Subtypes Of Neuroendocrine Tumors Research Articles

FAIM2, as a novel diagnostic maker and a potential therapeutic target for small-cell lung cancer and atypical carcinoid.

Lung neuroendocrine (NE) tumors are a heterogeneous group of tumors arising from neuroendocrine cells that includes typical carcinoid, atypical carcinoid, small cell lung cancer (SCLC), and large cell NE cancer. The subtyping of NE tumors is based on the number of mitoses per high powered field and the presences of necrosis. However, the best diagnostic criteria to differentiate various subtypes of lung NE tumors remains controversial and few diagnostic markers distinguish typical and atypical carcinoid. In this study, we show that FAIM2, an inhibitory molecule in the Fas-apoptosis pathway, is significantly overexpressed in SCLC compared to non-small cell lung cancer. In addition, FAIM2 expression is significantly higher in atypical carcinoid than typical carcinoid. As atypical carcinoid has been shown to have worse clinical outcomes than typical carcinoid, our data suggests that FAIM2 may be a useful diagnostic marker for atypical carcinoid. Knockdown of FAIM2 expression increases Fas-induced apoptotic cell death in SCLC cells. Etoposide treatment combined with FAIM2 inhibition also shows modest but significant reduction of viable SCLC cells. Taken together, our results suggest that FAIM2 is a potential NE tumor marker with higher expression in atypical carcinoid and SCLC, and could be a new therapeutic target for SCLC.

Notch Signaling in Neuroendocrine Tumors.

Carcinoids and neuroendocrine tumors (NETs) are a heterogeneous group of tumors that arise from the neuroendocrine cells of the GI tract, endocrine pancreas, and the respiratory system. NETs remain significantly understudied with respect to molecular mechanisms of pathogenesis, particularly the role of cell fate signaling systems such as Notch. The abundance of literature on the Notch pathway is a testament to its complexity in different cellular environments. Notch receptors can function as oncogenes in some contexts and tumor suppressors in others. The genetic heterogeneity of NETs suggests that to fully understand the roles and the potential therapeutic implications of Notch signaling in NETs, a comprehensive analysis of Notch expression patterns and potential roles across all NET subtypes is required.

Atypical carcinoid and large cell neuroendocrine carcinoma of the lung: a proteomic dataset from formalin-fixed archival samples.

Here we present a dataset generated using formalin-fixed paraffin-embedded archival samples from two rare lung neuroendocrine tumor subtypes (namely, two atypical carcinoids, ACs, and two large-cell neuroendocrine carcinomas, LCNECs). Samples were subjected to a shotgun proteomics pipeline, comprising full-length protein extraction, SDS removal through spin columns, in solution trypsin digestion, long gradient liquid chromatography peptide separation and LTQ-Orbitrap mass spectrometry analysis. A total of 1260 and 2436 proteins were identified in the AC and LCNEC samples, respectively, with FDR <1%. MS data are available in the PeptideAtlas repository at http://www.peptideatlas.org/PASS/PASS00375.

Folic-acid metabolism and DNA-repair phenotypes differ between neuroendocrine lung tumors and associate with aggressive subtypes, therapy resistance and outcome.

Purpose25% of all lung cancer cases are neuroendocrine (NELC) including typical (TC) and atypical carcinoid (AC), large-cell neuroendocrine (LCNEC) and small cell lung cancer (SCLC). Prognostic and predictive biomarkers are lacking.Experimental DesignSixty patients were used for nCounter mRNA expression analysis of the folic-acid metabolism (ATIC, DHFR, FOLR1, FPGS, GART, GGT1, SLC19A1, TYMS) and DNA-repair (ERCC1, MLH1, MSH2, MSH6, XRCC1). Phenotypic classification classified tumors (either below or above the median expression level) with respect to the folic acid metabolism or DNA repair.ResultsExpression of FOLR1, FPGS, MLH1 and TYMS (each p<0.0001) differed significantly between all four tumor types. FOLR1 and FPGS associated with tumor differentiation (both p<0.0001), spread to regional lymph nodes (FOLR1 p=0.0001 and FPGS p=0.0038), OS and PFS (FOLR1 p<0.0050 for both and FPGS p<0.0004 for OS).Phenotypic sorting revealed the Ft-phenotype to be the most prominent expression profile in carcinoids, whereas SCLC presented nearly univocal with the fT and LCNEC with fT or ft. These results were significant for tumor subtype (p<0.0001).ConclusionsThe assessed biomarkers and phenotypes allow for risk stratification (OS, PFS), diagnostic classification and enhance the biological understanding of the different subtypes of neuroendocrine tumors revealing potential new therapy options and clarifying known resistance mechanisms.

Carcinoid of the Duodenal Bulb: A Rare Occurrence

Introduction: The incidence of neuroendocrine tumors has increased significantly in the last few decades. Carcinoid tumor, a subtype of neuroendocrine tumors, arises from the enterochromaffin cells of the epithelial lining of the gastrointestinal tract, retroperitoneum and large bronchi. Duodenal carcinoids are extremely rare and can present with a variety of symptoms including epigastric pain, vomiting, anemia, and weight loss. We report a rare case of a patient who presented with iron deficiency anemia and was found to have multiple carcinoids of the duodenal bulb. Case: 60 year-old male presented to his primary care physician's office to establish care and reported a history of GERD for which he was taking Omeprazole 20 mg daily in the morning. He underwent routine laboratory investigations revealing iron deficiency anemia which prompted the need for an endoscopy. His initial EGD showed a 5 mm duodenal bulb polyp with biopsies showing changes suggestive of a hyperplastic polyp. Given his persistent anemia and an inconclusive workup otherwise including a colonoscopy, he underwent a second-look EGD after six months which showed two submucosal duodenal bulb lesions, 15 mm and 5 mm, both of which were biopsied with cold biopsy forceps and showed a neoplasm formed by nests of cells with moderately clear-to-pale eosinophilic cytoplasm and nuclei with finely stippled chromatin. A chromogranin stain was performed and was positive, thereby rendering a diagnosis of a carcinoid tumor. He underwent an octreoscan and a CT scan which showed no metastatic disease. The patient underwent a Billroth procedure. Intra-operatively, no evidence of diffuse peritoneal disease or metastases to the intra-abdominal viscera was observed. The liver did not have any palpable masses. He tolerated the procedure well and was discharged home with a surveillance EGD showing no evidence of recurrence. Discussion: Duodenal carcinoids, although rare, should be kept in the differential diagnosis of the polypoid lesions of the duodenum and may occasionally cause anemia. Two duodenal carcinoids occurring concomitantly and presenting as iron deficiency anemia is extremely rare. These lesions typically have a low metastatic potential and have a good curative rate if localized and diagnosed early.

Bone metastases and skeletal-related events from neuroendocrine tumors.

Neuroendocrine tumors (NETs) metastasize to bone; however, a multi-institution evaluation of the natural history and complications of bone metastases across multiple NET subtypes has not, to our knowledge, previously been conducted. At two tertiary academic centers, we identified patients with bone metastases from databases of patients with a diagnosis of NET between 2004 and 2008. Detection of bone metastases, occurrence of skeletal-related events (SREs), and interventions were analyzed using summary statistics and categorical methods. Time-to-event data were assessed using Kaplan–Meier estimates and log-rank tests. Between 2004 and 2008, 82 out of 691 NET patients (12%) were reported to have bone metastases. Of the 82 patients with bone metastases, 55% were men and their median age was 49. Bone metastases occurred in 25% of pheochromocytomas and paragangliomas, 20% of high-grade neuroendocrine carcinomas, 9% of carcinoid tumors, and 8% of pancreatic NETs. At time of detection of bone metastases, 60% reported symptoms, including pain; 10% developed cord compression, 9% suffered a pathological fracture, and 4% developed hypercalcemia. Occurrence of SREs did not differ significantly with regard to tumor histology. Of patients with bone metastases, 67 (82%) received at least one form of bone-directed treatment, 50% received radiation, 45% received a bisphosphonate, 18% underwent surgery, 11% received 131I-MIBG, 5% received denosumab, and 46% were treated with more than one treatment modality. Bone metastases occur in a substantial number of patients diagnosed with NETs. Patients are often symptomatic and many develop SREs. Given the recent therapeutic advances and increasing life expectancy of patients with NETs, development of guidelines for surveillance and clinical care of bone metastases from NETs is needed.

An Overview of Neuroendocrine Tumour Markers

As there are many different subtypes of neuroendocrine tumors (NETs), many kinds of markers are used for their diagnosis and follow-up. Most of these markers, such as calcitonin, catecholamines, 5-hydroxyindoleacetic acid (5-HIAA), insulin, gastrin, pancreatic polypeptide, and glucagon are specific to one subtype of NET. In addition, there are also general markers used in various NET subtypes; the most commonly used ones are chromogranin-A (CgA), neuron-specific enolase (NSE), and synaptophysin. The sensitivity and specificity levels of CgA are highest among all NET markers. However, specific markers, such as calcitonin in medullary thyroid carcinoma, insulin in insulinoma and cathecolamines in feocromocitoma are more useful than CgA. CgA is an auxiliary marker in cases with relapse or metastasis of such functional NETs. Carcinoid syndrome is characterized by serotonin hypersecretion with the other products and 5-HIAA level is used to determine the serotonin hypersecretion. Thus, 5-HIAA is the specific marker for carcinoid tumors which comprise two-thirds of all NETs. Turk Jem 2014; 18: 132-136

Different micro-RNA expression profiles distinguish subtypes of neuroendocrine tumors of the lung: results of a profiling study

MicroRNAs (miRNAs) are a class of small (∼22 nucleotides), non-coding, highly conserved single-stranded RNAs with posttranscriptional regulatory features, including the regulation of cell proliferation, differentiation, survival, and apoptosis. They are deregulated in a broad variety of tumors showing characteristic expression patterns and can, thus, be used as a diagnostic tool. In contrast to non-small cell carcinoma of the lung neuroendocrine lung tumors, encompassing typical and atypical carcinoids, small cell lung cancer and large cell neuroendocrine lung cancer, no data about deregulation of tumor entity-specific miRNAs are available to date. miRNA expression differences might give useful information about the biological characteristics of these tumors, as well as serve as helpful markers.In 12 pulmonary neuroendocrine tumors classified as either typical carcinoid, atypical, large cell neuroendocrine or small cell lung cancer, screening for 763 miRNAs known to be involved in pulmonary cancerogenesis was conducted by performing 384-well TaqMan low-density array real-time qPCR. In the entire cohort, 44 miRNAs were identified, which showed a significantly different miRNA expression. For 12 miRNAs, the difference was highly significant (P<0.01). Eight miRNAs showed a negative (miR-22, miR-29a, miR-29b, miR-29c, miR-367*; miR-504, miR-513C, miR-1200) and four miRNAs a positive (miR-18a, miR-15b*, miR-335*, miR-1201) correlation to the grade of tumor biology. The miRNAs let-7d; miR-19; miR-576-5p; miR-340*; miR-1286 are significantly associated with survival. Members of the miR-29 family seem to be extremely important in this group of tumors. We found a number of miRNAs, which showed a highly significant deregulation in pulmonary neuroendocrine tumors. Moreover, some of these deregulated miRNAs seem to allow discrimination of the various subtypes of pulmonary neuroendocrine tumors. Thus, the analysis of specific sets of miRNAs can be proposed as diagnostic and/or predictive markers in this group of neoplasias.

Optimising structural imaging of neuroendocrine tumours in the molecular imaging age

Aim To provide an educational update on structural imaging appearances of neuroendocrine tumours (NET), in the age of molecular imaging. PET/CT with Ga-68 DOTA-TATE and F-18 fluorodeoxyglucose (FDG) is providing new understanding of neuroendocrine tumours including patterns and heterogeneity of disease. This is also providing new insights of structural imaging findings including CT and MRI. It is also important to be aware of the limitations of PET/CT imaging, and we outline indications where structural imaging has a high impact for patient management. These changing paradigms are translating to revised imaging protocols in our institution that are enabling personalised medicine with appropriate selection of management for an individual patient. It is also allowing us to understand the structural imaging appearances of heterogeneity within the same tumour type. A range of new targeted therapies including peptide receptor radionuclide therapy (PRRT) are now available to treat patients with non-resectable metastatic NET. New patterns of response are emerging which are important to recognise, including cystic necrosis which may initially masquerade as progressive disease due to enlargement. We have a large population of patients with neuroendocrine tumours at Peter MacCallum Cancer Institute, providing wide experience of this spectrum of imaging findings across various subtypes of NET. We present a pictorial review of our experience.

Mixed endocrine-glandular carcinoma of cecum

Summary Colorectal mixed endocrine-glandular neoplasms, a subtype of neuroendocrine tumors, are mainly diagnosed based on pathological characterization. The rarity and unusual presentation of mixed endocrine tumors makes their prognosis relatively poor, and an optimal management strategy for the tumors has yet to be devised. Here, we report a case of cecal mixed adenocarcinoma and neuroendocrine carcinoma with ileal tumor seeding, lymph nodes, and left iliac crest metastasis. After undergoing right hemicolectomy, target therapy, chemotherapy, and radiotherapy for adenocarcinoma, the patient survived for more than 15 months and remains alive at the time of writing.

547: Different micro-RNA expression profiles distinguish subtypes of neuroendocrine tumours of the lung: results of a profiling study

547: Different micro-RNA expression profiles distinguish subtypes of neuroendocrine tumours of the lung: results of a profiling study

Prospective phase II study of capecitabine and temozolomide (CAPTEM) for progressive, moderately, and well-differentiated metastatic neuroendocrine tumors.

179 Background: We found in our lab that capecitabine (CAP), the prodrug of 5-FU, and temozolomide (TEM) were synergistic in inducing apoptosis in BON neuroendocrine tumor (NET) cell lines. We were the first to report in 2004 the use and mechanism of action of CAP and TEM (CAPTEM) in well differentiated NETs with promising results. Here we describe the interim analysis of an ongoing Phase II trial. Methods: 28 patients with metastatic well-moderately differentiated NET (ki-67 ≤20%) who had shown progression only on 60mg Sandostatin LAR (if octreotide scan positive) were treated with the following regimen: CAP 1,500mg/m2/day (PO divided BID, maximum 2,500 mg/day) on d1-14, and TEM 150-200mg/m2/day (PO divided BID, lower dose for patients who had prior chemotherapy or extensive radiation) on d10-14, with the next two weeks off, in a 28 day cycle. Primary objective was RR based upon RECIST, and secondary objectives included PFS, OS (from time of initiation of therapy), and toxicity evaluation. Other inclusion criteria were: age &lt;80, ECOG PS 0-2, and adequate hematologic, renal, and liver function, and failure on high dose Sandostatin LAR. Results: 28 of 38 planned patients were enrolled with various NET subtypes (table). Overall RR was 43% (11% CR) and SD rate was 54%, with clinical benefit in 97%. ORR was 41% in carcinoid tumors. Ongoing mPFS is &gt;20mo for all subtypes with 18/28 (64%) having progressed at this time. Twelve of 28 had died at this analysis with ongoing mOS of &gt;25.3mo. The most common G3/4 toxicities were lymphopenia (32%), hyperglycemia (15%, unlikely related), thrombocytopenia (3%), and diarrhea (3%). No hospitalizations, opportunistic infections, or deaths occurred from CAPTEM. Conclusions: CAPTEM is an effective treatment for patients with progressive NET who failed high dose octreotide, with high PR and SD rates in carcinoids and insulinomas. The ongoing PFS in pancreatic NETs (&gt;18.2 mo) is 150% greater than reported with everolimus and sutent. Clinical trial information: NCT00869050. [Table: see text]

A retrospective clinicopathological analysis of small-cell carcinoma of the uterine cervix

Cervical cancer encompasses several histological types, including neuroendocrine tumors (NETs). Small-cell carcinoma of the uterine cervix (SCCC) is the most common and aggressive subtype of cervical NET. The objective of this case report was to investigate SCCC using a retrospective clinicopathological approach. Four cases of large (≥4 cm) SCCCs are presented in this case study. The patients were diagnosed with SCCC through a sequential hierarchy of physical examinations, laboratory reports, radiological reports, immunohistochemical and pathological tests. The diagnosis for each case was made at various stages (Ib1, Ib2, IIa2 and IIb, according to the FIGO staging system, 2000) and each of the patients received different multimodality therapeutic regimens. All the patients underwent radical hysterectomy and pelvic lymphadenectomy, followed by adjuvant chemotherapy. Neoadjuvant chemotherapy was administered prior to surgery in two of the patients. The clinical and pathological analyses were assessed using a retrospective measure, maintaining timely follow-ups. SCCC is a rare but serious gynecological malignancy. This condition has a poor prognosis due to its high aggressiveness, high rate of metastases and mortality. Furthermore, the rarity of this disease represents a hindrance to adequate research and development of novel, efficient therapeutic regimens.

The Genetics of Neuroendocrine Tumors

Neuroendocrine tumors (NETs) present a wide spectrum of malignant diseases from rather benign to very malignant variants. The majority of these tumors are sporadic, but there are several familial (inherited) syndromes to consider, such as multiple endocrine neoplasia type 1 and type 2 (MEN-1 and MEN-2), von Hippel-Lindau syndrome (VHL), tuberosclerosis, and neurofibromatosis syndromes. The MEN-1 gene is mutated not only in MEN-1 families, but a recent study shows that more than 40% of sporadic pancreatic NETs (PNETs) harbor MEN-1 gene mutations. The same study reported that ATRX/DAXX genes are mutated in a significant number of tumors, as are genes encoding components of the mammalian target of rapamycin (mTOR) signal transduction pathway. These findings have implications for the new therapies that have been approved for the treatment of PNETs, such as the tyrosine kinase inhibitor sunitinib, as well the mTOR inhibitor everolimus. Small intestinal NETs show a less varied mutational pattern in that the majority of genetic alterations are found on chromosome 18. There seem to be no differences between the sporadic and the familiar type of small intestinal NETs (carcinoids). A wide range of genetic alterations have been described for the different subtypes of NETs, but the mechanisms underlying tumor development are essentially unknown except for MEN-2, in which an activating mutation of the RET proto-oncogene drives tumor progression and affords a direct genotype/phenotype correlation. Genome-wide screening of different types of NETs can now be performed for a reasonable price and is likely to generate new insights into the tumor biology and carcinogenesis in various subtypes of NETs.

Systemic Therapy for Advanced Pancreatic Neuroendocrine Tumors

Neuroendocrine tumors (NETs) occur throughout the body, and share similar histologic characteristics. However, it has become increasingly evident that pancreatic NETs tend to respond differently to therapeutic agents than do other NET subtypes. In most cases, systemic therapy has been more effective in NETs of pancreatic origin than in NETs arising from other locations. Traditional systemic treatment options for pancreatic NETs include somatostatin analogs or cytotoxic chemotherapy. Recently, the biologically targeted agents everolimus and sunitinib were approved for use in patients with metastatic disease. Novel agents, as well as novel drug combinations, are currently under investigation.

Prolonged Radiographic Stabilization of a Metastatic Octreotide Scan-Positive Poorly Differentiated Neuroendocrine Tumor Using Octreotide Acetate Therapy Alone

Pancreatic poorly differentiated neuroendocrine tumors (PDNETs) are a subtype of neuroendocrine Tumors (NETs) clinically distinguished by their much more rapid growth and immunohistochemically diagnosed by having a higher Ki-67 cancer cell staining percentage compared to their well or intermediately differentiated NET counterparts. While standard first line treatment for metastatic well or intermediately differentiated pancreatic NETs typically involves octreotide acetate therapy, here I report, to my knowledge, the first case of a patient with a pancreatic PDNET with radiographic stabilization of his disease with octreotide acetate use alone. Octreotide acetate was chosen after first establishing that, based on his octreotide scan, receptors might be targeted using the octreotide analog.

76IN - Targeted Treatment of Nets

ABSTRACT Low to intermediate grade neuroendocrine tumor (NET) constitutes a group of malignancies that share the capacity for secreting hormones and causing distinctive clinical syndromes. Until recently, there were few evidence-based treatment options. Recent advances in targeted therapy and completion of pivotal phase III studies have brought the approval of both everolimus and sunitinib for pancreatic NET. These large randomized studies demonstrated improvement of progression-free survival validating the PI3K/Akt/mTOR pathway and angiogenesis as important targets for further advances. These studies also showed some of the challenges of NET including patient accrual and disease heterogeneity. Ongoing phase III studies comparing bevacizumab versus interferon and everolimus versus placebo among patients with other NET subtypes may bring much needed advances in areas of unmet need. Development of rational combinations is also ongoing. These ongoing studies as well as our improved understanding of the underlying molecular biology will bring needed advances. Disclosure J.C. Yao: Consultant relationship with Ipsen, Lexicon, Novartis, Pfizer.

Imaging of neuroendocrine tumors

The imaging needs in the individual neuroendocrine tumor (NET) patient are very diverse and the choice of method, or combination of techniques, depends on the characteristics of the particular type of NET and its presentation. The various morphological and functional imaging methods and important methodological aspects are described. The imaging requirements for the various NET subtypes are explained and typical NET image findings are described and illustrated. The choice of the optimum imaging techniques is not only a matter of sensitivity and specificity but must also be considered in the light of the local availability and expertise in the department. Familiarity with contrast-enhancement technique for computed tomography (CT) and magnetic resonance imaging (MRI) is important in the interpretation and understanding of the imaging results. MRI including diffusion weighted imaging (DWI) for oncological imaging has been reported to improve tumor visualization and reader confidence and is expected to similarly be beneficial for NET imaging. Positron emission tomography (PET) using 68Ga-labeled somatostatin analogs is in several aspects superior to somatostatin receptor scintigraphy using Octreoscan®. Molecular imaging problem-solving tools, when PET/CT using 68Ga-labeled somatostatin analogs fails, are PET/CT with 11C-5-HTP and 18F-DOPA.

New Strategies for Advanced Neuroendocrine Tumors in the Era of Targeted Therapy

Low- to intermediate-grade neuroendocrine tumor (NET) constitutes a group of indolent malignancies that share the capacity for secreting hormones and neuroamines. Until recently, there were few therapeutic options for oncologic control. The PROMID study showed that octreotide long-acting repeatable formulation can delay tumor growth in midgut NETs. And, recent phase III studies showed both everolimus and sunitinib improved progression-free survival in pancreatic NETs, validating the phosphoinositide 3-kinase/Akt/mTOR pathway and angiogenesis as important targets for further advances. Ongoing and planned pivotal studies targeting these pathways in other NET subtypes may widen their therapeutic application. Development of rational combinations may further improve therapeutic outcome. These successes and our improved understanding of the underlying molecular biology are likely to lead to further important advances on the horizon.

Incidence and natural history of bone metastases in neuroendocrine tumors.

340 Background: Bone metastases (BM) occur in carcinoids and other neuroendocrine tumors (NET), however, a comparative analysis of the incidence and natural history of BM across different NET subtypes has not been performed. We retrospectively characterized BM incidence, complications, and management across five subtypes: carcinoid/unknown primary (CARC), pancreatic NET (PNET), pheochromocytomas/paragangliomas (PHEO), adrenal cortical carcinoma (ACC) and high grade NET (HGNET) using data collected in the context of the NCCN NET Outcomes Database. Methods: 296 NET patients (pts) presenting at UCSF from 2004 to 2007 were retrospectively identified. Eligibility criteria included presentation on or after Jan 1, 2004, continued management at UCSF within one year of consultation, age over 18, and pathological confirmation of an eligible NET subtype. BM identified radiographically and/or pathologically, and classified as symptomatic (pain, pathologic fracture, or spinal cord compression) or asymptomatic. BM treatments (tx) included radiation, surgery, bisphosphonate and/or denosumab. Results: BM identified in 36/296 (12%): 29% pts with HGNET (5/17), 10% pts with CARC (12/121), 7.4% pts with PNET (6/81), 17% pt with PHEO (11/66), 18% pt with ACC (2/11). BM occurred in 21 men/15 women; median age 54. 30/36 (83%) had stage IV disease at diagnosis (dx); 69% had BM at dx. 69% pts were eventually symptomatic: bone pain (24/25, 96%), cord compression (3/25, 12%) and/or pathologic fracture (6/25, 24%); 8/25 (32%) had more than one symptom from BM. Median survival from BM: 28 mo (21.1 mo if symptomatic; 34.3 mo if asymptomatic). Overall, 81% (29/36) pt received tx for BM: 53% XRT (19/36), 25% surgery (9/36), 39% bisphosphonate (14/36), and/or 11% denosumab (4/36). Conclusions: 12% of pts with NET in this database developed BM. Most pts with BM experienced pain. Serious complications such as cord compression and/or pathological fracture occurred in 36% (9/25) suggesting that bisphosphonate and/or denosumab tx may be of value in these patients. Accrual to the database is ongoing.