Expression of HIF-1α, Ki67, SMA and E-cadherin in endometriosis, endometrial and ovarian carcinoma

Introduction: Endometriosis is a benign gynecological condition that shares many characteristics with cancer cells, including immune evasion, survival, adhesion, invasion, and angiogenesis. The simultaneous investigation of tissue hypoxia, EMT, and proliferative index in endometriosis, endometrial, and ovarian carcinomas may provide new insight into the evolution and progression of gynecological neoplasms. Aim: The aim of our study was to follow the immunohistochemical expression in endometriosis, endometrial and ovarian carcinoma in relation to tissue hypoxia and necrosis, EMT, proliferative index, and fibrosis.

The present study used biopsy samples from 50 patients with endometriosis, endometrial carcinoma, and ovarian carcinoma in search for a correlation between HIF-1α, Ki67, SMA, and E-cadherin expression and various clinicopathological features.

We observed heterogeneity and different intensity of immunohistochemical expression in different groups of patients. Immu- nohistochemical expression was compared with the degree of tumor cell differentiation. Cells of poorly differentiated adenocarcinomas showed a higher proliferative index with Ki67, presence of epithelial-mesenchymal transition with reduced expression of E-cadherin with stronger expression of HIF-1α. Regarding SMA in pelvic and ovarian endometriosis foci, we reported strong diffuse expression in stromal cells with marked fibrosis.

Understanding the mechanisms of carcinogenesis and progression of gynecological tumors and endometriosis is impor - tant for prognosis, response to therapy, and possibly better treatment of patients.

endometriosis, endometrial carcinoma, hypoxia, immunohistochemistry, ovarian carcinoma

Of women of reproductive age, 5% to 15% have endometri- osis, which is defined as the presence of endometrial glands and stroma outside the uterus. [1] Ovarian cancer has been shown to develop in 0.5%–1% of cases of ovarian endome- triosis.[2] Clear cell carcinoma (CCC) is most commonly associated with ovarian endometriosis. 98 D. Markov et al. Folia Medica I 2024 I Vol. 66 I No. 1 Endometrial carcinoma is the most common gyneco - logical malignancy. Pathologically, it is classified into two groups, type I (endometrioid endometrial carcinoma) which accounts for 70%-80% of cases, and type II (non-en- dometrioid), including serous ones, and clear cell carcino - ma.[3] Understanding the molecular alterations underlying the endometrial carcinogenesis and progression may be helpful in identifying new molecular therapeutic targets. The current study sought to investigate the relationship between immunohistochemical expression of HIF-1α, epithelial, mesenchymal, and proliferative markers and clinicopathological parameters in endometriosis, endome - trial, and ovarian carcinomas. Hypoxia-inducible factor-1 (HIF-1) expression can be a marker of tissue hypoxia in solid tumors and can be used for therapeutic purposes due to its role in the progression of gynecological neoplasms.[4] In the literature, the results for HIF-1α in gynecological cancers are not always consistent. HIF-1α is the master regulator of cellular adaptation to hypoxia. It is a heterodimeric transcription factor composed of the HIF-1α and HIF-1β subunits.[5] Elevated levels of HIF- 1α are observed in a number of human malignancies and are associated with metastatic potential and poor prognosis. Decreased expression of E-cadherin is associated with positive EMT in tumor tissue and with proliferation, pro - gression and metastasis, respectively, and a worse progno - sis. In such cases, the tumors usually also have a high pro - liferative index. AIM The present study was conducted to investigate the correla- tion between HIF-1α expression in endometriosis and en - dometrial carcinomas by immunohistochemical technique. The expression of HIF-1α, Ki67, SMA and E-cadherin was studied and a comparative analysis of their expression was made in the three studied groups.

Fifty patients were included in the current study and were evaluated both prospectively and retrospectively. All of them are from the biopsy array of the Department of Clin- ical Pathology of Pulmed University Hospital in Plovdiv for a period of five years (2019-2023). DAKO antibodies were used. All patients were operated on and diagnosed in the Clin- ic of Obstetrics and Gynecology of Pulmed University Hos- pital of Plovdiv. The biopsy materials were reviewed by two independent pathologists to diagnose, the morphological type and stage the tumor according to FIGO. The histolog- ical and immunohistochemical investigation of the biopsy

was performed in the laboratory of the Morpho - logical Center of the Department of General and Clinical Pathology of the Medical University of Plovdiv. Immunohistochemical analysis The tissue was treated with standard histopathological technique according to standard protocols, and semi-quan- titative analysis of the results was performed. 4-μm thick paraffin sections were dewaxed and rehydrated through descending alcohols. Hematoxylin-eosin staining was per - formed according to standard methods. The immunohis - tochemical study was performed according to standard protocols. Immunohistochemistry was performed for the protein markers HIF-1α, Ki67, SMA and E-cadherin. An automatic immunostainer (Bond, DAKO) was used following the manufacturer’s protocols. Antibodies produced by Dako, Denmark and Abcam, USA were used: – rabbit monoclonal antibody against human HIF-1α, 1:100 dilution We reported nuclear staining. – mouse monoclonal antibody against human E-cadherin We reported cytoplasmic and membranous staining. – mouse monoclonal antibody against human Ki67 We reported nuclear staining. – mouse monoclonal antibody against human SMA Cytoplasmic and membranous staining were described. DAB was used as the chromogen. An automated coloring platform was used. Expression estimation system A semi-quantitative method was used to assess the im - munohistochemical expression: 1%–10%=1; 10%–50%=2; >50%=3. Intensity of immunohistochemical expression: 0=miss - ing; 1(+)=weak; 2(+)=moderate; 3(+)=strong. We reported diffuse, focal, and heterogeneous expres - sion patterns. Statistical analysis Descriptive and inferential statistics were performed. The non-normally distributed data were expressed as median and percentiles (25th; 75th). Comparisons between more than two independent groups were carried out using the nonparamet- ric Kruskal-Wallis test (H). Multiple-comparison post hoc test was used if significant differences were found. Categori- cal variables were presented as absolute/relative frequencies (counts/%) and z-test was applied to test for difference of rel- ative parts/shares between the groups. Statistical analysis of the data was performed using SPSS v. 26 for Windows (IBM Corp. Released 2019. Armonk, NY: IBM Corp). For all tests, p-value ˂0.05 indicated statistical significance.

A retrospective analysis was conducted on a total of 296 cases from 2019 to 2023. Among these cases, a subset of 50 Expression of HIF-1α, Ki67, SMA, and E-Cadherin 99 Folia Medica I 2024 I Vol. 66 I No. 1 was chosen for immunohistochemistry testing. The present study examined a cohort of women, whose median age was 64.5 years (54; 71 years), who were categorized into three distinct groups: 16 individuals (32.0%) diagnosed with en- dometriosis, 17 individuals (34.0%) diagnosed with endo - metrial carcinoma, and 17 individuals (34.0%) diagnosed with ovarian carcinoma. A distribution was generated to represent the number and proportion of patients in the three groups within the designated time frame. A statistically sig- nificant difference was seen in the age distribution of the pa- tients under examination across different groups (H=16.44, p=0.000). Following a post hoc analysis, it was seen that patients diagnosed with endometriosis with a median age of 51 years exhibited a statistically significant difference in age when compared to patients diagnosed with endometrial cancer, who had a median age of 68 years ( p=0.002). Fur- thermore, patients with endometriosis were also shown to be statistically substantially younger than those diagnosed with ovarian carcinoma, with a median age of 71 years (p=0.001). There was no difference between the median ages of individ- uals diagnosed with endometrial and ovarian carcinomas. The proportion of the heterogeneous E-cadherin stain - ing pattern in ovarian cancer (52.9%) was statistically sig - nificantly higher compared to the other two groups, name- ly endometriosis focus (6.3%) and endometrial carcinoma (11.8%) (z-test, p<0.05). Additionally, the prevalence of diffuse staining E-cadherin pattern was found to be sub - stantially greater in cases of endometriosis (93.8%) and endometrial carcinoma (88.2%) as compared to ovarian carcinoma (47.1%) (z-test, p<0.05). The results are shown in Table 1 and Fig. 1A. In cases with reduced expression of E-cadherin, we re - ported a positive EMT status, in case of preserved expres - Table 1. Relative proportions of E-cadherin expression categories by staining pattern by group N Endometriosis Endometrial cancer Ovarian cancer Heterogeneous pattern 1 (6.3%) 2 (11.8%) 9 (52.9%) Diffuse pattern 15 (93.8%) 15 (88.2%) 8 (47.1%) Total 16 (100%) 17 (100%) 17 (100%) sion – a negative EMT status. The proportion of negative epithelial-mesenchymal transition (EMT) in endometriosis (87.5%) was shown to statistically significantly higher compared to ovarian can - cer (23.5%) (z-test, p<0.05). Furthermore, the statistical analysis revealed a statistically significantly higher occur - rence of positive epithelial-mesenchymal transition (EMT) in ovarian cancer (76.5%) compared to endometriosis (12.5%) (z-test, p<0.05) (Table 2). HIF-1α, which serves as the principal functional pro - tein within the HIF-1 complex, had a high level of HIF-1α expression in instances of endometrial carcinoma cases, at the invasive tumor front, and in proximity to areas exhibit- ing necrotic tissue. In cases involving endometriosis, there was a notable increase in HIF-1α expression within adenomyosis and en- dometriosis foci as compared to the expression detected in normal endometrium, as shown in Fig. 1B. We observed increased expression at the tumor-invasive front. HIF-1α expression was found to be associated with tumor grade, indicating a progressive increase in strength. A statistically significantly higher proportion of HIF- 1α positive cells between 25% and 50% was found in en - dometrial carcinoma (58.8%) compared to ovarian carci - noma (11.8%) (z-test, p<0.05) (Fig 1C, D). In cases with high HIF-1α expression (more than 75%) is observed sta - tistically significant difference between ovarian carcino - ma (41.2%) compared to endometrial carcinoma (5.9%) (z-test, p<0.05). The relative share of the diffuse pattern of staining for HIF-1α in endometriotic focus (62.5%) compared to en - dometrial carcinoma was statistically significantly higher (11.8%) (z-test, p<0.05) (Table 3). Table 2. Relative proportions of the categories of E-cadherin expression along the epithelial-mesenchymal transition in the three studied groups N Endometriosis Endometrial cancer Ovarian cancer Negative EMT status (preserved expression of E-cadherin) 14 (87.5%) 10 (58.8%) 4 (23.5%) Positive EMT status (reduced to missing E-cadherin expression) 2 (12.5%) 7 (41.2%) 13 (76.5%) Total 16 (100%) 17 (100%) 17 (100%) Table 3. Relative proportions of anti HIF-1α expression categories according to the staining pattern by group N Endometriosis Endometrial cancer Ovarian cancer Perinecrotic 0 (0.0%) 4 (23.5%) 4 (23.5%) Diffuse 10 (62.5%) 2 (11.8%) 6 (35.3%) Mixed 3 (18.8%) 2 (11.8%) 4 (23.5%) Heterogeneous 3 (18.8%) 9 (52.9%) 3 (17.6%) Total 16 (100%) 17 (100%) 17 (100%) 100 D. Markov et al. Folia Medica I 2024 I Vol. 66 I No. 1 There is a statistically significant difference in the pro - portion of positive Ki67 cells, ranging from 1% to 10%, in endometriosis focus (87.5%) compared to the two other groups, endometrial carcinoma (29.4%) and ovarian can - cer (11.8%) (z-test, p<0.05). Moreover, there was a statis - tically significant increase in the proportion of Ki67-pos - itive cells ranging from 10% to 50% in endometrial cancer (58.8%) compared to endometriosis (12.5%) (z-test, p<0.05) (Fig. 1E). In ovarian cancer, the maximum relative percentage of Ki67 positive cells exceeds 50% (41.2%). In the other two groups, namely endometrial carcinoma and endometriotic focus, the relative proportions of Ki67 pos - itive cells are observed to be 11.8% and 0%, respectively. No statistically significant difference was observed be - tween the relative proportions of the SMA expression cate- gories in the three groups (z-test, p≥0.05). A moderate type of expression predominated in all three groups, as did a diffuse staining pattern (Fig. 1F). Figure 1. A. E-cadherin, IHC, diffuse expression pattern, low grade endometrial carcinoma, ×100; B. Nuclear and cytoplasmic expres- sion of HIF-1α in an endometriosis focus, ×100; C. Strong nuclear expression of HIF-1α in high grade endometrioid carcinoma, com- bined with endometriosis, strong perinecrotic expression in the tumor and weak diffuse expression in the endometriosis focus, ×40; D. Heterogeneous expression pattern of HIF-1α in clear cell variant ovarian carcinoma in the nucleus and cytoplasm of tumor cells, ×100; E. IHC expression of Ki67 - 75% proliferative index in moderately differentiated endometrial carcinoma, ×100; F. Cytoplasmic and membrane expression of SMA in endometrioid variant ovarian carcinoma, ×100. Expression of HIF-1α, Ki67, SMA, and E-Cadherin 101 Folia Medica I 2024 I Vol. 66 I No. 1

Hypoxia is a common change in the tumor microenviron- ment of solid malignancies due to an imbalance between the rapid growth of tumors and their blood supply. In addi- tion, hypoxia has been shown to induce resistance to che - motherapy and radiotherapy. We show that diffuse expres- sion of HIF-1α predominates in cases with endometriosis and endometrial carcinoma, and a heterogeneous expres - sion pattern is also observed in ovarian carcinomas. In type 1 endometrial carcinoma, HIF-1α expression correlates with tumor grading and FIGO stage, which has also been reported by other authors.[6] In type 2 endometrial carcinoma, stronger and diffuse expression, including perinecrotic expression of HIF-1α was observed in all examined patients, regardless of the depth of myometrial invasion, vascular invasion, and TNM stage of the tumor. This dependence is well expressed in high-grade carcinomas. Immunohistochemical expression of HIF-1α was great - er in high-grade endometrial carcinomas compared with low-grade carcinomas, but this difference was not statis - tically significant. We hypothesize that the lack of statisti - cal significance is due to the small number of cases in the sample. It is interesting that around areas with necrosis, we simultaneously observed positive EMT and perinecrotic strong expression of HIF-1α. Hypoxia is likely to underlie the mechanisms in both processes. The association between endometriosis and endometri- oid and clear cell carcinoma of the ovary is well known. [7] A threefold higher risk of developing endometriosis-asso - ciated ovarian carcinoma has been found in the presence of ovarian endometriosis.[8] However, the relationship be- tween endometriosis and endometrial carcinoma has not been well studied.[9] Endometriosis and endometrial carcinoma share com - mon etiologic factors, including estrogen stimulation and chronic inflammation. Atypical endometriosis is a pre - cursor lesion associated with malignant transformation and with increased the risk of endometrial carcinoma. [10] Endometriosis was found in 30% of cases of synchronous endometrioid carcinomas of the endometrium and the ovary. [11] In our study, in 11 cases of combination between endometriosis and endometrial carcinoma, we reported a more advanced FIGO stage. We hypothesize that endo - metriosis paves the way for tumor cells among the uterine myometrium in adenomyosis. Endometrioid ovarian carcinoma histologically resem - bles the endometrium, and recent studies have shown an association of endometriosis with endometrioid, clear cell, and low-grade serous ovarian carcinoma[12], as well as in the cases described by us. Adenomyosis is a condition in which endometrial glands and stroma are present in the myometri- um of the uterus.[13] In cases with endometrioid carcinoma and adenomyosis, we observed deep myometrial invasion. Loss of E-cadherin activates the Wnt-signaling path - way and leads to EMT. [14] E-cadherin-mediated cell ad - hesion is inactivated by different mechanisms in cancers. Suppression of the E-cadherin/β-catenin complex as well as upregulation of SMA are known to be key processes in EMT. An important aspect of EMT is the aberrant localiza- tion of β-catenin expression. [15] Tumor hypoxia decreases E-cadherin expression, leads to EMT, and helps tumor cells to avoid programmed cell death and adapt to unfavorable conditions.[16] Studies on the immunohistochemistry expression of E-cadherin in relation to endometriosis have yielded in - consistent findings. In our study, E-cadherin expression in peritoneal and ovarian endometriosis cases was weaker compared to the adenomyosis expression. Around areas of necrosis, we observed reduced expression of E-cadherin in tumor cells in ovarian and endometrial cancers. Ki67 protein is a cell proliferation marker. The number of Ki67-positive tumor cells often correlates with the clin - ical course.[17] The Ki67 index is higher in advanced stage tumors; a higher Ki67 index indicates more aggressive tu - mor behavior and worse clinical outcomes. [18] The same trend is observed with the proliferative index in low- and high-grade endometrial carcinomas. In Ki67 positive cases, positive EMT status predominated by frequency. Although we did not find a statistical relationship be - tween EMT status and proliferative index in each of the studied groups of working material, we performed a com - parative analysis of the same tumor areas in cases with EMT positive status with a heterogeneous pattern and high Ki67 expression (50-100%). In areas of reduced E-cadherin expression, we observed increased expression with Ki67. And the inverse was valid. Endometriosis is not a neoplastic disease, but it involves certain processes showing hallmarks of malignancy and carcinogenesis.[19] There is increasing interest in the role of the Ki67 monoclonal antibody in the development of en - dometriosis. Ki67 is a nuclear protein associated with cell proliferation.[20] Although little is known about the specific roles of Ki67, it is present in all active phases of the cell cycle but is absent in resting (G0) cells.[20] Endometrial cell proliferation in patients with endome- triosis was higher than that in patients without endome - triosis, as determined by the proliferation index Ki67. [21] A higher level of Ki67 is associated with malignant tumors and metastasis.[22] Whether Ki67 is associated with endo - metriosis recurrence is not yet known. HIF-1α and Ki67 may be useful in identifying endometriosis patients who are at risk and need more specialized care. An important histological feature of endometriosis is the presence of dense fibrous tissue in and around the lesions[23], especially in deep infiltrating endometriosis (DIE)[24]. Fibrosis can lead to subsequent adhesions, an - atomic deformity, and pelvic pain, and because fibrosis in many organs is generally difficult to treat, much less cure[25], fibrosis in endometriotic lesions is very likely to be responsible for resistance to therapy, especially in DIE[25]. Another feature of endometriosis is the universal pres - ence of smooth muscle in or around endometriotic lesions, 102 D. Markov et al. Folia Medica I 2024 I Vol. 66 I No. 1 often referred to as smooth muscle metaplasia (SMM). SMM is common in peritoneal [26], deep [27], ovarian [28] endometriosis, as well as in adenomyosis [29]. The most pronounced fibrosis was observed in cases with peritoneal endometriosis. The possibility of stromal cells differenti - ated into smooth muscle cells (SMCs) undergoing phys - iological SMM in the uterine connective tissue is not yet sufficiently evidenced.[30] Some authors associate the expression of SMA in endo- metriosis and endometrial carcinomas with EMT, other au- thors suggest that the strong expression of SMA in the stro- ma of endometrial lesions is the result of smooth muscle metaplasia of the stromal cells in the endometriotic focus. The observed strong diffuse expression of SMA in endome- triosis lesions support the second hypothesis.

The immunohistochemical profile of the different mor - phologic lesions of the endometrium and ovaries can be used to analyze the progression of endometriosis in tumor tissue, as well as to assess the progression of ovarian and endometrial carcinomas. Selected immunohistochemi - cal markers are relevant in the assessment of proliferative activity, invasion and tumor progression and may serve as prognostic factors and for future therapy. Endometriosis should be considered as a disease with the potential for malignancy. Morphological and immu - nohistochemical evaluation of endometriotic tissue can increase the clinicians’ awareness of the potential of an en- dometriotic lesion. Decreased expression of E-cadherin in endometriosis and a proliferative index greater than 10% are grounds for a follow-up and more of an increased dis - ease recurrence. Morphologic features such as intratumoral hypoxia and areas of necrosis in ovarian and endometrial carcinomas are poor prognostic markers, as is a high proliferative index.

The present study is funded by the Medical University of Plovdiv through doctoral project DPDP No. 04/2022.

1. De Souza Pinto LP , Ferrari G, Dos Santos IK, et al. Evaluation of safety and effectiveness of gestrinone in the treatment of endometriosis: a systematic review and meta-analysis. Arch Gynecol Obstet 2023; 307(1):21–37. 2. Guidozzi F . Endometriosis-associated cancer. Climacteric 2021; 24(6):587–92. 3. Kurman RJ, Shih IeM. The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol 2010; 34(3):433–43. 4. Berg A, Fasmer KE, Mauland KK, et al. Tissue and imaging biomark- ers for hypoxia predict poor outcome in endometrial cancer. Onco - target 2016; 7(43):69844–56. 5. Lou JJ, Chua YL, Chew EH, et al. Inhibition of hypoxiainducible fac- tor-1alpha (HIF-1alpha) protein synthesis by DNA damage inducing agents. PLoS One 2010; 5(5):e10522. 6. Engels K, du Bois A, Harter P , et al. VEGF-A and i-NOS expression are prognostic factors in serous epithelial ovarian carcinomas after complete surgical resection. J Clin Pathol 2009; 62(5):448–54. 7. Horne AW , Missmer SA. Pathophysiology, diagnosis, and manage - ment of endometriosis. BMJ 2022; 379:e070750. 8. Worley MJ, Welch WR, Berkowitz RS, et al. Endometriosis-associ - ated ovarian cancer: a review of pathogenesis. Int J Mol Sci 2013; 14(3):5367–79. 9. Stern RC, Dash R, Bentley RC, et al. Malignancy in endometriosis: frequency and comparison of ovarian and extraovarian types. Int J Gynecol Pathol 2001; 20(2):133–9. 10. Yu HC, Lin CY , Chang WC, et al., Task Force on Carcinogenesis of Endometrial Cancer. Increased association between endometriosis and endometrial cancer: a nationwide population-based retrospective cohort study. Int J Gynecol Cancer 2015; 25(3):447–52. 11. Zaino R, Whitney C, Brady MF , et al. Simultaneously detected en - dometrial and ovarian carcinomas – a prospective clinicopathologic study of 74 cases: a gynecologic oncology group study. Gynecol Oncol 2001; 83(2):355–62. 12. Pearce CL, Templeman C, Rossing MA, et al., Ovarian Cancer As - sociation Consortium. Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case- control studies. Lancet Oncol 2012; 13(4):385–94. 13. Bourdon M, Santulli P , Marcellin L, et al. Adenomyosis: An update regarding its diagnosis and clinical features. J Gynecol Obstet Hum Reprod 2021; 50(10):102228. 14. Katoh M. Multi-layered prevention and treatment of chronic in - flammation, organ fibrosis and cancer associated with canonical WNT/β-catenin signaling activation (Review). Int J Mol Med 2018; 42(2):713–25. 15. Pilzecker B, Buoninfante OA, Jacobs H. DNA damage tolerance in stem cells, ageing, mutagenesis, disease and cancer therapy. Nucleic Acids Res 2019; 47(14):71637181. 16. Beavon IR. Regulation of E-cadherin: does hypoxia initiate the meta- static cascade? Mol Pathol 1999; 52(4):179–88. 17. Giurgea LN, Ungureanu C, Mihailovici MS. The immunohistochemi- cal expression of p53 and Ki67 in ovarian epithelial borderline tu - mors. Correlation with clinicopathological factors. Rom J Morphol Embryol 2012; 53(4):967–73. 18. Kumar GS, Gokhan E, De Munter S, et al. The Ki67 and RepoMan mitotic phosphatases assemble via an identical, yet novel mechanism. Elife 2016; 5:e16539. 19. Králíčková M, Laganà AS, Ghezzi F , et al. Endometriosis and risk of ovarian cancer: what do we know? Arch Gynecol Obstet 2020; 301(1):1–10. 20. Miller I, Min M, Y ang C, et al. Ki67 is a graded rather than a binary marker of proliferation versus quiescence. Cell Rep 2018; 24(5):1105–12. 21. Park JS, Lee JH, Kim M, et al. Endometrium from women with en - dometriosis shows increased proliferation activity. Fertil Steril 2009; 92(4):1246–9. 22. Li LT, Jiang G, Chen Q, et al. Ki67 is a promising molecular target in the diagnosis of cancer (review). Mol Med Rep 2015; 11(3):1566–72. Expression of HIF-1α, Ki67, SMA, and E-Cadherin 103 Folia Medica I 2024 I Vol. 66 I No. 1 23. Guo SW . Endometriosis and ovarian cancer: potential benefits and harms of screening and risk-reducing surgery. Fertil Steril 2015; 104(4):813–30. 24. Rolla E. Endometriosis: advances and controversies in classification, pathogenesis, diagnosis, and treatment. F1000Res 2019; 8:F1000 Fac- ulty Rev-529. 25. Koninckx PR, Fernandes R, Ussia A, et al. Pathogenesis based diag - nosis and treatment of endometriosis. Front Endocrinol (Lausanne) 2021; 12:745548. 26. Matsuzaki S, Darcha C. Antifibrotic properties of epigallocatechin- 3-gallate in endometriosis. Hum Reprod 2014; 29(8):1677–87. doi: 10.1093/humrep/deu123. 27. Acloque H, Thiery J, Nieto M. The physiology and pathology of the EMT. Meeting on the epithelial-mesenchymal transition. EMBO Rep 2008; 9:322–6. 28. Donnez J, García-Solares J, Dolmans MM. Ovarian endometriosis and fertility preservation: a challenge in 2018. Minerva Ginecol 2018; 70(4):408–14. 29. Vannuccini S, Petraglia F . Recent advances in understanding and managing adenomyosis. F1000Res 2019; 8:F1000 Faculty Rev-283. 30. Mechsner S. Endometriosis, an ongoing pain – step-by-step treat - ment. J Clin Med 2022; 11(2):467. Экспрессия HIF-1α, Ki67, SMA и E-кадгерина при эндометриозе, раке эндометрия и яичников Даниел Марков 1, Елена Порязова 1, Ралица Райчева 2, Г алабин Марков 3 1 Кафедра общей и клинической патологии, Факультет медицины, Медицинский университет – Пловдив, Пловдив, Болгария 2 Кафедра „Социальная медицина и общественное здравохранение“, Факультет общественного здравоохранения, Медицинский университет – Пловдив, Пловдив, Болгария 3 Факультет медицины, Медицинский университет – Пловдив, Пловдив, Болгария Адрес для корреспонденции: Даниел Марков, Кафедра общей и клинической патологии, Факультет медицины, Медицинский университет – Пловдив, бул. „Васил Априлов“ № 15А, 4002 Пловдив, Болгария; E-mail: [email protected] Дата получения: 14 сентября 2023 ♦ Дата приемки: 10 ноября 2023 ♦ Дата публикации: 29 февраля 2024 Образец цитирования: Markov D, Poryazova E, Raycheva R, Markov G. Expression of HIF-1α, Ki67, SMA and E-cadherin in endometriosis, endometrial and ovarian carcinoma. Folia Med (Plovdiv) 2024;66(1):97-103. doi: 10.3897/folmed.66.e112757. Резюме Введение: Эндометриоз – доброкачественное гинекологическое заболевание, которое имеет много общих характеристик с раковыми клетками, включая уклонение от иммунитета, выживаемость, адгезию, инвазию и ангиогенез. Одновременное исследование тканевой гипоксии, ЭМП и пролиферативного индекса при эндометриозе, карциномах эндометрия и яичников может дать новое представление об эволюции и прогрессировании гинекологических новообразований. Цель: Целью нашего исследования было проследить иммуногистохимическую экспрессию при эндометриозе, карциноме эн - дометрия и яичников в связи с тканевой гипоксией и некрозом, ЭМП, пролиферативным индексом и фиброзом. Материалы и методы: В настоящем исследовании использовались образцы биопсии 50 пациенток с эндометриозом, карци - номой эндометрия и карциномой яичников с целью поиска корреляции между экспрессией HIF-1α, Ki67, SMA и E-кадгерина и различными клинико-патологическими особенностями. Результаты: Мы наблюдали гетерогенность и различную интенсивность иммуногистохимической экспрессии у разных групп пациентов. Иммуногистохимическую экспрессию сравнивали со степенью дифференцировки опухолевых клеток. Клетки низкодифференцированных аденокарцином показали более высокий пролиферативный индекс Ki67, наличие эпителиаль - но-мезенхимального перехода со сниженной экспрессией Е-кадгерина при более сильной экспрессии HIF-1α. Что касается SMA(гладкомышечный актин) в очагах эндометриоза органов малого таза и яичников, мы сообщили о сильной диффузной экспрессии в стромальных клетках с выраженным фиброзом. Заключение: Понимание механизмов канцерогенеза и прогрессирования гинекологических опухолей и эндометриоза важно для прогноза, ответа на терапию и, возможно, лучшего лечения пациенток. Ключевые слова эндометриоз, карцинома эндометрия, гипоксия, иммуногистохимия, рак яичников