High-grade Neuroendocrine Tumors Research Articles

DIFFUSE SUBCUTANEOUS NODULES AS A FIRST SIGN OF A METASTATIC PULMONARY NEUROENDOCRINE TUMOR

SESSION TITLE: Monday Fellow Case Report Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/21/2019 02:30 PM - 03:15 PM INTRODUCTION: Pulmonary neuroendocrine tumors are rare tumors that arise from cells of the endocrine and nervous systems with an incidence rate of 2/100,000 population/year in the United States, comprising 2% of all primary lung cancers. The most common described sites of metastases from Carcinoid tumors are liver , bone , and mediastinal lymph nodes . Subcutaneous metastases from carcinoid tumors are very rare. The behavior of these tumors depends upon their location within the lungs, whether they secrete hormones, or if they have metastasized. This tumors comprise a spectrum of progression, including: low grade neuroendocrine tumors , intermediate grade neuroendocrine tumors and high grade neuroendocrine tumors (large cell neuroendocrine tumors and small cell carcinomas) respectively. CASE PRESENTATION: A 72-year-old latin american female with a past medical history of breast cancer that was previously treated with chemotherapy and radiotherapy 10 years ago. Patient came to the institution due to multiple skin progressively painful enlarged skin nodules, fatigue, generalized weakness and melena of several days of evolution. Physical examination revealed multiple skin nodules measuring from 1 to 4 cm in diameter with the largest measuring 3 x 4 cm in the left neck area extremely tender and firm. A biopsy was performed with histopathology consistent with a carcinoid tumor with moderate amount of cytoplasm and eccentric nuclei. Immunohistochemistry of the neoplastic cells exhibited similar positive staining for the neuroendocrine markers chromogranin A and synaptophysin with positive markers for CD56, pankeratin with a Ki67 of 70%. Staining of the neoplastic cells also was positive for thyroid transcription factor 1 (TTF-1) . These results were consistent with cutaneous metastasis from pulmonary carcinoid tumor by which same cells were also seen by stomach biopsy of nodules present as well. DISCUSSION: Cutaneous metastases of internal malignancies are more common from carcinomas of the lungs, gastrointestinal tract, and breasts. The histology of cutaneous carcinoid metastases typically resembles the primary lesion. However, identifying source is a major role in this cases. Occasionally, the cutaneous metastasis will develop directly over the underlying malignancy but thats not the case in the majority of cases. Thats were histologic stains and cells characteristics play a major role. Our case of cutaneous metastasis of a carcinoid tumor presented as multiple tender subcutaneous nodules. The histology of the lesion was consistent with the known carcinoid tumor of the lung. CONCLUSIONS: Even though neuroendocrine tumors are rare, obtaining an concise clinical history , addressing risk factors and pertinent findings of medical presentation with the appropriate immunohistochemical panels is the cornerstone of this challenging cases when primary site is in doubt. Reference #1: Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practiceCaplin ME, Baudin E, Ferolla P, et al. Reference #2: Primary pulmonary carcinoid tumor: a long-term single institution experience/Primary pulmonary carcinoid tumor.Ryan F. Herde, MD, MS1, Kristine E. Kokeny, MD2, Chakravarthy B. Reddy, MD3, Wallace L. Akerley, MD4, Nan Hu, PhD5, Jonathan P. Boltax, MD3, and Ying J. Hitchcock, MD2. Reference #3: Cutaneous Metastasis of a Pulmonary Carcinoid Tumor Cutis. 2017 May;99(5):E13-E15 DISCLOSURES: No relevant relationships by Christian Castillo Latorre, source=Web Response No relevant relationships by Michael Cruz, source=Web Response No relevant relationships by Omar Mendez Melendez, source=Web Response No relevant relationships by Kelvin Rivera Manzano, source=Web Response

ES04.02 Pathology Overview for Carcinoid and NE Spectrum

ES04.02 Pathology Overview for Carcinoid and NE Spectrum

P1.12-04 A Phase I Study of the 177Lu-DOTA0-Tyr3-Octreotate in Combination with Nivolumab in Patients with Extensive-Stage Small Cell Lung Cancer

Despite initial sensitivity to systemic treatment, most patients with extensive-stage small cell lung cancer (ES-SCLC) relapse. It has been shown that somatostatin receptors are expressed in SCLC. Lutathera is a 177Lutetium-labeled somatostatin analog approved for treatment of gastroenteropancreatic neuroendocrine tumors (NETs). Nivolumab, an anti-PD-1 antibody, in combination with lutathera may act synergistically to generate anti-tumor immunity. Here we report the final results of the phase I study of this combination in patients with ES-SCLC. This is a phase I/II trial of lutathera and nivolumab in patients with ES-SCLC (NCT03325816). For phase I, patients with either relapsed/refractory ES-SCLC or non-progressing ES-SCLC after first-line platinum-based chemotherapy, or advanced grade I-II pulmonary NETs were eligible. The primary objective was to determine the recommended phase 2 dose (RP2D). The phase I portion followed the standard 3+3 design, assessing two dose levels (dose level 1: Lutathera 3.7 GBq Q8W for 4 doses with nivolumab 240 mg Q2W; dose level 2: Lutathera 7.4 GBq Q8W for 4 doses with nivolumab 240 mg Q2W). The DLT period was defined as first 8 weeks after treatment initiation. Adverse events (AEs) were assessed per CTCAE 4.03. A total of 9 patients were enrolled. Three patients with ES-SCLC (2 relapsed ES-SCLC, 1 non-progressing ES-SCLC after first-line chemotherapy) were enrolled at dose level 1 and no DLTs were observed. At dose level 2, six patients (3 relapsed/refractory ES-SCLC, 2 metastatic atypical carcinoid, and 1 high-grade NET) were enrolled. One patient with refractory ES-SCLC developed a DLT (grade 3 rash). The most common treatment-related AEs (trAEs) were lymphopenia (n=7), thrombocytopenia (n=4), anemia (n=3), and nausea (n=3). 5 (55.5%) of 9 patients had grade 3 trAEs, but the most common grade 3 trAE was lymphopenia (n=4). Grade 3 anemia, thrombocytopenia, pneumonitis, and rash occurred in one patient each. No grade 4/5 trAEs were reported. Among 7 patients with measurable disease, 1 patient with non-progressing ES-SCLC had a confirmed partial response and 2 patients with metastatic atypical carcinoid had stable disease lasting 6 months. The RP2D was lutathera 7.4 GBq Q8W for 4 doses with nivolumab 240 mg Q2W. Evidence from this phase I study of lutathera and nivolumab suggests that the combination has a manageable safety profile and showed initial signs of antitumor activity. The safety and efficacy of the combination may be further explored in phase II as maintenance therapy in patients with ES-SCLC.

P2.18-14 The Role of Surgery in High Grade Neuroendocrine Tumors of the Lung

P2.18-14 The Role of Surgery in High Grade Neuroendocrine Tumors of the Lung

1455 Double Trouble: A Rare Case of Colonic Mixed Adenoneuroendocrine Carcinoma (MANEC)

INTRODUCTION: Mixed adenoneuroendocrine carcinoma (MANEC) is a rare malignancy involving both epithelial and neuroendocrine components and accounts for fewer than 2% of all colorectal cancers. We present the case of a 34 yo male whose persistent weight loss and cramping abdominal pain led to the discovery of Stage IV MANEC. CASE DESCRIPTION/METHODS: 34 yo male with no significant past medical history presented with the chief complaint of diffuse abdominal cramps over the preceding 3 days. He had intermittent, non-bloody diarrhea, and endorsed 25-30 lb unintentional weight loss in the preceding 4 months. Labs were significant for a WBC of 17.3 U/L, CRP 94.4 mg/L, and sedimentation rate of 60 mm/hr. CT abdomen and pelvis was concerning for underlying inflammatory bowel disease. Before further work up, the patient left against medical advice. He returned 2 months later due to persistent symptoms. Gastrografin study and colonoscopy showed a circumferential, partially obstructing, ulcerated mass in the sigmoid colon (Figure 1). Biopsy of the lesion showed moderately differentiated adenocarcinoma. He underwent exploratory laparotomy, sigmoidectomy, and mesenteric lymph node dissection with pathology consistent for mixed adenoneuroendocine carcinoma with a high grade aggressive neuroendocrine component of the sigmoid with involvement of small bowel, bladder serosa, and lymph nodes (Figure 2). The metastatic component was exclusively high-grade neuroendocrine tumor. The patient subsequently underwent complete resection of primary and metastatic lesions and was started on Cisplatin and Etoposide for adjuvant chemotherapy. DISCUSSION: MANEC is a mixed tumor containing adenocarcinoma and neuroendocrine components each representing at least 30% of the tumor. It is hypothesized that the tumor arises from multi-potent endodermal progenitor cells with bi-directional differentiation into both epithelial and neuroendocrine neoplasms. Outcomes depend on each malignant component and the type of neuroendocrine cells present. Due to its neuroendocrine component, MANEC is more aggressive and advanced at the time of diagnosis with poorer outcomes as compared to adenocarcinoma. While no standardized treatment regimen has been identified for MANEC, currently accepted therapy involves complete resection of the primary and metastatic lesions with individually tailored adjuvant chemotherapy to help reduce its high recurrence rate.

EP1.12-22 The Expression and Prognostic Roles of PD-L1, PAPR1 and DLL3 in Small Cell Lung Cancer

Small cell lung cancer (SCLC) is an aggressive high-grade neuroendocrine tumor with limited treatment. Recently chemotherapy combined with anti-PD-L1 therapy was approved for SCLC. PARP1and DLL3 inhibitor are under clinical trials but the data revealed that these agents benefit a proportion of SCLC patients. Which patient can benefit from anti-PD-L1, PARP1 and DLL3 inhibitor therapy and whether combination of these agents can improve the survival of SCLC are unknown. We aim to examine the expression and prognostic roles of PD-L1, PARP1 and DLL3 and to analyze the correlation between them and clinicalpathological factors. All protocols were approved by the Ethics Committee of Xi'an Jiaotong University and informed consent was signed. FFPE samples were obtained from Department of Pathology at The First Affiliated Hospital of Xi'an Jiaotong University from 2011 to 2018. SCLC was confirmed in all patients by surgical pathology and graded by AJCC TNM staging system. The expression of PD-L1, PARP1 and DLL3 were detected by immunohistochemistry as previously described. The association between PD-L1, PARP1, DLL3 and clinicalpathological characteristics was performed by χ2 test. The survival curves were analyzed by the log-rank test and Cox proportional hazards model. Except for CYFRA21-1 and DLL3, no correlation between PD-L1, PARP1 and DLL3 and clinicalpathological factors were noticed (Table 1).Table 1Correaltion between PD-L1, PARP1, DLL3 and clinialpathological factors in SCLC patientsPD-L1 negativePD-L1 positiveχ2PPARP1 negativePARP1 positiveχ2PDLL3 negativeDLL3 positiveχ2PAge<601112176815>=608130.420.561730.800.747110.070.79GenderMale14212871528Female440.270.70620.101.00350.101.00Smoking statusSmoker (including previous smoker)12152341017Never-smoker6100.200.761151.640.265110.150.70Central or PeripheralCentral11162161017Peripheral790.041.001330.071.005110.150.70CEA levelCEA normal912165714CEA high4479247Unknown925.680.06920.130.90470.040.98CYFRA21-1 levelCYFRA21-1 normal711144513CYFRA21-1 high579393Unknown670.160.921120.030.83497.540.02NSE levelNSE normal201102NSE high10172161116Unknown683.040.221220.790.494101.730.42TNM stageTNM stage 1-210131310617TNM stage 3-47120.190.661633.730.059111.690.19 Open table in a new tab We also demonstrated that PD-L1 predicts poor prognosis (HR=0.26, P=0.01), while either PARP1 or DLL3 has no correaltion with prognosis in SCLC patients (HR=0.40, P=1.39 and HR=0.07, P=1.29 respectively). Interestingly, we found SCLC patients with negative PD-L1 and PARP1, negative PD-L1 and DLL3 performed the best survival (Figure 1). PD-L1 is a negative prognositc factor in SCLC. Different expression pattern of PD-L1 and PARP1, PD-L1 and DLL3 lead to significantly different prognosis in SCLC.

Defining the role of adjuvant therapy for early-stage large cell neuroendocrine carcinoma

IntroductionLarge cell neuroendocrine carcinoma is a rare, high-grade neuroendocrine tumor. The mainstay of treatment for early, node-negative disease is surgical resection, and optimal adjuvant treatment strategies are not well defined. MethodsPatients with early, node-negative large cell neuroendocrine carcinoma were identified in the National Cancer Database from 2004 to 2014. Patient, tumor, treatment, and hospital characteristics were examined. Survival differences in patients receiving adjuvant chemotherapy (AC) were evaluated using Kaplan-Meier curves, and adjusted multivariate Cox models were constructed. A conditional landmark analysis was used to address immortal time bias. T-stage-specific propensity score matching was used to address covariate imbalances between groups. ResultsOne thousand seven hundred seventy patients were identified, of whom 463 (26.2%) received AC. Patients receiving AC were younger, less comorbid, and more likely to have T2 tumors. AC was associated with significantly longer survival, which persisted after adjustment in Cox models, for patients overall (5-year overall survival, 59.2% vs 45.3%; hazard ratio, 0.69; 95% confidence interval, 0.58-0.82; P < .0001), T2 tumors (overall survival, 59.8% vs 42.1%; hazard ratio, 0.63; 95% confidence interval, 0.50-0.81; P < .0001), and tumors 2 to 3 cm (overall survival, 60.0% vs 42.6%; hazard ratio, 0.64; 95% confidence interval, 0.46-0.8; P = .002), but not tumors smaller than 2 cm. Adjuvant chest radiotherapy was not associated with longer survival. Sublobar resection was associated with worse overall survival compared with lobectomy (hazard ratio, 1.40; 95% confidence interval, 1.20-1.64; P < .0001). Propensity score matching confirmed these findings, but the association with survival for tumors 2 to 3 cm in size was not significant. ConclusionsIn this national study of early-stage large cell neuroendocrine carcinoma, AC was associated with significantly longer survival for tumors larger than 3 cm, and possibly for tumors 2 to 3 cm. Adjuvant radiation was not associated with prolonged survival.

Gastroenteropancreatic High-Grade Neuroendocrine Neoplasms: Histology and Molecular Analysis, Two Sides of the Same Coin

Background: In gastroenteropancreatic (GEP) high-grade neuroendocrine neoplasms (H-NENs), Ki-67 threshold of 55% defines three prognosis subclasses: neuroendocrine tumor (NET) G3, neuroendocrine carcinoma (NEC) <55%, and NEC ≥55%. We investigated whether the molecular profiling of H-NENs differs among these subcategories and evaluated potential therapeutic targets, including PD-L1. Methods: In GEP-NEN patients, we evaluated: (i) 55% threshold for Ki-67 labeling index for further stratifying NEC and (ii) immunoreactivity and gene mutations by immunohistochemistry and targeted next-generation sequencing (T-NGS). Results: Fifteen NETs G3 and 39 NECs were identified. Ki-67 labeling index was <55% in 9 NECs and ≥55% in 30 NECs. Gene mutations by NGS (TP53, 32.9%; KRAS, 5.5%; BRAF, 4.1%) were detected in 46.6% NENs, significantly enriched in NEC ≥55% (76.7%) compared to NEC <55% (55.6%) or NET (20.0%). PD-L1 staining in tumor-infiltrating lymphocytes was observed in NEC ≥55% (36.7%; p = 0.03). Median OS was 4.3 years in NET G3, 1.8 years in NEC <55%, and 0.7 years in NEC ≥55% (p <0.0001); it was 2.3 years with NGS wild-type, 0.7 years with ≥1 mutation (p <0.0001), 0.8 years in PD-L1-positive patients, and 1.7 years in PD-L1-negative subjects (p = 0.0004). In multivariate analysis, only the proposed subclassification approach yielded statistically significant differences between groups (NEC <55% vs. NET G3, HR 14.1, 95% CI 2.2–89.8, p = 0.005; NEC ≥55% vs. NET G3, HR 25.8, 95% CI 3.9–169, p = 0.0007). Conclusions: These findings identify NEC ≥55% as a biologically and prognostically distinct subtype and pave the way for more personalized treatment.

The diagnostic utility of zinc E-box 1 (ZEB1) transcription factor for identification of pulmonary sarcomatoid carcinoma in cytologic and surgical specimens

Although uncommon, pulmonary sarcomatoid carcinoma carries a worse prognosis due to poor chemotherapeutic response. Currently, a histologic spindle and/or giant cell component indicates sarcomatoid differentiation, with zinc E-box binding homeobox 1 (ZEB1) implicated in promoting epithelial-mesenchymal transition. However, diagnostic use of ZEB1 in limited specimens, including cell block (CB) preparations, remains unclear. Pulmonary sarcomatoid (SARC, n = 15), typical (TC, n = 10) and atypical carcinoid (AC, n = 10), small cell (SCLC, n = 8) and large cell neuroendocrine carcinoma (LCNEC, n = 9), squamous cell carcinoma (SQ, n = 7), and adenocarcinoma (ADC, n = 7) CBs along with 69 SARCs, 20 TCs, 21 ACs, 9 SCLCs, 10 LCNECs, 71 SQs, 402 ADCs, 16 large cell carcinoma (LCC) and 17 other thoracic tumor (OT) surgical specimens between 2007 and 2018 were retrieved. ZEB1 (Sigma Aldrich, St. Louis, Mo and Novus Biological, Centennial, Colo) immunohistochemistry was graded 1+ to 3+, with ≥1+ and >5% staining considered positive. Nuclear ZEB1 was seen in 80% SARC (12/15), 0% TC (0/10), 0% AC (0/10), 12.5% SCLC (1/8) and 11.1% LCNEC (1/9), 0% SQ (0/7), and 0% ADC (0/7) CBs. In surgical specimens, 75.4% SARCs (52/69), 0% TCs (0/20), 0% ACs (0/21), 11.1% SCLCs (1/9), 30% LCNECs (3/10), 0% SQs (0/71), 0.2% ADCs (1/402), 12.5% LCCs (2/16), and 11.8% OTs (2/17) demonstrated ZEB1. ZEB1 sensitivity and specificity in cytology and surgical specimens were 80% and 96.1%, and 75.4% and 98.1%, respectively. ZEB1 is sensitive and highly specific for pulmonary sarcomatoid carcinoma in limited cytologic and surgical specimens. Diagnostic pitfalls include high-grade neuroendocrine tumors and large cell carcinoma, which are resolvable by morphologic considerations.

Analysis of 72 patients with colorectal high-grade neuroendocrine neoplasms from three Chinese hospitals.

BACKGROUNDColorectal high-grade neuroendocrine neoplasms (HGNENs) are rare and constitute less than 1% of all colorectal malignancies. Based on their morphological differentiation and proliferation identity, these neoplasms present heterogeneous clinicopathologic features. Opinions regarding treatment strategies for and improvement of the clinical outcomes of these patients remain controversial.AIMTo delineate the clinicopathologic features of and explore the prognostic factors for this rare malignancy.METHODSThis observational study reviewed the data of 72 consecutive patients with colorectal HGNENs from three Chinese hospitals between 2000 and 2019. The clinicopathologic characteristics and follow-up data were carefully collected from their medical records, outpatient reexaminations, and telephone interviews. A survival analysis was conducted to evaluate their outcomes and to identify the prognostic factors for this disease.RESULTSAccording to the latest recommendations for the classification and nomenclature of colorectal HGNENs, 61 (84.7%) patients in our cohort had poorly differentiated neoplasms, which were categorized as high-grade neuroendocrine carcinomas (HGNECs), and the remaining 11 (15.3%) patients had well differentiated neoplasms, which were categorized as high-grade neuroendocrine tumors (HGNETs). Most of the neoplasms (63.9%) were located at the rectum. More than half of the patients (51.4%) presented with distant metastasis at the date of diagnosis. All patients were followed for a median duration of 15.5 mo. In the entire cohort, the median survival time was 31 mo, and the 3-year and 5-year survival rates were 44.3% and 36.3%, respectively. Both the univariate and multivariate analyses demonstrated that increasing age, HGNEC type, and distant metastasis were risk factors for poor clinical outcomes.CONCLUSIONColorectal HGNENs are rare and aggressive malignancies with poor clinical outcomes. However, patients with younger age, good morphological differentiation, and without metastatic disease can have a relatively favorable prognosis.

The added value of intravoxel incoherent motion diffusion weighted imaging parameters in differentiating high-grade pancreatic neuroendocrine neoplasms from pancreatic ductal adenocarcinoma.

The aim of the present study was to investigate the potential significance of intravoxel incoherent motion (IVIM)-diffusion weighted imaging (DWI) in differentiating high-grade pancreatic neuroendocrine neoplasms (pNENs) from pancreatic ductal adenocarcinoma (PDAC). A total of 50 patients, including 37 patients with PDAC and 13 patients with high-grade pNENs, underwent pancreatic multiple b-values DWI with 15 b-values including 0, 10, 20, 40, 60, 80, 100, 150, 200, 400, 800, 1,000, 1,200, 1,500 and 2,000 sec/mm2. Standard apparent diffusion coefficient (ADCstandard) and IVIM parameter [slow apparent diffusion coefficient (Dslow), fast apparent diffusion coefficient (Dfast), fraction of fast apparent diffusion coefficient (ƒ)] values of PDAC and pNENs were compared. P<0.05 was considered to indicate a statistically significant difference. Receiver operating characteristics analysis was performed in order to evaluate the diagnostic potential of IVIM parameters for differentiating high-grade pNENs from PDAC. Dslow of pNENs was significantly lower compared with that of PDAC (0.460 vs. 0.579×10−3 mm2/sec; P=0.001). Dfast of pNENs was significantly higher compared with that of PDAC (13.361 vs. 4.985×10−3 mm2/sec; P<0.001). Area under the curve of Dslow, Dfast and combined Dslow and Dfast was 0.793, 0.863 and 0.885 respectively. The specificity and sensitivity of Dslow≤0.472×10−3 mm2/sec were 97.3 and 53.9%, respectively, for differentiating high-grade pNENs from PDAC. The specificity and sensitivity of Dfast >9.58×10−3 mm2/sec were 91.9 and 69.2%, respectively, for differentiating high-grade pNENs from PDAC. When Dslow and Dfast were combined, the specificity and sensitivity for differentiating high-grade pNENs from PDAC were 76.9 and 100%, respectively. Taken together, these results indicated that the diffusion-associated parameter Dslow and the perfusion-associated parameter Dfast of IVIM-DWI may differentiate high-grade pNENs from PDAC with high diagnostic accuracy, and that IVIM-DWI may be a valuable biomarker in differentiating pancreatic neoplasms.

Integrative and comparative genomic analyses identify clinically\xa0relevant pulmonary carcinoid\xa0groups and unveil the supra-carcinoids

The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compare and contrast the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Here we report that the integrative analyses on 257 lung neuroendocrine neoplasms stratify atypical carcinoids into two prognostic groups with a 10-year overall survival of 88% and 27%, respectively. We identify therapeutically relevant molecular groups of pulmonary carcinoids, suggesting DLL3 and the immune system as candidate therapeutic targets; we confirm the value of OTP expression levels for the prognosis and diagnosis of these diseases, and we unveil the group of supra-carcinoids. This group comprises samples with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, further supporting the previously proposed molecular link between the low- and high-grade lung neuroendocrine neoplasms.

Management of Well-Differentiated High-Grade (G3) Neuroendocrine Tumors.

In 2017, the World Health Organization (WHO) classification for pancreatic NET was updated to include a new category of well-differentiated high-grade (Ki 67 > 20%) pancreatic tumors (NET G3), distinct from high-grade poorly differentiated neuroendocrine carcinoma (NEC). NET G3 are considered a molecularly, radiologically, and prognostically distinct entity compared to NEC and NET G1/G2. The optimal first-line management in NET G3 and sequencing therapies remains a challenge awaiting future trials taking into consideration the unique characteristics of this category. In this review, we aim to summarize the current evidence in the management of NET G3.

Therapeutic options in lung neuroendocrine tumors: between established concepts and new hopes.

Typical (TC) and atypical (AC) carcinoids are low-grade neuroendocrine tumors (NETs) of the lung and, are neglected diseases in respect of both high-grade NETs of the lung (i.e. small-cell lung cancer and large-cell neuroendocrine carcinoma) and gastroenteropancreatic (GEP)-NETs. AC and TC account for 2 and 0.2% of all thoracic malignancies, respectively, and have a 12.9% chance of metastatic spread at diagnosis, reaching up to 20% during disease history. There are very few trials specifically designed for lung NETs, and therapeutic options are mainly derived by studies carried out in patients with GEP-NETs. We report a case of a patient affected by AC progressed to available standard treatments who received off-label treatment with sunitinib, a well-known multitarget tyrosine-kinase inhibitor with marked antiangiogenic activity, used routinely for the treatment of GEP-NETs. During treatment, the patient required the administration of an alternative schedule to improve tolerability, with benefit, and achieved a partial response according to the RECIST criteria, which is unusual in NETs. We critically reviewed available data supporting the use of somatostatin analogs, chemotherapy, and target therapies (everolimus and sunitinib) in advanced lung NETs. In the review, ongoing trials in lung NETs and future developments in this research field are also discussed.

Erratum: Resection of hepatic and pulmonary metastasis from metastatic esophageal and gastric cancer: a nationwide study.

Through no fault of the authors, the following changes to the articlewere missed. These have since been corrected. The publisher apologizes for these errors. The contributors who were part of the Gastroesophageal Metastasectomy Group were mistakenly labelled as authors of the article. The author names and affiliations have since been corrected. The author name H. van Berge has been corrected to M. I. van Berge Henegouwen. The following footnote has been added to Table 1: ‘‡Both patients had a high-grade neuroendocrine neoplasm with a Ki-index of >20% or >20 mitoses per 10 high power fields, which were thus classified as euroendocrine carcinoma (40).’ The footnote numbering in this table has also been adjusted. Reference 40 has been added. The word ‘predominantly’ has been added to the second sentence of the Discussion section.

Pancreatic High-Grade Neuroendocrine Neoplasms in the Korean Population: A Multicenter Study.

PurposeThe most recent 2017 World Health Organization (WHO) classification of pancreatic neuroendocrine neoplasms (PanNENs) has refined the three-tiered 2010 scheme by separating grade 3 pancreatic neuroendocrine tumors (G3 PanNETs) from poorly differentiated pancreatic neuroendocrine carcinomas (PanNECs). However, differentiating between G3 PanNETs and PanNECs is difficult in clinical practice.Materials and MethodsEighty-two surgically resected PanNENs were collected from 16 institutions and reclassified according to the 2017 WHO classification based on the histological features and proliferation index (mitosis and Ki-67). Immunohistochemical stains for ATRX, DAXX, retinoblastoma, p53, Smad4, p16, and MUC1 were performed for 15 high-grade PanNENs.ResultsRe-classification resulted in 20 G1 PanNETs (24%), 47 G2 PanNETs (57%), eight G3 well-differentiated PanNETs (10%), and seven poorly differentiated PanNECs (9%). PanNECs showed more frequent diffuse nuclear atypia, solid growth patterns and apoptosis, less frequent organoid growth and regular vascular patterns, and absence of low-grade PanNET components than PanNETs. The Ki-67 index was significantly higher in PanNEC (58.2%± 15.1%) compared to G3 PanNET (22.6%±6.1%, p < 0.001). Abnormal expression of any two of p53, p16, MUC1, and Smad4 could discriminate PanNECs from G3 PanNETs with 100% specificity and 87.5% sensitivity.ConclusionHistological features supporting the diagnosis of PanNECs over G3 PanNETs were the absence of a low-grade PanNET component in the tumor, the presence of diffuse marked nuclear atypia, solid growth pattern, frequent apoptosis and markedly increased proliferative activity with homogeneous Ki-67 labeling. Immunohistochemical stains for p53, p16, MUC1, and Smad4 may be helpful in distinguishing PanNECs from G3 PanNETs in histologically ambiguous cases, especially in diagnostic practice when only small biopsied tissues are available.

Abstract 4509: Overexpression of CADM1 enhances malignant features of small-cell lung cancer

Abstract Small-cell lung cancer (SCLC) is one of the representative intractable cancers with the 5-year survival of less than 10 %. Novel approaches to the treatment of SCLC are required because recurrence arises inevitably after the initial chemotherapy. CADM1 was originally identified as a tumor suppressor of non-small cell lung cancer (NSCLC) which encodes a member of immunoglobulin superfamily cell adhesion molecules. CADM1 consists of an extracellular domain with three immunoglobulin-like loops, a trans-membrane domain and a short cytoplasmic domain containing a protein 4.1-binding motif (4.1BM) and a PDZ-II-binding motif. We have reported that CADM1 is highly expressed in 90% of human SCLC cell lines and promotes subcutaneous tumor formation of SCLC cells in nude mice. In this study, we performed clinicopathological evaluation of CADM1 in SCLC and analyzed the molecular mechanisms of malignant progression of SCLC by overexpressing CADM1. Firstly, we performed immunohistochemical analysis of CADM1 expression in high-grade neuroendocrine tumor (HGNEC) of the lung, including SCLC and large cell neuroendocrine carcinoma (LCNEC). We found that CADM1 protein was expressed in 75% (33/44) of SCLC tumors and correlated with the nodal involvement in lung HGENC. To understand pathological significance of CADM1 overexpression in SCLC, we introduced a full-length CADM1 and its mutants in the extracellular or intracellular domain into SCLC cells, SBC5, lacking endogenous CADM1 expression and assessed their malignant features in comparison with control SBC5 cells. CADM1 expression significantly enhanced colony formation in soft agar and subcutaneous tumor formation in nude mice of SBC5, whereas a mutant in 4.1BM did not. Then, we screened chemical library of 170 small molecules of known function to identify compounds which inhibit anchorage-independent growth of SCLC cells enhanced by CADM1. Inhibitors of PI3K, Akt and PKA significantly suppressed cell growth of SBC5, suggesting that CADM1 activates PI3K/Akt and PKA signaling pathways through its 4.1BM and promotes anchorage-independent growth of SCLC cells. We also found that orthotopic injection of NCI-N417 cells overexpressing CADM1 into the lung of nude mice significantly enhanced their metastasis to mediastinal lymph nodes. These results suggest that CADM1 enhances tumor growth and metastasis of SCLC cells probably by activating PI3K/Akt and PKA pathways through its binding proteins at 4.1BM. Citation Format: Toko Funaki, Takeshi Ito, Yoshinori Murakami. Overexpression of CADM1 enhances malignant features of small-cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4509.

METASTATIC NEUROENDOCRINE PROSTATE CANCER, AN AGGRESSIVE PROSTATE MALIGNANCY: A REPORT OF TWO CASES WITH ORAL MANIFESTATIONS

Objectives Neuroendocrine prostate cancer (NEPC) is a lethal prostate malignancy with a median survival of less than 1 year from time of detection. NEPC can occur de novo or more commonly as a treatment emergent phenomenon (t-NEPC). t-NEPC occurs in a subset of patients with metastatic-castration resistant prostate cancer. Two cases of t-NEPC with oral manifestations are presented highlighting the pathologic features and the varied clinical context in which these lesions presented. Patients and Methods Case 1) A 79 year-old man with a history of prostate adenocarcinoma undergoing hormone treatment presented with a fungating mass of the right maxilla and palate, clinically suspicious for squamous cell carcinoma. Biopsy revealed a high grade neuroendocrine carcinoma. Case 2) A 76 year-old man with a history of metastatic prostate adenocarcinoma receiving zoledronic acid and denosumab treatment for bony metastases, presented with mandibular fracture. A segmental resection without reconstruction with debridement was performed with a clinical diagnosis of medication-related osteonecrosis of the jaw (MRONJ). The pathology revealed a high grade neuroendocrine cell tumor. Both cases were positive for neuroendocrine markers chromogranin, synaptophysin, and CD56, and stained negative for prostate specific antigen (PSA) and prostate specific acid phosphatase (PSAP). Both tumors demonstrated a proliferative index (Ki-67) of 60-70%. An extended panel of immunostains appeared to eliminate other entities from consideration. Conclusions Awareness of t-NECP is of importance to correctly diagnosis the entity, recognizing that tumor markers such as PSA and PSAP are negative, and standard serum markers for prostate carcinoma may be stable or show no increase with progression of disease. Neuroendocrine carcinoma in the setting of medication related osteonecrosis of the jaw in a patient with prostate carcinoma needs to be included in the differential diagnosis.

Identification of key modules and hub genes for small-cell lung carcinoma and large-cell neuroendocrine lung carcinoma by weighted gene co-expression network analysis of clinical tissue-proteomes.

Small-cell lung carcinoma (SCLC) and large-cell neuroendocrine lung carcinoma (LCNEC) are high-grade lung neuroendocrine tumors (NET). However, comparative protein expression within SCLC and LCNEC remains unclear. Here, protein expression profiles were obtained via mass spectrometry-based proteomic analysis. Weighted gene co-expression network analysis (WGCNA) identified co-expressed modules and hub genes. Of 34 identified modules, six were significant and selected for protein–protein interaction (PPI) network analysis and pathway enrichment. Within the six modules, the activation of cellular processes and complexes, such as alternative mRNA splicing, translation initiation, nucleosome remodeling and deacetylase (NuRD) complex, SWItch/Sucrose Non-Fermentable (SWI/SNF) superfamily-type complex, chromatin remodeling pathway, and mRNA metabolic processes, were significant to SCLC. Modules enriched in processes, including signal recognition particle (SRP)-dependent co-translational protein targeting to membrane, nuclear-transcribed mRNA catabolic process of nonsense-mediated decay (NMD), and cellular macromolecule catabolic process, were characteristically activated in LCNEC. Novel high-degree hub genes were identified for each module. Master and upstream regulators were predicted via causal network analysis. This study provides an understanding of the molecular differences in tumorigenesis and malignancy between SCLC and LCNEC and may help identify potential therapeutic targets.

Development of chimeric and bifunctional antagonists for CLR/RAMP receptors.

CGRP, adrenomedullin (ADM), and adrenomedullin 2 (ADM2) family peptides are important neuropeptides and hormones for the regulation of neurotransmission, vasotone, cardiovascular morphogenesis, vascular integrity, and feto‒placental development. These peptides signal through CLR/RAMP1, 2 and 3 receptor complexes. CLR/RAMP1, or CGRP receptor, antagonists have been developed for the treatment of migraine headache and osteoarthritis pain; whereas CLR/RAMP2, or ADM receptor, antagonists are being developed for the treatment of tumor growth/metastasis. Based on the finding that an acylated chimeric ADM/ADM2 analog potently stimulates CLR/RAMP1 and 2 signaling, we hypothesized that the binding domain of this analog could have potent inhibitory activity on CLR/RAMP receptors. Consistent with this hypothesis, we showed that acylated truncated ADM/ADM2 analogs of 27–31 residues exhibit potent antagonistic activity toward CLR/RAMP1 and 2. On the other hand, nonacylated analogs have minimal activity. Further truncation at the junctional region of these chimeric analogs led to the generation of CLR/RAMP1-selective antagonists. A 17-amino-acid analog (Antagonist 2–4) showed 100-fold selectivity for CLR/RAMP1 and was >100-fold more potent than the classic CGRP receptor antagonist CGRP8-37. In addition, we showed (1) a lysine residue in the Antagonist 2–4 is important for enhancing the antagonistic activity, (2) an analog consisted of an ADM sequence motif and a 12-amino-acid binding domain of CGRP exhibits potent CLR/RAMP1-inhibitory activity, and (3) a chimeric analog consisted of a somatostatin analog and an ADM antagonist exhibits dual activities on somatostatin and CLR/RAMP receptors. Because the blockage of CLR/RAMP signaling prevents migraine pain and suppresses tumor growth/metastasis, further studies of these analogs, which presumably have better access to the tumor microenvironment and nerve endings at the trigeminal ganglion and synovial joints as compared to antibody-based therapies, may lead to the development of better anti-CGRP therapy and alternative antiangiogenesis therapy. Likewise, the use of bifunctional somatostatin-ADM antagonist analogs could be a promising strategy for the treatment of high-grade neuroendocrine tumors by targeting an antiangiogenesis agent to the neuroendocrine tumor microenvironment.