Research ArticleClinical Studies
Open Access

Clinicopathological Significance of Claudin-6 Immunoreactivity in Low-grade, Early-stage Endometrioid Endometrial Carcinoma

YURIMI LEE and HYUN-SOO KIM
In Vivo January 2025, 39 (1) 367-374; DOI: https://doi.org/10.21873/invivo.13837

Abstract

Background/Aim: Dysregulation of claudin 6 (CLDN6) expression has been widely documented in various malignancies. CLDN6 is aberrantly expressed in many types of human carcinomas; however, its clinical significance in endometrial carcinoma has seldom been investigated. This study aimed to examine the immunohistochemical expression status of CLDN6 in low-grade, early-stage endometrioid endometrial carcinoma (LGES-EEC) and to assess its clinicopathological significance. Materials and Methods: We performed immunostaining for CLDN6 in 118 tissue samples from LGES-EECs. Protein expression levels were interpreted using a semi-quantitative histoscore method. All statistical analyses were performed. Results: CLDN6 was primarily localized along the membranes of the tumor cells. We considered histoscore ≥10 (the staining proportion ≥5% and intensity ≥2) as positive immunoreactivity for CLDN6. Twenty-six of the 118 patients (22.0%) showed CLDN6 positivity. Positive CLDN6 expression was significantly associated with deeper myometrial invasion (p=0.001), higher initial stage (p=0.015), and substantial lymphovascular space invasion (p=0.018). Conclusion: Aberrant CLDN6 expression is involved in tumor progression in LGES-EECs. In addition, targeting CLDN6 may offer clinical utility in patients with endometrial carcinoma.

Key Words:

Endometrial carcinoma (EC) is the most common gynecological malignancy in developed countries, with a steadily increasing incidence (1, 2). The incidence of EC has reached 27.7 per 100,000, and approximately 66,200 women in the United States will be newly diagnosed with EC by 2023 (3-5). Most ECs present at an early stage are categorized as low-risk and can be treated with surgery alone. Early-stage (stages I-II) EC demonstrates a favorable overall survival exceeding 80%; however, the prognosis drastically worsens in cases with advanced disease, where the 5-year overall survival falls below 20% (3, 6). Furthermore, 5-10% of patients with early-stage EC may still be at risk of disease-related mortality, and 15-20% of patients with presumed uterine-confined disease at primary treatment develop tumor recurrence (7, 8). Therefore, there is a need for an accurate risk stratification model for EC and the identification of predictive biomarkers that determine which patients could benefit from postoperative adjuvant therapy.

Endometrioid EC (EEC) is the most common type of EC, accounting for 75-80% of all EC cases. More than 85% of EECs present with low-grade (grade 1-2) histology. According to the recently introduced EC molecular classification (9), tumors without DNA polymerase epsilon, catalytic subunit mutations, mismatch repair deficiency, or tumor protein 53 mutations are classified as a nonspecific molecular profile (NSMP) subgroup, accounting for approximately 50% of all EC cases. Its histological type is mostly low-grade EEC, and its genetic features include low tumor mutational burden and low copy number variation (10). NSMP ECs are heterogeneous and vary from indolent to aggressive tumors (11, 12). As this subgroup displays strikingly different clinical outcomes, the identification of high-risk NSMP EC is feasible in clinical practice and will help clinicians establish effective management strategies for patients with NSMP EC.

Claudins (CLDNs) comprise 27 members essential for the regulation of paracellular permeability because of their roles as key components of tight junctions (13). CLDNs bind to signaling and cytoskeletal proteins and participate in cellular responses to intracellular and external signal transmissions (14). CLDN6, the only specific CLDN (15), is expressed in various epithelia, induces epithelial cell junction formation and polarity, and plays a crucial role in maintaining tight junction functions (16). In addition, CLDN6 is expressed in different types of human malignancies (17). Considering its diverse features in tumors, CLDN6 plays a paradoxical role in suppressing and promoting tumor development and progression (13). For example, CLDN6 expression has been detected in gastric carcinoma, and silencing of CLDN6 inhibited the proliferation and invasive abilities of gastric carcinoma cells (18). In contrast, CLDN6 over-expression suppresses breast carcinoma progression (19), and DNA methylation of the CLDN6 promoter down-regulates its gene expression and promotes the migration and invasion of breast carcinoma cells. The discrepancies between the dual roles of CLDN6 may be due to the intratumoral heterogeneity and complexity of tumors.

Despite accumulating evidence that CLDN6 plays a key role in various malignancies, the clinicopathological significance of CLDN6 expression in EC remains unclear. This study aimed to analyze the immunohistochemical expression patterns of CLDN6 and to assess its clinicopathological significance in patients with low-grade early-stage EEC (LGES-EEC), most of which were molecularly classified into the NSMP subgroup. Our findings provide evidence that CLDN6 expression is linked to the progression of LGES-EEC and that CLDN6 expression can serve as a biomarker indicating the aggressive behavior of LGES-EEC.

Materials and Methods

Case selection. This study protocol was reviewed and approved by the Institutional Review Board (IRB) of the Samsung Medical Center (Seoul, Republic of Korea; protocol number: 2024-09-073). Owing to the retrospective nature of this study, the IRB waived the requirement for the investigators to obtain signed informed consent. We searched patients who underwent surgery for primary EEC in our institutional databases. All available slides were examined by a single gynecological pathologist (H.-S.K.). Diagnoses were established based on the 2020 World Health Organization Classification of Female Genital Tumors (20). The inclusion criteria were International Federation of Gynecology and Obstetrics (FIGO) grade 1 or 2, initial FIGO stage I or II, and wild-type p53 expression. Finally, we included 118 patients who underwent hysterectomy for primary LGES-EEC at the Samsung Medical Center (Seoul, Republic of Korea).

Data collection. The following clinicopathological information was collected from the electronic medical records and pathology reports: patient age at initial diagnosis, FIGO grade, initial FIGO stage, lymphovascular space invasion (LVSI), postoperative recurrence, survival status, and follow-up period between the time of surgery and the last follow-up. As the initial stages of all patients were determined based on the 2009 FIGO staging system, they were restaged according to the updated 2023 FIGO staging system (21). The extent of LVSI was categorized into focal (<5 vessels) and substantial (≥5 vessels) groups to classify the cases into 2023 FIGO stages IB and IIB, respectively (20).

Immunostaining. Formalin-fixed, paraffin-embedded tissue blocks were cut into 5-μm-thick sections, deparaffinized in xylene, and rehydrated using graded alcohols. Sections were then incubated with hydrogen peroxide to block endogenous peroxidase activity. After antigen retrieval, the sections were incubated with a CLDN6 antibody (dilution 1:100, clone EPR28103-113, Abcam, Cambridge, UK). Immunostaining was performed using a Bond-RX automated stainer (Leica Biosystem, Melbourne, Australia) using a Bond Polymer Refine Detection System (DS9800; Vision Biosystems, Melbourne, Australia) (22-27). After chromogenic visualization, the slides were counterstained with hematoxylin. Positive and negative controls were stained concurrently. Human testicular seminoma exhibiting membranous CLDN6 immunoreactivity served as a positive control (28), whereas non-immune serum substituted for the primary antibody was used as a negative control, resulting in undetectable staining. Staining intensity was designated as negative (score 0), weak (score 1), moderate (score 2), or strong (score 3). Staining proportions were determined in increments of 5% across a 0-100% range. Histoscore was calculated as the sum of the proportion of stained area at each intensity level multiplied by the weighted staining intensity (6, 23, 29). All immunostained slides were scored by a single board-certified pathologist (Y.L.) who was blinded to the patients’ identities.

Statistical analysis. Pearson’s chi-squared test or Fisher’s exact test was used to examine the association between CLDN6 expression and the clinicopathological characteristics of patients with LGES-EEC. All statistical analyses were performed using an IBM SPSS Statistics for Windows (version 23.0; IBM Corp., Armonk, NY, USA). Statistical significance was set at p<0.05.

Results

Baseline characteristics. Table I summarizes the clinicopathological characteristics of the 118 patients with LGES-EEC. Patients’ ages ranged from 30 to 88 years (median=57 years; mean=57.1 years). Thirty-three (28.0%) and 85 (72.0%) patients were diagnosed with grade 1 and 2 EECs, respectively. Seventy-eight (66.1%) tumors invaded less than half of the myometrium, whereas 40 (33.9%) tumors involved equal to or more than half of the myometrium. Cervical stromal extension was identified in 20 (16.9%) patients. The distribution of initial FIGO stages was as follows: IA1 (6/118; 5.1%), IA2 (36/118; 30.5%), 1A3 (3/118; 2.5%), IB (33/118; 28.0%), IIA (18/118; 15.3%), and IIB (22/118; 18.6%). LVSI was absent in more than half of the patients (65/118, 55.1%), whereas 22 (18.6%) patients showed substantial LVSI. In particular, 13 of 22 patients whose tumors invaded less than half of the myometrium without cervical stromal extension (2009 FIGO stage IA) were upstaged to IIB because of the presence of substantial LVSI. Areas of mucinous and squamous differentiation were identified in 15 (12.7%) and 29 patients (24.6%), respectively. Five patients (4.2%) experienced recurrence. Three patients (2.5%) died due to disease progression.

View this table:
Table I.

Baseline characteristics of 118 patients with low-grade, early-stage endometrioid endometrial carcinoma.

CLDN6 immunoreactivity. Figure 1A illustrates the typical morphology of LGES-EEC. Figure 1B-E illustrates the immunoreactivity of CLDN6, including focal weak (histoscore 3; Figure 1B), focal strong (histoscore 30; Figure 1C), and diffuse strong (histoscore 210; Figure 1D and E). CLDN6 was primarily localized along the membranes of tumor cells, and the staining intensities and proportions varied among cases. We considered tumors showing both a staining proportion of ≥5% and an intensity of ≥2 (resulting in histoscore ≥10) as CLDN6-positive ones. Based on semi-quantification using the histoscore (Table II), 26 of 118 cases (22.0%) were positive for CLDN6 expression. In this group, 15 (12.7%), 5 (4.2%), and 6 (5.1%) patients had histoscores of 15-30, 60-90, and 120-210, respectively. CLDN6 reacted with more than half of the tumor cells in five cases (4.2%). Regarding staining intensity, 39 cases (33.1%) exhibited moderate to strong immunoreactivity for CLDN6. CLDN6 exhibited intratumoral heterogeneity in some cases, in which CLDN6-positive and CLDN6-negative subpopulations were observed in adjacent glands (Figure 1F). CLDN6 was localized within the invasive tumor front in a few cases, whereas in other cases, its expression was observed in areas of endometrial intraepithelial neoplasia. Cytoplasmic and nuclear CLDN immunoreactivity was observed in two (1.7%) and one (0.8%) cases, respectively, while in another case (0.8%), CLDN6 was localized on the luminal surface of the neoplastic glands.

Figure 1.
Figure 1.

Histological features and variable claudin-6 (CLDN6) immunoreactivities of low-grade, early-stage endometrioid endometrial carcinoma (EEC). (A) Grade 1 EEC showing crowding of well-formed neoplastic glands lined by pseudostratified, columnar epithelia, with minimal intervening stroma. (B) Focal CLDN6 expression (yellow arrows; histoscore 3). (C) Focal CLDN6 expression (histoscore 30). (D) Diffuse CLDN6 expression (histoscore 210). (E) A high-power magnification of image D, showing strongly and intensely expressed CLDN6 along the membrane. (F) Interglandular and intraglandular heterogeneity of CLDN6 expression, characterized by strong (green arrow) and weak (blue arrow) positivity, as well as a complete lack of immunoreactivity (purple arrows) in closely adjacent neoplastic glands. Staining method: A, hematoxylin and eosin staining; B-F, immunostaining using polymer method. Original magnification: A, 400×; B, 200×; C, 200×; D, 60×; E, 600×; F, 100×.

View this table:
Table II.

Claudin-6 immunoreactivity in 118 cases of low-grade, early-stage endometrioid endometrial carcinoma.

Clinicopathological significance of CLDN6 expression. To reveal the clinical relevance of CLDN6 expression in patients with LGES-EEC, we investigated whether there is a significant relationship between CLDN6 expression and clinicopathological parameters, including age at diagnosis, histological grade, myometrial invasion, cervical stromal extension, stage, LVSI, mucinous and squamous differentiation, and recurrence. As shown in Table III, positive CLDN6 expression was significantly associated with deeper myometrial invasion (p=0.001), higher stage (p=0.015), and substantial LVSI (p=0.018). Patients with CLDN6-low tumors tended to be less prone to recurrence, but the difference was not significant (p=0.070). In early-stage (stage I) tumors, a significant relationship between positive CLDN6 expression and deeper myometrial invasion was observed (p=0.012; Table IV).

View this table:
Table III.

Clinicopathological significance of claudin-6 (CLDN6) expression in 118 patients with low-grade, early-stage endometrioid endometrial carcinoma.

View this table:
Table IV.

Clinicopathological significance of claudin-6 (CLDN6) expression in 78 patients with low-grade, stage I endometrioid endometrial carcinoma.

Discussion

In this study, we demonstrated that aberrant CLDN6 expression in LGES-EEC tissues, in which the positive CLDN6 immunoreactivity on the cell membranes was observed in 22.0% (26/118) when a histoscore cutoff value of 10 was applied, was significantly associated with deeper myometrial invasion, higher initial stage, and substantial LVSI. Our results are consistent with those of Kojima et al. (30), who reported that high CLDN6 expression is related to stage III-IV, non-endometrioid type, grade 3, LVSI, lymph node metastasis, and distant metastasis. Although we did not examine the prognostic significance of CLDN6 expression, they found that CLDN6 expression is an independent prognostic factor for overall survival in patients with EC. Similarly, Cao et al. (31) analyzed RNA sequencing data obtained from The Cancer Genome Atlas database and reported that CLDN6 is over-expressed in EC tissues. They observed that increased CLDN6 expression levels correlate with non-endometrioid type, higher grade, higher stage, and worse overall survival in patients with EC. In addition, Zhang et al. (13) analyzed RNA sequencing data and relevant clinical data downloaded from the TCGA and Genotype-Tissue Expression databases and noted that CLDN6 expression is higher in patients older than 60 years, with stage III-IV disease, grade 3, and serous type, and that a high CLDN6 expression level is an independent risk factor for worse disease-specific survival and shorter progression-free interval in variable clinical subgroups of EC. Although previous studies have been conducted using both low- and high-grade ECs of various histological types and stages, we focused only on LGES-EECs and obtained concordant results. Collectively, these data underscore the significance of CLDN6 in EC progression.

It is unknown how high CLDN6 expression leads to tumor progression and poor prognosis in patients with EC. Previous studies have assessed the biological function of CLDN6 and the molecular mechanisms underlying altered CLDN6 expression in EC. Cao et al. (31) transfected small interfering RNA targeting CLDN6 into an EC cell line to establish CLDN6-knockdown EC cells and noted that the knockdown of CLDN6 significantly inhibited cellular proliferation and colony formation and restrained the invasive and migratory abilities of EC cells. They also found that the inhibition of CLDN6 remarkably decreased the expression levels of phosphorylated Akt, phosphorylated phosphatidylinositol 3-kinase (PI3K), and mammalian target of rapamycin (mTOR) in EC cells, indicating that the up-regulation of CLDN6 expression results in a malignant phenotype mediated through PI3K/Akt/mTOR signaling in EC. Sugimoto et al. (16) demonstrated that CLDN6 recruits and activates Src family kinases (SFKs), which, in turn, phosphorylate CLDN6 and propagate the PI3K/Akt pathway. They showed that the CLDN6/SFK/PI3K/Akt signaling axis targets retinoic acid receptor γ and estrogen receptor (ER)-α and stimulates their activities. In addition, Kojima et al. (32) revealed that CLDN6/SFK/PI3K-dependent Akt signaling stimulates the transcriptional activity of ER-α in EC cells, thereby promoting tumor progression. Taken together with the notion that ER acts as a master transcription factor in EC (33), aberrant CLDN6 signaling may promote the malignant behavior of EC cells by hijacking the CLDN6/ER pathway. Accumulating evidence has shown that increased CLDN6 expression contributes to the malignant progression of EC and that CLDN6 may be a promising therapeutic target for patients with EC. It would also be interesting to determine whether the link between cell adhesion and nuclear receptor signaling regulates tumor progression in EC.

Study limitations. First, our cohort was obtained from a single institution, which limits the reproducibility of the data. Second, owing to the limited number of deaths and recurrences, statistical analysis of survival differences was not feasible. Further studies using more extensive prognostic data from larger cohorts are warranted. Third, molecular analyses of the mechanisms underlying CLDN6 aberrations were beyond the scope of this study. Finally, we did not examine the clinical implications of intratumoral CLDN6 heterogeneity observed in a small number of our cases. Since spatial heterogeneity in biomarker expression may have prognostic significance and influence therapeutic response, further studies are required to clarify the role of intratumoral heterogeneity in CLDN6 expression in EC.

Conclusion

We demonstrated aberrant CLDN6 immunoreactivity in tumor cell membranes in LGES-EEC tissues. Positive CLDN6 expression is significantly associated with deeper myometrial invasion, a higher initial stage, and substantial LVSI in patients with LGES-EEC. In stage I tumors, a significant association was also observed between positive CLDN6 expression and deeper myometrial invasion. CLDN6 may be involved in tumor progression in EC; thus, CLDN6 may be a promising therapeutic target for patients with EC. Further studies are warranted to clarify the molecular mechanisms underlying the alteration of CLDN6 expression and its biological function in EC.

Acknowledgements

This study was supported by the Samsung Medical Center Grant (SMO1240641) and the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIT) (2023R1A2C2006223).

Footnotes

  • Authors’ Contributions

    All Authors made substantial contributions to the conception and design of this work, acquisition and interpretation of data, drafting and critical revision of the manuscript for important intellectual content, and approval of the final version to be published.

  • Conflicts of Interest

    All Authors have no conflicts of interest or financial ties to declare that are relevant to the content of this article.

  • Received September 26, 2024.
  • Revision received October 11, 2024.
  • Accepted October 14, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Clinicopathological Significance of Claudin-6 Immunoreactivity in Low-grade, Early-stage Endometrioid Endometrial Carcinoma
YURIMI LEE, HYUN-SOO KIM
In Vivo Jan 2025, 39 (1) 367-374; DOI: 10.21873/invivo.13837
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