scholarly journals Markers of Lymphocytic-Macrophagal Infiltration and Their Association With the Receptor Phenotype and Proliferative Activity of Tumor Tissue in Various Molecular-Biological Types of Endometrial Cancer

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A1026-A1026
Author(s):  
Lev M Berstein ◽  
Alexander O Ivantsov ◽  
Aglaya Iyevleva

Abstract Background and Aims: The last years were characterized by a shift from the former subdivision of endometrial cancer (EC) into two main types [1, 2] to modern molecular biological classifications of this disease [3-5]. The purpose of this investigation was an attempt to compare such prognostic indicators for EC as features of lymphocytic [6] and macrophage infiltration of tumor tissue with markers of its hormonal sensitivity (receptor phenotype) and the proliferation index Ki-67 [7], taking into account the molecular biological type of the disease. Materials and Methods: The study involved material from untreated patients with endometrial cancer (a total of 219 people). The average age of patients was close to 55-60 years. Using classification of Talhouk et al. [5] allowed to perform a search for POLE mutations, evaluate by IHC the expression of the oncoprotein p53 and MMR (mismatch-repair) proteins /MLH1, MSH2, MSH6 and PMS2/, and also identify the type of disease without a characteristic molecular profile (WCMP). The IHC method was also used to study the rate of estrogen (ER) and progesterone (PR) receptors, Ki-67 proliferative activity index, as well as the severity of macrophage-lymphocytic tissue infiltration of EC based on the analysis of the macrophage (CD68) and lymphocytic cells (cytotoxic CD8 and regulatory FoxP3) markers using reagents from Ventana and Dako. Statistical assessment of the relationships of the studied indicators was carried out by the Spearman rank correlation coefficient. Results: FoxP3 (in contrast to CD8 and CD68) positively and significantly correlates (ρ varies from 0.2895 to 0.3477) more often with ER, but not with PR. Ki-67 index in EC tissue positively and reliably correlates with FoxP3 both in the MMR-D and WCMP groups and in the combined cohort of EC patients. In the latter case, a similar relationship with Ki-67 extends to other studied markers of lymphocytic-macrophage infiltration, namely CD8 and CD68 (ρ 0,1746-0,3294). Only in the entire group of EC patients there is a positive rank correlation (0.4119!) between ER and PR expression. Conclusions: In patients with certain types of EC the connection between the estrogenic signal and PR induction is lost; it is especially noticeable in the MMR-D group, as exemplified by the negative correlation (-0.2951) of FoxP3 and PR expression. Taken together with existing data this indicates an important role of the endocrine component for differentiating separate groups of patients with EC, that may also be of practical importance. References: 1. Bokhman JV. Gynecol Oncol 1983; 15: 10-17. 2. Suarez AA et al. Gynecol Oncol 2017;144(2):243-249. 3. Murali R et al. Lancet Oncol 2014; 15: e268-278. 4.Berstein LM et al. Future Oncol. 2017 13(28):2593-2605. 5. Talhouk A. et al. Cancer. 2017;123(5):802-813. 6. Gargiulo P. et al. Cancer Treat Rev. 2016;48:61-8. 7. Kitson S. et al. Mod Pathol. 2017; 30(3): 459-468.

2018 ◽  
Vol 18 (3) ◽  
pp. 52-56
Author(s):  
D P Kovtun ◽  
N M Anichkov ◽  
O G Polushin ◽  
E V Ponomaryeva ◽  
A I Lyubimov ◽  
...  

Aim of the study. To analyze the correlation between proliferative activities determined on the basis of routine histological staining and immunohistochemical reaction to the nuclear antigen Ki-67 in colorectal adenocarcinomas. Methods. Thirty adenocarcinomas of the colon and rectum were retrospectively evaluated. Evaluation of proliferative activity was performed on serial histological preparations stained with hematoxylin and eosin and treated with antibodies to Ki-67. Calculation was carried out in the “hot spots” under four microscope high power fields (≈1 mm2). Results. An estimate of the Kendall rank correlation coefficient demonstrated a high degree of direct relationship between the number of mitoses counted by routine staining and proliferative activity estimated by the immunohistochemical method (τ = 0.708, p < 0.05). All observations on the dispersion diagram could be divided into three “cloud” clusters with similar values for Ki-67 with practically the same number of mitoses. Conclusions. On the basis of routine histological examination, it is possible to separate colorectal carcinomas from tumors with a low (1-2/mm2), moderate (3-5/mm2), and high (≥6/mm2) mitotic activity corresponding to the proliferation index values of Ki-67 <30%, 30%-50%, and >50%, respectively.


2021 ◽  
Vol 67 (3) ◽  
pp. 405-410
Author(s):  
Lev Bershtein ◽  
Aleksandr Ivantsov ◽  
Aglaia Ievleva ◽  
Dmitrii Vasilev ◽  
Igor` Berlev

Recent years have been marked by a gradual shift from the previous division of endometrial cancer (EC) into two main types to modern molecular biological classifications of this disease, one of which (at present, most likely, the most popular: Talhouk et al., 2017, 2019) is based on the use of a combination of genetic and immunohistochemical analysis. The study involved material from untreated EC patients, the number of which varied depending on the method used. The average age of patients was close to 55-60 years, and over 80% of patients were postmenopausal. Deparaffinized blocks of EC tissue were analyzed for POLE (DNA polymerase epsilon) mutations, evaluated by immunohistochemistry (IHC) the expression of the oncoprotein p53 and MMR (mismatch-repair) proteins / MLH1, MSH2, MSH6 and PMS2 /, and also helped to identify the type of disease without a characteristic molecular profile (WCMP). In addition to studying the expression of p53 and MMR proteins, the IHC method was also used to study the expression of estrogen (ER) and progesterone (PR) receptors, the Ki-67 proliferative activity index, and the severity of macrophage-lymphocytic infiltration of the EC tissue based on the analysis of the macrophage marker (CD68) and markers of lymphocytic cells (cytotoxic CD8 and regulatory FoxP3) using reagents from Ventana and Dako.


2021 ◽  
Author(s):  
Bo Li ◽  
Shunli Jiang ◽  
Guangning Zhang ◽  
Junchen Zhang

Abstract Objectives: Glioma patients with brain tumor-related epilepsy (BTRE) have a complex profile due to the simultaneous presence of two pathologies: glioma and epilepsy. However, the underlying pathophysiology of BTRE remains poorly understood. The purpose of this study is to investigate the correlation between molecular neuropathology and glioma with BTRE.Methods: A retrospective cohort study of 186 glioma patients was evaluated at our hospital, with 64 presenting with BTRE. Chi-square test, spearman rank correlation and multivariate logistic analyses were used to identify clinicopathological factors associated with BTRE. Results: Of the 186 patients examined in this study, 64 (34.4 %) had BTRE. By analyzing the characteristics of these patients, the results showed that patient age (over 40 years; p=0.007), low WHO grade (grade I, II; p = 0.001), IDH-1 positive mutation (p=0.027), ATR-X low expression level (OR=0.44; 95% CI: 0.21, 0.92) and low Ki-67 proliferation index (OR=0.25; 95% CI: 0.10, 0.68) were associated with the occurrence of BTRE. BTRE did not differ by sex, tumor location, expression of olig-2 or CD34. The results of the matching study showed that low Ki-67 proliferation index and negative ATR-X expression level were independent factors for a higher incidence of preoperative seizures in glioma patients. Conclusion: The current study updates existing information on genetic markers in gliomas with BTRE and explores the correlation of a wide range of clinicopathological factors and glioma patients with BTRE. Our study suggests that three putative biomarkers for BTRE: positive IDH1 mutation, low Ki-67 proliferation index and negative ATR-X expression. These factors may provide insights for developing a more thorough understanding of the pathogenesis of epilepsy and effective treatment strategies aimed at seizure control.


2007 ◽  
Vol 131 (4) ◽  
pp. 530-537 ◽  
Author(s):  
John A. Ozolek ◽  
E. Leon Barnes ◽  
Jennifer L. Hunt

Abstract Context.—The pathogenesis of respiratory epithelial adenomatoid hamartoma (REAH) and inverted papilloma (IP) is poorly understood, especially compared with sinonasal adenocarcinoma (SNAC). One feature of malignant glandular lesions is loss of the basal/myoepithelial layer. The immunophenotype of the basal/myoepithelial layer has not been fully examined in benign glandular lesions of the sinonasal tract. Objective.—To examine benign and malignant glandular lesions in the sinonasal tract for the immunophenotype of basal/myoepithelial cells, proliferation index, and cytokeratin and intestinal differentiation profiles. Design.—Sinonasal adenocarcinoma (intestinal-type adenocarcinoma [ITAC] and nonintestinal type adenocarcinoma [non-ITAC]), REAH, IP, and chronic sinusitis (CS) were stained for cytokeratin (CK) 7, CK20, 34βE12, CDX-2, p63, Ki-67, smooth muscle actin (SMA), S100 protein, and calponin. Results.—Basal/myoepithelial cells in CS and REAH were positive for p63 and 34βE12 but negative for SMA, S100 protein, and calponin. Proliferative activity was localized to the compartment containing p63-positive cells. Inverted papilloma demonstrated broad areas staining for p63 and 34βE12, with intermediate proliferative activity in these areas. Sinonasal adenocarcinoma had the highest Ki-67 labeling index, and p63-positive SNACs had higher proliferation indices than p63-negative SNACs. REAH, IP, CS, and most SNACs expressed CK7. Only SNAC expressed CK20. Sixty percent of morphologic ITACs expressed CDX-2. Conclusions.—Basal/myoepithelial cells in CS and REAH should be considered basal and not myoepithelial cells. In benign lesions, proliferative activity is limited to the compartments with p63 staining. In SNAC and IP, p63 expression correlates with proliferation index. REAH, IP, and CS share similar immunoprofiles (CK7+, CK20−, and CDX-2−), contrasting with SNAC (CK7+, CK20+/−, CDX-2−/+).


2021 ◽  
pp. 34-48
Author(s):  
T. Yu. Skvortsova ◽  
Zh. I. Savintceva ◽  
D. V. Zakhs ◽  
A. F. Gurchin ◽  
A. I. Kholyavin ◽  
...  

The purpose of the study was to explore the correlation between 11С-methionine (Met) uptake measured by combined positron emission and computed tomography (PET/CT) in newly diagnosed cerebral gliomas and tumor proliferative activity as measured by Ki-67 labeling index (Ki-67 LI).The results of PET/CT with 11С-methionine (PET-Met) of 236 adult patients with pretreated glial brain tumors were included in retrospective analysis. The final diagnosis of glioma according to WHO classification of CNS tumors (2007) was based on both histology and immunohistochemistry using Ki-67 antibodies. On PET-Met tumor-to normal brain uptake ratio (TBR) was calculated by dividing maximum Met uptake in the tumor (hot spot 10 mm in diameter) to activity concentration in the contralateral cortex. The Spearmen rank correlation test was used to analyze the relationships between TBR and Ki-67 LI.PET-Met analysis showed that TBR increases with an increase in the aggressiveness of the glial tumor. The differences of TBR values between gliomas grade II vs III and grade III vs IV were significant (p < 0,001). Among grades II-III gliomas Met uptake was significantly higher in oligodendroglial and mixed gliomas than in astrocytomas (p < 0,001), but the differences did not depend on Ki-67 LI.Correlation analysis demonstrated significant correlation between Ki-67 LI and TBR values (r = 0,49, p < 0,05, Spearman rank test). With analyzing glioma subgroups TBR values correlated with Ki-67 LI in diffuse astrocytomas (r = 0,52, p < 0,05), oligodendrogliomas (r = 0,40, p < 0,05), oligoastrocytomas (r = 0,47, p < 0,05) and in high-grade gliomas (r = 0,45, p < 0,05) but not in low-grade gliomas. Comparison between TBR value and Ki-67 LI in each glioma showed a lack of coincidence in 22 % of cases (high Met uptake but low Ki-67 LI and vice versa). The main reasons for such discrepancies were tumor molecular biology or incorrect biopsy target.Met uptake in diffuse gliomas correlates with proliferative activity which justifies the use of PET-Met for glioma grading. In case of mismatch between two biomarkers one should rely on the indicator that implies a higher aggressiveness of the glioma.


2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Lev M Berstein ◽  
Alexander Ivantsov ◽  
Dmitry Vasilyev ◽  
Aglaya Iyevleva

Abstract Background and aims : In Risk Classifier for Endometrial Cancer/EC (ProMisE) 4 molecular biological types of this tumor are described recently [1,2,3] and need an additional research, including evaluation of hormone-associated characteristics of both tumor tissue and patients [4]. Aim of the work was a study of estrogen (ER) and progesterone (PR) receptors in comparison with CD68+ macrophage infiltration (which promotes the invasion of tumor cells into the myometrium [5]) and expression of MDM2 protein, a negative regulator of p53 [6], in EC types presented in the ProMisE classification. Materials and methods: The tumor tissue of 218 EC patients included in the study (mean age 60.6 years) was assigned according to the data of genetic and immunohistochemical analysis to the types of carcinomas with gene POLE mutations, deficiency of mismatch repair proteins (MMR-D), expression (positive or diffuse) of p53 oncoprotein and to the type without characteristic molecular profile, WCMP. Immunohistochemistry was used also for evaluation of ER (Ventana antibodies, clone SP1) and PR (Ventana antibodies, clone 1E2) according to Allred, MDM2 (antibodies ABCAM, dilution 1:200) and macrophage marker CD68 (DAKO antibodies, clone CD8/144B). Results: According to the averaged data, the highest expression of ER and PR was found in EC types MMR-D and WCMP, and the lowest, respectively, in types POLE and p53+. Most often, positive expression of MDM2 (in 93.2% and 96.9% of studied cases) was detected respectively in MMR-D and p53+ type of EC, indicating, therefore, a positive relationship between MDM2 and the presence of steroid receptors in the first of these types (MMR-D) and negative - in the second of them (p53+). Expression of CD68+ macrophages demonstrated (contrary to the EC types POLE and p53+) a tendency to the lower values in types MMR-D and WCMP (128.0 ± 8.1 and 113.5 ± 6.3 cond.un.), i.e. in tumors with potential sensitivity to estrogen. Conclusions: The results indicate the importance of taking into account of both - the molecular biological type of the EC as well as the role of microenvironment of tumor cells, including the colonization of the neoplasm’ tissue by macrophages (and possibly lymphocytes) and the features of hormonal signal transmission in it. For further analysis, it is desirable to consider also the EC histotype, as one of the factors underlying various prognostic groups of this tumor [7]. References: 1.Talhouk A, McAlpine JN. Gynecol Oncol Res Pract. 2016; 3:14. 2. Talhouk et al., Cancer. 2017; 123(5):802–813. 3. Kommoss FK et al., Br J Cancer. 2018;119(4):480–486. 4. Berstein et al. Future Oncol. 2019; 15(12):1335–1346. 5. Jing X. et al. Immunol Cell Biol. 2019; 97(6):563–576. 6. Zou X. et al. Medicine (Baltimore).2018;97(49):e13273. 7. Bosse T. et al. Am J Surg Pathol. 2018 May;42(5):561–568.


1999 ◽  
Vol 19 (3-4) ◽  
pp. 175-185 ◽  
Author(s):  
Romana Tomaszewska ◽  
Krzysztof Okoń ◽  
Krystyna Nowak ◽  
Jerzy Stachura

The increasing frequency and poor prognosis in pancreatic cancer prompt us to search for morphological lesions being a substrate for its development. Studies of autopsy and surgically resected material as well as recent molecular studies have proved that one of the possible pathways of pancreatic neoplasia is the intraepithelial proliferation – dysplasia – cancer sequence. In the present paper we studied the proliferative activity (Ki‐67 index) in pancreatic intraepithelial proliferative lesions and its correlation with geometric features of cell nuclei as signs of increasing dysplasia. The studies were carried out in a group of 35 patients operated on for pancreatic cancer, chronic pancreatitis and other conditions not associated with the pancreas. We used immunohistochemical methods and basic morphometric parameters. The results of our studies indicate that the cell proliferative activity depends both on the type of epithelial proliferation and underlying pancreatic disease. The values of Ki‐67 index are significantly different in low‐grade proliferation (flat and papillary hyperplasia) and high‐grade proliferation (atypical papillary hyperplasia and carcinomain situ). A set of karyometric features correlates with Ki‐67 index but there is no single feature which would have a diagnostic value.


2018 ◽  
Vol 14 (2) ◽  
pp. 142-154
Author(s):  
I. V. Kosova ◽  
O. B. Loran ◽  
L. A. Sinyakova ◽  
L. V. Gundorova ◽  
V. A. Kosov ◽  
...  

Background. Viral infection is a major factor in virus-associated carcinogenesis.Objective: to evaluate the expression of growth factors and markers of apoptosis, proliferative activity, and angiogenesis in patients with viral DNA-positive bladder cancer.Materials and methods. The study included 100 bladder cancer patients (72 males and 28 females) aged between 38 and 90 years (mean age 65 ± 10). Tumor tissue samples were tested by polymerase chain reaction to detect DNA of herpes simplex virus types 1 and 2 (HSV-1 and HSV-2 respectively), high-risk human papillomavirus (HPV), cytomegalovirus (CMV), and Epstein—Barr virus (EBV). Immunohistochemical analysis was performed in 32 patients and included the following markers: proliferation marker Ki-67, p63, apoptosis regulator Bcl-2, p53, angiogenesis marker CD31, adhesion protein CD44, and epidermal growth factor receptor (EGFR).Results. Viral DNA in tumor tissue was detected in 34 patients; of them, 50 % had poorly-differentiated tumors. Twenty-seven patients were found to have EBV DNA in their tumor tissue; 6 patients had CMV DNA; 5 patients had high-risk HPV DNA (types 16, 39, 45, 52, and 59); 1 patient had HSV1 and HSV2 DNA. Four out of 34 participants had mixed infections (1 case of HPV 59 + EBV; 2 cases of EBV + CMV; 1 case of CMV + EBV + HPV 31 and 52). We observed a strong correlation between the presence of EBV DNA and levels of CD31 and Ki-67 expression as well as between high-risk HPV DNA and Bcl-2 expression. High levels of antibodies against EBV capsid antigen were associated with EGFR and Ki-67 expression, whereas the level of antibodies against EBV nuclear antigen correlated with CD44 expression. We evaluated specific characteristics of expression of the markers analyzed depending on the tumor stage, grade of anaplasia, and recurrence. We also assessed morphological characteristics of changes in lymphocytic and plasma cell infiltrates.Conclusion. We found a correlation between the presence of viral DNA in bladder cancer tissue and markers of proliferative activity, angiogenesis, and apoptosis. Viral infection is likely to increase proliferative activity and suppression of apoptosis, which may cause tumor progression. Further studies are needed to assess this correlation.


2020 ◽  
Author(s):  
Yangkun Wang ◽  
Zhishang Zhang ◽  
Bo Jiang ◽  
Chaoya Zhu ◽  
Sunan Wang ◽  
...  

Abstract Background To investigate the histopathological characteristics, immunophenotype and differential diagnosis of primary gastric invasive fibromatosis.Methods The clinical manifestations, histological morphology and immunophenotype of 4 cases of primary gastric invasive fibromatosis were observed and related literatures were reviewed.Results Among the 4 patients, 2 were males and 2 were females, aged 28 and 47 years, respectively. The lesions were located in the stomach in 2 cases, the gastric antrum in 1 case and cardia in 1 case. Under the microscope, the tumor was located in the submucosa, growing infiltratingly, and infiltrating into the gastric wall muscularis, serous membrane and extraserous fatty tissue. Tumor cells were rich in cytoplasm, with unclear cell boundaries, long rod-shaped nuclei, deep chromatin, no atypia, and rare mitotic figures. The tumor tissue was composed of proliferating spindle-shaped fibroblasts and collagen fibers, and the cell morphology was relatively uniform, arranged in parallel bundles or staggered weaves. Tumor tissue invaded and destroyed smooth muscle, blood vessels, nerve tissue and adipose tissue of the gastric wall. Immunophenotype: positive expression of vimentin, β-catenin, SMA positive expression; CKpan, EMA, S-100 protein, desmin, CD99, Bcl-2, ALK, CD34, CD117, DOG1, hormone receptors were all negative; The cell proliferation index ki-67 positive cells were 3–5%.Conclusion Primary invasive fibromatosis of the stomach is a relatively rare spindle cell tumor, which needs to be differentiated from tumors and pathological lesions such as inflammatory myofibroblastic tumor, plexiform mucinous fibroma, gastrointestinal stromal tumor, etc.


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