Cancer Research and Treatment

Original Articles

Gastrointestinal cancer

Presence of RB1 or Absence of LRP1B Mutation Predicts Poor Overall Survival in Patients with Gastric Neuroendocrine Carcinoma and Mixed Adenoneuroendocrine Carcinoma: In Hye Song, Bokyung Ahn, Young Soo Park, Deok Hoon Kim, Seung-Mo Hong; Cancer Res Treat. 2025;57(2):492-506. Published online September 27, 2024; DOI: https://doi.org/10.4143/crt.2024.667

Abstract PDF Supplementary Material PubReader ePub: Purpose
Neuroendocrine carcinomas (NECs) of the stomach are extremely rare, but fatal. However, our understanding of the genetic alterations in gastric NECs is limited. We aimed to evaluate genomic and clinicopathological characteristics of gastric NECs and mixed adenoneuroendocrine carcinomas (MANECs).
Materials and Methods
Fourteen gastric NECs, three gastric MANECs, and 1,381 gastric adenocarcinomas were retrieved from the departmental next-generation sequencing database between 2017 and 2022. Clinicopathological parameters and next-generation sequencing test results were retrospectively collected and reviewed.
Results
Gastric NECs and MANECs frequently harbored alterations of TP53, RB1, SMARCA4, RICTOR, APC, TOP1, SLX4, EGFR, BRCA2, and TERT. In contrast, gastric adenocarcinomas exhibited alterations of TP53, CDH1, LRP1B, ARID1A, ERBB2, GNAS, CCNE1, NOTCH, and MYC. Mutations of AKT3, RB1, and SLX4; amplification of BRCA2 and RICTOR; and deletion of ADAMTS18, DDX11, KLRC3, KRAS, MAX, NFKBIA, NUDT7, and RB1 were significantly more frequent in gastric NECs and MANECs than in gastric adenocarcinomas. The presence of LRP1B mutation was significantly associated with longer overall survival (OS), whereas RB1 mutation and advanced TNM stage were associated with shorter OS.
Conclusion
We identified frequently mutated genes and potential predictors of survival in patients with gastric NECs and MANECs.

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Endocrine cancer

Phase 1 Study of No-Carrier Added ¹⁷⁷Lu-DOTATATE (SNU-KB-01) in Patients with Somatostatin Receptor–Positive Neuroendocrine Tumors: The First Clinical Trial of Peptide Receptor Radionuclide Therapy in Korea: Hyun Gee Ryoo, Minseok Suh, Keon Wook Kang, Dae-Won Lee, Sae-Won Han, Gi Jeong Cheon; Cancer Res Treat. 2023;55(1):334-343. Published online April 22, 2022; DOI: https://doi.org/10.4143/crt.2021.1022

Abstract PDF Supplementary Material PubReader ePub

Purpose
To provide a wider choice of treatment opportunities for patients with neuroendocrine tumor (NET) in Korea, we have conducted a phase 1, open-label, single-arm, dose-escalation study of SNU-KB-01, a no-carrier added (NCA) ¹⁷⁷Lu-labeled DOTATATE.
Materials and Methods
Seven patients with inoperable, progressive, metastatic, or locally advanced, somatostatin receptor-positive NET with Ki67 index ≤ 20% were enrolled according to the rolling six design. The study consisted of two cohorts to receive 4 cycles of SNU-KB-01 every 8 weeks for the first dose of 5.55 GBq (n=3) and 7.40 GBq (n=4). We assessed the incidence of dose-limiting toxicity (DLT) and adverse event, absorbed dose of kidneys and bone marrow, and objective tumor response.
Results
Seven patients completed 4 cycles (21.3-30.1 GBq total dose) of SNU-KB-01. The mean absorbed doses to kidneys and bone marrow were 0.500 mGy/MBq and 0.053 mGy/MBq, respectively, and the total body effective dose was 0.115 mSv/MBq. No DLT was observed and the maximum tolerated dose was 7.40 GBq/cycle. Grade 3 thrombocytopenia occurred in one patient, but no other grade 3 or 4 major hematologic or renal toxicity was observed. The best objective response to SNU-KB-01 was partial response. Overall response rate was 42.9% and disease control rate was 85.7%.
Conclusion
Treatment with 4 cycles of SNU-KB-01 was well tolerated and resulted in control of disease in most of the patients. Our results indicate SNU-KB-01, an NCA ¹⁷⁷Lu-labeled DOTATATE, as a potentially safe and efficacious treatment option for NET patients in Korea.

Citations

Citations to this article as recorded by

Peptide-drug conjugates: A new paradigm for targeted cancer therapy
Mo Wang, Jiawei Liu, Mingjing Xia, Libinghan Yin, Ling Zhang, Xifu Liu, Yu Cheng
European Journal of Medicinal Chemistry.2024; 265: 116119. CrossRef
Electrochemical separation and purification of no-carrier-added 177Lu for radiopharmaceutical preparation: Translation from bench to bed
Sourav Patra, Rubel Chakravarty, Khajan Singh, K.V. Vimalnath, Sudipta Chakraborty
Chemical Engineering Journal Advances.2023; 14: 100444. CrossRef

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Review Article

Systemic Treatment of Advanced Gastroenteropancreatic Neuroendocrine Tumors in Korea: Literature Review and Expert Opinion: Changhoon Yoo, Chung Ryul Oh, Seung-Tae Kim, Woo Kyun Bae, Hye-Jin Choi, Do-Youn Oh, Myung-Ah Lee, Baek-Yeol Ryoo; Cancer Res Treat. 2021;53(2):291-300. Published online December 29, 2020; DOI: https://doi.org/10.4143/crt.2020.1233

Abstract PDF PubReader ePub

Neuroendocrine tumors (NETs) are a group of malignancies arising from neuroendocrine cells and frequently originate in the gastrointestinal tract and pancreas. Although curative resection is the main treatment for localized disease, systemic therapy is needed for relapsed or metastatic/unresectable gastroenteropancreatic NETs (GEP-NETs). Although there are several NET treatment guidelines from various countries, the geographical discrepancies between patient clinical characteristics, the regulatory approval status for therapeutic agents, and medical practices necessitate specific guidelines for Korean patients. We here provide a consensus review of the diagnosis, staging and systemic treatment of Korean GEP-NET patients. Systemic therapy options and the current Korean expert consensus on these treatments, including somatostatin analogs, targeted therapies such as everolimus and sunitinib, peptide receptor radionuclide treatments, and cytotoxic chemotherapies are addressed.

Citations

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Efficacy and Safety of Lu-177 DOTATATE Peptide Receptor Radionuclide Therapy in Patients with Unresectable or Metastatic Neuroendocrine Tumors in Korea
Yeokyeong Shin, Bo Hyun Moon, Baek-Yeol Ryoo, Heung-Moon Chang, Kyu-pyo Kim, Yong Sang Hong, Tae Won Kim, Jin-Sook Ryu, Yong-il Kim, Changhoon Yoo
Targeted Oncology.2024; 19(1): 41. CrossRef
Effectiveness and Safety of Retreatment with177Lu-DOTATATE in Patients with Progressive Neuroendocrine Tumors: A Retrospective Real-World Study in the United States
Ebrahim S. Delpassand, Soheil M. Yazdi, Shashank Ghantoji, Antonio Nakasato, Corinne Strickland, Rodolfo Nunez, Afshin Shafie, Susan Cork, Clare Byrne, Jackson Tang, Jeetvan Patel
Journal of Nuclear Medicine.2024; 65(5): 746. CrossRef
Advances in hydrogel materials applied to pancreatic-related diseases
Yuan Zhou, Maoen Pan, Ronggui Lin, Heguang Huang
Journal of Pancreatology.2024; 7(3): 222. CrossRef
Prognostic value of interim [68Ga]Ga-DOTA-TOC PET/CT in patients with neuroendocrine tumour who underwent peptide receptor radionuclide therapy
Eonwoo Shin, Yong-il Kim, Changhoon Yoo, Yeokyeong Shin, Baek-Yeol Ryoo, Dong Yun Lee, Jin-Sook Ryu
European Radiology.2024; 35(5): 2559. CrossRef
Consideration of quality of life in the treatment decision-making for patients with advanced gastroenteropancreatic neuroendocrine tumors
Boris G. Naraev, Josh Mailman, Thorvardur R. Halfdanarson, Heloisa P. Soares, Erik S. Mittra, Julie Hallet
Expert Review of Anticancer Therapy.2023; 23(6): 601. CrossRef
KSNM60 in Nuclear Endocrinology: from the Beginning to the Future
Chae Moon Hong, Young Jin Jeong, Hae Won Kim, Byeong-Cheol Ahn
Nuclear Medicine and Molecular Imaging.2022; 56(1): 17. CrossRef
Efficacy of Immune Checkpoint Inhibitors against Advanced or Metastatic Neuroendocrine Neoplasms: A Systematic Review and Meta-Analysis
Eun-Joo Park, Hyo-Jung Park, Kyung-Won Kim, Chong-Hyun Suh, Changhoon Yoo, Young-Kwang Chae, Sree Harsha Tirumani, Nikhil H. Ramaiya
Cancers.2022; 14(3): 794. CrossRef
Advances in the Diagnosis and Therapeutic Management of Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs)
Krzysztof Kaliszewski, Maksymilian Ludwig, Maria Greniuk, Agnieszka Mikuła, Karol Zagórski, Jerzy Rudnicki
Cancers.2022; 14(8): 2028. CrossRef
Capecitabine plus temozolomide in patients with grade 3 unresectable or metastatic gastroenteropancreatic neuroendocrine neoplasms with Ki-67 index <55%: single-arm phase II study
H. Jeong, J. Shin, J.H. Jeong, K.-p. Kim, S.-M. Hong, Y.-i. Kim, J.-S. Ryu, B.-Y. Ryoo, C. Yoo
ESMO Open.2021; 6(3): 100119. CrossRef

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Original Articles

Pancreatic High-Grade Neuroendocrine Neoplasms in the Korean Population: A Multicenter Study: Haeryoung Kim, Soyeon An, Kyoungbun Lee, Sangjeong Ahn, Do Youn Park, Jo-Heon Kim, Dong-Wook Kang, Min-Ju Kim, Mee Soo Chang, Eun Sun Jung, Joon Mee Kim, Yoon Jung Choi, So-Young Jin, Hee Kyung Chang, Mee-Yon Cho, Yun Kyung Kang, Myunghee Kang, Soomin Ahn, Youn Wha Kim, Seung-Mo Hong, on behalf of the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists; Cancer Res Treat. 2020;52(1):263-276. Published online July 12, 2019; DOI: https://doi.org/10.4143/crt.2019.192

Abstract PDF Supplementary Material PubReader ePub

Purpose
The 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 Pan- NETs and PanNECs is difficult in clinical practice.
Materials and Methods
Eighty-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.
Results
Re-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.
Conclusion
Histological 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.

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Fei Qi, Minghang Zhang, Yi Han, Juan Du, Hongjie Yang, Hongmei Zhang, Yong Zhang, Tongmei Zhang
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Pancreatic neuroendocrine neoplasms (pNENs): Genetic and environmental biomarkers for risk of occurrence and prognosis
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Rapid Evolution of Metastases in Patients with Treated G3 Neuroendocrine Tumors Associated with NEC-Like Transformation and TP53 Mutation
Atsuko Kasajima, Nicole Pfarr, Eva-Maria Mayr, Ayako Ura, Elisa Moser, Alexander von Werder, Abbas Agaimy, Marianne Pavel, Günter Klöppel
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Xin Chen, Chuangen Guo, Wenjing Cui, Ke Sun, Zhongqiu Wang, Xiao Chen
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Validation of the 8th AJCC Cancer Staging System for Pancreas Neuroendocrine Tumors Using Korean Nationwide Surgery Database: Yunghun You, Jin-Young Jang, Song Cheol Kim, Yoo-Seok Yoon, Joon Seong Park, Chol Kyoon Cho, Sang-Jae Park, Jae Do Yang, Woo Jung Lee, Tae Ho Hong, Keun Soo Ahn, Chi-Young Jeong, Hyeon Kook Lee, Seung Eun Lee, Young Hoon Roh, Hee Joon Kim, Hongbeom Kim, In Woong Han; Cancer Res Treat. 2019;51(4):1639-1652. Published online April 19, 2019; DOI: https://doi.org/10.4143/crt.2019.023

Abstract PDF PubReader ePub

Purpose
The 8th edition of the American Joint Committee on Cancer (AJCC) staging system for pancreatic neuroendocrine tumor (PNET) included several significant changes. We aim to evaluate this staging system compared to the 7th edition AJCC staging system and European Neuroendocrine Tumors Society (ENETS) system.
Materials and Methods
We used Korean nationwide surgery database (2000-2014). Of 972 patients who had undergone surgery for PNET, excluding patients diagnosed with ENETS/World Health Organization 2010 grade 3 (G3), only 472 patients with accurate stage were included.
Results
Poor discrimination in overall survival rate (OSR) was noted between AJCC 8th stage III and IV (p=0.180). The disease-free survival (DFS) curves of 8th AJCC classification were well separated between all stages. Compared with stage I, the hazard ratio of II, III, and IV was 3.808, 13.928, and 30.618, respectively (p=0.007, p < 0.001, and p < 0.001). The curves of OSR and DFS of certain prognostic group in AJCC 7th and ENETS overlapped. In ENETS staging system, no significant difference in DFS between stage IIB versus IIIA (p=0.909) and IIIA versus IIIB (p=0.291). In multivariable analysis, lymphovascular invasion (p=0.002), perineural invasion (p=0.003), and grade (p < 0.001) were identified as independent prognostic factors for DFS.
Conclusion
This is the first large-scale validation of the AJCC 8th edition staging system for PNET. The revised 8th system provides better discrimination compared to that of the 7th edition and ENETS TNM system. This supports the clinical use of the system.

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Prognostic Significance of Defining L-Cell Type on the Biologic Behavior of Rectal Neuroendocrine Tumors in Relation with Pathological Parameters: The Gastrointestinal Pathology Study Group of Korean Society of Pathologists, Jin Hee Sohn, Mee-Yon Cho, Yangsoon Park, Hyunki Kim, Woo Ho Kim, Joon Mee Kim, Eun Sun Jung, Kyoung-Mee Kim, Jae Hyuk Lee, Hee Kyung Chan, Do Youn Park, Mee Joo, Sujin Kim, Woo Sung Moon, Mi Seon Kang, So-Young Jin, Yun Kyung Kang, Sun Och Yoon, HyeSeung Han, EunHee Choi; Cancer Res Treat. 2015;47(4):813-822. Published online February 26, 2015; DOI: https://doi.org/10.4143/crt.2014.238

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Purpose
In 2010, the World Health Organization categorized L-cell type neuroendocrine tumors (NETs) as tumors of uncertain malignancy, while all others were classified as malignant. However, the diagnostic necessity of L-cell immunophenotyping is unclear, as are tumor stage and grade that may guide diagnosis and management. To clarify the predictive markers of rectal neuroendocrine neoplasms (NENs), 5- and 10-year overall survival (OS) was analyzed by pathological parameters including L-cell phenotype. Materials and Methods A total of 2,385 rectal NENs were analyzed from our previous multicenter study and a subset of 170 rectal NENs was immunophenotyped.
Results
In univariate survival analysis, tumor grade (p < 0.0001), extent (p < 0.0001), size (p < 0.0001), lymph node metastasis (p=0.0063), and L-cell phenotype (p < 0.0001) showed significant correlation with the prognosis of rectal NENs; however, none of these markers achieved independent significance in multivariate analysis. The 10-year OS of tumors of NET grade 1, < 10 mm, the mucosa/submucosa was 97.58%, 99.47%, and 99.03%, respectively. L-Cell marker, glucagon II (GLP-1&2), with a cut off score of > 10, is useful in defining L-Cell type. In this study, an L-cell immunophenotype was found in 83.5% of all rectal NENs and most, but not all L-cell type tumors were NET G1, small (< 10 mm) and confined to the mucosa/submucosa. Conclusion From these results, the biological behavior of rectal NENs does not appear to be determined by L-cell type alone but instead by a combination of pathological parameters.

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Gastroenteropancreatic Neuroendocrine Tumors with Liver Metastases in Korea: A Clinicopathological Analysis of 72 Cases in a Single Institute: Yooju Shin, Sang Yun Ha, Jiyeon Hyeon, Boram Lee, Jeeyun Lee, Kee-Taek Jang, Kyoung-Mee Kim, Young Suk Park, Cheol-Keun Park; Cancer Res Treat. 2015;47(4):738-746. Published online February 16, 2015; DOI: https://doi.org/10.4143/crt.2014.224

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Purpose
Management of gastroenteropancreatic (GEP) neuroendocrine tumors with liver metastases (NETLM) presents many clinical challenges. Assessment of the extent of disease and primary tumor site is crucial for management. In this study, we investigated the primary tumor sites and prognostic factors in GEP NETLM among Korean patients. Materials and Methods We reviewed the medical records of 72 Korean patients diagnosed with GEP NETLM between January 1999 and May 2013, focusing on their clinical and pathologic characteristics.
Results
The most frequently encountered primary tumor sites were the pancreas (n=25, 35%), stomach (n=8, 11%), gall bladder (n=4, 6%) and rectum (n=3, 4%). Twenty-five patients (35%) had occult primary tumor. Twelve patients (17%) had histological grade G1 tumors, 30 patients (42%) had G2 tumors, and 30 patients (42%) had G3 tumors. The mean follow-up period after histological confirmation of hepatic metastases was 11.30±2.44 months for G3 tumors, 19.67±4.09 months for G2 tumors, and 30.67±6.51 months for G1 tumors. Multivariate analyses revealed that an unknown primary tumor site (p=0.001) and higher histological grade (p < 0.001) were independent prognostic indicators for shorter overall survival (OS). Most long-term survivors (OS > 24 months) had received antitumor treatment. Conclusion The primary tumor site most frequently associated with GEP NETLM was the pancreas. Unknown primary tumor and higher histological grade were independent prognostic indicators for shorter OS. Patients identified as being at a risk of shorter OS should be followed up closely.

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Case Report

Multiple Cardiac Metastases from a Nonfunctioning Pancreatic Neuroendocrine Tumor: Yong Hyeok Choi, Hye-Suk Han, Sung-Nam Lim, Sang Yeub Lee, Ji Hae Koo, Ok-Jun Lee, Ki Hyeong Lee, Seung Taik Kim; Cancer Res Treat. 2013;45(2):150-154. Published online June 30, 2013; DOI: https://doi.org/10.4143/crt.2013.45.2.150

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Pancreatic neuroendocrine tumors (pNETs) are rare neoplasms, which most commonly metastasize to the liver. However, intrathoracic metastases from pNETs are encountered infrequently. This report describes a case of nonfunctioning pNET with multiple cardiac metastases. A 56-year-old male presented with a palpable abdominal mass that showed progressive enlargement. Findings on computed tomography (CT) of the abdomen revealed two relatively well-marginated inhomogeneous low-attenuation masses, one in the head of the pancreas and the other in the tail. Multiple enhancing masses in the left pericardium with myocardial involvement were observed on chest CT and transthoracic echocardiography. Needle biopsies were performed on the mass in the tail of the pancreas and the left ventricular apical pericardium; histologic examination by hematoxylin and eosin morphology and immunohistochemical staining showed pNET in both. This is the first report of pNET with multiple cardiac metastases to previously undescribed metastatic sites.

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Original Articles

Current Trends of the Incidence and Pathological Diagnosis of Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs) in Korea 2000-2009: Multicenter Study: Mee-Yon Cho, Joon Mee Kim, Jin Hee Sohn, Mi-Jung Kim, Kyoung-Mee Kim, Woo Ho Kim, Hyunki Kim, Myeong-Cherl Kook, Do Youn Park, Jae Hyuk Lee, HeeKyung Chang, Eun Sun Jung, Hee Kyung Kim, So-Young Jin, Joon Hyuk Choi, Mi Jin Gu, Sujin Kim, Mi Seon Kang, Chang Ho Cho, Moon-Il Park, Yun Kyung Kang, Youn Wha Kim, Sun Och Yoon, Han Ik Bae, Mee Joo, Woo Sung Moon, Dae Young Kang, Sei Jin Chang; Cancer Res Treat. 2012;44(3):157-165. Published online September 30, 2012; DOI: https://doi.org/10.4143/crt.2012.44.3.157

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PURPOSE
As a result of various independently proposed nomenclatures and classifications, there is confusion in the diagnosis and prediction of biological behavior of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). A comprehensive nationwide study is needed in order to understand the biological characteristics of GEP-NETs in Korea.
MATERIALS AND METHODS
We collected 4,951 pathology reports from 29 hospitals in Korea between 2000 and 2009. Kaplan-Meier survival analysis was used to determine the prognostic significance of clinicopathological parameters.
RESULTS
Although the GEP-NET is a relatively rare tumor in Korea, its incidence has increased during the last decade, with the most significant increase found in the rectum. The 10-year survival rate for well-differentiated endocrine tumor was 92.89%, in contrast to 85.74% in well differentiated neuroendocrine carcinoma and 34.59% in poorly differentiated neuroendocrine carcinoma. Disease related death was most common in the biliary tract (62.2%) and very rare in the rectum (5.2%). In Kaplan-Meier survival analysis, tumor location, histological classification, extent, size, mitosis, Ki-67 labeling index, synaptophysin expression, lymphovascular invasion, perineural invasion, and lymph node metastasis showed prognostic significance (p<0.05), however, chromogranin expression did not (p=0.148). The 2000 and 2010 World Health Organization (WHO) classification proposals were useful for prediction of the prognosis of GEP-NET.
CONCLUSION
The incidence of GEP-NET in Korea has shown a remarkable increase during the last decade, however, the distribution of tumors in the digestive system differs from that of western reports. Assessment of pathological parameters, including immunostaining, is crucial in understanding biological behavior of the tumor as well as predicting prognosis of patients with GEP-NET.

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Clinical Significance of Protein Expression of Cyclooxygenase-2 and Somatostatin Receptors in Gastroenteropancreatic Neuroendocrine Tumors: Hee Sung Kim, Hye Seung Lee, Woo Ho Kim; Cancer Res Treat. 2011;43(3):181-188. Published online September 30, 2011; DOI: https://doi.org/10.4143/crt.2011.43.3.181

Abstract PDF PubReader ePub

PURPOSE
This study was undertaken to evaluate the significance of cyclooxygenase-2 (COX2) overexpression and the expression of somatostatin receptor (SSTR) subtypes in gastroenteropancreatic neuroendocrine tumors (GEP-NETs).
MATERIALS AND METHODS
Two hundred and forty-seven cases of GEP-NET, comprising 86 foregut and 156 hindgut primary NETs, and 5 metastatic NETs in the liver, were studied retrospectively with immunohistochemistry for COX2, chromogranin A, Ki-67, SSTR1, SSTR2, and SSTR5.
RESULTS
COX2 overexpression was observed in 54%(126 of 234), and SSTR1, SSTR2, and SSTR5 positivity in 84%(196 of 233), 72%(168 of 233), and 55%(128 of 232), respectively. COX2 overexpression was found to be positively correlated with Ki-67 labeling index and inversely correlated with the expression of SSTR subtypes. In addition, the expression of SSTR subtypes was tightly correlated in any comparative pairs. A significant inverse correlation was found between COX2 and SSTR2 expression in the foregut, but not hindgut NETs. Kaplan-Meier analyses showed that COX2 overexpression (p=0.003) and high Ki-67 labeling index (p<0.001) were associated with poor overall survival (OS), whereas expression of SSTR2 (p<0.001) was associated with better OS of GEP-NET patients. Multivariate analysis revealed negative SSTR2 expression as an independent prognostic marker in GEP-NET patients (p<0.001).
CONCLUSION
Our results suggest that expression of SSTR subtypes is associated with favorable prognosis, whereas COX2 overexpression is associated with poor prognosis in GEP-NETs. Taken together, COX2 could be a possible therapeutic target in some subsets of GEP-NETs.

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Endocrine Related Cancer.2014; 21(5): 691. CrossRef

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Clinical Features of Pulmonary Large Cell Neuroendocrine Carcinoma: Moo Suk Park, Kil Dong Kim, Jae Ho Chung, Dong Hwan Shin, Kyung Young Chung, Joo Hang Kim, Chang Yul Lee, Young Sam Kim, Hyung Joong Kim, Se Kyu Kim, Chul Min Ahn, Sung Kyu Kim, Joon Chang; Cancer Res Treat. 2003;35(3):245-253. Published online June 30, 2003; DOI: https://doi.org/10.4143/crt.2003.35.3.245

Abstract PDF

PURPOSE
This study was performed to investigate the clinical features of large cell neuroendocrine carcinomas (LCNEC). MATERIALS AND METHODS: We retrospectively reviewed the histopathology and clinical information of 37 patients with LCNEC, diagnosed between June 1992 and May 2002 at the Severance Hospital, and performed immunohistochemical (IHC) staining. RESULTS: The prevalence of LCNEC among primary lung cancers was 0.3%, 37 out of 13, 012 cases over a 10 year period. The mean age was 61+/-12 years old, with 34 (92%) males and 3 (8%) females. 30 patients smoked, with an average of 42 packs per year. A cough was the most frequent symptom. The tumor was located at the periphery of the lung in 24 cases (65%). Among the 30 cases that underwent surgery, 4 were diagnosed pathological stage IA, 11 IB, 1 IIB, 13 IIIA and 1 IIIB. The 7 clinically non-operable cases were IIIB in 3, and IV in 4. The positive rates of CD56, thyroid transcription factor-1 (TTF-1), chromogranin A, synaptophysin and 34betaE12 for tumor cells were 88.9, 55.6, 42.1, 31.6 and 21.1%, respectively, from the IHC staining. The median survival time and 5 year-survival rate were 24 months and 27%, respectively. The group that underwent surgery had a better prognosis than those that did not.
CONCLUSION
The positive rates for the tumor markers varied, but those of the CD56 and TFT-1 were the highest. The possibility of LCNEC needs to be evaluated for the following situations: small cell carcinomas located at the periphery and not responding chemotherapy, small cell carcinomas diagnosed by percutaneous needle aspiration, poorly differentiated non-mall cell carcinomas, with uncertain histologic type, and unclassified neuroendocrine tumor, etc.

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