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.

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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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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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Treatment status, survival and gene expression analysis of large-cell neuroendocrine lung carcinoma: a real-world study in China
Fei Qi, Minghang Zhang, Yi Han, Juan Du, Hongjie Yang, Hongmei Zhang, Yong Zhang, Tongmei Zhang
Therapeutic Advances in Medical Oncology.2025;[Epub] CrossRef
Pancreatic neuroendocrine neoplasms (pNENs): Genetic and environmental biomarkers for risk of occurrence and prognosis
Matteo Tacelli, Manuel Gentiluomo, Paolo Biamonte, Justo P. Castano, Maja Cigrovski Berković, Mauro Cives, Sanja Kapitanović, Ilaria Marinoni, Sonja Marinovic, Ilias Nikas, Lenka Nosáková, Sergio Pedraza-Arevalo, Eleonora Pellè, Aurel Perren, Jonathan Str
Seminars in Cancer Biology.2025; 112: 112. CrossRef
Malignant potential of neuroendocrine microtumor of the pancreas harboring high-grade transformation: lesson learned from a patient with von Hippel-Lindau syndrome
Jongwon Lee, Kyung Jin Lee, Dae Wook Hwang, Seung-Mo Hong
Journal of Pathology and Translational Medicine.2024; 58(2): 91. CrossRef
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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The Complex Histopathological and Immunohistochemical Spectrum of Neuroendocrine Tumors—An Overview of the Latest Classifications
Ancuța-Augustina Gheorghișan-Gălățeanu, Andreea Ilieșiu, Ioana Maria Lambrescu, Dana Antonia Țăpoi
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Mauro D. Donadio, Ângelo B. Brito, Rachel P. Riechelmann
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CD56 Expression Is Associated with Biological Behavior of Pancreatic Neuroendocrine Neoplasms

Xin Chen, Chuangen Guo, Wenjing Cui, Ke Sun, Zhongqiu Wang, Xiao Chen
Cancer Management and Research.2020; Volume 12: 4625. CrossRef
Prognostic and predictive factors on overall survival and surgical outcomes in pancreatic neuroendocrine tumors: recent advances and controversies
Lingaku Lee, Tetsuhide Ito, Robert T Jensen
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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

Abstract PDF PubReader ePub

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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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

Abstract PDF PubReader ePub

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 Article

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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