Well-differentiated Endocrine Carcinoma Research Articles

First case of huge classic papillary thyroid cancer rupturing spontaneously leading to ischemic necrosis, perforation and inflammation of overlying skin: Case report and review of the literature.

IntroductionPapillary thyroid cancer (PTC) is the commonest form of well-differentiated endocrine carcinoma. It is categorized into indolent and aggressive, where the indolent subtypes (classic, follicular) rarely demonstrate aggressive behavior. We present a classic PTC presenting with a rapidly growing huge anterior neck mass that subsequently spontaneously ruptured subcutaneously resulting in ischemia, necrosis, and perforation of overlying skin leading to inflammation.Presentation of caseA 37-year-old female with no comorbidities presented to our emergency department with a neck swelling of 2 years duration that rapidly enlarged one week prior to presentation. Though the mass initially appeared of inflammatory nature, the tumor was a PTC, and she underwent total thyroidectomy with selective right side neck dissection and debridement of necrotic skin. The gross specimen revealed a fragmented non-intact right thyroid lobe mass causing pressure ischemia, necrosis and perforation of the skin. Histopathology showed a 9 × 9 × 5 cm classic PTC staged as pT3b N1b. Postoperative course was uneventful, she was discharged by the eighth postoperative day, and then she received a high dose of radioactive iodine ablation (RAI).DiscussionClassic PTC is usually of a smaller size and a relatively benign course compared to other PTC subtypes and thyroid cancers. It is indolent with favorable prognosis. Although it is associated with increased risk of lymph node metastases at the time of diagnosis, it is slow growing with high survival rates approaching 95%.ConclusionDespite that classic PTC progresses slowly, it should still be suspected in neck swellings presenting with rapid and aggressive behavior. Prompt and systematic assessment is required with surgical intervention and radioactive iodine ablation therapy.

P53, KI-67, CD117 expression in gastrointestinal and pancreatic neuroendocrine tumours and evaluation of their correlation with clinicopathological and prognostic parameters.

Gastrointestinal and pancreatic neuroendocrine tumors (GEPNETs) originate from the cells of the endocrine system. Their molecular genetic mechanism of development and progression is complex and remains largely unknown. The purpose of this study was to review the gastrointestinal and pancreatic neuroendocrine tumors and to evaluate p53, Ki-67 and CD 117 expressions with their clinicopathological correlations. Twenty-one patients were reviewed and classified as having well-differentiated neuroendocrine neoplasm (WDET, Grade I), well-differentiated neuroendocrine carcinoma (WDEC, Grade II) and poorly differentiated neuroendocrine carcinoma (PDEC, Grade III). We performed immunohistochemical tests to characterize the expession of the immunoreactivity for synaptophysin, chromogranin, p53, Ki67 and CD 117. Median age of 21 patients was 43 years. Thirteen (61.9%) patients were male and eight (38.1%) patients were female. Tumors were located in the stomach (38.1%), appendix (38.1%), duodenum (4.8%), ileum (4.8%), colon (9.5%), and pancreas (4.8%). There was a statistically significant difference between well-differentiated endocrine neoplasm (Grade I), and well-differentiated endocrine carcinoma (WDEC, Grade II) and PDEC for Ki-67 >20% (p<0.001) (Pearson chi-square test). There was a statistically significant difference between WDET (Grade I), WDEC (Grade II) and PDEC (Grade III) for p53 positivity (p<0.05) (Pearson chi-square test).

Prognostic Value of Volume-Based Metabolic Parameters Measured by (18)F-FDG PET/CT of Pancreatic Neuroendocrine Tumors.

To date, the prognostic value of (18)F-FDG PET/CT for patients with pancreatic neuroendocrine tumors (PNETs) has not been well characterized. We investigated the prognostic value of volumetric parameters using (18)F-FDG PET/CT in this patient population. We retrospectively reviewed 20 cases of pathologically proven PNET in patients who had undergone pre-therapeutic (18)F-FDG PET/CT. PET parameters including maximum and average standardized uptake values (SUVmax, SUVave), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the primary tumor were measured using a threshold SUV to determine the boundaries of the tumors. Univariate and multivariate survival analyses were performed with adjustments for PET parameters and other clinical values. The median clinical follow-up was 22.3 (range, 1.2-95.4)months. Cancer-related death occurred in 5 of 20 patients (25%). Patients had clinical or pathological stages of I in seven patients, II in six patients, III in three patient, and IV in four patients. According to the WHO histological classification of subtypes, 3 patients exhibited well-differentiated PNETs, 13 patients had well-differentiated endocrine carcinomas, and 4 had poorly differentiatedendocrine carcinomas. Univariate analysis showed that tumor size (p = 0.028), AJCC stage (p = 0.009), T stage (p = 0.028), M stage (p = 0.029), treatment modality (p = 0.045), MTV (p = 0.003) and TLG (p = 0.027) were significant predictors of overall survival. On multivariate analysis, MTV (HR = 10.859, p = 0.031) was a significant independent predictor of overall survival along with the AJCC stage (HR = 11.556, p = 0.027). In patients with PNETs, the MTV of the primary tumor as measured by (18)F-FDG PET/CT along with the AJCC stage may be a significant independent prognostic factor for overall survival.

Pancreatic neuroendocrine tumors: an analysis of 88 patients

Objective To analyze the clinicopathological characteristics,diagnosis,treatment outcomes and prognosis of patients with pancreatic neuroendocrine tumors (PanNETs).Methods The clinicopathological characteristcs and prognostic factors of 88 patients who were diagnosed with pancreatic neuroendocrine tumors by postoperative pathology were analyzed retrospectively.The data included age,sex,symptoms,tumor size,pathological grades,TNM staging,treatment and follow up.Results There were 28 males and 60 females.The ratio of male to female was 1 ∶ 2.1,with a mean age of 42 (range 8～75) years.Of the 88 PanNETs,74(84.1％) were nonfunctional tumors.Using the WHO 2000 pathological classification system,there were 35 well differentiated endocrine tumors (WDET),29 well differentiated endocrine carcinomas (WDEC),and 24 poorly differentiated endocrine carcinomas (PDEC).Using the 7th AJCC TNM staging system,23(26.1％),46(52.3％),13(14.8％) and 6 patients (6.8％) were diagnosed to have stage Ⅰ,Ⅱ,Ⅲ and Ⅳ,respectively.The overall 5-year survival rate was 72.0 ％.Univariable analysis revealed tumor size,histopathological grades,TNM staging and radical surgery were associated with prognosis.Multivariate analysis showed histopathological grades,TNM staging and radical surgery were independent risk factors of survival.Conclusions PanNETs are rare pancreatic neoplasms with high heterogeneity and low malignant potential.PanNETs have various clinical manifestations and the preoperative misdiagnosis rate is high.A definitive diagnosis depends on pathological examination.The new TNM and pathological classification systems have good predictive abilities on survival.The majority of patients who received radical surgery or surgical comprehensive therapy have good prognosis. Key words: Pancreatic neoplasms; Diagnosis; Therapy; Prognosis

Comparison of WHO Classifications (2004, 2010), the Hochwald Grading System, and AJCC and ENETS Staging Systems in Predicting Prognosis in Locoregional Well-differentiated Pancreatic Neuroendocrine Tumors

It is difficult to predict prognosis in patients with locoregional well-differentiated (WD) pancreatic neuroendocrine tumors (PanNET). We aimed to examine commonly used stratification systems [World Health organization (WHO) 2004 and 2010 classifications, American Joint Committee on Cancer (AJCC) and European Neuroendocrine Tumor Society (ENETS) staging, and the Hochwald grading system] for their power in predicting recurrence-free survival (RFS) in these patients. Seventy-five such patients (mean age 56 y, mean follow-up 79 mo) who underwent resection with sufficient tissue material and follow-up data were studied. RFS was correlated with variable clinicopathologic features and stratified with above-mentioned systems. Concordance index (CI) was then calculated. With the WHO 2004 classification, 16, 35, and 24 PanNETs were classified as benign behavior, uncertain behavior, and WD endocrine carcinoma, respectively. By the WHO 2010 classification, 26, 41, and 8 tumors were grade 1, 2, and 3, respectively. Using the Hochwald system, 47 were low grade, and 28 were intermediate grade. The AJCC staging information was complete for 62 patients (13 had the lymph node status Nx) and included: stages IA (19/62), IB (10/62), IIA (10/62), and IIB (23/62). The ENETS staging information was stages I (16/62), IIa (8/62), IIb (14/62), IIIa (0/62), and IIIb (24/62). The average Ki-67 proliferation index (PI) was 8.1%. Factors that predicted RFS included tumor size, nodal metastasis, vascular invasion, perineural invasion, necrosis, mitosis, and Ki-67 PI (all P<0.01). The CI for each system was: 0.6361 for WHO 2004, 0.6735 for WHO 2010, 0.6495 for AJCC staging, 0.6642 for ENETS staging, and 0.6851 for the Hochwald grading system. When these systems were analyzed in conjunction with various additional important pathologic features, combination of the Hochwald grading system and Ki-67 PI achieved the highest CI (0.7946). Therefore, although all these systems predict RFS well in locoregional WD PanNETs, the Hochwald grading system achieves the highest predictive ability. Further predictive power can be achieved by combining the Hochwald grading system and Ki-67 PI.

An unusual case of metastatic well-differentiated endocrine carcinoma (carcinoid syndrome) presenting with a telangiectatic rash and flushing

An unusual case of metastatic well-differentiated endocrine carcinoma (carcinoid syndrome) presenting with a telangiectatic rash and flushing

Well-Differentiated Endocrine Carcinoma Originating From the Bile Duct in Association With a Congenital Choledochal Cyst

We encountered a rare case of a well-differentiated endocrine carcinoma originating from the bile duct in association with a congenital choledochal cyst (CCC). The patient is a 28-year-old woman referred to our clinic for pruritus. Laboratory data showed mild elevation of serum hepatobiliary enzymes. Computed tomography and magnetic resonance imaging demonstrated pancreatobiliary maljunction and a Todani type IV-A CCC from the inferior bile duct to the bilateral intrahepatic bile ducts. A solid tumor was detected in the middle portion of the common bile duct. Pancreatoduodenectomy and total extrahepatic bile duct resection was performed. Based on pathologic and immunohistochemical examinations, a diagnosis of well-differentiated endocrine carcinoma was made according to the World Health Organization criteria. To our knowledge, this is the third report of a neuroendocrine tumor originating from the bile duct in association with a CCC.

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.

1164P - Somatostatin Receptor (SSTR) Expression and Proliferative Index (KI 67) in 100 Patients (PTS) with Gastroenteropancreatic Neuroendocrine Tumors (Gep-Nets). Clinical-Pathological Correlation

ABSTRACT Introduction The expression of somatostatin receptors, mainly subtype 2 and 5 is a characteristic of well-differentiated GEP-NET. Its expression has prognostic and predictive implications for the use of somatostatin analogs. The Ki 67 is a nuclear antigen associated with cell proliferation, present during the cycle phases (G1, S, G2 and M). Objectives To describe the expression of SSTR, and Ki-67 in patients with GEP-NET. To evaluate in this population the correlation between the expression pattern of the 5 SSTR subtypes, Ki-67 and survival. Material and methods We performed the analysis on 100 pts. diagnosed with a GEP -NET, included in the database of Argentum Group. In all cases, was centralized pathology review to confirm the diagnosis. The survival analysis was performed by the Kaplan-Meier method. Log-rank was used to test the comparative analysis of the variables of interest in the study. Results We analyzed 100 pts: 73 pts. Well-Differentiated Endocrine Carcinoma (WDEC), 17 pts Had Well-differentiated neuroendocrine tumors (WDET) and 10 pts. Poorly differentiated endocrine carcinoma (PDEC). Age (median) 54 a. (r 18-84). Primary Location: small intestine 40, pancreas 26 pts. Appendix 9 pts., Stomach 8, rectum 6, unknown 6, colon 4, and esophagus 1 pte. Metastatic disease 76 pts., Localized disease in 24 pts. The expression of SSTR was: Subtype 2 (positive 80 pts.) and subtype 5 (positive 46 pts.). Ki 67 was less than or equal to 2% in 36 pts., between 3 and 15%, 49 pts. and more than 15% in 12 pts. 26/100 pts. had functioning tumors. The analysis included 55 pts. with SSTR 2 / 5 pos. Ki 67 less than or equal to 2% (Group 1), 38 pts. with SSTR 2 / 5 pos and Ki 67 more than 2% (Group 2), 5 pts. with SSTR 2 / 5 neg. Ki 67 less than or equal to 2% (Group 3) and 2 pts. with SSTR 2 / 5 neg and Ki 67 more than 2% (Group 4). Univariate analysis showed significant differences for the expression of SSTR 2 (p. 009), and Ki 67 (p. 001). Survival was higher in Group 1 versus Group 2, median OS was 97 months vs 49 months, and 36 to 23 months, in groups 3 and 4 respectively (p. 0001). Conclusions In this population of pts with GEP-NET we could identify a subgroup of better prognosis associated with expression of SSTR 2 / 5 and Ki 67 less than or equal to 2%. The assessment of SSTR 2 and 5 in tissue, and proliferative index are useful tools for evaluating prognosis in this setting. Disclosure All authors have declared no conflicts of interest.

Type 2 diabetes mellitus in a patient with malignant insulinoma manifesting following surgery

Insulinomas, although they are rare, are the most common of pancreatic islet cell tumours. The incidence is estimated at only four per million person-years and only 5-12% of reported cases are malignant. Distinction between malignant and benign tumours can only be made by the presence of metastasis, as there are no specific morphologic, biochemical or genetic features distinguishing them. Most patients with malignant insulinoma have lymph node or liver metastases and, rarely, bone involvement. The coincidence of insulinoma and diabetes mellitus is an extremely rare condition and reported only in a few cases. We report a 45-year-old woman who was diagnosed with insulinoma on the basis of clinical and laboratory findings and endoscopic examination. Histopathological diagnosis revealed well-differentiated endocrine carcinoma of the pancreas with lymph node metastases. The case was accepted as malignant insulinoma and the patient underwent surgery. Interestingly, hyperglycaemia occurred after the removal of the insulinoma, with the requirement for insulin in the post-operative 3 weeks, which was changed to oral anti-diabetic agents as a permanent treatment. The patient is still being treated with oral anti-diabetic agents. We think that the patient might have had diabetes mellitus, because of insulin resistance that developed with a high-caloric intake stimulated by hypoglycaemia, and which had been masked for many years, but manifested overtly after removal of the tumour. Although this is a rare condition, clinicians should bear in mind that insulinomas may exist together with diabetes mellitus, and it is important to have this suspicion when considering the perioperative approach and for the prevention of morbidities.

Connective tissue growth factor in tumor pathogenesis

Key roles for connective tissue growth factor (CTGF/CCN2) are demonstrated in the wound repair process where it promotes myofibroblast differentiation and angiogenesis. Similar mechanisms are active in tumor-reactive stroma where CTGF is expressed. Other potential roles include prevention of hypoxia-induced apoptosis and promoting epithelial-mesenchymal transistion (EMT). CTGF expression in tumors has been associated to both tumor suppression and progression. For example, CTGF expression in acute lymphoblastic leukemia, breast, pancreas and gastric cancer correlates to worse prognosis whereas the opposite is true for colorectal, lung and ovarian cancer. This discrepancy is not yet understood.High expression of CTGF is a hallmark of ileal carcinoids, which are well-differentiated endocrine carcinomas with serotonin production originating from the small intestine and proximal colon. These tumors maintain a high grade of differentiation and low proliferation. Despite this, they are malignant and most patients have metastatic disease at diagnosis. These tumors demonstrate several phenotypes potentially related to CTGF function namely: cell migration, absent tumor cell apoptosis, as well as, reactive and well vascularised myofibroblast rich stroma and fibrosis development locally and in distal organs. The presence of CTGF in other endocrine tumors indicates a role in the progression of well-differentiated tumors.

The Importance of Clinical Information in Patients with Gastroenteropancreatic Neuroendocrine Tumor

The WHO 2010 grading system for gastroenteropancreatic neuroendocrine tumors(GEP-NETs) is used to evaluate the malignant potential without clinicopathological information. This study was conducted to examine whether the new index is superior to the previous WHO 2004 classification, e.g.for well-differentiated endocrine carcinoma (WEC),involving clinical information. Between 2000 and 2011, 77 patients with sporadic GEP-NETs were treated at our institution and statistically estimated risk factors for overall survival (OS) were evaluated. Cox proportional hazards regression analyses were performed to estimate risk factors for OS. Overall 1-, 3- and 5-year survival rates were 92.8%, 78.4% and 76.0%, respectively. Median OS was 551 days in WEC-patients (odds ratio (OR)for OS=13.1, 95% confidence interval (CI)=2.90-59.5;p=0.001). The median OS was 813 days in G3-patients as compared with 1885 days in G1/G2-patients(OR for OS= 2.64, p=0.002). Multivariate analyses according to baseline characteristics revealed WEC as independent risk factor (OR=9.06, p=0.01). WEC was the only predictor of prognosis with an area under the receiver operating characteristic curves of 0.78(p=0.001). Clinical information was the best predictor for the prognosis of NETs.

Unusually aggressive type 1 gastric carcinoid

Gastric carcinoids are rare tumors of the stomach. Gastric carcinoid type 1 is associated with chronic atrophic gastritis, and because of a low metastatic potential, is the most benign type. Death from metastatic disease has been reported in only three patients in a review including 724 cases. The present report refers to a 60-year-old man who was affected by type 2 diabetes mellitus and pernicious anemia and died from metastatic gastric carcinoid type 1. In 1998, a well-differentiated 1.2 cm gastric neuroendocrine tumor, immunoreactive for chromogranin A, with a Ki-67 index less than 2% and with infiltration to the submucosal layer was diagnosed and enucleated. In 2002, a new well-differentiated gastric endocrine tumor 6 mm in size with a Ki-67 of approximately 2% was detected, and endoscopic ultrasound confirmed it to be limited to the submucosal layer. The patient refused antrectomy and started long-acting somatostatin analog (lanreotide) in 2005 when the Ki-67 index was 7%, but he stopped the treatment after 4 months. In 2007, despite previous endoscopic stability, endoscopic ultrasound showed an infiltrating gastric lesion of 7 cm. At surgery, the disease appeared to be extended to the liver and to the peritoneum (well-differentiated endocrine carcinoma, Ki-67 40%) with both hepatic and massive peritoneal metastases. A regimen of somatostatin analog was soon restarted; however, the disease continued to spread, and the patient died 6 months later. Overall, despite their generally benign course, type 1 gastric carcinoids may have malignant potential, a finding that should be considered when planning the medical workup of these patients.

Systemic treatment of neuroendocrine tumors with hepatic metastases

Neuroendocrine tumors, 1-2% of all malignancies, are relatively slow-growing neoplasms. The majority of neuroendocrine tumors belong to the World Health Organization Group 2 with well-differentiated endocrine carcinomas, but some tumors can be aggressive. The most common are gastroenteropancreatic-neuroendocrine tumors, followed by bronchopulmonary neuroendocrine tumors; less frequent locations are the ovaries, testis and hepatobiliary locations. They can be either non-functioning tumors with symptoms related to mass effects and malignant tumor disease or functioning tumors with specific hormones/neuropeptides autonomously secreted to induce specific clinical syndromes. Localized neuroendocrine tumors are less frequent than metastatic ones; in fact, up to 75% of patients with small bowel neuroendocrine tumors and 30-85% of pancreatic neuroendocrine tumors present with liver metastases either at the time of diagnosis or during the course of the disease. The predominant metastatic site is the liver, which is the best prognostic marker of survival regardless of the primary site. If surgical resection or interventional therapies of the hepatic tumor burden are not feasible, or if the metastases are not confined to the liver, systemic treatment remains the only option. None of the systemic therapies is liver-specific, but rather acts on all metastatic sites. The lack of prospective studies comparing different treatment modalities in homogeneous cohorts of patients makes the best treatment strategy poorly defined. Standard systemic therapy options are somatostatin analogues (octreotide and lanreotide), interferon-α and chemotherapy. Somatostatin analogues not only control symptoms related to functioning tumors but tumor growth as well. Because of the studies challenging its efficacy, as well as the potential for side effects, the more widespread acceptance of interferon-α in the treatment of metastatic neuroendocrine tumors has been limited. Well-differentiated neuroendocrine tumors do not show high sensitivity to chemotherapy because of their low mitotic rates, high levels of antiapoptotic protein bcl-2 and increased expression of the multi-drug resistant gene. Traditional chemotherapeutic agents are streptozotocin in combination with 5-fluorouracil or doxorubicin, or to some extent dacarbazine. Temozolomide, capecitabine and oxaliplatin, as monoagents or in combination therapy, show efficacy in phase II trials. Patients with poorly differentiated neuroendocrine tumor, regardless of the primary tumor localization, are candidates for cisplatin and etoposide chemotherapy regimen. Peptide receptor radionuclide therapy is reported to be an effective treatment option for patients with good performance status and high somatostatin-receptor scintigraphy uptake as well as without major liver involvement. Basic fibroblast growth factor, vascular endothelial growth factor, platelet-derived growth factor, transforming growth factor alpha and beta, insulin-like growth factor type 1, epidermal growth factor, stem cell factor (c-kit), and corresponding receptors have been shown to be expressed in Neuroendocrine tumors. Current phase II-III clinical trials with molecular-targeted therapies revealed promising agents such as everolimus (RAD001), an oral mTOR inhibitor, and sunitinib malate (SU-11248), an oral multitargeted tyrosine kinase inhibitor against vascular endothelial growth factor receptors, platelet-derived growth factor receptors, c-kit receptors, glial cell linederived neurotrophic factor, and FMS-like tyrosine kinase-3 (Flt 3), which were approved for the treatment of advanced pancreatic neuroendocrine tumors. Ongoing clinical trials with bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, will further define the role of angiogenesis inhibitors in advanced intestinal neuroendocrine tumors. Various further novel strategies of targeted therapy and microRNA-regulated pathways in neuroendocrine tumors are under development.

EUS-FNA Diagnosis Cytology of Endocrine Tumor Recurrence

We examined a recurrent endocrine tumor patient who had undergone preoperative diagnosis by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). The cytomorphology and immunostaining patterns at onset were different from those seen at recurrence, and according to WHO classification we diagnosed the former condition as well-differentiated endocrine tumor and the latter condition as well-differentiated endocrine carcinoma. Endocrine tumors show great diversity of cytomorphology according to their malignancy, and we consider that understanding this is important to conducting cytoscreening diagnosis by cytomorphology.

Can papillary carcinomas be treated by endoscopic ampullectomy?

The utility of endoscopic ampullectomy versus surgical ampullectomy remains a topic of debate, particularly for the treatment of malignant tumors. The goal of this study was to prospectively establish the outcomes of endoscopic ampullectomy, with focus on carcinoma. From February 2002 to December 2008, 61 patients underwent endoscopic ampullectomy. The ampulloma was discovered fortuitously in the majority of cases (43 patients, 70%). All patients had had an echoendoscopy revealing a T1N0 lesion without invasion of the orifice. Forty-three patients (70%) underwent a monobloc resection. Histological analysis revealed a low-grade dysplastic adenoma in 21 patients (35%), a high-grade dysplastic adenoma in 11 patients (18%), no dysplasia in 16 patients (26%), an adenocarcinoma in 10 patients (16%), and a well-differentiated endocrine carcinoma in 3 patients (5%). Among the ten patients with adenocarcinoma, four with adenocarcinoma of poor prognosis were treated by pancreaticoduodenectomy (PD) with R0 resection, of whom one patient had no more lesion. Two intramucosal adenocarcinomas were cured by endoscopic ampullectomy without any recurrence. Four patients received palliative care after endoscopic ampullectomy due to cephalic pancreatico-duodenectomy contraindication. For the three patients with well-differentiated endocrine carcinomas, one was treated by PD with R0 resection and two were treated solely by endoscopic ampullectomy, without recurrence. Eleven patients (18%) presented with complications. The complication rate was 30.5% for carcinomas versus 14.5% for benign tumors (p < 0.05). Endoscopic ampullectomy allows for the oncologic resection of well-differentiated intramucosal carcinomas with negative margins. The risk of complications is greater for papillary carcinomas.

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.

Nonfunctioning pancreatic endocrine tumor with extension into the main pancreatic duct: Report of a case

Pancreatic endocrine tumors (PETs) rarely involve the main pancreatic duct. We report a case of malignant nonfunctioning pancreatic endocrine tumor (NFPET) with prevalent intraductal growth. A 47-year-old woman was referred to us after ultrasonography at a routine health check showed diffuse swelling of the pancreas. Preoperative imaging showed a solid mass in the tail of the pancreas and a bulging intraductal mass in the main pancreatic duct. We performed total pancreatectomy because the tumor occupied almost the entire lumen of the main pancreatic duct. Histological examination confirmed well-differentiated endocrine carcinoma. We review reported cases of the intraductal growth of NFPETs and discuss the pathogenesis of these unusual tumors.

Mammalian target of rapamycin expression in poorly differentiated endocrine carcinoma: clinical and therapeutic future challenges

While the mammalian target of rapamycin (mTOR) signaling pathway is a promising target for well-differentiated endocrine carcinoma therapy with the mTOR inhibitor everolimus (RAD001), poorly differentiated endocrine carcinomas (PDECs) are usually excluded from clinical trials due to their aggressiveness. So far, mTOR activity in PDECs has only been tested in cell lines. This study reviewed 36 mono-institutional PDECs to determine mTOR expression. Slides of normal kidney as positive control were used to optimize mTOR staining. To ensure antibody specificity, consecutive sections were incubated in the absence of primary antibody. Immunoreactivity was evaluated on a semi-quantitative scale scoring the extent and intensity of staining. The product of these two scores was used to obtain a total immunostaining score. The main primary site of disease was the pancreas, and 83% of patients had stage IV disease. In 80% of samples, mTOR expression was maintained at similar levels, with no relationship to tumor origin or proliferation rate determined by MIB-1. This study seems to demonstrate that mTOR is expressed in human PDECs regardless of tumor site. Its role in relation to the activity of everolimus in this subset of patients needs to be confirmed.

Clinical effect of temozolomide‐based chemotherapy in poorly differentiated endocrine carcinoma after progression on first‐line chemotherapy

Patients with metastatic poorly differentiated endocrine carcinoma (PDEC) usually have a short survival. The chemotherapy combination of cisplatin and etoposide is frequently used as first-line palliative chemotherapy. There are, however, no published studies concerning second-line treatment of the disease. Temozolomide has shown clinical effect in well-differentiated endocrine carcinomas. This study was performed to evaluate the effect of temozolomide in PDEC patients who had progressed on first-line treatment. Twenty-five patients with PDEC (mainly gastrointestinal) were treated with temozolomide alone or in combination with capecitabine. A subset of patient also received bevacizumab. MGMT methylation was analyzed in tissue specimens. Data were collected retrospectively. One patient had a complete response, and 7 patients had partial response (33% response rate). Median duration of response was 19 months. Another 9 (38%) patients had a stable disease, after progression at inclusion, with a median duration of 18 months. Median progression-free survival for all patients was 6 months, and median overall survival was 22 months. Only 1 patient had a MGMT methylation. Treatment with temozolomide alone or in combination with capecitabine and bevacizumab resulted in objective response or stabilization in 71% of PDEC patients who failed on first-line chemotherapy. These results indicated that temozolomide may be used as second-line treatment in PDEC.