Cancer Research and Treatment

Original Articles

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

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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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

Abstract PDF PubReader ePub

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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Chang Geun Lee, Yun Jeong Lim, Seun Ja Park, Byung Ik Jang, Seok Reyol Choi, Jae Kwang Kim, Yong-Tae Kim, Joo Young Cho, Chang Hun Yang, Hoon Jai Chun, Si Young Song
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Swapnil D. Kachare, Kendall R. Liner, Nasreen A. Vohra, Emmanuel E. Zervos, Timothy L. Fitzgerald
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The Korean Journal of Gastroenterology.2013; 62(5): 301. CrossRef
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Young Suk Park
Korean Journal of Medicine.2013; 85(4): 354. CrossRef
Role of radiotherapy for pancreatobiliary neuroendocrine tumors
Jeongshim Lee, Jinhyun Choi, Chihwan Choi, Jinsil Seong
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Co-Expression of Cox-2, C-Met and β-catenin in Cells Forming Invasive front of Gallbladder Cancer: Woo Sung Moon, Ho Sung Park, Ho Lee, Rama Pai, Andrzej S. Tarnawski, Kyung Ryoul Kim, Kyu Yun Jang; Cancer Res Treat. 2005;37(3):171-176. Published online June 30, 2005; DOI: https://doi.org/10.4143/crt.2005.37.3.171

Abstract PDF PubReader ePub

Purpose

Gallbladder cancer is a malignancy with poor prognosis, predominantly resulting from invasion and metastasis. Our previous studies have demonstrated that prostaglandin E₂ (PGE₂), generated by cyclooxygenase 2 (Cox-2), transactivates epidermal growth factor receptor (EGFR), c-Met and β-catenin; thus, enhancing colon cancer cell growth and invasiveness in vitro. To determine whether these findings are applicable to clinical conditions, we examined the expression and cellular localization/co-localization of Cox-2, c-Met, β-catenin, EGFR and c-erbB2 in gallbladder cancer.

Materials and Methods

Thirty-five specimens of invasive gallbladder cancer, 8 in situ carcinoma and 7 adenoma specimens were immunostained with specific antibodies against Cox-2, c-Met, β-catenin, EGFR and c-erbB2. The cellular distribution, localization and colocalization were examined, and the signal intensities quantified in: a) the central area of gallbladder cancer and b) cancer cells forming the invasive front.

Results

Cox-2, c-Met, β-catenin, c-erbB2 and EGFR were over-expressed in 80, 74, 71, 62 and 11% of invasive gallbladder cancers, respectively. β-catenin was expressed in 80% of non-malignant specimens, exclusively in the cell membrane, while the cancer specimens showed cytoplasmic and/or nuclear staining. Significantly higher Cox-2, c-Met and β-catenin expressions were present in cancer cells of the invasive front than in the tumor central areas (p<0.001), and these expressions were significantly (p=0.01) associated with the invasion depth. Co-expressions of Cox-2, c-Met, β-catenin and c-erbB2 were present in 42% of the specimens in cancer cells forming the invasive front.

Conclusion

The overexpressions, and often co-localizations, of Cox-2, c-Met and β-catenin in cancer cells forming the invasive front indicate their local interactions and important roles in invasion.

Citations

Citations to this article as recorded by

Arachidonic acid metabolism as a novel pathogenic factor in gastrointestinal cancers
Weiqin Lu, Aihemaitijiang Aihaiti, Paziliya Abudukeranmu, Yajun Liu, Huihui Gao
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Global gene expression landscape of gallbladder cancer and advances in targeted therapeutic strategies
Sounetra Choudhury, Arunima Maiti, Arnab Bandopadhyay, Anusri Tripathi, Nilabja Sikdar
World Journal of Clinical Oncology.2025;[Epub] CrossRef
EGFR, HER2, and MET gene amplification and protein expression profiles in biliary tract cancer and their prognostic significance
Yeseul Kim, Seungyun Jee, Hyunsung Kim, Seung Sam Paik, Dongho Choi, Su Hyun Yoo, Su-Jin Shin
The Oncologist.2024; 29(8): e1051. CrossRef
Immunohistochemical appraisal of epithelial mesenchymal transition type III in gall bladder cancer
Kamini Yadav, Preeti Agarwal, Madhu Kumar, Sameer Gupta, Medha Mishra, Malti Kumari Maurya, Sumaira Qayoom, Madhu Mati Goel
Indian Journal of Pathology and Microbiology.2023; 66(1): 44. CrossRef
Krukenberg Tumor Related to Gallbladder Cancer in a Young Woman: A Case Report and Review of the Literature
Giulia Grizzi, Michele Ghidini, Margherita Ratti, Marianna D’Ercole, Giulia Tanzi, Annalisa Abbiati, Andrea Celotti, Daniele Spada, Gian Luca Baiocchi, Maria Bonomi
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Molecular Targets and Emerging Therapies for Advanced Gallbladder Cancer
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UCP2 promotes proliferation and chemoresistance through regulating the NF-κB/β-catenin axis and mitochondrial ROS in gallbladder cancer
Jianhua Yu, Lawrence Shi, Weiguo Lin, Baochun Lu, Yunfeng Zhao
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Yeseul Kim, Seong Sik Bang, Seungyun Jee, Sungeon Park, Su-Jin Shin, Kiseok Jang
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Genetic mutational analysis of β-catenin gene affecting GSK-3β phosphorylation plays a role in gallbladder carcinogenesis: Results from a case control study
Ruhi Dixit, Manoj Pandey, Sunil Kumar Tripathi, Amit Nandan Dhar Dwivedi, Vijay Kumar Shukla
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Xiaoling Song, Yunping Hu, Yongsheng Li, Rong Shao, Fatao Liu, Yingbin Liu
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Sofia M. Clemente, Oscar H. Martínez-Costa, Maria Monsalve, Alejandro K. Samhan-Arias
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β-Catenin expression is associated with cell invasiveness in pancreatic cancer
Jin Niang Nan, Ok Ran Kim, Myung Ah Lee
The Korean Journal of Internal Medicine.2019; 34(3): 618. CrossRef
Epithelial-to-mesenchymal transition in gallbladder cancer: from clinical evidence to cellular regulatory networks
Sunwang Xu, Ming Zhan, Jian Wang
Cell Death Discovery.2017;[Epub] CrossRef
New Horizons for Precision Medicine in Biliary Tract Cancers
Juan W. Valle, Angela Lamarca, Lipika Goyal, Jorge Barriuso, Andrew X. Zhu
Cancer Discovery.2017; 7(9): 943. CrossRef
Molecular genetics and targeted therapeutics in biliary tract carcinoma
Eric I Marks
World Journal of Gastroenterology.2016; 22(4): 1335. CrossRef
CIZ1 promoted the growth and migration of gallbladder cancer cells
Dexiang Zhang, Yueqi Wang, Yuedi Dai, Jiwen Wang, Tao Suo, Hongtao Pan, Han Liu, Sheng Shen, Houbao Liu
Tumor Biology.2015; 36(4): 2583. CrossRef
Prognostic significance of COX-2 and β-catenin in colorectal carcinoma
Amani Kazem, Khaled El Sayed, Yasser El Kerm
Alexandria Journal of Medicine.2014; 50(3): 211. CrossRef
A genetic model for gallbladder carcinogenesis and its dissemination
S.G. Barreto, A. Dutt, A. Chaudhary
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Significance of epithelial growth factor in the epithelial–mesenchymal transition of human gallbladder cancer cells
Takamitsu Sasaki, Hiroki Kuniyasu, Yi Luo, Daisuke Kato, Satoshi Shinya, Kiyomu Fujii, Hitoshi Ohmori, Yuichi Yamashita
Cancer Science.2012; 103(6): 1165. CrossRef
E-cadherin and c-Met expression in actinic cheilits and lip squamous cell carcinoma
A. Martínez, M.L. Spencer, J. Borlando, M. Flores, I.G. Rojas
Revista Clínica de Periodoncia, Implantología y Rehabilitación Oral.2011; 4(3): 122. CrossRef

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Phenylacetate Induces Growth Inhibition and Apoptosis of Human Osteosarcoma Cells: Jong Hyuk Park, Min Young Park, Ho Sung Park, Kyu Yun Jang, Myoung Ja Chung, Woo Sung Moon, Dong Geun Lee, Myoung Jae Kang; Cancer Res Treat. 2004;36(5):324-329. Published online October 31, 2004; DOI: https://doi.org/10.4143/crt.2004.36.5.324

Abstract PDF PubReader ePub

Purpose

Phenylacetate has potent antiproliferative effects in many malignant tumors. However, the exact mechanism as to how phenylacetate induces cell growth arrest remains unclear and very little is known about its effects on human osteosarcoma cells. In this study, we investigated whether phenylacetate is effective against two osteosarcoma cell lines (HOS and U-2 OS) in vitro.

Materials and Methods

The viability of phenylacetate-treated cell lines was assessed by trypan blue exclusion assay, and the cell cycle distribution was measured by flow cytometry. To measure cell apoptosis, poly (ADP-ribose) polymerase cleavage assay and flow cytometry were employed. The expressions of cell cycle-regulatory proteins and the apoptosis-related genes were evaluated by western blot analysis.

Results

Phenylacetate was found to inhibit the growth of osteosarcoma cells, induce cell cycle arrest in the G1 phase, and induce apoptosis. A significant decrease in Bcl-2 expression and a mild up-regulation of Bax were also observed in both phenylacetate-treated cell lines. Reduced phosphorylation of the pRb and the increased expression of p21^Cip1 were observed subsequent to treatment with phenylacetate.

Conclusion

These findings support the idea that phenylacetate may be an effective chemotherapeutic agent to be employed in the future against osteosarcoma, because phenylacetate acts to inhibit the growth of osteosarcoma cells through cell cycle arrest and apoptosis.

Citations

Citations to this article as recorded by

Recent advances in small molecular inhibitors of pyruvate carboxylase for human diseases
Weikai Guo, Danyang Liu, Ying Chen, Borui Ma, Fengling Yuan, Hui Li, Fujun Dai, Yanzhong Hu, Yihua Chen
Bioorganic Chemistry.2025; 163: 108658. CrossRef
Evaluation of α-hydroxycinnamic acids as pyruvate carboxylase inhibitors
Daniel J. Burkett, Brittney N. Wyatt, Mallory Mews, Anson Bautista, Ryan Engel, Chris Dockendorff, William A. Donaldson, Martin St. Maurice
Bioorganic & Medicinal Chemistry.2019; 27(18): 4041. CrossRef

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Case Reports

Primary Trabecular Carcinoid of the Ovary: Hyun Jin Son, Kyu Yun Jang, Jong Myoung Hong, Woo Sung Moon, Ho Yeol Choi; J Korean Cancer Assoc. 1999;31(4):855-860.

Abstract PDF: Primary trabecular carcinoid of the ovary is very rare and less than 30 cases have been reported. Herein is reported a primary trabecular carcinoid of the ovary which contained an epidermoid cyst in a 80-year-old woman. Gross examination showed 12 x 11 x 7 cm- sized mass in the right ovary. On cut-surface, the mass was composed of multilocular cyst containing serous and keratinized material and of 5 x 3.5 cm-sized solid area with extensive necrosis and hemorrhage. Microscopic examination revealed that the tumor cells are almost arranged in trabeculae and focally in insular pattern. Also, the tumor contained an epidermoid cyst but not other teratomatous elements. Tumor cells were immunoreactive for cytokeratin, neuron specific enolase (NSE) and chromogranin. Electron microscopic tindings revealed characteristic, round-shaped neurosecretory granules and perinuclear microfilaments.

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Solitary Fibrous Tumor Clinico: Pathological Analysis of 11 Cases: Woo Sung Moon, Kwang Min Lee; J Korean Cancer Assoc. 1999;31(4):847-854.

Abstract PDF: The clinico-pathological features of 11 solitary fibrous tumors (SFT) are described. The age of the patients ranged from 19 to 70 years (average, 43 years); 6 were male patients. Ten tumors were benign and arose in the pleura (three tumors), peritoneum (two), mediastinum (two), nasal cavity (one), thymus (one), and lacrimal gland (one). One tumor was histologically malignant and arose in the pleura. All of the tumors were grossly well circumscribed. The tumors measured from 0.8 cm to 50 cm in greatest diameter. Histologically, the tumors were composed of cytologically bland spindle cells arranged without obvious pattern; focally storiform, fascicular growth patterns and hemangioperi- cytoma-like vascular patterns were seen. Tumor cells were separated by thick bands of collagen demonstrating foci of keloid-like hyalinization. Increased mitotic activity (4 mitoses in 10 high-power fields) and high cellularity with mild cytologic atypia was noted in a pleural case, suspicious of malignant tumor, Immunohistochemically, all cases tested attained positivity for vimentin, CD34, and two cases showed focal myofibroblastic differentiation. Ultrastructural study of three cases showed mesenchymal cells with fibroblastic differentiation. Follow-up for 3 to 96 months (average, 39 months) showed no tumor recurrence or metastasis. SFT are easily overdiagnosed if strict criteria are not carefully applied, and strict diagnostic criteria are necessary to avoid confusion of SFT with more aggressive lesions.

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