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

Immunohistochemical Study of the Vascular Endothelial Growth Factor in Gastric Carcinoma.: Tae Jung Jang, Jung Ran Kim; Korean J Pathol. 1997;31(5):401-409.

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Abstract PDF: Many studies have shown that angiogenesis plays an important role in the growth, the progression, and the metastasis of a solid tumor. The vascular endothelial growth factor(VEGF) is thought to be a selective mitogen for endothelial cells. Twenty eight advanced gastric carcinomas and twenty early gastric carcinomas were investigated by staining with polyclonal antibody against the VEGF. Correlation between the expression of the VEGF and the clinicopathologic features of gastric carcinoma were studied. The VEGF was mainly localized to the cytoplasm of carcinoma cells. Normal gastric foveolar epithelium was not immunoreactive, but some endothelial cells were weakly immunoreactive with an anti-VEGF antibody. Expression of the VEGF was significantly higher in advanced gastric carcinoma than in early gastric carcinoma (p=0.003). Expression of the VEGF was correlated with the depth of tumor, the lymph node metastasis, and the stage (p<0.05). The VEGF positivity was significantly higher in moderately and poorly differentiated gastric carcinoma than in well differentiated gastric carcinoma. The VEGF scores of the metastatic foci in the lymph nodes were higher than that of the primary tumors, which were followed by deep and superficial portions of the primary tumors in a descending order (p<0.05). In summary, the expression of the VEGF may be associated with progression and metastasis of a gastric carcinoma and may also be a good prognostic factor in a gastric carcinoma.

Expressions of Vascular Endothelial Growth Factor (VEGF), Phospholipase C-gammal and Ki-67 in Squamous Cell Carcinoma and High Grade Squamous Intraepithelial Lesion of Uterine Cervix.: Ki Kwon Kim, Jung Ran Kim; Korean J Pathol. 1998;32(4):290-297.

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Abstract PDF: Angiogenesis is an early event in tumorigenesis and facilitates tumor progression and metastasis. This study was performed to evaluate the expression of vascular endothelial growth factor (VEGF), phospholipase C-gamma1 (PLC-gamma1) and Ki-67, and to assess the relationship between them in cervical squamous cell neoplasia. The materials were fifty cervical squamous cell lesions, consisted of thirty HSIL (6 moderate dysplasia, 11 severe dysplasia, 13 carcinoma in situ), and twenty invasive squamous cell carcinoma (ISCC) cases. Immunohistochemical stain for VEGF, PLC-gamma1 and Ki-67 were done. Expression rate of VEGF was significantly higher in ISCC than in HSIL (p=0.012). PLC-gamma1 expression was significantly higher in ISCC than in HSIL (p=0.004). Ki-67 labelling index was significantly higher in ISCC than in HSIL (p=0.001) and higher in VEGF-positive tumors than in VEGF-negative tumors (p=0.018), but there were no significant differences between PLC-gamma1 expression and Ki-67 labelling index (p>0.05), and between PLC-gamma1 and VEGF (p>0.05). This study suggests that PLC-gamma1 and VEGF may play an important role in tumor cell proliferation and invasion, and these may be a useful marker to predict the possibility of invasion in cervical cancer.

VEGF Expression and Angiogenesis in Uterine Cervical Carcinomas.: Jin Sook Lee, Kang Suek Suh; Korean J Pathol. 1999;33(2):96-102.

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Abstract: Angiogenesis is a critical factor in the progression of solid tumors, including cervical cancers. The mechanisms responsible for angiogenesis in uterine cervical neoplasia are not well defined. To determine the relationship between angiogenesis and the expression of vascular endothelial growth factor (VEGF) in the cervical neoplasia, the author studied 63 cases of the cervical neoplasia diagnosed between the years 1993 to 1997 at Pusan National University Hospital. The expression of VEGF was semiquantitatively analyzed in paraffin sections by immunohistochemical method. Histologic sections immunostained for factor VIII-related antigen were evaluated for microvessel density. Increased expression of VEGF and microvessel counts was significantly correlated with depth of invasion. Increased microvessel counts were also significantly associated with increased VEGF expression. These results suggest that VEGF is an important angiogenic factor and associated with progression of the cervical neoplasia.

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.

Tumor Angiogenesis and Vascular Endothelial Growth Factor Expression in Cervical Intraepithelial Neoplasia.: Hye Jean Park, Hye Jin Park, Hye Sung Moon, Woon Sup Han, Sun Hee Sung; Korean J Pathol. 2000;34(7):524-530.

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Abstract PDF: Angiogenesis is an essential requirement for development, progression, and metastasis of malignant tumors. Vascular endothelial growth factor (VEGF) is one of the important angiogenic factors. Recently the role of angiogenesis has been known in premalignant lesions. This study was performed to determine whether the angiogenesis and VEGF expression were increased in association with histological grade of cervical intraepithelial neoplasia (CIN) and to see the relationship between the angiogenesis and VEGF. Immunostainings for factor VIII and VEGF were performed on 52 cases of cervical neoplasia (12 cases of CIN I, 11 cases of CIN II, 15 cases of CIN III, 7 cases of microinvasive squamous cell carcinoma, and 7 cases of invasive carcinoma) and 5 cases of normal cervix. The results showed a significant increase of microvessel count from normal cervix through CIN grades to invasive squamous cell cacinoma. VEGF expression was increased in proportion to the CIN grades. There was no significant correlation between microvessel count and VEGF expression. In conclusion, the tumor angiogenesis is an early event in tumorigenesis of uterine cervix. In addition, no significant relationship between the microvessel count and VEGF expression in CIN suggests the possibility of other growth factors affecting mainly angiogenesis of premalignant lesion of uterine cervix.

Expression of Vascular Endothelial Growth Factor-C in Breast Carcinoma.: Myoung Ja Chung, Sun Ho Yang, Kyu Yun Jang, Woo Sung Moon, Myoung Jae Kang, Dong Geun Lee; Korean J Pathol. 2005;39(6):401-405.

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Abstract PDF: BACKGROUND
Vascular endothelial growth factor-C (VEGF-C) is a novel growth factor that regulates lymphangiogenesis and/or angiogenesis via binding to the vascular endothelial growth factor receptor-3 (VEGFR-3) or VEGFR-2. Recent studies have suggested that VEGF-C may play a role in lymph node metastasis. This study was conducted to examine whether the expression of VEGF-C is associated with the clinicopathologic parameters, and especially lymph node metastasis, of invasive ductal carcinoma.
METHODS
Immunohistochemical staining was performed for VEGF-C and CD31 in the surgically resected specimens from 83 patients with invasive breast carcinoma.
RESULTS
Of the 83 breast carcinomas, 61 (74%) cases showed cytoplasmic VEGF-C imunoreactivity. VEGF-C expression was associated with lymph node metastasis (p=0.03), but it did not correlate with tumor size, the histologic grade, and the presence of estrogen receptor or progesteron receptor. The mean microvessel density in the cases without VEGF-C expression was 51.9+/-30.1 and it was 72.9+/-33.0 in the cases with 2+ expression for VEGF-C (p=0.07).
CONCLUSIONS
This study suggests that VEGF-C expression may have an association with lymph node metastasis in the patients with breast carcinoma.

Expression of bcl-2, p53 and VEGF in Non-Small Cell Lung Carcinomas: Their Relation with the Microvascular Density and Prognosis.: Jinyoung Yoo, Ji Han Jung, Hyun Joo Choi, Seok Jin Kang, Chang Suk Kang; Korean J Pathol. 2005;39(2):74-80.

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Abstract PDF: BACKGROUND
The aim of this study was to investigate the expression of bcl-2, p53 and vascular endothelial growth factor (VEGF) in non-small cell lung cancer (NSCLC), and to examine the relationship between those protein expressions and neovascularization. We also analyzed the prognostic impact of these biological parameters on the patients' overall survival rate.
METHODS
The archival tumor tissues from 147 previously untreated patients with NSCLC were examined by immunohistochemistry for bcl-2, p53 and VEGF proteins. The vascularity was measured by the average microvascular density (MVD) of the CD34-positive vessels. Clinical information was obtained through the computerized retrospective database from the tumor registry.
RESULTS
Immunoreactivity for bcl-2 was detected in 17% (25/147), p53 in 72% (106/147) and VEGF in 75% (110/147) of the tumors. An inverse association was found between bcl-2 expression and VEGF expression (p=0.012). There was a significant correlation between the bcl-2 expression and the MVD (p=0.009), and also between the p53 expression and the MVD (p=0.045). The mean survival time was associated with the patients' age (p=0.032), the T status (p=0.038), the tumor stage (p=0.009), and expressions of bcl-2 (p=0.016) and VEGF (p=0.039). On multivariate analysis, only the tumor stage and VEGF expression maintained their prognostic influence.
CONCLUSIONS
Our data suggest that bcl-2 and p53 alterations are involved in the angiogenesis of NSCLC, and are either dependent on or independent of VEGF. It is further noteworthy that the tumor stage and VEGF expression may be useful in predicting patients' survival.

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