Journal of Pathology and Translational Medicine

Original Articles

High Expression of Galectin-1, VEGF and Increased Microvessel Density Are Associated with MELF Pattern in Stage I-III Endometrioid Endometrial Adenocarcinoma: Dmitry Aleksandrovich Zinovkin, Sergey Leonidovich Achinovich, Mikhail Grigoryevich Zubritskiy, Jacqueline Linda Whatmore, Md Zahidul Islam Pranjol; J Pathol Transl Med. 2019;53(5):280-288. Published online June 27, 2019; DOI: https://doi.org/10.4132/jptm.2019.05.13

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Background
In this study, we investigate the expression of markers of angiogenesis and microvessel density (MVD) in cases of microcystic, elongated and fragmented (MELF) pattern, with its prognostic role in the survival of endometrioid endometrial adenocarcinomas (EA) patients.
Methods
In this study, 100 cases of EA, 49 cases with MELF pattern and 51 without, were immunohistochemically stained for galectin-1, vascular endothelial growth factor (VEGF), and MVD. Morphometry and statistical (univariate and multivariate) analyses were performed to assess overall survival (OS) and disease-free survival.
Results
The expression of VEGF (p<.001) and galectin-1 (p<.001), as well as MVD area (p<.001) and number of vessels/mm2 (p<.050), were significantly higher in the +MELF pattern group compared to the –MELF group. A low negative correlation between MELFpattern and the number of days of survival (p<.001, r=–0.47) was also found. A low positive correlation of MELF-pattern with galectin-1 expression (p<.001, r=0.39), area of vessels/mm2 (p<.001, r=0.36), outcome of EA (p<.001, r=0.42) and VEGF expression (p<.001, r=0.39) suggests potential pathological relevance of these factors in the prognosis of EA. A univariate survival analysis indicated a role for all parameters of survival. Multivariate Cox proportional hazard regression analysis revealed that only area of vessels/mm2 (hazard ratio [HR], 1.018; 95% confidence interval [CI], 1.002 to 1.033), galectin-1 (HR, 1.049; 95% CI, 1.025 to 1.074) and VEGF (HR, 1.049; 95% CI, 1.022 to 1.077) play key roles in OS.
Conclusions
This study reports an increase in MVD, VEGF and galectin-1 expression in EA with MELF pattern and suggests that MELF pattern, along with the angiogenic profile, may be a prognostic factor in EA.

Citations

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Association of Local and Distant Organ Metastases With MELF Pattern in Endometrial Cancer
Varol Gülseren, Ertuğrul Şen, Mehmet Dolanbay, Fulya Çağli, Nahit Topaloğlu, Figen Öztürk, Bülent Özçelik, Serdar Serin, Kemal Güngördük
International Journal of Gynecological Pathology.2024;[Epub] CrossRef
Tumour budding, MELF-pattern and tumour-infiltrating lymphocytes as possible pathomorphological parameters of the course of endometrioid adenocarcinoma of the uterine corpus
D. A. Zinovkin, I. V. Veyalkin, S. L. Achinovich, I. I. Slepokurova, Yu. A. Lyzikova, A. Farooq
Tumors of female reproductive system.2024; 20(2): 83. CrossRef
Determining the level of stromal and epithelial cells activity in normal and hyperplastic endometrium of late reproductive and perimenopausal women
Zinaida Vasilyvna Chumak, Volodymyr Victorovich Artyomenko, Mykola Vitaliiovich Shapoval, Liudmyla Volodymyrivna Mnih, Ganna Volodymyrivna Kozhukhar, Serhii Vasilyovich Derishov
Journal of Medicine and Life.2023; 16(2): 210. CrossRef
Endocervical Adenocarcinoma Showing Microcystic, Elongated, and Fragmented (MELF) Pattern of Stromal Invasion: A Single-Institutional Analysis of 10 Cases with Comprehensive Clinicopathological Analyses and Ki-67 Immunostaining
Hyunsik Bae, Hyun-Soo Kim
Biomedicines.2023; 11(11): 3026. CrossRef
Clinicopathologic association and prognostic impact of microcystic, elongated and fragmented pattern invasion, combined with tumor budding in endometrioid endometrial cancer
Xiqin Qi, Lun Zhu, Bei Zhang
Journal of Obstetrics and Gynaecology Research.2022; 48(9): 2431. CrossRef
Role of adipocytokines in endometrial cancer progression
Ran Li, Fang Dong, Ling Zhang, Xiuqin Ni, Guozhi Lin
Frontiers in Pharmacology.2022;[Epub] CrossRef
Advances in Anti-Cancer Immunotherapy: Car-T Cell, Checkpoint Inhibitors, Dendritic Cell Vaccines, and Oncolytic Viruses, and Emerging Cellular and Molecular Targets
Emilie Alard, Aura-Bianca Butnariu, Marta Grillo, Charlotte Kirkham, Dmitry Aleksandrovich Zinovkin, Louise Newnham, Jenna Macciochi, Md Zahidul Islam Pranjol
Cancers.2020; 12(7): 1826. CrossRef

The Potential Roles of MELF-Pattern, Microvessel Density, and VEGF Expression in Survival of Patients with Endometrioid Endometrial Carcinoma: A Morphometrical and Immunohistochemical Analysis of 100 Cases: Dmitry Aleksandrovich Zinovkin, Md Zahidul Islam Pranjol, Daniil Rudolfovich Petrenyov, Eldar Arkadievich Nadyrov, Oleg Gennadievich Savchenko; J Pathol Transl Med. 2017;51(5):456-462. Published online September 14, 2017; DOI: https://doi.org/10.4132/jptm.2017.07.19

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Abstract PDF

Background
In this study, we hypothesized that microcystic, elongated, fragmented (MELF)-pattern, vascular endothelial growth factor (VEGF) expression by cancer cells and microvessel density of cancer stroma may be associated with progression of endometrioid adenocarcinoma. Methods: The study used data from the Belarus Cancer Registry and archival histological material of 100 patients with retrospectively known good (survival) and poor (disease progression and death) outcomes. All cases were immunohistochemically stained for CD34 and VEGF. Two independent samples were compared for the characteristics of signs, and obtained results were analyzed by receiver operating characteristic analysis, Mann-Whitney U test, χ² test (Yates correction), and Mantel-Cox test. Multivariate Cox hazard analysis and Spearman correlation test were used. A p-value of less than .05 was considered statistically significant. Results: The observed survival rate of patients with endometrioid adenocarcinoma was significantly lower (p = .002) in MELF-pattern positive patients when compared with MELF-pattern negative patients. The overall survival rate of patients whose tumors had more than 114 vessels/mm² of tissue was significantly low (p < .001). Interestingly, a similar observation was found in patients with increased vessel area, evidenced by VEGF expression in the glandular tumor component. Conclusions: Our study suggests, for the first time, that these criteria may be used as risk factors of endometrioid adenocarcinoma progression during 5 years after radical surgical treatment. However, a large independent cohort of samples should be considered in the future to validate our findings.

Citations

Citations to this article as recorded by

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Baohui Ju, Jianghua Wu, Lin Sun, Chunrui Yang, Hu Yu, Quan Hao, Jianmei Wang, Huiying Zhang
International Journal of Gynecological Pathology.2024; 43(3): 233. CrossRef
Association of Local and Distant Organ Metastases With MELF Pattern in Endometrial Cancer
Varol Gülseren, Ertuğrul Şen, Mehmet Dolanbay, Fulya Çağli, Nahit Topaloğlu, Figen Öztürk, Bülent Özçelik, Serdar Serin, Kemal Güngördük
International Journal of Gynecological Pathology.2024;[Epub] CrossRef
The vasculogenic mimicry, CD146 + and CD105 + microvessel density in the prognosis of endometrioid endometrial adenocarcinoma: a single-centre immunohistochemical study
Dmitry A. Zinovkin, Hongbo Wang, Zhicheng Yu, Qian Zhang, Yang Zhang, Sitian Wei, Ting Zhou, Qi Zhang, Jun Zhang, Eldar A. Nadyrov, Abdullah Farooq, Yulia Lyzikova, Ilya V. Vejalkin, Irina I. Slepokurova, Md Zahidul Islam Pranjol
Biomarkers.2024; : 1. CrossRef
Dynamic contrast-enhanced MR imaging of uterine endometrial carcinoma with/without squamous differentiation
Mayumi Takeuchi, Kenji Matsuzaki, Yoshimi Bando, Masafumi Harada
Abdominal Radiology.2023; 48(8): 2494. CrossRef
Role of adipocytokines in endometrial cancer progression
Ran Li, Fang Dong, Ling Zhang, Xiuqin Ni, Guozhi Lin
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Endometrial carcinoma: use of tracer kinetic modeling of dynamic contrast-enhanced MRI for preoperative risk assessment
Zhijun Ye, Gang Ning, Xuesheng Li, Tong San Koh, Huizhu Chen, Wanjing Bai, Haibo Qu
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Microcystic elongated and fragmented (MELF) pattern of invasion: Molecular features and prognostic significance in the PORTEC-1 and -2 trials
A.S.V.M. van den Heerik, K.T.S. Aiyer, E. Stelloo, I.M. Jürgenliemk-Schulz, L.C.H.W. Lutgens, J.J. Jobsen, J.W.M. Mens, E.M. van der Steen-Banasik, C.L. Creutzberg, V.T.H.B.M. Smit, N. Horeweg, T. Bosse
Gynecologic Oncology.2022; 166(3): 530. CrossRef
Pathological features, immunoprofile and mismatch repair protein expression status in uterine endometrioid carcinoma: focus on MELF pattern of myoinvasion
Angela Santoro, Giuseppe Angelico, Frediano Inzani, Saveria Spadola, Damiano Arciuolo, Michele Valente, Teresa Musarra, Giovanni Capelli, Francesco Fanfani, Valerio Gallotta, Giovanni Scambia, Gian Franco Zannoni
European Journal of Surgical Oncology.2021; 47(2): 338. CrossRef
Prognostic impact of tumor budding in endometrial carcinoma within distinct molecular subgroups
Tilman T. Rau, Eva Bettschen, Carol Büchi, Lucine Christe, Amanda Rohner, Michael D. Müller, Joseph W. Carlson, Sara Imboden, Inti Zlobec
Modern Pathology.2021; 34(1): 222. CrossRef
Sentinel Nodal Metastasis Detection in Endometrial Carcinoma With Microcystic, Elongated, and Fragmented (MELF) Pattern by Cytokeratin Immunostaining
Kimmie M Rabe, Molly E Klein, Sayak Ghatak, Irina Stout, Alexandra Schefter, Britt K Erickson, Mahmoud A Khalifa
American Journal of Clinical Pathology.2021; 156(5): 846. CrossRef
Patterns of Myometrial Invasion in Endometrial Adenocarcinoma with Emphasizing on Microcystic, Elongated and Fragmented (MELF) Glands Pattern: A Narrative Review of the Literature
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Increase in FoxP3, CD56 immune cells and decrease in glands PGRMC1 expression in the endometrium are associated with recurrent miscarriages
Yulia Anatolievna Lyzikova, Dmitry Aleksandrovich Zinovkin, Md Zahidul Islam Pranjol
European Journal of Obstetrics & Gynecology and Reproductive Biology.2020; 245: 121. CrossRef
Clinicopathologic Association and Prognostic Value of MELF Pattern in Invasive Endocervical Adenocarcinoma (ECA) as Classified by IECC
Sheila E. Segura, Lien Hoang, Monica Boros, Cristina Terinte, Anna Pesci, Sarit Aviel-Ronen, Takako Kiyokawa, Isabel Alvarado-Cabrero, Esther Oliva, Kay J. Park, Robert A. Soslow, Simona Stolnicu
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High Expression of Galectin-1, VEGF and Increased Microvessel Density Are Associated with MELF Pattern in Stage I-III Endometrioid Endometrial Adenocarcinoma
Dmitry Aleksandrovich Zinovkin, Sergey Leonidovich Achinovich, Mikhail Grigoryevich Zubritskiy, Jacqueline Linda Whatmore, Md Zahidul Islam Pranjol
Journal of Pathology and Translational Medicine.2019; 53(5): 280. CrossRef
The Roles of Melf Patterns, the Depth of Invasion and Number of Tumor Emboli as the Predictive Factors of the Survival Rate Among Patients with Endometrioid Adenocarcinoma of the Corpus Uterus
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Tumor-Associated T-Lymphocytes and Macrophages are Decreased in Endometrioid Endometrial Carcinoma with MELF-Pattern Stromal Changes
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MELF pattern of myometrial invasion and role in possible endometrial cancer diagnostic pathway: A systematic review of the literature
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European Journal of Obstetrics & Gynecology and Reproductive Biology.2018; 230: 147. CrossRef
CORRELATIVE INTERRELATIONS OF THE TUMOR MICROENVIRONMENT AND RELATIVE RISK OF UNFAVOURABLE OUTCOME OF ENDOMETRIOID ADENOCARCINOMA OF THE CORPUS UTERI
D. A. Zinovkin
Health and Ecology Issues.2018; (3): 48. CrossRef

Microvessel Quantification, Expression of p53 Protein and MIB-1 in Colorectal Adenoma and Carcinoma.: Tae Jung Jang, Jung Ran Kim, Han Ik Bae; Korean J Pathol. 1997;31(1):40-50.

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Abstract PDF: Angiogenesis is a crucial step in tumor growth and progression. Scarce data is available on angiogensis in gastrointestinal tumors. We studied 16 normal colon, 44 adenomas and 29 carcinomas to evaluate angiogenesis in colorectal tumors and to assess the correlation among p53 protein, proliferative activity and other clinical prognostic parameters. Endothelial cells were immunostained with an anti-Factor VIII mAb; in each case three microscopic fields(x 200) were counted: average number of the three fields was defined as microvessel density (MVD). p53 protein expression was 45.5%(20/44) in adenomas, and 79.3%(23/29) in carcinomas (p<0.01). p53 protein expression of carcinomas was 57.1%(4/7) in diploid tumors, 100%(8/8) in aneuploid tumors (p=0.07), 100%(8/8) in well differentiated tumors, and 50%(2/4) in poorly differentiated tumors (p=0.09). MIB-1 score was 2.3+/-0.7(38) in adenomas, 3.4+/-0.5(29) in carcinomas (p<0.01). There was no significant correlation between p53 protein and MIB-1 score. MVD was 10.4+/-4.1(16) in the normal mucosa, 21.5+/-7.9(39) in the adenomas, 35.3+/-9.7(26) in carcinomas (normal versus adenomas, p<0.01; adenomas versus carcinomas, p<0.01). MVD was 25.8+/-5.4(2) in carcinomas confined to mucosa, and 36.1+/-9.6(24) in carcinomas with transmural invasion. The higher MIB-1 score was in carcinomas the more MVD increased but there was no statistical significance (r=0.38, p=0.055). MVD of carcinomas was not associated with nodal metastasis, p53 expression, and DNA ploidy. p53 protein and MIB-1 expression are useful methods for the evaluation of malignancy, and tumor angiogenesis is an early event in a colorectal tumor but MVD does not correlate with prognostic parameters except for the tumor depth.

Microvessel Density and Vascular Endothelial Growth Factor Expression in Invasive Breast Carcinomas.: Mi Yeong Jeon, Mee Young Sol, Kyung Sun Park, Hye Kyoung Yoon; Korean J Pathol. 2000;34(2):138-144.

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Abstract PDF: Angiogenesis is essential for tumor growth and metastasis, however, the prognostic value of neovascularization is undetermined. The aim of this study is to evaluate the prognostic significance of microvessel density (MVD) and vascular endothelial growth factor (VEGF) expression in breast carcinomas. An immunohistochemical stains for CD 31 (DAKO) to estimate MVD and VEGF (Santa Cruz) were done on 40 cases of invasive breast carcinoma. MVD was calculated as an average count of vessels per 200 power field in the most vascularized areas. VEGF expression was interpreted according to staining intensity and number of positive cells. Mean MVD was 35, and MVD was not correlated with lymph node metastasis or histologic grade, but high MVD (mean MVD>35) showed an increasing tendency in cases with larger size, negative ER/PR, and positive cathepsin D. All of the cases showed VEGF expression, but VEGF expression was not correlated with tumor size, histologic grade, lymph node metastasis, ER/PR status, and cathepsin D expression. These results suggest that MVD and VEGF expressions are not reliable prognostic factors.

VEGF Expression and Microvessel Density in Oral Squamous Cell Carcinomas.: Ji Jun Lim, Sam Pyo Hong, Jae Il Lee, Seong Doo Hong, Chang Yun Lim; Korean J Pathol. 2000;34(3):190-198.

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Abstract PDF: Angiogenesis is an essential process in tumor growth and metastasis. VEGF has been considered a leading candidate inducing tumor angiogenesis. VEGF expression was significantly correlated with clinical stage, lymph node matastasis, and prognosis of cancers of various parts of body. However, little has been known about the correlation between VEGF expression and clinicopathologic parameters in oral squamous cell carcinoma. The aim of this study was to correlate VEGF expression with the clinicopathological parameters and microvessel density. Forty six oral squamous cell carcinomas were analyzed using immunohistochemical method with primary antibodies to VEGF and CD31. VEGF expression was detected in 33 (71.7%) of the 46 cases. The microvessel density was significantly correlated with VEGF expression (P=0.002). There was no correlation between microvessel density and tumour size, clinical stage, and lymph node metastasis, respectively. VEGF expression did not correlate with the histological grade of tumour differentiation, tumour size, and clinical stages. The VEGF-positive rate seemed to be higher in patients with cervical lymph nodal metastasis than in those without it, but it was not statistically significant. In conclusion, the overexpression of VEGF in the oral squamous cell carcinoma seemed to be associated with a more aggressive course of the disease. Further study is necessary to define the role of VEGF in oral squamous cell carcinoma.

Expression of Matrix Metalloproteinase and Tissue Inhibitor of Metallproteinase in Breast Carcinoma Related to Angiogenesis and Invasion.: Yoon Jung Choi, Woo Hee Jung, Hy De Lee, Kwang Gil Lee; Korean J Pathol. 2000;34(9):652-664.

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Abstract PDF: Among the enzymes which are responsible for basement membrane breakdown, matrix metalloproteinases (MMP) form a family of neutral proteases that are regulated at the levels of gene transcription, proenzyme activation by the cleavage of protein, and the inhibition of the active enzyme by tissue inhibitors of matrix metalloproteinases (TIMP). Recent reports have demonstrated that the expression of these proteolytic enzymes are elevated in several solid tumors and that it can be associated with invasiveness and poor prognosis. We examined the expression of MMP-2, MMP-9, TIMP-1 and TIMP-2 by immunohistochemistry in 160 cases of infiltrating ductal carcinoma. And we compared these data with the established prognostic parameters - tumor size, nodal status, clinical stage, hormonal receptor status, microvessel density, and TGF-beta1 expression in order to evaluate how MMP and TIMP expression are associated with breast cancer progression and prognosis. Microvessel density in invasive breast carcinoma was significantly correlated with tumor size and recurrence (p<0.05). The immunohistochemical expression of TGF-beta1 was significantly associated with tumor size, lymph node metastasis, and clinical stage (p<0.05). The microvessel density was significantly correlated with TGF-beta1 expression in more than 50% of tumor cells. The immunohistochemical expression of MMP-2 and MMP-9 were significantly correlated with nodal metastasis and absence of immunoreactivity for estrogen and progesterone receptors. The immunohistochemical expression of TIMP-1 was inversely correlated with clinical stage and microvessel density while that of TIMP-2 was inversely correlated with clinical stage (p<0.05). Small size of tumor, presence of progesterone receptor, highly differentiated histologic grade, and absence of immunoreactivity for MMP-9 were significantly associated with higher survival rate, but in multivariate analysis only tumor size and MMP-9 expression appeared to affect survival independently.

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