tumors for metastatic potential and clinical prognosis.

The prognostic significance of several pathological factors (tumor size, mitotic index, Ki-67 labeling index, and vascular invasion) and expression of exocrine markers (CA19-9, CEA, AFP, and trypsin) in pancreatic endocrine tumors was studied. A total of 20 specimens of metastasizing (n = 10) and non-metastasizing (n = 10) tumors were subjected to histological and immunohistochemical examination. The metastasizing tumors showed significantly larger size, higher Ki-67 labeling index, increased number of mitotic cells, and more frequent vascular invasion in comparison with the non-metastasizing tumors. It was difficult to determine the effect of individual factors on clinical outcome because of slow disease progression in almost all cases. Numerous mitotic cells and widespread necrosis, however, were thought to indicate a poor prognosis, and tumors with these characteristics were regarded as high-grade malignant endocrine carcinomas. In one case, one-third of the tumor tissue comprised trypsin-positive cells, the outcome was comparatively poor, and the behavior of the tumor resembled that of mixed acinar-endocrine carcinoma. A simple multifactorial approach may be effective for the identification of tumors at increased risk of metastasis, but it remains difficult to determine clinical prognosis. It is essential to at least distinguish high-grade endocrine carcinomas from the more common endocrine tumors.

Neuroendocrine carcinomas of the pancreas with 'Rhabdoid' features.

Neuroendocrine carcinomas of the pancreas are rare neoplasms whose morphologic features generally mirror those seen in neuroendocrine tumors in other organs. Rarely, however, they may display unusual morphologic appearances that can introduce difficulties for diagnosis. We report four cases of primary neuroendocrine carcinomas of the pancreas (islet cell tumors) that were characterized by prominent "rhabdoid" features of the tumor cells. The lesions occurred in two men and two women 37-79 years of age who presented with symptoms of biliary obstruction and epigastric pain; one patient had recurrent gastric ulcers and an elevated gastrin level. The tumors were located in the head and tail of the pancreas and measured 2.5-4.5 cm in greatest diameter. Histologic examination revealed sheets of monotonous tumor cells with uniform round nuclei showing dispersed chromatin and containing abundant densely eosinophilic cytoplasmic inclusions that displaced the nuclei toward the periphery. In all cases, the rhabdoid elements appeared to merge with areas showing a more conventional neuroendocrine morphology. Immunohistochemical studies in all cases showed strong cytoplasmic positivity of the rhabdoid tumor cells for chromogranin, synaptophysin, and cytokeratin. Recognition of this unusual morphologic appearance is of importance to avoid mistaking these lesions for other types of malignant neoplasm.

Dpc4 is expressed in virtually all primary and metastatic pancreatic endocrine carcinomas.

DPC4/Smad4 is inactivated in about 50% of pancreatic ductal cancers. It has been recently reported that this gene is also inactivated in neoplasms arising from pancreatic islet cells, a phenomenon suggested to be related to similar progressions of malignancy found in common ductal cancers. To evaluate this possibility, we analysed 20 metastases of pancreatic endocrine carcinomas and their corresponding primary lesion for inactivation of DPC4 using immunohistochemical staining. In fact, immunohistochemical labelling has been shown to correlate with DPC4 gene status with high sensitivity and specificity. The cancers included 18 nonfunctioning tumours, one gastrinoma and one ViPoma all with liver, nodal and/or adrenal metastases. Seventeen were well-differentiated and three poorly differentiated endocrine carcinomas. Dpc4 expression was absent in only one primary well-differentiated endocrine cancer and its liver metastasis, while all the remaining 19 primary tumours and their metastases stained positive for the protein. All positively staining cases showed diffuse cytoplasmic and nuclear staining in virtually all neoplastic cells. Our data suggest that DPC4 is only rarely involved in pancreatic endocrine tumourigenesis and give further weight to the hypothesis that tumours arising from pancreatic exocrine and endocrine epithelia are genetically distinct.

Isolation, maintenance, and characterization of human pancreatic islet tumor cells expressing vasoactive intestinal peptide.

Tissue from a vasoactive intestinal peptide (VIP)-secreting human tumor has been used to establish and characterize human neuroendocrine primary cell cultures from which permanent, clone-derived cell lines have been established. Viable cells were obtained by enzymatic and mechanical dissociation of freshly resected pancreatic islet tumor and hepatic metastatic tumor tissues. Aliquots of tumor cells were established ex vivo under culture conditions including porous substrata coated with type IV collagen and laminin and a low serum, hormonally defined culture medium. The small (<10 microm) rounded, grape-like cells had a very slow growth rate of doubling times estimated at several weeks or more. After several passages, morphologically uniform cells were derived that strongly expressed neuroendocrine markers of synaptophysin and synaptobrevin. Although chromogranin A and VIP had somewhat weaker expression, both demonstrated phorbol ester-stimulated secretion. The morphologic and secretory properties were maintained by the cells for nearly 2 years in culture. The establishment of this novel VIP-secreting human neuroendocrine cell line (HuNET) makes available a culture model with which to study a transformed version of this pancreatic islet cell type and offers approaches by which to establish islet tumor cell lines.

Multiple intracerebral metastases from an islet cell carcinoma of the pancreas: case report.

Computed tomography and magnetic resonance imaging of an 85-year-old woman with bitemporal headaches revealed cystic lesions in the basal ganglia and cerebellum. The patient remained neurologically asymptomatic until just before her death at age 89. Autopsy revealed tumors of the brain, lungs, liver, periaortic lymph nodes, adrenal gland, and the pancreas. Light microscopy demonstrated a malignant small cell tumor with scant cytoplasm. Electron microscopy revealed intracytoplasmic dense core vesicles, characteristic of neuroendocrine tumors, which prompted the diagnosis of islet cell carcinoma. All lesions were found to be microscopically similar. Previous reports of islet cell carcinoma metastatic to the brain could not be found. This case emphasizes the importance of electron microscopy in cases of small cell neoplasms in the brain.

Hepatic arterial chemoembolization with streptozotocin in patients with metastatic digestive endocrine tumours.

BACKGROUND: Hepatic arterial chemoembolization (CE) with anthracyclines is an effective treatment for progressive liver metastases of digestive endocrine tumours. Streptozotocin (STZ) is widely used for systemic chemotherapy, but its efficacy by the hepatic arterial route has not been evaluated. PATIENTS AND METHODS: Fifteen consecutive patients, mean age 57.8 years, were prospectively included between July 1993 and January 1997. All patients had progressive liver metastases from either a carcinoid tumour (eight patients) or an islet cell carcinoma (ICC) (seven patients) that had increased in size (> or = 25%) before CE. Five patients had the carcinoid syndrome. STZ was administered, as an emulsion with iodized oil, into the hepatic artery before embolization with gelatin sponge particles. Two to six procedures (median, 3) were performed in 12 patients (one in three patients). Changes in the size of the liver metastases were evaluated by CT scan or MRI according to WHO criteria. The median follow-up was 15 months (1-50). RESULTS: An objective response was achieved in 8/15 patients (53%; median duration of 10.5 months) whatever the primary tumour (carcinoid or ICC). The carcinoid syndrome disappeared in 3/5 patients for 10, 11 and 17 months, respectively. CE effectively controlled hypoglycaemic attacks (decrease of > 50%) in the patient with insulinoma. The biological response was complete in four patients for a median duration of 7 months. CE induced minor side effects, namely nausea, fever and abdominal pain. Acute and reversible tubular necrosis due to CE was observed in one patient who had previously undergone a nephrectomy. CONCLUSION: Hepatic arterial chemoembolization with STZ is an effective treatment for patients with liver metastases caused by digestive endocrine tumours.

Fine needle aspiration diagnosis of neuroendocrine tumors in the liver.

Ten neuroendocrine tumors (NET) in the liver are presented, in which the diagnosis was made on fine needle aspiration cytology and cell blocks from the aspirate. In seven of the patients with liver metastasis, a biopsy-proven extrahepatic primary NET had been previously diagnosed, while in three patients no extrahepatic neoplasm could be identified, suggesting that the NET may have been a primary in the liver. Based on cytomorphological findings the cases were typed as either round cell type, spindle cell type or polygonal cell type. In all cases, immunopositivity for neuroendocrine markers provided reliable evidence of the cell of origin and distinguished them from well-differentiated hepatocellular carcinoma, adenocarcinomas and other neoplasms, which sometimes may present a diagnostic dilemma.

Laparoscopic resection of a pancreatic polypeptidoma with a solitary liver metastasis.

Pancreatic neuroendocrine tumor is an uncommon disease, and surgery is the only potentially curative treatment even when there is hepatic metastasis. A patient undergoing concomitant laparoscopic distal pancreatectomy and hepatectomy for pancreatic polypeptidoma with a solitary liver metastasis is reported.

Doxorubicin, streptozocin, and 5-fluorouracil chemotherapy for patients with metastatic islet-cell carcinoma.

Metastatic islet-cell carcinoma is considered to be a slow-growing tumor. Patients are considered for systemic chemotherapy only when they are symptomatic or have impending organ failure, and streptozocin has been the chemotherapeutic agent of choice for the treatment of this disease. Chemotherapy regimens that include streptozocin have shown a higher response rate and a longer duration of response when compared with streptozocin alone. This study evaluates the objective response, response duration, and survival in patients having metastatic islet-cell carcinoma treated with a combination of doxorubicin, streptozocin, and 5-fluorouracil (DSF). Between January 1993 and March 1996, 12 patients were treated with doxorubicin, 40 mg/m2 intravenous bolus on day 1; streptozocin, 400 mg/m2 intravenous bolus on days 1 through 5; and 5-FU, 400 mg/m2 intravenous bolus on days 1 through 5. Courses were repeated every 28 days. Patients were required to have measurable disease, a Zubrod performance status < or = 2, adequate renal and liver function, and a survival expectancy of at least 12 weeks. Six (54.5%) of 11 evaluable patients achieved a partial response (durations in months: 1+, 3.5+, 13+, 17, 22, 26+); one had a minor response, two had stable disease, and two had progressive disease. One patient was lost to follow-up. No complete responses were observed. The median response duration was 15+ months and the median survival 21+ months (range, 3 to 32.5 months). No grade 3 or 4 nonhematologic or hematologic effects were observed. The DSF regimen appears to have significant activity in patients who have metastatic pancreatic islet-cell carcinoma, and patient tolerance of the regimen is excellent, thus warranting further investigation.

Expression of somatostatin receptor subtypes 1 to 5 in tumor tissue and intratumoral vessels in malignant endocrine pancreatic tumors.

Somatostatin analogs are well established in the treatment of malignant endocrine pancreatic tumors (EPTs). Our goal is to individualize their treatment using receptor-subtype-specific analogs and, therefore, exploring the receptor expression is highly important. We have examined the expression of somatostatin receptor (sst) subtypes 1-5 on tumor cells and in intratumoral vessels in 28 tumor tissues from malignant EPTs with immunohistochemistry using sst-subtype-specific polyclonal antibodies. We found that sst(2) and sst(4) stained positive in 90% and sst(1) in 70% of the tumor tissues, whereas sst(3) and sst(5) stained positive in only 50% of the tumor tissues. Sst expression in intratumoral vessels was high for sst(2) and sst(4) (80%), moderate for sst(1) (40%), and low for sst(3) and sst(5) (10%). The ssts were evenly distributed among the different tumor subtypes. However, tumors belonging to the same subgroup of EPTs showed a variable expression of receptor subtypes. No differences in receptor-subtype expression could be seen between poorly and welldifferentiated tumors, nor between primary tumors and metastases. Prior medical treatment did not influence sst expression pattern. In conclusion, sst(2) and sst(4) were expressed in most tumor tissues and intratumoral vessels from EPTs. However, sst(3) and sst(5) were lacking in half of the tumor tissues and in most of the intratumoral vessels. These differences indicate the importance of determining each tumor s subset of receptors before treatment with receptor-subtype-specific analogs is initiated. The importance of sst expression in intratumoral vessels is not yet known.

Mixed ductal-endocrine carcinoma of the pancreas: a possible pathogenic mechanism for arrhythmogenic right ventricular cardiomyopathy.

We describe herein a case of a mixed ductal-endocrine pancreatic carcinoma. Rare cases of mixed pancreatic tumors have been described, with endocrine and exocrine components each making up a significant proportion of the neoplasm; to our knowledge, only one case has been reported with a mixed liver metastasis. In our case, ductal and endocrine cells were intimately admixed in the primary tumor and in a peripancreatic lymph node metastasis, diagnosed by standard light microscopy and double immunostaining for cytokeratin 19 and synaptophysin. The endocrine component was immunoreactive for somatostatin. Tumors with admixed endocrine and exocrine components support the hypothesis of a common endodermal histogenesis for the ductal and endocrine cells in the human pancreas.

Natural history of a patient with malignant nonfunctioning islet cell tumor associated with unresectable multiple liver metastases.

Islet cell tumors of the pancreas are uncommon. Approximately 15% of islet cell tumors are nonfunctioning and have a higher malignancy rate than their functioning counterparts. Though, because of the rarity of malignant nonfunctioning islet cell tumors, the natural history of a patient with this tumor has not been clearly defined. We describe a young patient with unresectable malignant nonfunctioning islet cell tumor associated with multiple liver metastases. He was treated with palliative therapies to improve his quality of life, but did not undergo surgical removal of tumors or systemic chemotherapy. He survived for 46 months since laparotomy for histological diagnosis. Our findings may represent the natural history of patients with unresectable malignant nonfunctioning islet cell tumor, and suggest that palliative therapy may contribute not only to the improvement of a patients' quality of life but also the prolongation of survival.