Well-differentiated Neuroendocrine Research Articles

Recent Advances in The Diagnosis of Well-Differentiated Colon Neuroendocrine Tumors

Neuroendocrine tumors (NETs) are rare tumors that appear with secondary symptoms based on the release of vasoactive peptides and hormones into the blood as an answer to a signal from the nervous system. Neuroendocrine neoplasms of the colon are epithelial neoplasms with neuroendocrine differentiation and are classified in step with the foremost recent WHO 2022 classification as well- differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinoma- mas (NECs. NETs can be divided into serotonin-producing enterochromaffin-cell neuroendocrine tumor and glicentin-PYY-producing L-cell neuroendocrine tumor. Compared to NECs, NETs are often idle lesions occurring as incidental findings, being generally characterized by indolent course and relatively frequent ab- since of specific symptoms, which underscores the significance of establishing a prompt and accurate diagnosis, colonic neuroendocrine tumors generally presenting as a large tumor with local or distant metastasis (generally liver) at the time of diagnosis. While utmost colon NETs are considered non-aggressive tumors, a few cases may show a more aggressive clinical course. Clinical/pathological characteristics to select cases at high threat of recurrence/metastases are sadly inadequately consolidated. Diagnosis is based on the combination of clinical presentation, biochemical markers, endoscopy, imaging and confirmed by histopathology. Differential diagnostic for NETs can cause various problems: the rare appendiceal tubular and clear cell variants (which may be confused with non-neuroendocrine cancers). This review presents the updates in established diagnostic tests and tests that require further development, investigation, and validation before use [1,7].

Neuroendocrine prostate tumors: histologic features and therapy

Neuroendocrine (NE) tumors of the prostate are rare tumors, that can arise de novo but much more commonly occur after androgen deprivation therapy for prostate adenocarcinoma. NE tumors of the prostate are classified into: adenocarcinoma with NE differentiation, well-differentiated NE tumor/carcinoid, small-cell NE carcinoma, large cell NE carcinoma, adenocarcinoma with Paneth cell NE differentiation and mixed NE carcinoma—acinar adenocarcinoma. IHC plays a vital role and should be approached at two levels. For the issue of confirming NE differentiation, markers for NE differentiation include synaptophysin, chromogranin, and CD56. If there is any uncertainty about the histogenesis, that is, whether a tumor is primary to the prostate, markers for prostatic lineage—PSA, PSAP, PSMA, prostein (p501s), NKX3.1, ERG (by IHC or FISH)—may be used. Actually, platinum-based chemotherapy is commonly administered to patients with pure small cell carcinoma based on small cell lung cancer (SCLC) data and the accumulating data for aggressive variants of castration-resistant prostate cancer (AVPC). This may consist of a combination of carboplatin (or sometimes cisplatin) plus either etoposide (based on SCLC) or a taxane (especially if mixed histology or AVPC features). A combination regimen of cisplatin, etoposide, and doxorubicin has been also investigated but the benefit-risk ratio of the three-drug combination was considered unfavorable. Unfortunately, platinum-based chemotherapy often presents high toxicity and a short overall survival. Results of currently ongoing preclinical and clinical studies are expected to enhance our understanding of these tumors’ underlying biology and guide our efforts toward the development of personalized medicine through targeted diagnostic and therapeutic approaches.

Uncovering the immune profile in well-differentiated gastroenteropancreatic neuroendocrine tumors

Uncovering the immune profile in well-differentiated gastroenteropancreatic neuroendocrine tumors

Collision Neoplasms of the Vermiform Appendix

Neoplasms of the vermiform appendix represent 1% of all gastrointestinal tumors, with epithelial and neuroendocrine histological subtypes being the most frequent. When two or more neoplasms with different components originate synchronically in the appendix with clear margin between them, it is called a collision tumor, with exceptional cases being reported in literature. The purpose is to present two new cases of collision tumors of the appendix and perform a review of the published literature. Two cases of an 82-year-old female and a 41-year-old male with collision tumors of the vermiform appendix are presented, with clinical presentation, radiological evaluation and surgical treatment exposed. Our results are compared with other published reports. In accordance with the other reported cases, both patients presented with low-grade appendiceal mucinous neoplasm (LAMN). Female patient with synchronous goblet cell carcinoma managed with a completion right colectomy and Hyperthermic intraperitoneal chemotherapy (HIPEC) and the other patient with well-differentiated neuroendocrine (NET) tumor managed with laparoscopic appendectomy without adjuvant treatment. Since very few cases have been reported, no diagnostic and therapeutic consensus and guidelines exist up to date. We agree that local, regional, and systemic therapies should be chosen according to the tumor that represents the worst prognosis.

Somatostatin-derived amyloidosis: a novel type of amyloidosis associated with well-differentiated somatostatin-producing neuroendocrine tumours

Objective To report the clinicopathologic and proteomic characteristics of a novel form of amyloidosis derived from the precursor protein somatostatin. Materials and methods Cases were identified by searching the Mayo Clinic amyloid liquid chromatography and tandem mass spectrometry (LC-MS/MS) typing database from 1 January 2008 to 1 September 2020 for specimens with the amyloid signature proteins and abundant somatostatin, in the absence of other amyloid precursor proteins. All available medical records and pathologic materials were examined. Results Somatostatin-derived amyloid deposits were found in four patients, two females and two males, with a median age of 61.5 years (range 47–73 years). One patient also had neurofibromatosis-1. The amyloid in each case was associated with a well-differentiated, somatostatin-producing neuroendocrine tumour arising in the small bowel or pancreas. The amyloid deposits were Congo Red-positive and were readily identified by LC- MS/MS analysis. Somatostatin was present exclusively in somatostatin-associated amyloid cases (p < .001), compared to small bowel and pancreas amyloidosis cases of other types. Long-term follow-up is available for one patient who is alive 6 years after initial presentation. Conclusion We propose that somatostatin-related amyloidosis is a novel localised human amyloid type that arises in association with well-differentiated somatostatin-producing enteropancreatic neuroendocrine tumours. Treatment of the associated neuroendocrine tumour may be adequate therapy for these patients.

Abstract 674: A phase I trial of Triapine and Lutetium Lu 177 Dotatate in combination for well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs)

Abstract Radiolabeled somatostatin analogues provide a means of delivering targeted radiation with a high therapeutic index to NETs that express somatostatin receptors (SSTRs). Radiolabeled somatostatin analogue Lutetium Lu 177 Dotatate (Lutathera) is a beta- and gamma-emitting radionuclide. Lutathera has been recently FDA approved for use in SSTR positive gastroenteropancreatic neuroendocrine tumors (GEPNETS) in the US based on NETTER-1 Phase III trial. Despite favorable PFS, and safety profile, the drug has limited cytoreductive capability. NETTER-1 reported 17% ORR. PRRT also doesn't seem to be very effective in treating peritoneal disease. We hypothesize that addition of an effective radiation sensitizer can help improve antitumor activity of Lutathera. Rationale: Triapine is a ribonucleotide reductase (RNR) inhibitor. Radiation is a potent inducer of DNA double-strand breaks (DSBs). Targeting signaling networks involved in DSB repair is a promising approach for enhancing cellular radio sensitivity. RNR is the rate-limiting enzyme in the synthesis and repair of DNA, and it is directly involved in the cellular response to radiation, making RNR-targeted therapy to enhance radiation treatment a rational therapeutic strategy. RNR is the only enzyme responsible for conversion of ribonucleoside diphosphate to deoxyribonucleotide diphosphate (dNDP), the key building blocks for DNA synthesis. This study will test the hypothesis that triapine is an effective radiation sensitizer which can be safely combined with peptide receptor radionuclide therapy and can improve antitumor activity of Lutetium Lu 177 Dotatate. Method: This study is an investigator initiated, NCI sponsored, multicenter phase 1 trial of triapine and Lutetium Lu 177 Dotatate in combination for well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumor (GEP-NETs) after the failure of at least one line of prior systemic cancer treatment. A total of 29 patients will be enrolled in the dose escalation (BOIN design) and dose expansion cohorts. The study will be open through the entire ETCTN. Patients will be treated with 177 lutetium dotatate in combination with Triapene. Triapene will be administered orally from D1-14 with each dose of PRRT. Primary endpoint is to evaluate RP2D. Secondary endpoints are looking into clinical activity (ORR, PFS and OS). We are also evaluating NETEST, a novel blood based predicting as well as prognosticating test. In addition, the study will evaluate baseline somatostatin receptor density, somatic tumor mutations and germline mutations and correlate with clinical outcome. ClinicalTrials.gov Identifier: NCT04234568 Citation Format: Aman Chauhan, Charles Kunos, Riham El Khouli, Jill Kolesar, Heidi L. Weiss, Bill Carson, Mark Kidd, Jan Beumer, Susanne Arnold, Elise Kohn, Lowell Anthony. A phase I trial of Triapine and Lutetium Lu 177 Dotatate in combination for well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 674.

INSM1 Expression in Breast Neoplasms with Neuroedocrine Features

According to the 2019 WHO classification of breast tumors, neuroendocrine neoplasms (NENs) are classified into well-differentiated NE tumors (NET) and poorly differentiated NE carcinomas (NEC), while other breast cancers (BCs) of special and no special type with neuroendocrine (NE) features are not incorporated in this scheme anymore. We aimed to assess whether INSM1, a novel NE marker, could have a role in breast NEN subtyping. We selected 63 BCs operated from 2003 to 2018, classified as BCs with NE features, with available clinico-pathological data. Following 2019 WHO criteria, this cohort was reclassified into 37 NETs/NECs, the remaining 26 tumors representing solid-papillary (7), mucinous (7), and mixed type (12) carcinomas with NE differentiation. Chromogranin A (CGA) and synaptophysin (SYN) immunostains were reviewed, and INSM1 was tested by immunohistochemistry. Thirty CGA- and SYN-negative no special type BCs served as negative control. INSM1 was expressed in 52/63 cases of the whole cohort (82.54%). INSM1 positive and negative cases had no significantly different clinico-pathological characteristics. INSM1 expression was not significantly different between the newly reclassified NET/NEC group and other BCs with NE features. No immunoexpression was observed in control BCs. The sensitivity and specificity of INSM1 for the NE phenotype was 82.5% and 100%, respectively, compared to 61.9% and 100% for CGA, and 95.2 and 100% for SYN. In conclusion, INSM1 is as accurate as traditional NE biomarkers to identify NE differentiation in BC. In analogy to standard NE markers, INSM1 could not distinguish NET and NEC from the other BC histotypes with NE differentiation.

Neuroendocrine cystic carcinoma in the pancreas tail. Asymptomatic

Introduction: Pancreatic neuroendocrine neoplasms are second most common neoplasm. Incidence are fewer than 1 per 100 000 individuals per year. 2017 World Health Organisation (WHO) classification: As well-differentiated pancreatic neuroendocrine tumours (PanNETs), poorly differentiated pancreatic neuroendocrine carcinomas (PanNECs) and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) of the pancreas. PanNETs are much more common than PanNECs and present typically in adults between the fifth and sixth decades and may be asyntomatic or syntomatic due to inappropriate hormone secretion. Methods: INCIDENTAL FINDING DURING MAGNETIC RESONANCE A 60-year-old male patient presented with spondylolisthesis and underwent thoracoabdominal magnetic resonance, incidentally finding lumps in the pancreas tail measuring 10X12 centimeters. Laboratory tests and tumor markers were performed in normal range, he was sent to our service. Results: Was performed tail resection of pancreas of 10X12 centimeters, in the postoperative period it presented an acid base imbalance so it is handled in Intensive Care, it evolves favorably and it is discharged from the hospital 4 weeks after the surgery. Pathology report: Tumor in pancreas tail, cystic, well differentiated neuroendocrine, with focal invasion to the capsule and free edges of lesion of low malignant potential. Conclusion:1.Pancreatic neuroendocrine tumors are usually asymptomatic and are diagnosed by incidental findings.2.The success in the postoperative evolution is that they are treated by surgeons who are experts in liver, pancreas and biliary tract surgery.

Carcinoid Tumors of the Orbit and Ocular Adnexa.

Well-differentiated neuroendocrine or carcinoid tumors are found most commonly in the gastrointestinal tract. When metastatic to the orbit, they tend to have a propensity for the extraocular muscles. The purpose of this study was to better understand the diversity in presentation of orbital carcinoid disease and to determine predictors for survival. In this observational cross-sectional cohort study, data from 8 tertiary orbital practices were compiled. Demographic, clinical, pathologic, American Joint Committee on Cancer stage and grade, imaging, and management data were extracted for all the patients. Descriptive statistics were calculated. Subgroups were compared utilizing analysis of variance analyses and Kaplan-Meier curves. Time to progression and disease-specific and overall mortality were calculated. Comparisons were performed for the following a priori pairs: unknown versus known primary tumor, single versus multiple extraocular muscle involvement, unilateral versus bilateral orbital disease, extraocular muscle versus other orbital involvement, and excisional versus incisional surgery. A total of 28 patients with carcinoid tumors of the orbit were identified. Of these, 57.1% of patients were female, the mean age at diagnosis of the primary tumor was 58.8 years and the mean age at diagnosis of orbital disease was 62.6 years. At primary presentation, all patients were American Joint Committee on Cancer stage III or IV and 21.4% demonstrated carcinoid syndrome. Muscle involvement was noted in 78.6% of patients, and of these, 72% were noted to have single muscle disease. Eight patients had no primary tumor identified; 3 of these 8 demonstrated disseminated disease at the time of diagnosis. The overall 5-year survival rate was 81.8% from diagnosis of primary tumor and 50% from diagnosis of orbital disease. Subgroup analysis revealed that patients with unilateral orbital disease when compared with bilateral orbital disease had a longer progression-free survival and time to death from all causes (p = 0.025). Patients with disease localized to the orbit at presentation had longer time to death than those with disseminated disease. Treatment with surgery, radiation, or octreotide did not appear to affect survival. Patients managed with systemic chemotherapy had a shorter time of survival than the rest of the group. All other subgroup comparisons were not found to be statistically significant. Neuroendocrine tumors of the orbit represent a wide spectrum of disease, with some cases being part of disseminated disease, while others being localized presentations. This heterogeneity may be responsible for the slightly higher overall survival in these patients than others with metastatic carcinoid tumors in other locations.

Oxaliplatin and 5-fluorouracil (FOLFOX) in advanced well-differentiated digestive neuroendocrine tumors: A multicenter national retrospective study from the French Group of Endocrine Tumors (GTE).

4104 Background: Oxaliplatin-based regimens have shown promising antitumor activity in digestive neuroendocrine tumors (NETs), however the available data are limited. Our aim was to assess the tumor response and survival in a large series of patients treated with oxaliplatin and 5-fluorouracil (FOLFOX) for advanced digestive NETs.Oxaliplatin-based regimens have shown promising antitumor activity in digestive neuroendocrine tumors (NETs), however the available data are limited. Our aim was to assess the tumor response and survival in a large series of patients treated with oxaliplatin and 5-fluorouracil (FOLFOX) for advanced digestive NETs. Methods: All patients with advanced well-differentiated digestive NETs treated with at least 3 cycles of FOLFOX between 2004 and 2018 in 12 centers of the French GTE, were retrospectively included. Best response according to the RECIST 1.1 criteria, progression-free survival (PFS) and overall survival (OS) were evaluated. The prognostic factors for PFS were investigated by multivariate analysis using a Cox proportional hazard model including variables with a p value ⩽ 0.20 in univariate analysis. Results: One hundred and forty-nine patients were included. Primary tumor location was pancreas (n = 88), small intestine (n = 37), stomach (n = 7), rectum (n = 4) and unknown without lung tumor at CT scan (n = 13). Partial response rate was of 31% for pancreatic NETs, 13% for small intestine NETs, 14% for gastric NETs, 25% for rectal NETs and 38% for unknown primary NETs. Median PFS were, respectively, 9, 9, 14, 4 and 6 months, and median OS were 30, 28, 31, 25 and 15 months. Significant poor prognostic factors for PFS after FOLFOX in digestive NETs were: progressive disease (HR = 2.5, p = 0.018), hepatic involvement &gt; 50% (HR = 1.8, p = 0.009), prior targeted therapy (HR = 1.5, p = 0.048) and rectal primary tumor (HR = 4.2, p = 0.01). Among pancreatic NETs, the 9 insulinomas had a 22 months PFS versus 9 months for the others (p = 0.025), and serum glucose normalization was obtained in 8 out of 9 cases. Conclusions: FOLFOX has a promising clinical activity for gastroenteropancreatic NETs, especially in insulinomas.

The emerging role of targeted therapies for advanced well-differentiated gastroenteropancreatic neuroendocrine tumors

ABSTRACTIntroduction: Gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) are unique and complex neoplasms, exhibiting a wide spectrum of diverse clinical behaviors. The contemporary management of well-differentiated GEP-NETs is marked by the availability of a wide range of targeted therapies.Areas Covered: For patients with localized or oligometastatic disease, surgical resection remains the preferred approach and is associated with excellent long-term outcomes. For patients with unresectable but isolated liver metastases, multiple liver-directed therapies, including hepatic arterial based therapies and ablative techniques, exist. For patients with metastatic and progressive disease, a number of systemic therapies exist: molecular targeted agents, peptide receptor radionuclide therapy (PRRT), and systemic chemotherapy. Furthermore, somatostatin analogs (SSA) are an important component of therapy, both effectively controlling symptoms of hormonal overproduction and contributing to slowing tumor progression.Expert Opinion: In the near future, advances in our understanding of tumor biology, genetics, immunology, nanotechnology, and radiation pharmacology should only continue to expand the availability of targeted therapies, improving the outcomes of patients with GEP-NETs. We herein review the management of advanced well-differentiated GEP-NETS with a particular emphasis on the role of targeted therapies.

Prognostic factors in nonfunctional well-differentiated gastroenteropancreatic neuroendocrine tumors: Single Institute Experience.

e16176Background: Grade 1 & 2 gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are well-differentiated (WD). Methods: We evaluated 115 nonfunctional WD GEP-NETs retrospectively. Results: Med...

Consensus and controversy on subtype classification of gastric neuroendocrine neoplasms

Gastric neuroendocrine neoplasms (g-NENs) are a heterogeneous group of tumors. Often silent, g-NENs may however be aggressive and sometimes mimic the course of gastric adenocarcinoma. Well-differentiated gastric neuroendocrine tumors (NET) can be subclassified into 3 distinct groups (type1, type 2 and type 3) according to Neuroendocrine Neoplasm Society (ENETS) guideline version 2006 as well as North America Neuroendocrine Tumor Society (NANETS) and National Comprehensive Cancer Network (NCCN) guidelines. However, since the publication of ENETS guideline version 2012, the subtype classification of g-NENs has been confusing due to the revised definition of type 3 g-NEN in versions 2012 and 2016. ENETS version 2012 indicated that type 3 g-NEN was usually solitary and its pathology was mostly WHO grade 3 (neuroendocrine carcinoma, NEC G3) with higher Ki-67 index, greater tumor diameter and infiltrative growth. While ENETS version 2006 showed that type 3 g-NEN was well-differentiated or moderate-differentiated, neither type 1 nor type 2, and other g-NENs without basic diseases. Besides, in renewal consensus guidance of ENETS version 2016, description about clinical and histological features altered as "well-differentiated g-NEN can be classified as type 3", but its pathology is still NEC G3. According to such classification, those gastric NET patients with well-differentiated, neither type 1 nor type 2 tumors, seem to be unable to classify. In this article, description about the subtype classification of g-NENs in several guidelines, including ENETS versions 2006, 2012 and 2016, NANETS version 2010 and NCCN version 2016, is introduced and the controversy focuses on type 3 g-NEN definition by ENETS versions 2012 and 2016. Hence, the four-type classification of g-NENs is recommended, which has been written in Chinese Consensus for the Diagnosis and Management of GEP-NEN (version 2016). Well-differentiated gastric NET is classified as type 3, and poor-differentiated gastric NEC as type 4. This four-type classification of g-NENs covers all the patients with g-NENs. Advances on clinical research of g-NENs in China are reviewed and the existing problems are analyzed. We also put forward the research direction in the future.

High Frequency of Malignant Transformation of Ovarian Mature Teratoma into Squamous Cell Carcinoma in Young Patients in Northeast Brazil.

The malignant behavior of an ovarian teratoma is related to immaturity, or rarely to the malignant transformation of a somatic component in a mature teratoma (MT). The aim of this work was to review 189 consecutive ovarian teratomas diagnosed between 2006 and 2010 at a public referral center for cancer in Brazil, focusing on cases of MT with malignant transformation. MTs with transformation to squamous cell carcinoma (SCC) were further analyzed by immunohistochemistry for p16 staining. The median age of all patients was 36 yr (mean age, 39.6 yr; SD±4.9). Mature and immature teratomas represented 95.7% (181/189) and 4.2% of the cohort, respectively. Immature teratoma occurred mainly in adolescents under 18 yr. Malignant transformation of the somatic component in MT was observed in 10 of 181 patients (5.5%). SCC was the most common subtype (4/10), followed by differentiated thyroid carcinoma in struma ovarii(3/10), adenosquamous carcinoma (1/10), mucinous intestinal-type adenocarcinoma (1/10), and a well-differentiated neuroendocrine tumor/carcinoid (1/10). Two of 4 SCC cases were strong and diffusely positive for p16, and 2 were negative. In 5 further patients, MT was synchronously observed with other benign and malignant ovarian neoplasms in the ipsilateral ovary (3 mucinous cystadenomas and 1 Brenner tumor) and 1 cystadenocarcinoma in the contralateral ovary. MTs with malignant transformation were larger than those without transformation (P<0.001), but did not demonstrate any association with age. Indeed, our patients with SCC in MT were much younger [median and mean age, 37 and 38 yr (SD±4.9), respectively] than those described previously. As p16 is considered a surrogate marker for HPV infection, the malignant transformation of MT into SSC in young patients raises the possibility of HPV infection as a risk factor in some of these cases. However, molecular studies are needed to clarify the possible role of HPV in the malignant transformation of MT to SCC.

A phase I study of veliparib (ABT-888) in combination with capecitabine (C) and temozolomide (T) in patients (pts) with advanced well-differentiated unresectable neuroendocrine tumors (wdNET).

TPS466 Background: Veliparib (V) is a novel orally bioavailable PARP-1 and -2 inhibitor which potentially synergizes with temozolomide (T). A single arm phase II study combining C and T has shown promising activity in well-differentiated NETs with overall response rate of 43%. Hence, we propose to combine V with C and T optimizing the interaction of V with T by dosing the V during the T to produce improved clinical activity in pts with wdNETs. Methods: This is an investigator initiated, single institution, phase I, dose-escalation trial using a modified Toxicity Probability Interval (mTPI) design. The primary objective is to estimate the maximum tolerable dose (MTD), which is defined as the dose level at which the probability of dose limiting toxicities (DLTs) is 0.33. Secondary objectives include assessing safety profile, antitumor activity and progression free survival. Inclusion criteria: Pathologically confirmed metastatic unresectable well-differentiated (low grade and intermediate grade) NETs that demonstrate progressive disease in the prior 12 months, ECOG PS 0-2 and adequate organ function. Exclusion criteria: severe hypersensitivity reaction to C, 5-FU, T or dacarbazine or uncontrolled chronic illness. Prior treatment with both C and T. Administration and design: We initially will fix doses of C and T at C: 750 mg/m2 po twice a day (BID) on days 1-14 and T at 100 mg/m2 po BID on days 10-14. V is given orally on days 10-14 along with T. We have 5 planned V dose levels (20, 40, 60, 80, 100 mg). If dose level 1 is too toxic we will go to C 600 mg/m2, T 75 mg and V 20 mg. Patients will be enrolled in cohorts of 3. The dose escalation/de-escalation will be as per pre-specified guidelines from the mTPI design. The planned sample size is 21 based on the anticipated number of patients available for this study within 18 months. This trial will be terminated when the maximum sample size (21) is reached or if the lowest dose is deemed too toxic. The study will start enrolling patients October 2015.

Features Associated With Metastases Among Well-Differentiated Neuroendocrine (Carcinoid) Tumors of the Appendix: The Significance of Small Vessel Invasion in Addition to Size.

The risk of metastatic disease among carcinoid tumors of the appendix increases with tumor size. However, it is unclear if any features other than size are also associated with an increased risk of metastatic disease. The aim of this study was to review the characteristics of appendiceal carcinoid tumors and determine if other histologic features besides size should guide surgical decision making. This study involved a retrospective case series. This study was conducted at a single tertiary acute care hospital. Patients diagnosed with an appendiceal carcinoid tumor between 2000 and 2014 were identified. Goblet cell carcinoids, adenocarcinomas with neuroendocrine features, and tumors from other primary locations were excluded. Simple appendectomy or segmental/total colectomy with lymphadenectomy was performed. The primary outcomes measured were metastases, recurrence, and overall survival. Seventy-nine patients were included. The overall incidence of metastatic disease was 10%. Patients with metastatic disease were more likely to be male (75% vs 28%, p = 0.008), have small-vessel invasion (43% vs 5%, p = 0.001), and have larger tumors (median 2.0 cm vs 0.5 cm, p < 0.001). Among tumors <2 cm, the incidence of metastases among tumors with small-vessel invasion was 60% compared with 0% among those without small-vessel invasion (p < 0.001). Among tumors ≥2 cm, the incidence of metastases was 50% irrespective of small-vessel invasion. If small-vessel invasion was used as a second indication for performing a right hemicolectomy along with size ≥2 cm, both the sensitivity and negative predictive value would have been 100% compared with 63% and 96% if size was used alone. Patients with metastatic disease had a higher incidence of recurrence (13% vs 0%, p = 0.003), but overall survival was 100% in both groups. Small sample size, retrospective design, and limited long-term follow-up were the limitations of this study. Carcinoid tumors of the appendix <2 cm with small-vessel invasion have similar metastatic potential as tumors ≥2 cm. Therefore, a recommendation for a right hemicolectomy should be considered for tumors <2 cm with small-vessel invasion. Additional prospective multicenter studies are warranted.

Gly388Arg FGFR4 polymorphism is not predictive of everolimus efficacy in well-differentiated digestive neuroendocrine tumors

Introduction: Preclinical data suggest that the single nucleotide polymorphism substituting a glycine for an arginine in codon 388 of the FGFR4 transmembrane doma

Tu1918 Correlation Between the 18F-FDG Uptake Assessed by PET/CT and Pathological Data in Well-Differentiated Digestive Neuroendocrine Tumors

The 18F-FDG uptake assessed by PET/CT is correlated to prognosis in most tumors. The aim of our study was to compare the 18F-FDG uptake with tumor proliferation (Ki67) and expression of molecules related to cell metabolism [hypoxia (VHL), glucose transport (GLUT1), regulation of cellular pH (CA9)] in well differentiated digestive neuroendocrine tumors (NET). Patients and Methods: This retrospective study included 22 patients. 18F-FDG uptake was assessed by the SUVmax value (Standardized Uptake Values). An immunohistochemical study was performed with Ki67, VHL, GLUT-1 and CA9 antibodies. A score (0-300) was calculated for each antibody. Results: NET were of pancreatic (15), midgut (3), esophageal (1), rectal (1), undetermined origin (2). 7, 9 and 6 tumors were of grade 1, 2 and 3 respectively; the average/median Ki67 was 15.86%/12% [1-60%]. The mean/median SUVmax was 6.26/5.09 [1.47 to 18.70]. Two tumor with SUVmax <2 were considered as negative at PET scan. Grade 1, 2 and 3 tumors exhibited a median SUVmax 4.45 [1.62 to 6.6]; 5.79 [1.46 to 18.7] and 6.7 [3.05 to 9.61] respectively. The SUVmax correlated with high tumor size (p=0.009), high Ki-67 (p=0.03) and low VHL expression (p=0.08). Conclusion: Our study highlights that well-differentiated digestive neuroendocrine tumors, even of grade 1, are frequently positive at PET scan. The accumulation of 18 F-FDG increases with tumor size and cell proliferation in these tumors and seems to be correlated with the expression of effectors of cellular metabolism.

Tu1919 A Case of Duodenal Gastrinoma Associated With Multiple Endocrine Neoplasia Type 1 (MEN1) Detected by Esopagogastrodudenoscopy (EGD), Which Is Considered Having Been Buried Under Peptic Ulcer

The 18F-FDG uptake assessed by PET/CT is correlated to prognosis in most tumors. The aim of our study was to compare the 18F-FDG uptake with tumor proliferation (Ki67) and expression of molecules related to cell metabolism [hypoxia (VHL), glucose transport (GLUT1), regulation of cellular pH (CA9)] in well differentiated digestive neuroendocrine tumors (NET). Patients and Methods: This retrospective study included 22 patients. 18F-FDG uptake was assessed by the SUVmax value (Standardized Uptake Values). An immunohistochemical study was performed with Ki67, VHL, GLUT-1 and CA9 antibodies. A score (0-300) was calculated for each antibody. Results: NET were of pancreatic (15), midgut (3), esophageal (1), rectal (1), undetermined origin (2). 7, 9 and 6 tumors were of grade 1, 2 and 3 respectively; the average/median Ki67 was 15.86%/12% [1-60%]. The mean/median SUVmax was 6.26/5.09 [1.47 to 18.70]. Two tumor with SUVmax <2 were considered as negative at PET scan. Grade 1, 2 and 3 tumors exhibited a median SUVmax 4.45 [1.62 to 6.6]; 5.79 [1.46 to 18.7] and 6.7 [3.05 to 9.61] respectively. The SUVmax correlated with high tumor size (p=0.009), high Ki-67 (p=0.03) and low VHL expression (p=0.08). Conclusion: Our study highlights that well-differentiated digestive neuroendocrine tumors, even of grade 1, are frequently positive at PET scan. The accumulation of 18 F-FDG increases with tumor size and cell proliferation in these tumors and seems to be correlated with the expression of effectors of cellular metabolism.

In vitro chemotherapy profiling of well-differentiated midgut neuroendocrine tumors (NETs) based on individual patient tumor biomarkers analysis.

235 Background: Midgut neuroendocrine tumors (NETs) are rare malignancies with indolent clinical courses. In general, they are well differentiated with most tumor cells in the G0 phase of the cell cycle, consistent with the poor response rate of NETs to chemotherapy in vivo. We hypothesize that insults, such as surgery, can drive NET cells from G0 into S phase and that biomarker analysis of individual patient tumors harvested and grown in the lab will provide useful practical guide for future intra and post operative adjuvant therapy. Methods: 97 well-differentiated midgut NET patients underwent cytoreductive surgery at our institution between 5/2012 and 10/2012. 148 surgical specimens were collected and submitted to a single commercial lab for processing. Primary tumors, lymph nodes and liver metastases were harvested and cultured. Their RNAs were then extracted to analyze the expressivity a total of 88 different biomarkers. Based on our patients specific tumor biomarker expressivity and known correlations between 36 anti-neoplastic agents with their linked biomarkers, recommendations were reported as clinically benefit or lacking such benefit. Results: A total of 148 specimens from 97 patients were tested. In four of the 97 patients, no clinically beneficial chemotherapy agent could be identified. Among the remaining 93 patients, the top three agents that are most likely to be clinically beneficial are: Fluorouracil, Cisplatin and Carboplatin. These were reported to be clinically beneficial in 135/148 (91.2%), 103/148 (69.6%), and 103/148 (69.6%) patients respectively. Conclusions: Midgut NETs are slow growing tumors which are chemotherapeutically inert owing to the fact that most of the tumor cells are in G0 cell cycle. Surgical insult drives NET cells into active synthetic phase where they begin to express biomarkers specific to their tumor cells. Analysis of these biomarkers guides further potential beneficial therapy based on the current known associations among biomarkers and chemotherapy agents. These results must then be compared and confirmed against a direct in-vitro chemo sensitivity assessment conducted simultaneously on the same patients.