Poorly-differentiated Neuroendocrine Tumors Research Articles

Ga-68 DOTATATE PET/CT and F-18 FDG PET/CT in the evaluation of low and intermediate versus high-grade neuroendocrine tumors.

We investigated the role of Ga-68 DOTATATE PET/CT in comparison to F-18 FDG PET/CT in patients with low and intermediate versus high-grade neuroendocrine tumors (NETs). We identified 81 patients who underwent Ga-68 DOTATATE PET/CT at our institution between May 2017 and December 2018 and met inclusion criteria of biopsy-proven NET with known Ki-67 index, histologic grade, or differentiation. Patients were divided into two groups. Control group included Ki-67 ≤20%, grade 1 or 2, or well-differentiated tumors. Experimental group included Ki-67 >20%, grade 3, or poorly-differentiated tumors. Mean age was 57 years, with 36 males and 45 females. Most common primary sites were small bowel, pancreas, and lung. Most common distant metastatic sites were liver and bone. In the control group (n = 67), median Ki-67 was 4% (range 1-30%). 55/67 (82.1%) DOTATATE and 6/11 (54.5%) FDG scans were positive (P = 0.04). Positive scans showed >10 lesions in 25/55 (45.5%) DOTATATE and 1/6 (16.7%) FDG scans (P = 0.18). 40/55 (72.7%) positive DOTATATE and 3/6 (50%) FDG scans showed distant disease (P = 0.25). In the experimental group (n = 14), median Ki-67 was 68% (range 25-95%). All 14 DOTATATE and all nine FDG scans were positive. Positive scans showed >10 lesions in 4/14 (28.6%) DOTATATE and 5/9 (55.6%) FDG scans (P = 0.20). 10/14 (71.4%) positive DOTATATE and 7/9 (77.8%) FDG scans showed distant disease (P = 0.74). All patients with high grade, poorly-differentiated NETs had positive DOTATATE PET/CTs. In these patients, DOTATATE PET/CT did not significantly differ from FDG PET/CT in identifying >10 lesions or distant disease.

Characterization of a novel entity of high-grade well-differentiated colorectal neuroendocrine tumors.

e15696 Background: Small studies suggest that a new pathologic entity of high-grade (by Ki-67 or mitotic index) well-differentiated (by histologic features) neuroendocrine tumors (NETs) exist throughout the GI tract, but the prognosis and characteristics of affected patients are unknown. We sought to further characterize the prognosis and demographics of patients with high-grade (HG) well-differentiated (WD) colorectal NET. Materials and Methods: We used the Surveillance Epidemiology and End Results (SEER) database to study patients with NETs of the colon and rectum diagnosed from 2000 to 2015. We identified patient demographics, clinical and tumor characteristics, and studied associations with tumor grade. We compared overall survival (OS) between patients with low-grade (LG)(grade 1-2) well-differentiated (ICD-0-3 = carcinoid), high-grade (grade 3-4) well-differentiated, and high-grade poorly-differentiated NETs (ICD-0-3 = small cell neuroendocrine). We used logistic regression to detect associations with grade and Cox proportional hazards models to examine predictors of survival. Results: We identified 5,894 cases with colorectal carcinoid tumor (5780 [98.1%] LG and 114 [1.9%] HG); the cohort was 68% white, 48% male, and had a median age of 54. Patients diagnosed with HG carcinoid tumors were more likely to be of older age (OR 2.23; 95% CI 1.19-4.19 for age 60-69 vs < 50) and unmarried (OR 1.56; 95% CI 1.02-2.38), and less likely to be diagnosed after 2010 (OR 0.09; 95% CI 0.06-0.15). OS for patients with HG carcinoids (median 36 m; 95% CI 13-92) fell in between OS for those with HG small cell NETs (median 7 m; 95% CI 6-8), and LG carcinoid tumor (median not reached, > 120 m). Among patients with carcinoid tumors, black patients (HR 1.31; 95% CI 1.03-1.67, older patients (HR 3.60; 95% CI 2.50-5.19 for age 60-69 vs < 50), unmarried patients (HR 1.52; 95% CI 1.24-1.87), and those with HG features (HR 3.85; 95% CI 2.88-5.15) had worse survival. Conclusions: We defined a subset of high-grade well-differentiated NETs, more commonly diagnosed in older, unmarried patients, with a prognosis between that of high grade small cell NETs and low grade carcinoid tumors. Our analysis adds the first national registry study to the literature in support of a new classification of non-pancreatic high-grade well differentiated NETs.

Transcript profiling of neuroendocrine tumors (NETs) to identify new targets and mechanism of progression.

292 Background: Few studies have characterized the molecular drivers of NET growth and mechanisms differentiating poorly differentiated (PD) and well differentiated (WD) NETs. We explored the role of dysregulated transcriptome as the principal molecular mechanism of NETs with the goal to identify novel targets and biomarkers of differentiation. Methods: With IRB approval, de-identified, formalin fixed NET samples were used to extract total RNA for transcriptome analysis. All pathology specimens were centrally reviewed. Gene expression profiles of 774 genes were obtained using nCounter platform (PanCancer pathway panel, Nanostring TechnologiesTM). The resulting count data was voom normalized and differentially expressed genes between PD and WD NETs were identified using linear modeling methods available in R-Bioconductor LIMMA package. Candidate genes with potential therapeutic implications were validated in tissue microarrays by immunohistochemistry (IHC). Results: Analysis of gene count data between 16 PD and 23 WD NETs resulted in 154 differentially expressed genes on the 774 gene panel (FDR < 10% and 2 fold change (FC) up- or down-regulated), some of which may be potential drug targets (Figure 1). E.g. Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase responsible for transcriptional repression, and CHK1, a G2/M cell cycle regulator, were upregulated in PD compared to WD NETs (2.7 and 3.1 FC, respectively) and serine/threonine-protein kinase PAK 3, involved in cytoskeleton reorganization, was upregulated in WD NETs (3.4 FC). IHC staining also suggested overexpression of EZH2 and its enzymatic substrate H3K27me in PD NETs (p < 0.001). PAK 3, another novel therapeutic candidate overexpressed in WD NETs (p < 0.001) was confirmed using IHC, validating the transcriptome analysis at protein level. Conclusions: These findings, combined with previously reported pathway analysis (Vijayvergia et.al 2017)], highlight biological differences between PD and WD NETs and serve as a platform for future research. They also support investigation of novel drugs that inhibit activity of EZH2 (e.g. EPZ6438) in PD NETs and PAK3 (e.g FRAX597) in WD NETs.

Bevacizumab-based Chemotherapy for Poorly-differentiated Neuroendocrine Tumors

To assess and report the efficacy of and tolerance to bevacizumab-based chemotherapy in treatment outcome of metastatic poorly differentiated neuroendocrine tumors. From 2007 to 2018, 11 consecutive patients with metastatic poorly differentiated neuroendocrine treated in first- or second-line with bevacizumab-based chemotherapies were included in this monocentric retrospective cohort. Tumor response was evaluated by computed tomographic scans. Administered treatment included 5-fluorouracil and irinotecan (FOLFIRI) bevacizumab, 5-fluorouracil and oxaliplatin (FOLFOX) bevacizumab and 5-fluorouracil, oxaliplatin and irinotecan (FOLFIRINOX) bevacizumab for four, two and five patients, respectively. Three were treated in first-line and eight in second-line after cisplatin-etoposide regimen. Using Response Evaluation Criteria in Solid Tumors, partial response was observed for seven patients, and stable disease for one patient, giving a response rate of 63.6% (95% confidence interval=35.2-92.1%) and disease control rate of 72.7% (95% confidence interval=46.6-99.0%). All patients had died by the time of analysis, median progression-free survival was 14 months, and median overall survival was 15.3 months. Observed toxicity with such protocols was classical with 10 grade 3-4 toxic events, including three of hematological toxicity, three of infection, and three of digestive toxicity. Bevacizumab-based chemotherapy gave surprising efficacy and safety in first-or second-line treatment for metastatic poorly differentiated neuroendocrine tumor in this retrospective cohort. Prospective randomized trials of such therapy are warranted.

Predicting Survival and Response to Treatment in Poorly-Differentiated Neuroendocrine Tumors of the Esophagus and Stomach

Predicting Survival and Response to Treatment in Poorly-Differentiated Neuroendocrine Tumors of the Esophagus and Stomach

A Rare Case of a Poorly Differentiated Neuroendocrine Rectal Tumor With Shared CLL Histology

Introduction: Poorly differentiated neuroendocrine tumors (PDNETs) are rarely found in the GI tract1. Also uncommon is CLL infiltration of the GI tract. We report a rare case of a patient presenting with a rectal tumor that included both CLL and PDNET histology. Case Report: A 56 year old male with a history of CLL in remission presented with the complaint of 3 weeks of foul smelling diarrhea with blood spotting, bloating, and anorexia. The patient was taken for a colonoscopy, during which a 4cm friable, fungating mass was visualized on the right side of the distal rectum near the anal verge. A biopsy was performed which showed co-existing poorly differentiated neuroendocrine carcinoma and CLL. It was was strongly reactive for chromogranin and synaptophysin. It was also positive for CD5, CD20, and CD23. A CT scan revealed liver masses and extensive lymphadenopathy. Liver biopsy revealed PDNET histology. The patient was started on his first cycle of cisplatin and etoposide. Discussion: PDNETs comprise far less than 1% of GI malignancies. They are usually metastasized at discovery and may present similarly to adenocarcinomas. They are diagnosed by biopsy and histologic examination, demonstrating high mitotic rates and necrosis1. Untreated, survival is 6 months, in comparison to treatment with a regimen of etoposide and cisplatin, which offered an average survival of 15 months. In localized disease, adjuvant chemoradiation with surgery is recommended3. Management strategies for PDNETs rely on experience with small cell lung cancer therapies due to their rarity2. As for CLL, it is uncommon to see in GI tract biopsies unless it has converted to a diffuse large cell lymphoma. The prevalence of GI involvement in asymptomatic CLL patients based on autopsy studies is estimated at 7-13%3. On review of the literature, no case of co-existing CLL and PDNET was found. However, there are reports of increased rates of secondary malignancies in CLL patients, which may be related to immunological dysfunction or the effects of chemotherapy4.

Sa1144 Clinical Impact of Endoscopic Ultrasonography for Small Diameter Rectal Neuroendocrine Tumors

as PDNET, and 7 PDNEC based on morphologic features. WDNETs had low-grade cytology and mitotic figures less than 20 per 10 high-power fields. PDNECs demonstrated high grade cytology, sheet-like growth, and higher mitotic activity. PDNETs had intermediate features. Ki-67, p53, and p16 expression data are shown in Table 1. P53 expression in less than 30% of the tumor was considered negative. Conclusion: Tumors with morphologic features of well-differentiated neuroendocrine tumors do not express p53 and rarely express p16. Poorly-differentiated neuroendocrine tumors exhibit Ki-67 indices between 15-40%, with intermediate expression of p53 and p16. Poorly-differentiated neuroendocrine carcinoma with Ki-67 expression greater than 40% had the highest levels of p53 and p16 expression and the worst survival from the time of diagnosis. These data support the hypothesis that patients with neuroendocrine neoplasms of the gastrointestinal tract currently classified as grade 3 (neuroendocrine carcinoma) have variable survival. Further stratification of these patients based on proliferative indices may better predict clinical behavior, and further investigation with larger cohorts is warranted. Moreover, these data suggest expression of p53 and p16 by immunohistochemistry correlate with increasing grade and worse survival, and these markers may be useful in stratifying patients. Table 1

Sa1143 Comparison of Gallium-68 DOTATATE With 18-Fdopa PET/CT in Patients With Familial Midgut Carcinoid Tumor

as PDNET, and 7 PDNEC based on morphologic features. WDNETs had low-grade cytology and mitotic figures less than 20 per 10 high-power fields. PDNECs demonstrated high grade cytology, sheet-like growth, and higher mitotic activity. PDNETs had intermediate features. Ki-67, p53, and p16 expression data are shown in Table 1. P53 expression in less than 30% of the tumor was considered negative. Conclusion: Tumors with morphologic features of well-differentiated neuroendocrine tumors do not express p53 and rarely express p16. Poorly-differentiated neuroendocrine tumors exhibit Ki-67 indices between 15-40%, with intermediate expression of p53 and p16. Poorly-differentiated neuroendocrine carcinoma with Ki-67 expression greater than 40% had the highest levels of p53 and p16 expression and the worst survival from the time of diagnosis. These data support the hypothesis that patients with neuroendocrine neoplasms of the gastrointestinal tract currently classified as grade 3 (neuroendocrine carcinoma) have variable survival. Further stratification of these patients based on proliferative indices may better predict clinical behavior, and further investigation with larger cohorts is warranted. Moreover, these data suggest expression of p53 and p16 by immunohistochemistry correlate with increasing grade and worse survival, and these markers may be useful in stratifying patients. Table 1

Sa1142 Prognosis Analysis of Rectal Neuroendocrine Neoplasm With Different Pathological Grade

as PDNET, and 7 PDNEC based on morphologic features. WDNETs had low-grade cytology and mitotic figures less than 20 per 10 high-power fields. PDNECs demonstrated high grade cytology, sheet-like growth, and higher mitotic activity. PDNETs had intermediate features. Ki-67, p53, and p16 expression data are shown in Table 1. P53 expression in less than 30% of the tumor was considered negative. Conclusion: Tumors with morphologic features of well-differentiated neuroendocrine tumors do not express p53 and rarely express p16. Poorly-differentiated neuroendocrine tumors exhibit Ki-67 indices between 15-40%, with intermediate expression of p53 and p16. Poorly-differentiated neuroendocrine carcinoma with Ki-67 expression greater than 40% had the highest levels of p53 and p16 expression and the worst survival from the time of diagnosis. These data support the hypothesis that patients with neuroendocrine neoplasms of the gastrointestinal tract currently classified as grade 3 (neuroendocrine carcinoma) have variable survival. Further stratification of these patients based on proliferative indices may better predict clinical behavior, and further investigation with larger cohorts is warranted. Moreover, these data suggest expression of p53 and p16 by immunohistochemistry correlate with increasing grade and worse survival, and these markers may be useful in stratifying patients. Table 1

Are Targeted Therapies a Consideration in Poorly Differentiated Neuroendocrine Tumors?

The close relationship between poorly differentiated NETs (PDNETs) and well or intermediately differentiated neuroendocrine tumors (NETs) is evidenced by the World Health Organization criteria for distinguishing these groups and by recognition by the National Comprehensive Cancer Network that octreotide therapy should be considered in some PDNETs. Based on the possible derivation from similar normal cells and the somewhat arbitrary World Health Organization distinction, particularly between intermediate and poorly differentiated NETs, it seems reasonable that future studies of targeted agents in the treatment of NETs should evaluate patients with PDNETs as well.

Predicting neuroendocrine tumor (carcinoid) neoplasia using gene expression profiling and supervised machine learning

A more accurate taxonomy of small intestinal (SI) neuroendocrine tumors (NETs) is necessary to accurately predict tumor behavior and prognosis and to define therapeutic strategy. In this study, the authors identified a panel of such markers that have been implicated in tumorigenicity, metastasis, and hormone production and hypothesized that transcript levels of the genes melanoma antigen family D2 (MAGE-D2), metastasis-associated 1 (MTA1), nucleosome assembly protein 1-like (NAP1L1), Ki-67 (a marker of proliferation), survivin, frizzled homolog 7 (FZD7), the Kiss1 metastasis suppressor (Kiss1), neuropilin 2 (NRP2), and chromogranin A (CgA) could be used to define primary SI NETs and to predict the development of metastases. Seventy-three clinically and World Health Organization pathologically classified NET samples (primary tumor, n = 44 samples; liver metastases, n = 29 samples) and 30 normal human enterochromaffin (EC) cell preparations were analyzed using real-time polymerase chain reaction. Transcript levels were normalized to 3 NET housekeeping genes (asparagine-linked glycosylation 9 or ALG9, transcription factor CP2 or TFCP2, and zinc finger protein 410 or ZNF410) using geNorm analysis. A predictive gene-based model was constructed using supervised learning algorithms from the transcript expression levels. Primary SI NETs could be differentiated from normal human EC cell preparations with 100% specificity and 92% sensitivity. Well differentiated NETs (WDNETs), well differentiated neuroendocrine carcinomas, and poorly differentiated NETs (PDNETs) were classified with a specificity of 78%, 78%, and 71%, respectively; whereas poorly differentiated neuroendocrine carcinomas were misclassified as either WDNETs or PDNETs. Metastases were predicted in all cases with 100% sensitivity and specificity. The current results indicated that gene expression profiling and supervised machine learning can be used to classify SI NET subtypes and accurately predict metastasis. The authors believe that the application of this technique will facilitate accurate molecular pathologic delineation of NET disease, better define its extent, facilitate the assessment of prognosis, and provide a guide for the identification of appropriate strategies for individualized patient treatment.

Retrospective analysis of pulmonary neuroendocrine/carcinoid tumors at Ohio State University

18176 Background: Neuroendocrine tumors are a unique malignant neoplasm which can arise from the respiratory tree. Bronchial neuroendocrine tumors account for 25% of all neuroendocrine tumors, but only about 1–2% of all lung cancers. The epidemiology, clinical behavior, treatment, and prognosis of carcinoid tumors differ from other lung malignancies in significant ways. Located most often in the major bronchi, these tumors secrete neuroendocrine granules such as serotonin, histamine, and prostaglandins. Classic carcinoid syndrome (diarrhea, flushing, palpitations, wheezing), however, is rare in these patients. Treatment is primarily surgical resection for cure. The purpose of our study was to identify the experience with these malignancies at our institution and compare it to other series. Methods: A total of 64 patients were identified using diagnostic codes via our institutional cancer registry from 1980–2006. Poorly-differentiated neuroendocrine tumors and small cell lung cancer cases were excluded from analysis. Data collected included survival after diagnosis, staging, epidemiologic characteristics, and treatment. Additional variables included smoking history, laterality, and tumor staging. Results: The patient age distribution ranged from 17 years old to 82 years old, with a median age of 57 years old. Most of the patients were female (73%). Tobacco use is variable in carcinoid - 54% of our patients were never smokers, whereas 17% were previous smokers, 20% were current smokers, and history was unknown in 7%. Staging was unknown in over half of the patients. Treatment was generally surgical; lobectomy (40%) was the most common intervention, followed by wedge resection (17%), radiation therapy (14%), bronchial sleeve resections (3.5%), and pneumonectomies (3.5%). Survival was generally good - at the time of last contact, 50 patients (78%) were still alive with a median follow up of 39 months since diagnosis. Conclusion: Neuroendocrine tumors of the bronchial tree remain a unique and uncommon malignancy among lung cancers. The findings at our medical center are consistent with reported series as far as epidemiologic characteristics, treatments, and outcomes. The future direction of non-surgical therapy in this malignancy remains investigational. No significant financial relationships to disclose.

Paclitaxel/carboplatin/etoposide (PCE) therapy for advanced poorly differentiated neuroendocrine (PDNE) carcinoma: A Minnie Pearl Cancer Research Network phase II trial

4058 Background: PDNE carcinoma may arise from a variety of primary sites or present as an unknown primary. PDNE tumors have historically been sensitive to platinum/etoposide-based chemotherapy, as opposed to very poor activity in well differentiated neuroendocrine tumors. This phase II trial expands our experience with PCE in the treatment of patients (pts) with PDNE carcinoma. The objectives were to determine the objective response rate and survival. Methods: Eligibility requirements: small cell carcinoma (except small cell lung cancer) or poorly differentiated carcinoma (PDC) with diagnostic IP staining or electron microscopy; unknown or known primary; metastatic or locally advanced tumor; well differentiated carcinoid-type tumors excluded; ECOG PS 0–2; no previous chemotherapy; measurable disease; adequate organ function; informed consent. Pts received P 200mg/m2 IV, day 1; C AUC 6.0 IV, day 1; E 50/100mg po alternating, days 1–10; (repeated q 21 days x 4 courses). Local radiotherapy was subsequently administered to patients with advanced local tumor. Responding/stable pts received P 70mg/m2 IV, 6 of 8 weeks, for 24 weeks. Results: Between 1/99 and 11/04, 66 pts were treated. Pt characteristics: median age 58 years; male/female, 40/26 [small cell (12 pts); PDC (54 pts)]; primary site known/unknown, 27/39; visceral metastases, 51 pts (77%); ≥ 2 metastatic sites, 44 pts (66%). 59 pts were evaluable for response: complete, 9 pts (15%); partial, 24 pts (40%); stable/minor, 21 pts (35%); progression, 5 pts (10%). Median response duration was 9 months. After a median follow-up of 32 months, median survival is 14.8 months, with 1-, 2-, 3-, 4-, and 5-year survivals of 57%, 34%, 23%, 15%, and 15%, respectively. There was no difference (p=0.43 log rank) in survival comparing pts with known to unknown primary (median 15.6 vs. 13.8 and 1-, 2-year survivals 58%, 39% vs. 55%, 30%, respectively). Grade 3/4 toxicity was predominantly myelosuppression. Conclusions: PCE is active against PDNE and produces clinical benefit and prolongation of survival. A minority of pts remain alive, some progression-free, for several years. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb

The treatment of undifferentiated neuroendocrine tumors

The aggressiveness of poorly-differentiated neuroendocrine tumors is similar to small-cell lung cancer within a median survival of 6 months without treatment. Most patients have metastatic disease and poor condition at the time of diagnosis, and cannot be approached surgically with curative intent. Moertel et al. [Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin, Cancer 1991;68:227–232] reported an objective response rate of 67% with a chemotherapy regimen combining etoposide plus cisplatin, with a median survival of 19 months and a median time to progression of 11 months. Since this publication, this regimen has been considered as the reference treatment for poorly-differentiated neuroendocrine tumors. A French retrospective study has recently confirmed the high chemosensitivity of those tumors. However, the prognosis remains poor with a 2-year survival lower than 20% and other therapeutic approaches should be developed.