Pancreatic Endocrine Carcinoma Research Articles

1336 A Rare Case of a Non-Functioning Pancreatic Neuroendocrine Tumor

INTRODUCTION: Pancreatic neuroendocrine tumors (PNETs) are very rare, representing 1–2% of all pancreatic tumors and 7% of all NETs. 85% of PNETs are non-functional PNETs (NF-PNETs). Most are found incidentally at an advanced stage because patients are asymptomatic and the tumors do not secrete hormones that would manifest with symptoms. We report a case of a 32-yr-old female diagnosed with widely metastatic intermediate grade NF-PNET. For pancreatic neuroendocrine tumors that have metastasized, prognosis is poor, with a survival of only 1–3 years. CASE DESCRIPTION/METHODS: A 32-yr-old female presented with increasing abdominal girth and lower extremity swelling. A CT of abdomen and pelvis showed a massively enlarged liver with diffuse metastases, pancreatic tail mass, vaginal and peritoneal masses, sigmoid colon mass, and gallbladder masses. Core biopsy of her liver showed a metastatic NF-PNET. Following 6 cycles of chemotherapy with capecitabine and temozolomide, repeat CT showed a significant decrease in her pancreatic mass and metastases. Her chromogranin A level decreased from 5800 to 35 ng/dL. Then she had an exploratory laparotomy, lysis of adhesions, and bilateral oopherectomy. Postoperatively she was changed to octeotide and everolimus until MRI showed a progression of her liver metastases. She was switched to 4 cycles of treatment with doxorubicin, 5-fluorouracil (5-FU), and streptozocin as well as Y90 to her liver. Repeat MRI showed stable disease in her liver. DISCUSSION: Based on histology and pathology Ki 67 of 40% and 10 mitoses/10 HPF our patient's tumor was classified as G2 intermediate grade. Our patient had none of the potential risk factors for PNETs. Imaging includes an Octreoscan, negative for our patient, and CT scans in 3 phases. Our patient tested negative for increased levels of all hormones and biomarkers seen with newly diagnosed NETs. Serum levels of CgA are elevated in the 80-90% of patients with advanced NETs and can be used to monitor disease progression and treatment as seen in our case. Surgery is the only treatment proven to prolong survival as seen with our patient. Medical treatment with somatostatin analog octreotide plus chemotherapy regimen of doxorubicin, 5-FU and streptozocin are used for locally advanced and metastatic pancreatic endocrine carcinomas like with our case. This case is important because it illustrates an atypical presentation in a younger patient and it is important for practitioners to be vigilant in diagnosing rare diseases.

Inhibition of Human Pancreatic Cancer Cell Proliferation by Devil's Club Oplopanax horridus and Its Polyacetylene Bioactive Compound

Devil's club Oplopanax horridus (DC) is a close relative of ginseng; its inner root and stem bark extract showed antiproliferation activity on human leukemia, ovarian, breast and colon cancer cells. We study here the effects of DC 70% ethanol extract alone, or in combination with cisplatin, gemcitabine, and paclitaxel on pancreatic endocrine HP62 and pancreatic ductal carcinoma PANC-1 and BxPC-3 cells. Antiproliferation activity assay, cell cycle analysis by flow cytometry, apoptosis-related markers by antibody array, and RT-PCR assay were used for this study. DC extract inhibited proliferation of HP62 with IC50 (50% inhibition concentration) at 0.037±0.002% (v/v), PANC-1 at 0.0058 ± 0.0004% and BxPC-3 at 0.021 ± 0.003%. DC at 0.0033% combined with 1 nM of paclitaxel showed inhibition synergy on PANC-1 cells with a combination index of 0.44. Apoptosis focused antibody array profile indicated upregulation of cytochrome C, claspin, cIAP-2 and HTRA2/Omi apoptosis-related markers in DC-treated HP62 and PANC-1. Our data suggest that DC acts through targeting the intrinsic mitochondrial apoptosis pathway in the pancreatic cancer cells. The high antiproliferation potency of DC on PANC-1 is potentially useful as an adjunct therapy for treating pancreatic cancer, which is known for developing resistance to conventional chemotherapeutics.

Endoscopic Guided Pancreatobiliary Sampling without Rapid On-site Evaluation in One Primary Care Center, Savings or Losses?

s S73 Results: Out of 3832 EUS-FNA, we identified three cases (0.1%) that were diagnosed as acinar cell carcinoma. On cytology, only one was considered possible acinar cell carcinoma. Of the two other cases, one was diagnosed as adenocarcinoma and the other as neoplasm present, with a differential that did not include acinar cell carcinoma. On histology, two cases were diagnosed as acinar cell carcinoma, and the third was diagnosed as ductal adenocarcinoma with acinar differentiation. The PAS stain and IHC studies for trypsin and chymotrypsin show positive staining. Electron microscopy shows cytoplasmic dense zymogen granules, and one case shows elongated filamentous structures that have been reported in association with acinar cell carcinoma. Conclusions: On fine needle aspiration cytology, the differential diagnosis of acinar cell carcinoma of the pancreas includes pancreatic endocrine neoplasm, ductal carcinoma, and solid pseudopapillary neoplasm of the pancreas. In order to differentiate between these neoplasms, one must incorporate the use of ancillary techniques such as IHC. Positive staining for trypsin, chymotrypsin and PAS, along with electron microscopy, are useful markers to indicate the presence of acinar cell differentiation.

Immunohistochemical Analysis of Pancreatic Fine Needle Aspiration Cell Block and Biopsy with SMAD-4 and hENT1

s S73 Results: Out of 3832 EUS-FNA, we identified three cases (0.1%) that were diagnosed as acinar cell carcinoma. On cytology, only one was considered possible acinar cell carcinoma. Of the two other cases, one was diagnosed as adenocarcinoma and the other as neoplasm present, with a differential that did not include acinar cell carcinoma. On histology, two cases were diagnosed as acinar cell carcinoma, and the third was diagnosed as ductal adenocarcinoma with acinar differentiation. The PAS stain and IHC studies for trypsin and chymotrypsin show positive staining. Electron microscopy shows cytoplasmic dense zymogen granules, and one case shows elongated filamentous structures that have been reported in association with acinar cell carcinoma. Conclusions: On fine needle aspiration cytology, the differential diagnosis of acinar cell carcinoma of the pancreas includes pancreatic endocrine neoplasm, ductal carcinoma, and solid pseudopapillary neoplasm of the pancreas. In order to differentiate between these neoplasms, one must incorporate the use of ancillary techniques such as IHC. Positive staining for trypsin, chymotrypsin and PAS, along with electron microscopy, are useful markers to indicate the presence of acinar cell differentiation.

Multiple endocrine neoplasia type 1 associated with breast cancer: A case report and review of the literature.

Multiple endocrine neoplasia type 1 (MEN1) is a cancer predisposition syndrome that includes a combination of endocrine and non-endocrine tumors. The present study reports a rare case of MEN1 associated with breast cancer with the MEN1 gene mutation. A 45-year-old female was diagnosed with breast cancer subsequent to presenting with a right breast mass. Pre-operative radiological studies indicated right breast cancer with a suspicious metastatic nodule of the lung. Further studies demonstrated bilateral thyroid nodules, a neuroendocrine tumor of the pancreas, paraganglioma, a left adrenal adenoma, gallstones, uterine subserosal myoma and pituitary macroadenoma. Laboratory examinations revealed hypercalcemia, hypophosphatemia and an increased intact parathyroid hormone level. The workup for the suspected MEN syndrome revealed an increased basal plasma level of insulin-like growth factor-1, prolactin and calcitonin, and an increased 24-h urinary free cortisol level. The patient underwent surgical removal of the breast cancer and the tumors of the pancreas, adrenal gland, thyroid and parathyroid glands, uterus, anterior mediastinum and lung. The pathological diagnosis of the resected breast was of invasive ductal carcinoma. Otherwise the pathological diagnosis was of calcitonin-producing pancreatic endocrine carcinoma, adrenal cortical adenoma, bilateral papillary thyroid carcinomas, parathyroid adenomas, uterine leiomyoma with adenomyosis, a thymic carcinoid tumor and lung hamatoma. Gene analysis was performed to determine the association between gene mutations and the development of tumors in this patient, and a germ-line MEN1 gene mutation was consequently detected. It could be assumed that MEN1 syndrome may have possibly predisposed the present patient to breast cancer. However, additional observations and further studies are required to demonstrate this association.

Hypomethylation of Long Interspersed Nuclear Element-1 is Involved in the Early Tumorigenesis of Hepatocellular Carcinoma

Objective: Hypomethylation of long interspersed nucleotide elements 1 (LINE-1) promoter has been reported in many cancer types including pancreatic endocrine tumors, colon cancers, and stomach carcinomas. Hypomethylation of LINE-1 is also frequently observed in hepatocellular carcinoma (HCC). However, it still unknown how LINE-1 is involved in the hepatocarcinogenesis. Methods: The level of LINE-1 promoter methylation in 28 HCC was detected by a methylation specific polymerase chain reaction (MSP) at CpG site seven of LINE-1 promoter region (gene bank: X58075). A fractional allelic loss (FAL) of these tumors was evaluated by a combination of loss of heterozygosity with microsatellite markers D4S1545, D4S2920, D8S264, D8S1752, D16S498, D16S514, and p53. The associations between the level of LINE-1 hypomethylation status and the clinico-pathological parameters were finally observed. The clinicopathological parameters were included hepatitis B virus (HBV) status, cirrhosis, tumor size, tumor differentiation and FAL. Results: High level of hypomethylation of LINE-1 promoter was found both in the advanced tumors (>3 cm), (7/18, 39%) and in the early tumors ( 0.535). There were 41% (7/17) tumors with a high level of hypomethylation in the low FAL group and 54.5% (6/11) tumors with a high level of hypomethylation in the high FAL group. No associations between the level of hypomethylation of LINE-1 and HBV infection, age, sex, and cirrhosis were found. Conclusions: These results are strongly suggested that the hypomethylation of LINE-1 plays a role in the hepatocarcinogenesis; moreover, the hypomethylation of LINE-1 occurs not only in the progression of HCC, but also in the early stage of HCC tumorigenesis.

Pancreatic Endocrine Tumour with Disseminated Pulmonary Thromboembolism in an Owl Monkey (Aotus nancymae)

Pulmonary thromboembolism associated with pancreatic endocrine neoplasia is extremely uncommon in man and animals. Post-mortem examination of an adult owl monkey (Aotus nancymae) revealed extensive pulmonary arterial thromboembolism and a well-demarcated mass attached to the pancreas. Microscopically, the mass consisted of areas of interstitial fibrosis with loss of acini and islets and replacement by nests and sheets of polygonal cells with amphophilic cytoplasm, an eccentric round nucleus with stippled chromatin and, in some cells, with a single prominent eccentric nucleolus. Clusters of these cells were noted within vessels and adjacent lymph nodes. The cells did not express S100 or insulin, but were labelled strongly with SP-1/chromogranin. Rare individual cells expressed glucagon and somatostatin. A few cells in pulmonary thrombi/emboli and the adjacent lymph node also expressed SP-1/chromogranin. Based on cell morphology, location and immunohistochemistry the tumour was classified as pancreatic endocrine (islet cell) carcinoma with metastasis to regional lymph nodes and lung.

門脈内腫瘍栓を伴った非機能性膵内分泌癌の1例

門脈内腫瘍栓を伴った非機能性膵内分泌癌の1例

O3-006 - A Phase II Trial of Gemcitabine for Chemo-Naive Metastatic Pancreatic Endocrine Tumor

ABSTRACT Background Pancreatic endocrine carcinoma (PEC) is a fairly rare, heterogeneous disease entity. Gemcitabine is generally well tolerated and is active against pancreatic carcinoma and a wide range of malignancies including small-cell lung carcinoma, which shares many clinicopathological features with neuroendocrine carcinoma. Therefore, we conducted a phase II study of gemcitabine for chemo-naive metastatic pancreatic endocrine carcinoma. Methods Histologically proven chemo-naive PEC patients with an inoperable metastatic clinical stage were enrolled. Gemcitabine (1000 mg/m2) was administered as an intravenous 30-min infusion on days 1, 8, and 15 every 28 days. The primary end point of this study was an objective response. Results Fifteen patients were enrolled between January 2005 and December 2010. The median patient age was 59 years (range, 40–69 years). Ten patients (67%) had well-differentiated endocrine carcinoma (WDEC), and five patients (33%) had poorly differentiated endocrine carcinoma (PDEC, WHO 2004). The most common grade 3 or 4 adverse reactions were neutropenia (47%) and leukocytopenia (27%), although all the adverse reactions were tolerable and reversible. One confirmed radiologic response in a PDEC was observed (7% of all eligible patients and 20% of PDEC). Fourteen of the patients had stable diseases, and none of the patients had progressive disease. The median progression-free survival time and overall survival time of WDEC were 10.6 and 50.4 months. The median progression-free survival time and overall survival time of PDEC were 3.2 and 8.5 months, respectively. Conclusion Gemcitabine monotherapy revealed an insufficient response rate. However, gemcitabine seems to have some potentiality of activity in PDEC. In view of the favorable toxicity profile, its evaluation in combination with other agents might be of particular interest in improving the therapeutic results.

Prolonged Survival in a Patient with Metastatic Vasoactive Intestinal Peptide Producing Pancreatic Neuroendocrine Tumors

VIPomas are rare neuroendocrine tumors that secrete vasoactive intestinal peptide. They are detected in 1 in ten million people per year. The majority of these tumors arises within the pancreas, but may also arise as other VIP-secreting tumors as in bronchogenic carcinoma, colon carcinoma, ganglioneuroblastoma, pheochromocytoma, hepatoma and adrenal tumors. They are characterized by profound diarrhea, hypokalemia, and achlorhydria and were first described by Verner and Morrison in 1958. It was also named pancreatic cholera as the cholera toxin acts; the Vasoactive Intestinal Peptide (VIP) causes elevation of the cyclic adenosine monophosphate, resulting in intestinal smooth muscle relaxation, inhibition of electrolyte absorption and profound secretory diarrhea. We are reporting a case involving a 42 year old male patient who presented with intermittent attacks of watery diarrhea up to 10 times per day for 3 weeks mostly worsening in the last 3 days prior to seeking medical advice. Stool studies were negative, but patient had hyperglycemia and mild hyponatremia. Further evaluation revealed a pancreatic mass with multiple hepatic focal lesions encountered in abdominal ultrasound and CT scan. Ultrasound guided biopsy revealed metastatic pancreatic endocrine carcinoma with VIP expression. Serum VIP level was elevated to 496 (Normal <100). We report a case of metastatic well-differentiated VIPoma treated mainly with long acting octreotide and streptozocin/5fluorouracil combination showing marked improvement of symptoms, minimal response of the tumor size but more significantly, more than 2 year period survival/follow up in a patient that was not a candidate for surgical resection. Review of literature focused on cases with metastatic VIPoma who were not surgical candidates, but had prolonged survival of more than 2 years disease. We reviewed the different therapeutic options offered for this patient population exploring the response rates, survival and recent recommendations.

6557 POSTER Pancreatic Endocrine Carcinoma – Lymph Node Ratio and KI67 Are Predictors of Recurrence After Curative Resections

6557 POSTER Pancreatic Endocrine Carcinoma – Lymph Node Ratio and KI67 Are Predictors of Recurrence After Curative Resections

Phase II study of first-line FOLFIRI for progressive metastatic well-differentiated pancreatic endocrine carcinoma

Background Pancreatic endocrine carcinomas are rare and heterogeneous. Published results concerning treatment of advanced tumours are inconsistent and responses to standard chemotherapy remain unsatisfactory. Aim To investigate the ability of the FOLFIRI regimen to manage progressive unresectable metastatic well-differentiated endocrine carcinomas of the pancreas as first-line chemotherapy. Methods 20 patients with metastatic or advanced well-differentiated endocrine carcinomas of the pancreas and progressive disease were enrolled in a prospective multicentre phase II trial to receive chemotherapy with FOLFIRI schedule (irinotecan 180 mg/m 2 infusion combined with simplified LV5FU2) every 14 days. The primary end point was the non-progression rate at 6 months. Results The 6-month non-progression rate was 80% (95% confidence interval [56–94%]), with stabilisation in 15 patients and 1 objective response. Overall survival at 24 months was 65% [40–82%]. Median progression-free survival was 9.1 months [6.5–17.3 months]. The median number of administered cycles was 12 [range 1–28]. Grade 3/4 haematologic toxicity occurred in 5 patients (25%) and grade 3 digestive toxicity in 11. Conclusion The FOLFIRI regimen, as first-line chemotherapy, achieved stabilisation in most patients whose tumours had been progressing and was well-tolerated. It could be an alternative therapy for advanced well-differentiated endocrine carcinomas of the pancreas.

Metastatic and Locally Advanced Pancreatic Endocrine Carcinomas: Analysis of Factors Associated With Disease Progression

Knowledge of clinical course of pancreatic endocrine carcinomas (PECs) is poor. This study aimed to determine the time to progression of advanced PECs, and to identify predictors capable of selecting subgroups with higher risk of progression. In this multicenter retrospective analysis, patients with advanced PECs were enrolled. Staging was according to European Neuroendocrine Tumors Society guidelines. Grading was based on proliferation index using Ki67 immunohistochemistry. The primary end point was progression-free survival (PFS), which was assessed using the Kaplan-Meier method. The Cox regression proportional hazard model was used to identify predictors for tumor progression. Two hundred two patients with PECs were enrolled, including 172 with well-differentiated and 30 with poorly differentiated endocrine carcinomas. There were 34 patients with stage III and 168 with stage IV tumors. G1 tumors were present in 19.7% of patients, whereas 60.1% of patients had G2 tumors, and the remaining 20.2% had G3 tumors. Disease progression occurred in 166 patients (82.2%), at a median interval of 10 months (interquartile range, 5 to 22) from diagnosis. Median PFS was 14 months. Different PFS were observed depending on G grade (P < .001) and tumor differentiation (P < .001) and in patients who did not receive any antitumor treatment (P = .002). The major risk factor for progression was the proliferation index Ki67 (hazard ratio, 1.02 for each increasing unit; P < .001). Overall 5-year survival was 44.1%. The vast majority of patients with advanced PECs undergo disease progression. The major risk factor for progression is Ki67 index, which should lead physicians dealing with PECs to plan appropriate follow-up programs and therapeutic strategies.

Bilateral adrenocortical carcinoma in a patient with multiple endocrine neoplasia type 1 (MEN1) and a novel mutation in the MEN1 gene

The incidence of adrenal involvement in MEN1 syndrome has been reported between 9 and 45%, while the incidence of adrenocortical carcinoma (ACC) in MEN1 patients has been reported between 2.6 and 6%. In the literature data only unilateral development of ACCs in MEN1 patients has been reported. We report a 31 years-old female MEN1-patient, in whom hyperplasia of the parathyroid glands, prolactinoma, non functioning pancreatic endocrine carcinoma and functioning bilateral adrenal carcinomas were diagnosed. Interestingly, a not previously described in the literature data, novel germline mutation (p.E45V) in exon 2 of MEN1 gene, was detected. The association of exon 2 mutation of the MEN1 gene with bilateral adrenal carcinomas in MEN1 syndrome, should be further investigated.

First‐line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas

Temozolomide is an active agent in metastatic pancreatic endocrine carcinomas. In vitro data indicate that the combination of capecitabine and temozolomide is synergistic for induction of apoptosis in neuroendocrine tumor cell lines. The authors retrospectively evaluated the efficacy of capecitabine and temozolomide in 30 patients with metastatic pancreatic endocrine carcinomas to assess response rate, progression free survival (PFS), and overall survival (OS). Patients with metastatic, well, or moderately differentiated pancreatic endocrine carcinomas who had not received prior systemic chemotherapy were treated with capecitabine (750 mg/m² twice daily, days 1-14) and temozolomide (200 mg/m² once daily, days 10-14) every 28 days. Among 30 patients treated, 21 (70%) patients achieved an objective radiographic response. Median progression-free survival was 18 months. The rate of survival at two years was 92%. Only 4 patients (12%) experienced grade 3 or 4 adverse events. The combination of capecitabine and temozolomide is associated with an exceptionally high and durable response rate in metastatic endocrine carcinomas of the pancreas. Clinical endpoints, including response rate, survival, and toxicity, are superior to those observed with streptozocin-based regimens.

Pancreatic Cystic Endocrine Tumors: A Different Morphological Entity Associated with a Less Aggressive Behavior

Background: Cystic pancreatic endocrine tumors (CPETs) are rare lesions and their biological features have been scarcely investigated. Aim: To compare clinical and pathological features of resected non-functioning sporadic CPETs (NF-CPETs) with solid pancreatic endocrine tumors (SPETs) in a single-institution experience. Methods: All patients with a pathologically confirmed diagnosis of sporadic non-functioning pancreatic endocrine tumors who underwent curative resection between 1990 and 2008 were included. A comparison of demographic, clinical and pathological characteristics between CPETs and SPETs was made. Univariate and multivariable analyses were performed to identify preoperative predictors of carcinoma (non-functioning pancreatic endocrine carcinoma). Results: Twenty-one (11.5%) patients with a histological diagnosis of NF-CPET were identified. The median age was 60 years (IQR 46.5–73.5 years) and a diagnosis of carcinoma (non-functioning pancreatic endocrine carcinoma) was made in 3 (14.3%) cases. In the comparison with NF-SPETs, no differences were found in terms of gender (p = 0.75), age (p = 0.81), presenting symptoms (p = 0.43), localization of the tumors (p = 0.46) and type of resection (p = 0.31). The incidence of non-functioning pancreatic endocrine carcinoma was significantly lower in the NF-CPET versus the NF-SPET group (14.3 vs. 40.4%, p = 0.04). By univariate analysis, preoperative predictors of non-functioning pancreatic endocrine carcinoma included the presence of symptoms (OR 3.96, 95% CI 2.06–7.63) and an increase in the absolute value of radiological diameter (OR 1.05, 95% CI 1.03–1.07). A cystic morphology of the lesion turned out to be a negative predictor of carcinoma (OR 0.25, 95% CI 0.70–0.87). These results were confirmed by multivariable analysis. Conclusions: NF-CPETs have a measurable propensity to be benign. In those patients affected by small and asymptomatic NF-CPET a more conservative surgical approach or a follow-up policy could be considered.

Hepatoid Carcinoma of the Pancreas Combined with Neuroendocrine Carcinoma

Hepatoid carcinoma is a primary extrahepatic carcinoma whose morphology, immunohistochemistry, and behavior are similar to those of hepatocellular carcinoma. The most common sites of extrahepatic carcinoma are the stomach and ovary, but nine cases of hepatocellular differentiation of the pancreas have been reported in the literature. We report another case of hepatoid carcinoma of the pancreas that was associated with the development of a pancreatic endocrine carcinoma in a 46-year-old man. Serum alpha-fetoprotein (AFP) was elevated to 262.49 IU/mL and radiological examinations revealed a mass measuring 7.5 cm in diameter in the head of the pancreas. He underwent a conventional Whipple operation, and light microscopy showed adenocarcinoma that was immunopositive for AFP, hepatocyte antigen, cytokeratin, chromogranin, synaptophysin, and alpha-1 antichymotrypsin. Although hepatoid differentiation was not shown unequivocally histologically, other immunohistochemistry findings supported the diagnosis of hepatoid carcinoma combined with neuroendocrine carcinoma. The patient was healthy and had no evidence of recurrence at 4 months after the surgery. This report describes why hepatoid carcinoma should be considered as a differential diagnosis of a pancreatic mass, especially when serum AFP is elevated.

First-Line Treatment of Metastatic Pancreatic Endocrine Carcinomas With Capecitabine and Temozolomide

Background: Temozolomide is an active agent in metastatic pancreatic endocrine carcinomas. In-vitro data indicates that the combination of capecitabine and temozolomide is synergistic for induction of apoptosis in neuroendocrine tumor cell lines. We evaluated the efficacy of capecitabine and temozolomide in 33 patients with metastatic pancreatic endocrine carcinomas to assess response rate, progression free survival (PFS) and overall survival (OS). Methods: Patients with metastatic, differentiated pancreatic endocrine carcinomas who had not received prior systemic chemotherapy were treated with capecitabine 750 mg/m2 twice daily days 1-14 and temozolomide 200 mg/m2 once daily days 10-14 every 28 days. Response rates were assessed by RECIST criteria. Results: Among 33 patients treated, 22 (67%) patients achieved an objective radiographic response. Median progression-free survival was 18 months. The rate of survival at two years was 92%. Only four patients (12%) experienced grade 3 or 4 adverse events. Conclusion: The combination of capecitabine and temozolomide is associated with an exceptionally high and durable response rate in metastatic endocrine carcinomas of the pancreas. Clinical endpoints, including response rate, survival and toxicity, are superior to those observed with streptozocin-based regimens.

RUNX1T1

Background: Clinical outcome of patients with well-differentiated pancreatic endocrine tumors (PETs) and carcinomas (PECAs) is often difficult to predict based on conventional pathologic characteristics. We identified a set of candidate progression genes with differential expression in the primary PECAs with liver metastases relative to non-metastatic primary PETs by using gene expression profiling and validated the selected candidates by real-time-PCR. One of the leading progression genes was RUNX1T1. The aim of this analysis was to validate the differential expression of RUNX1T1 at the protein level on independent test sets of PETs and PECAs, and determine if loss of RUNX1T1 expression was predictive of liver metastases in well-differentiated primary PETs. Methods: We determined immunohistochemical expression of RUNX1T1 protein in archival PECAs with liver metastases (N = 13) and non-metastatic PETs (N = 24), using a custom tissue microarray. Allred score (0-8) was used as an independent semi-quantitative measure of RUNX1T1 expression by two pathologists. Results: RUNX1T1 protein was expressed by all 37 primary tumors, however, median RUNX1T1 Allred score was 2 (range 2-7) in metastatic PECAs compared to a median of 6 (range 3-8) in non-metastatic PETs (p < 0.0001). Allred scores of ≤4 were observed in 11 of 13 metastatic PECAs, but in only 1 of 24 non-metastatic PETs (p < 0.0001). If an Allred score of ≤4 was considered predictive, the sensitivity of this test for predicting hepatic metastases was 85%, with a specificity of 96%. Low RUNX1T1 expression was highly associated with the presence of hepatic metastases (p < 0.0001), while conventional histologic criteria (Ki67 proliferation index, mitotic rate, presence of necrosis) were only weakly associated with metastases (p = 0.08-0.15). Conclusions: RUNX1T1 is differentially expressed in metastatic pancreatic endocrine carcinomas relative to non-metastatic pancreatic endocrine tumors and is a promising marker for prediction of liver metastases in well-differentiated, primary pancreatic endocrine neoplasms.

RUNXT1 and Palladin Outperform Pathologic Criteria of Malignancy in Predicting Liver Metastases in Primary Pancreatic Endocrine Carcinomas

RUNXT1 and Palladin Outperform Pathologic Criteria of Malignancy in Predicting Liver Metastases in Primary Pancreatic Endocrine Carcinomas