Startseite Medizin Immunohistochemical profiling and neuroepithelial heterogeneity in immature ovarian teratomas: a retrospective digital pathology-based study
Artikel Open Access

Immunohistochemical profiling and neuroepithelial heterogeneity in immature ovarian teratomas: a retrospective digital pathology-based study

  • Nino Tavdgiridze ORCID logo , Tamar Svanadze , George Tevdorashvili , Shota Kepuladze ORCID logo EMAIL logo und George Burkadze ORCID logo
Veröffentlicht/Copyright: 17. Dezember 2025

Abstract

Objectives

Immature ovarian teratomas are rare malignant germ cell tumours with variable neuroepithelial differentiation and limited prognostic markers. Their grading is subjective and challenging, with heterogeneous clinical behaviour and limited therapeutic targets. To evaluate the immunohistochemical expression of key markers related to proliferation, stemness, apoptosis, neuroepithelial differentiation, and immune modulation in immature ovarian teratomas and to correlate these markers with tumor grade, neuroepithelial heterogeneity, and metastatic potential.

Methods

This retrospective study analysed 26 cases of immature ovarian teratomas diagnosed between 2017 and 2025. Immunohistochemistry was performed for Ki67, BCL2, CD44, SOX2, GFAP, PGP9.5, FOXP3, ER, PR, OCT3/4, and CD117 using Leica Bond-III. Digital pathology using MOTIC EasyScan Pro enabled quantitative assessment. Statistical analyses correlated marker expression with tumour grade, metastasis, and survival.

Results

Higher tumour grades correlated with increased Ki67, CD44, FOXP3, and BCL2 expression. SOX2 and PGP9.5 were upregulated in undifferentiated neuroepithelial components, while GFAP marked more differentiated regions. Metastatic lesions showed elevated Ki67, CD44, FOXP3, and SOX2, with a loss of GFAP. Survival analysis revealed significantly poorer progression-free survival in Grade 3 tumours and those with high proliferative and immune-evasive phenotypes.

Conclusions

Immature ovarian teratomas exhibit significant immunophenotypic and neuroepithelial heterogeneity, impacting progression and prognosis. Ki67, CD44, and FOXP3 are independent prognostic markers. The findings support integrating molecular profiling and immune markers into routine evaluation to guide risk stratification and potential targeted therapy.

Introduction

Ovarian teratomas are germ cell tumours from totipotent cells exhibiting differentiation into various somatic tissue types. These tumours are classified into mature teratomas, which are benign and composed of well-differentiated tissues, and immature teratomas, which contain embryonic or fetal-like tissue with malignant potential [1]. Mature teratomas, commonly called dermoid cysts, are characterised by fully differentiated tissues such as skin, hair, sebaceous glands, and occasionally neural or thyroid tissue. They are almost always benign. In contrast, immature teratomas contain varying proportions of immature neuroepithelial, mesenchymal, and endodermal elements, with immature neural tissue as a key determinant of malignancy risk and grading [2].

Immature teratomas account for approximately one per cent of all ovarian teratomas and represent 20 to 30 % of malignant ovarian germ cell tumours [3]. They predominantly occur in adolescent girls and young women, with a median age of 19–25 [4]. Due to their rarity, clinical data and standardised treatment approaches remain limited. These tumours can present with multiple complications, including local invasion and recurrence, peritoneal spread due to rupture, malignant transformation into secondary somatic-type malignancies such as neuroectodermal tumours, sarcomas, or carcinomas, and distant metastases, most commonly involving the lungs, liver, and central nervous system [5].

The histopathological diagnosis of immature teratomas poses significant challenges due to the heterogeneity of neuroepithelial elements and the subjective grading criteria. These tumours are graded based on the proportion of immature neuroepithelial tissue, with Grade 1 tumours exhibiting focal immaturity, Grade 2 showing moderate immaturity, and Grade 3 demonstrating extensive neuroepithelial differentiation [2]. However, interobserver variability among pathologists remains a significant issue. Furthermore, distinguishing immature teratomas from mature teratomas with secondary malignancy and other small round blue cell tumours such as yolk sac tumours, primitive neuroectodermal tumours, and metastatic neuroblastomas can be difficult.

Histopathologically, the diagnosis of immature teratomas relies on identifying immature neuroepithelial tubules, rosettes, and primitive neural tissue on hematoxylin and eosin (H&E) staining [6]. The degree of mitotic activity and necrosis further influences the grading. Immunohistochemical analysis plays a crucial role in further characterising these tumours. Proliferation markers such as Ki67 help assess cellular proliferation rates, while BCL2 is an anti-apoptotic marker. Neuroepithelial differentiation can be further evaluated using markers such as SOX2, Nestin, and GFAP, indicating the presence of neural stem-like components. Stemness and adhesion markers, including CD44, provide insights into tumour aggressiveness, invasive potential, and metastatic risk. Hormonal receptor expression, particularly estrogen receptor (ER) and progesterone receptor (PR), has been explored for potential correlations with tumour differentiation and progression [7]. CD117, a marker associated with germ cell differentiation, may help distinguish teratomas from other tumours. Additionally, PGP9.5, a neuronal differentiation marker, may help define neural lineage differentiation within immature teratomas.

Despite advancements in molecular pathology, several aspects of immature teratomas remain poorly understood. The factors that predict metastasis are not established, as not all high-grade tumours exhibit metastatic behaviour. The role of neuroepithelial heterogeneity in tumour progression remains inadequately explored, and the prognostic significance of various immunohistochemical markers requires further validation. In addition, standardised panels for grading and prognosis are lacking and targeted therapeutic approaches remain limited, with management relying primarily on surgical resection and chemotherapy.

Immature teratomas metastasise via hematogenous and lymphatic routes, with the lungs being the most common site of distant metastasis. Other sites of spread include the liver, peritoneum, brain, and retroperitoneal lymph nodes [5]. The treatment of immature teratomas typically involves complete surgical resection, followed by chemotherapy for Grade 2 and Grade 3 tumours and metastatic cases. The standard chemotherapy regimen includes a combination of bleomycin, etoposide, and cisplatin (BEP) [8]. The prognosis of these tumours depends on the grade, with Grade 1 tumours having an excellent prognosis following surgical excision. In contrast, higher-grade tumours carry a higher risk of recurrence and require adjuvant chemotherapy. Metastatic disease has a variable prognosis depending on the response to chemotherapy [2].

Recent research on immature teratomas has focused on molecular profiling to identify genetic mutations and pathways involved in tumour progression and immunohistochemical studies evaluating markers correlating with proliferation, apoptosis, and metastasis [9]. The tumour microenvironment, particularly the immune response in aggressive cases, has been a growing area of interest. FOXP3, a marker of regulatory T cells, may provide insight into immune evasion mechanisms in high-grade and metastatic immature teratomas. Additionally, CD44 and BCL2 expression in primary vs. metastatic lesions may help elucidate mechanisms underlying tumour progression and survival advantages in metastatic settings.

Further studies are needed to refine classification criteria, identify prognostic markers, and explore therapeutic approaches for patients with immature ovarian teratomas.

This study aims to analyse the immunohistochemical profile of Ki67, BCL2, CD44, SOX2, ER, PR, CD117, PGP9.5, FOXP3, and GFAP in a cohort of immature ovarian teratomas, correlating marker expression with tumour grade and metastatic potential. By integrating immunohistochemical expression patterns with clinicopathological data, this study seeks to improve the understanding of immature ovarian teratomas and provide potential prognostic markers for clinical practice.

Materials and methods

This retrospective study was conducted on ovarian immature teratoma cases diagnosed between 2017 and 2025 at the Scientific, Diagnostic, and Research Laboratory of Tbilisi State Medical University (TSMU). It includes archived cases with available formalin-fixed paraffin-embedded (FFPE) tissue blocks and corresponding clinical and histopathological data. The Ethics Committee of TSMU granted Ethical Approval, allowing the use of anonymised patient data. Only non-personalized clinical variables such as age, clinical diagnosis, surgical procedures, histopathological diagnosis, and IHC results were analysed.

Case Selection and Inclusion Criteria: A total of 26 cases of histologically confirmed ovarian immature teratomas were included. The selection criteria were as follows: 1. Histological confirmation of immature ovarian teratomas, graded according to the World Health Organization (WHO) classification (Grade 1, Grade 2, and Grade 3).2. Availability of FFPE blocks suitable for immunohistochemical analysis; 3. Documented clinical and histopathological parameters; 3. At least one year of follow-up data for recurrence or metastatic progression.

Clinical and Histopathological Data Collection: Retrospective data extraction was performed from pathology archives and electronic medical records. The following parameters were recorded for each case: Patient demographics, age, Clinical characteristics, Initial diagnosis, presenting symptoms, and surgical intervention type (oophorectomy, cystectomy, or tumour resection).

Histopathological parameters: Tumor grade (WHO classification: Grade 1, Grade 2, Grade 3); Presence and extent of immature neuroepithelial differentiation; Mitotic index (mitoses per 10 high-power fields (HPF)); Tumor size; Necrosis assessment (focal vs. extensive); Tumor-infiltrating lymphocytes (TILs); Follow-up data: Tumor recurrence, metastasis (if any), and survival status.

Immunohistochemistry (IHC) was performed on 4-μm thick sections of FFPE blocks using an automated Leica Bond-III immunostainer (Leica Biosystems, Germany). Table 1 lists the primary antibodies, their respective clones, and their sources.

Table 1:

The primary antibodies, their respective clones, and their sources.

Marker Clone Dilution Localization Supplier
Ki67 (proliferation marker) MIB-1 1:100 Nuclear Leica biosystems
BCL2 (anti-apoptotic marker) 124 1:150 Cytoplasmic Leica biosystems
CD44 (stemness marker) DF1485 1:100 Membranous Leica biosystems
SOX2 (neuroepithelial marker) SP76 1:200 Nuclear Leica biosystems
GFAP (glial marker) GA5 1:250 Cytoplasmic Leica biosystems
OCT3/4 (pluripotency marker) C-10 1:100 Nuclear Leica biosystems
CD117 (germ cell marker) YR145 1:100 Membranous Leica biosystems
PGP9.5 (neuronal differentiation marker) 13C4 1:150 Cytoplasmic Leica biosystems
FOXP3 (regulatory T-cell marker) 236 A/E7 1:100 Nuclear Leica biosystems
ER (estrogen receptor) 6F11 1:100 Nuclear Leica biosystems
PR (progesterone receptor) 16 1:100 Nuclear Leica biosystems

The Bond Polymer Refine Detection System (Leica Biosystems) was used for signal amplification. Depending on the marker, the placental, neural, or lymphoid tissues served as positive controls.

The immunohistochemical expression of each marker was assessed semi-quantitatively based on the percentage of positively stained tumour cells and staining intensity. The following scoring system was applied:

Score Staining intensity Percentage of positive tumor cells
0 (negative) No staining 0 %
1+ (weak) Faint staining <10 %
2+ (moderate) Moderate staining 10–50 %
3+ (strong) Strong staining >50 %

All stained slides were digitised using the MOTIC EasyScan Pro Digital Slide Scanner (Motic, Hong Kong) at 40 × magnification. Quantitative IHC analysis was performed using MOTIC DSAssistant software, which enabled automated scoring and tumour region selection to minimise observer bias.

Figure 1: 
(See Figure 1) Use of MOTIC digital pathology analysis for standardised immunohistochemical quantification, reducing observer bias and improving reproducibility in marker evaluation.
Figure 1:

(See Figure 1) Use of MOTIC digital pathology analysis for standardised immunohistochemical quantification, reducing observer bias and improving reproducibility in marker evaluation.

Figure 2: 
(See Figure 2) Immunohistochemical expression analysis and tumor heterogeneity: The expression of key immunohistochemical markers was analysed across tumor grades, highlighting the heterogeneous nature of immature teratomas, particularly within the neuroepithelial component.
Figure 2:

(See Figure 2) Immunohistochemical expression analysis and tumor heterogeneity: The expression of key immunohistochemical markers was analysed across tumor grades, highlighting the heterogeneous nature of immature teratomas, particularly within the neuroepithelial component.

Statistical analysis was conducted using SPSS (Version30.). The following statistical tests were applied: Descriptive statistics: Mean, median, and standard deviation for age, tumour size, and mitotic index; Comparison of marker expression across tumour grades [1], [2], [3]: Kruskal-Wallis test (for non-parametric distribution), One-way ANOVA (if the normal distribution was confirmed); Comparison between primary and metastatic tumours: Wilcoxon signed-rank test (for paired marker expression comparison); Correlation analysis: Spearman’s correlation coefficient to assess relationships between marker expression and tumour grade, mitotic index, and metastatic potential; Survival analysis: Kaplan-Meier curves for progression-free and overall survival; Log-rank test to compare survival between different tumour grades.

This retrospective study provides an extensive immunohistochemical analysis of immature ovarian teratomas, focusing on proliferation, apoptosis, neuroepithelial differentiation, and immune evasion markers. By integrating IHC expression patterns with tumour grade and metastatic behaviour, this study aims to define potential prognostic markers and improve the classification of immature ovarian teratomas, with implications for future diagnostic and therapeutic strategies.

Results

Clinicopathological Characteristics: The study included 26 cases of ovarian immature teratomas. The distribution of tumour grades was as follows: Grade 1 (n=12, 46.2 %), Grade 2 (n=8, 30.8 %), and Grade 3 (n=6, 23.0 %).

The mean age at diagnosis was 20.2 years (median 20 years, range 10–30 years). The mean age per tumour grade was 18.5 years for Grade 1, 21.0 years for Grade 2, and 22.8 years for Grade 3, with a trend toward older age in higher-grade tumours. The majority of cases were diagnosed in adolescent and young adult females.

Histological specimens were obtained from oophorectomy (69.2 %) and cystectomy (30.8 %). The mean tumour size was 8.2 cm (median 7 cm, range 3–18 cm), with Grade 1 tumours averaging 6.5 cm, Grade 2 tumours 8.1 cm, and Grade 3 tumours 10.2 cm. Grade 3 tumours were significantly larger than Grade 1 and Grade 2 (p<0.05). The mitotic index increased with tumour grade, with a mean of 2.5 mitoses/10 HPF in Grade 1, 5.8 mitoses/10 HPF in Grade 2, and 12.1 mitoses/10 HPF in Grade 3 (p<0.001).

Neuroepithelial differentiation was present in all Grade 2 and Grade 3 tumours, whereas Grade 1 tumours exhibited only focal neuroepithelial elements. Tumour necrosis was identified in 25.0 % of Grade 2 and 66.7 % of Grade 3, with a significant association between necrosis and higher-grade tumours (p<0.05). Tumour-infiltrating lymphocytes (TILs) were observed in 38.5 % of all cases, with TIL density increasing with tumour grade (p<0.05).

Table 2:

(see Table 2) Summary of key clinical and histopathological parameters across tumor grades, including age, size, mitotic index, neuroepithelial differentiation, and necrosis.

Tumor Grade Number of cases (n) Percentage (%) Mean age (years) Mean tumor size (cm) Mitotic index (mitoses/10 HPF) Neuroepithelial differentiation Tumor necrosis (%)
Grade 1 12 46.2 18.5 6.5 2.5 Focal 0 %
Grade 2 8 30.8 21.0 8.1 5.8 Present 25.0 %
Grade 3 6 23.0 22.8 10.2 12.1 Present 66.7 %

Immunohistochemical Expression Analysis and Tumor Heterogeneity: The expression of key immunohistochemical markers was analysed across tumor grades, highlighting the heterogeneous nature of immature teratomas, particularly within neuroepithelial components. The Ki67 proliferation index was significantly higher in Grade 3 tumours compared to Grade 1 (p<0.001), with median expression values of 12 % in Grade 1, 35 % in Grade 2, and 65 % in Grade 3.

BCL2, an anti-apoptotic marker, exhibited weak to moderate expression in Grade 1 tumours, whereas Grade 2 and Grade 3 tumours demonstrated significantly higher BCL2 positivity (p<0.05), indicating a possible role in tumour progression.

The stemness marker CD44 was weakly expressed in Grade 1 tumours but showed moderate to strong positivity in Grade 2 and Grade 3 tumours (p<0.01). A similar pattern was observed for SOX2, with high expression levels correlating with increasing tumour grade (p<0.01). Notably, neuroepithelial differentiation was not uniform within tumours, with SOX2, GFAP, and PGP9.5 showing focal expression within neuroepithelial structures, particularly in Grade 2 and 3 tumours.

Neuronal differentiation markers (GFAP and PGP9.5) showed heterogeneous expression across neuroepithelial regions. GFAP positivity was predominantly seen in well-differentiated glial-like components, while PGP9.5 expression was strongest in primitive neuroepithelial areas, particularly in Grade 3 tumours. OCT3/4 and CD117 expression was weakly positive in isolated areas of high-grade tumours, suggesting a possible role in maintaining an undifferentiated neuroepithelial phenotype, though statistical significance was not reached.

Spearman’s correlation analysis revealed a significant positive correlation between Ki67 and CD44 expression (r=0.72, p<0.01), suggesting that tumours with higher proliferative activity exhibit a more stem-like phenotype. Similarly, BCL2 expression correlated with FOXP3 levels (r=0.65, p<0.05), indicating a possible link between apoptosis resistance and immune modulation. Heterogeneity in neuroepithelial differentiation was further supported by the weak correlation between GFAP and SOX2 expression (r=0.48, p=0.07), reflecting the variability in glial vs. neural lineage differentiation within tumours (Figure 3).

Figure 3: 
Immunohistochemical marker expression in a non-metastatic immature ovarian teratoma (400 × magnification). (400 × magnification). (A) SOX2: Strong nuclear staining in neuroepithelial components; (B) OCT3/4: No detectable expression in tumour cells; (C) Ki67: Focal nuclear positivity indicating variable proliferative activity; (D) CD44: Combined cytoplasmic and membranous expression in scattered tumor cells, reflecting stem-like characteristics.
Figure 3:

Immunohistochemical marker expression in a non-metastatic immature ovarian teratoma (400 × magnification). (400 × magnification). (A) SOX2: Strong nuclear staining in neuroepithelial components; (B) OCT3/4: No detectable expression in tumour cells; (C) Ki67: Focal nuclear positivity indicating variable proliferative activity; (D) CD44: Combined cytoplasmic and membranous expression in scattered tumor cells, reflecting stem-like characteristics.

Figure 4: 
(See Figure 4) Heatmap showing Spearman correlation coefficients among key markers. A strong correlation was observed between Ki67 and CD44 (r=0.72, p<0.01), and BCL2 and FOXP3 (r=0.65, p<0.05).
Figure 4:

(See Figure 4) Heatmap showing Spearman correlation coefficients among key markers. A strong correlation was observed between Ki67 and CD44 (r=0.72, p<0.01), and BCL2 and FOXP3 (r=0.65, p<0.05).

Figure 5: 
(See Figure 5) Immunohistochemical expression of SOX2 and FOXP3 in metastatic immature ovarian teratoma (400 × magnification). A. SOX2: Strong nuclear positivity in metastatic neuroepithelial tumor cells; B. FOXP3: Prominent nuclear expression in tumour-infiltrating lymphocytes and scattered tumor cells.
Figure 5:

(See Figure 5) Immunohistochemical expression of SOX2 and FOXP3 in metastatic immature ovarian teratoma (400 × magnification). A. SOX2: Strong nuclear positivity in metastatic neuroepithelial tumor cells; B. FOXP3: Prominent nuclear expression in tumour-infiltrating lymphocytes and scattered tumor cells.

Comparison Between Primary Tumors and Metastatic Cases: No lung metastasis cases were observed Among the study cohort. However, two cases developed peritoneal metastases, classified as Grade 3 immature teratomas. Ki67, CD44, and FOXP3 expression were significantly higher in metastatic lesions compared to their primary counterparts (p<0.01), suggesting a role for these markers in metastatic potential. Interestingly, SOX2 and GFAP expression patterns were altered in metastatic lesions, with a loss of GFAP expression and an increase in SOX2 positivity, suggesting a shift toward an undifferentiated neuroepithelial phenotype in metastases.

Kaplan-Meier survival analysis demonstrated that Grade 3 tumours had significantly poorer progression-free survival (PFS) compared to Grade 1 and Grade 2 tumours (log-rank test, p<0.001). Increased Ki67 and CD44 expression were associated with shorter PFS (p<0.05), whereas FOXP3 expression predicted an immunosuppressive tumour microenvironment. Additionally, patients with tumours exhibiting high neuroepithelial heterogeneity (variability in SOX2 and GFAP expression) tended toward poorer survival outcomes, although statistical significance was not reached.

These findings highlight the prognostic significance of proliferative, stemness, and immune-related markers in immature ovarian teratomas, particularly emphasising tumor heterogeneity within neuroepithelial differentiation. This study provides potential avenues for future targeted therapeutic strategies to address these tumours’ aggressive and heterogeneous nature.

Discussion

This study provides a detailed clinicopathological and immunohistochemical characterisation of 26 cases of immature ovarian teratomas, highlighting key differences in tumour grade, proliferation, neuroepithelial differentiation, apoptosis regulation, immune infiltration, and metastatic potential. Our findings emphasise the heterogeneous nature of immature teratomas, particularly in neuroepithelial marker expression, and offer potential insights into prognostic biomarkers for risk stratification and treatment approaches.

This study presents several novel findings contributing to understanding immature ovarian teratomas: 1. First systematic evaluation of neuroepithelial differentiation heterogeneity using SOX2, GFAP, and PGP9.5 across different tumor grades. This reveals a potential link between differentiation patterns and tumour behaviour, particularly in metastatic progression; 2. identification of FOXP3 as a possible immune evasion marker in aggressive immature teratomas. While FOXP3 has been studied in epithelial ovarian cancers, its role in immature teratomas has not been systematically explored before; 3. Correlation of Ki67, CD44, and FOXP3 with tumour grade and progression. This supports the hypothesis that high-proliferation tumours exhibit stem-like and immunosuppressive characteristics, which may have therapeutic implications [10]; 4. First, a detailed comparison of immunohistochemical expression between primary tumours and metastatic lesions was made, highlighting a shift toward undifferentiated neuroepithelial phenotypes in metastases and suggesting a possible mechanism for tumour progression; 5. Use of MOTIC digital pathology analysis for standardised immunohistochemical quantification, reducing observer bias and improving reproducibility in marker evaluation.

Histologically, neuroepithelial differentiation remains the defining feature of immature teratomas, but our data underscore the heterogeneity of these components across different grades. SOX2, GFAP, and PGP9.5 expression patterns varied significantly, with SOX2 being more prominent in undifferentiated neuroepithelial areas, while GFAP was restricted to more differentiated glial-like components. This suggests that the maturation spectrum within immature teratomas may have prognostic relevance, an area warranting further investigation.

The Ki67 proliferation index was significantly higher in Grade 3 tumours, supporting its role as a marker of tumour progression. In addition, CD44, a stemness and adhesion molecule, correlated with Ki67 expression, suggesting that high-proliferation tumours exhibit a more stem-like, invasive phenotype. This aligns with prior studies in other germ cell tumours, where CD44 is implicated in tumour aggressiveness and metastatic potential.

Interestingly, BCL2, an anti-apoptotic marker, was significantly upregulated in higher-grade tumours, particularly in cases with peritoneal metastases. This finding suggests that apoptotic resistance may contribute to tumour persistence and progression, making BCL2 a potential therapeutic target in high-risk cases.

One of the most striking findings in this study is the heterogeneous expression of neuroepithelial markers (SOX2, GFAP, and PGP9.5) across different tumor grades. While SOX2 was consistently expressed in immature neuroepithelial elements, GFAP expression was restricted to more differentiated glial-like structures. This suggests that tumours with a higher degree of differentiation may have a less aggressive clinical course, a hypothesis that requires further validation in larger cohorts.

In metastatic cases, we observed a shift toward undifferentiated neuroepithelial phenotypes, with increased SOX2 expression and loss of GFAP positivity. This suggests that tumour dedifferentiation may play a role in metastatic progression, potentially influencing therapeutic strategies. In most cases, the absence of OCT3/4 and CD117 expression differentiates these tumours from dysgerminomas and other germ-cell tumours, reinforcing the distinct nature of immature teratomas.

Our study also highlights the potential role of immune regulation in immature ovarian teratomas, as evidenced by FOXP3 expression, which was significantly higher in Grade 3 tumours and metastatic cases. FOXP3-positive regulatory T cells (Tregs) have been implicated in tumour immune evasion, facilitating an immunosuppressive microenvironment. This raises the possibility that FOXP3 could serve as an immune-modulating target in advanced or recurrent cases.

The findings of this study reinforce the importance of tumor grading, proliferation, and neuroepithelial heterogeneity in predicting prognosis. Kaplan-Meier survival analysis demonstrated significantly poorer progression-free survival (PFS) in Grade 3 tumours, with Ki67 and CD44 emerging as independent prognostic markers. While surgical resection remains the primary treatment, additional molecular profiling may help refine risk stratification.

The observation that FOXP3 expression correlates with CD44 and BCL2 suggests a complex interaction between tumour proliferation, immune evasion, and apoptosis resistance. Future studies should explore whether immune-modulating or BCL2-inhibiting therapies could improve outcomes in aggressive immature teratomas.

Although the primary focus of this study was on immunohistochemical heterogeneity, it is important to acknowledge the broader clinical implications of immature ovarian teratomas, particularly in adolescent and reproductive-age patients. These tumours often require oophorectomy or salpingo-oophorectomy, procedures which may compromise future fertility. As in other malignancies such as breast or endometrial cancer, fertility-sparing strategies – including oocyte vitrification before treatment – are increasingly relevant and should be considered prior to surgery. Additionally, thyroid dysfunction has been implicated as a contributing factor to reproductive failure and should be actively managed in this patient population. Assisted reproductive technologies (ART), including IVF and frozen embryo transfer, are frequently required for achieving pregnancy post-treatment. Recent literature also stresses the importance of long-term neonatal and neurodevelopmental follow-up in children born through ART after fertility-preserving treatment for malignancies. Integration of oncofertility counselling and endocrine evaluation in the multidisciplinary care of patients with immature ovarian teratomas is therefore essential for optimising both oncologic and reproductive outcomes [11], 12].

Finally, it is important to acknowledge that in rare cases, ovarian immature teratomas may be initially misdiagnosed or overlap clinically with metastatic endometrial carcinomas, particularly in advanced presentations. Awareness of these diagnostic pitfalls is vital to ensure appropriate treatment planning and prognosis (17).

Furthermore, for patients who conceive after fertility-sparing treatment, non-invasive prenatal testing (NIPT) is increasingly recommended at the beginning of pregnancy to ensure early detection of chromosomal abnormalities. Follow-up of pregnancies achieved via assisted reproductive technologies (ART) such as frozen embryo transfer is essential. Recent studies demonstrate that neonatal and long-term developmental outcomes in children born from cryopreserved embryos in cancer survivors are reassuring, though ongoing surveillance remains crucial (15,16).

An important clinical aspect of immature ovarian teratomas, particularly in adolescent and reproductive-age patients, is the impact on fertility. Fertility-sparing surgery combined with oocyte or embryo cryopreservation has become an essential part of multidisciplinary care. Vitrification before treatment allows preservation of future reproductive potential, especially in patients requiring adjuvant chemotherapy. Oncofertility counselling should therefore be integrated into routine management of these patients (13,14).

Limitations and Future Directions: While this study provides detailed immunohistochemical profiling of immature teratomas, certain restrictions should be acknowledged. First, the sample size is limited (n=26), restricting statistical power. Second, while the MOTIC digital analysis system minimises observer bias, inter-institutional validation is necessary to standardise immunohistochemical scoring in immature teratomas. Third, follow-up beyond one year would be beneficial to assess long-term recurrence and survival outcomes. Another limitation is the absence of a mature ovarian teratoma comparison group. While this study focuses exclusively on immature teratomas, comparative evaluation with mature teratomas would enhance understanding of immunophenotypic distinctions between benign and malignant germ cell tumours. In particular, assessing the expression of markers such as ER, PR, CD117, and PGP9.5 in mature teratomas could clarify their diagnostic and biological significance. Future studies incorporating mature teratomas as controls may improve differential diagnostic accuracy and deepen insights into tumour development pathways.

Future research should focus on molecular profiling of immature teratomas, particularly the role of stem cell and apoptosis pathways, to identify targetable vulnerabilities. Additionally, the role of immune checkpoints in the pathogenesis of these tumours warrants further investigation.

Conclusions

This study characterises immature ovarian teratomas, focusing on tumor heterogeneity, proliferation, immune regulation, and neuroepithelial differentiation. Evaluating Ki67, CD44, FOXP3, BCL2, SOX2, GFAP, and PGP9.5 across tumour grades reveals novel prognostic markers and insights into their biological behaviour.

Higher-grade immature teratomas show increased proliferation (Ki67), stemness (CD44), immune evasion (FOXP3), and apoptotic resistance (BCL2), correlating with aggressive behaviour. The expression patterns of neuroepithelial markers, with SOX2 prevalent in undifferentiated regions and GFAP in differentiated glial components, indicate that intratumoral variability affects tumor progression and metastasis. The dedifferentiation in metastatic lesions, marked by loss of GFAP and rise of SOX2, supports tumour plasticity’s role in disease spread.

Clinically, Ki67, CD44, and FOXP3 emerge as independent prognostic markers, with CD44 and FOXP3 linked to aggressiveness and immune evasion. BCL2’s role in apoptotic resistance suggests targeting apoptosis may benefit aggressive tumours.

Using MOTIC digital pathology enhanced standardised, quantitative assessment, minimising bias and improving reproducibility, setting a benchmark for integrating digital tools in histopathological evaluation of immature teratomas.

Future research should delve deeper into the molecular basis of tumour heterogeneity, immune checkpoints, and targeting stemness pathways. More extensive, multicenter studies with longer follow-ups are essential to validate Ki67, CD44, and FOXP3’s prognostic value. Additionally, exploring therapies targeting BCL2 or immune modulation may provide new treatment options for high-risk patients.

This research represents the most detailed immunohistochemical profiling of immature ovarian teratomas, introducing new insights into grading, immune regulation, and metastatic behaviour. It emphasises the integration of molecular profiling for precise risk assessment and personalised therapy in aggressive cases.


Corresponding author: Shota Kepuladze, Tbilisi State Medical University, Tbilisi, Georgia, E-mail:

  1. Funding information: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The study was not funded by Tbilisi State Medical University (TSMU).

  2. Author contribution: N. Tavdgiridze and T. Svanadze contributed to the study design and the interpretation of pathological data. G. Tevdorashvili and G. Burkadze were responsible for coordinating clinical data and conducting histological reviews. Sh. Kepuladze conducted the digital analysis, statistical evaluation, and manuscript preparation. All authors contributed to the manuscript revision and approved the final version for submission.

  3. Conflict of interest: The authors declare no conflict of interest.

  4. Data Availability Statement: The data that support the findings of this study are not publicly available due to ethical restrictions but are derived from anonymised formalin-fixed paraffin-embedded (FFPE) tissue blocks and clinical records held by the institution. Data may be available from the corresponding author upon reasonable request and with appropriate ethical approval.

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Received: 2025-04-11
Accepted: 2025-10-17
Published Online: 2025-12-17

© 2025 the author(s), published by De Gruyter, Berlin/Boston

This work is licensed under the Creative Commons Attribution 4.0 International License.

Artikel in diesem Heft

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  124. Glutathione attenuates sepsis-associated encephalopathy via dual modulation of NF-κB and PKA/CREB pathways
  125. FAHD1 prevents neuronal ferroptosis by modulating R-loop and the cGAS–STING pathway
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  127. Investigation of the pathogenic variants induced Sjogren’s syndrome in Turkish population
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  129. TGF-β–Smad2/3 signaling in high-altitude pulmonary hypertension in rats: Role and mechanisms via macrophage M2 polarization
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  135. Prognostic relevance of PRSS2 and its immune correlates in papillary thyroid carcinoma
  136. Association of SGLT2 inhibition with psychiatric disorders: A Mendelian randomization study
  137. Motivational interviewing for alcohol use reduction in Thai patients
  138. Luteolin alleviates oxygen-glucose deprivation/reoxygenation-induced neuron injury by regulating NLRP3/IL-1β signaling
  139. Polyphyllin II inhibits thyroid cancer cell growth by simultaneously inhibiting glycolysis and oxidative phosphorylation
  140. Relationship between the expression of copper death promoting factor SLC31A1 in papillary thyroid carcinoma and clinicopathological indicators and prognosis
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  146. Identification and external validation of a prognostic signature based on hypoxia–glycolysis-related genes for kidney renal clear cell carcinoma
  147. Engineered RBC-derived nanovesicles functionalized with tumor-targeting ligands: A comparative study on breast cancer targeting efficiency and biocompatibility
  148. Relationship of resting echocardiography combined with serum micronutrients to the severity of low-gradient severe aortic stenosis
  149. Effect of vibration on pain during subcutaneous heparin injection: A randomized, single-blind, placebo-controlled trial
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  152. Serum uric acid to albumin ratio and C-reactive protein as predictive biomarkers for chronic total occlusion and coronary collateral circulation quality
  153. Multiple organ scoring systems for predicting in-hospital mortality of sepsis patients in the intensive care unit
  154. Single-cell RNA sequencing data analysis of the inner ear in gentamicin-treated mice via intraperitoneal injection
  155. Suppression of cathepsin B attenuates myocardial injury via limiting cardiomyocyte apoptosis
  156. Influence of sevoflurane combined with propofol anesthesia on the anesthesia effect and adverse reactions in children with acute appendicitis
  157. Identification of hub genes related to acute kidney injury caused by sevoflurane anesthesia and endoplasmic reticulum stress
  158. Efficacy and safety of PD-1/PD-L1 inhibitors in pancreatic ductal adenocarcinoma: a systematic review and Meta-analysis of randomized controlled trials
  159. The value of diagnostic experience in O-RADS MRI score for ovarian-adnexal lesions
  160. Health education pathway for individuals with temporary enterostomies using patient journey mapping
  161. Serum TLR8 as a potential diagnostic biomarker of coronary heart disease
  162. Intraoperative temperature management and its effect on surgical outcomes in elderly patients undergoing lichtenstein unilateral inguinal hernia repair
  163. Immunohistochemical profiling and neuroepithelial heterogeneity in immature ovarian teratomas: a retrospective digital pathology-based study
  164. Associated risk factors and prevalence of human papillomavirus infection among females visiting tertiary care hospital: a cross-sectional study from Nepal
  165. Comparative evaluation of various disc elution methods for the detection of colistin-resistant gram-negative bacteria
  166. Effect of timing of cholecystectomy on weight loss after sleeve gastrectomy in morbidly obese individuals with cholelithiasis: a retrospective cohort study
  167. Causal association between ceramide levels and central precocious puberty: a mendelian randomization study
  168. Novel predictive model for colorectal liver metastases recurrence: a radiomics and clinical data approach
  169. Relationship between resident physicians’ perceived professional value and exposure to violence
  170. Multiple sclerosis and type 1 diabetes: a Mendelian randomization study of European ancestry
  171. Rapid pathogen identification in peritoneal dialysis effluent by MALDI-TOF MS following blood culture enrichment
  172. Comparison of open and percutaneous A1 pulley release in pediatric trigger thumb: a retrospective cohort study
  173. Impact of combined diaphragm-lung ultrasound assessment on postoperative respiratory function in patients under general anesthesia recovery
  174. Development and internal validation of a nomogram for predicting short-term prognosis in ICU patients with acute pyelonephritis
  175. The association between hypoxic burden and blood pressure in patients with obstructive sleep apnea
  176. Promotion of asthenozoospermia by C9orf72 through suppression of spermatogonia activity via fructose metabolism and mitophagy
  177. Review Articles
  178. The effects of enhanced external counter-pulsation on post-acute sequelae of COVID-19: A narrative review
  179. Diabetes-related cognitive impairment: Mechanisms, symptoms, and treatments
  180. Microscopic changes and gross morphology of placenta in women affected by gestational diabetes mellitus in dietary treatment: A systematic review
  181. Review of mechanisms and frontier applications in IL-17A-induced hypertension
  182. Research progress on the correlation between islet amyloid peptides and type 2 diabetes mellitus
  183. The safety and efficacy of BCG combined with mitomycin C compared with BCG monotherapy in patients with non-muscle-invasive bladder cancer: A systematic review and meta-analysis
  184. The application of augmented reality in robotic general surgery: A mini-review
  185. The effect of Greek mountain tea extract and wheat germ extract on peripheral blood flow and eicosanoid metabolism in mammals
  186. Neurogasobiology of migraine: Carbon monoxide, hydrogen sulfide, and nitric oxide as emerging pathophysiological trinacrium relevant to nociception regulation
  187. Plant polyphenols, terpenes, and terpenoids in oral health
  188. Laboratory medicine between technological innovation, rights safeguarding, and patient safety: A bioethical perspective
  189. End-of-life in cancer patients: Medicolegal implications and ethical challenges in Europe
  190. The maternal factors during pregnancy for intrauterine growth retardation: An umbrella review
  191. Intra-abdominal hypertension/abdominal compartment syndrome of pediatric patients in critical care settings
  192. PI3K/Akt pathway and neuroinflammation in sepsis-associated encephalopathy
  193. Screening of Group B Streptococcus in pregnancy: A systematic review for the laboratory detection
  194. Giant borderline ovarian tumours – review of the literature
  195. Leveraging artificial intelligence for collaborative care planning: Innovations and impacts in shared decision-making – A systematic review
  196. Cholera epidemiology analysis through the experience of the 1973 Naples epidemic
  197. Risk factors of frailty/sarcopenia in community older adults: Meta-analysis
  198. Supplement strategies for infertility in overweight women: Evidence and legal insights
  199. Scurvy, a not obsolete disorder: Clinical report in eight young children and literature review
  200. A meta-analysis of the effects of DBS on cognitive function in patients with advanced PD
  201. Protective role of selenium in sepsis: Mechanisms and potential therapeutic strategies
  202. Strategies for hyperkalemia management in dialysis patients: A systematic review
  203. C-reactive protein-to-albumin ratio in peripheral artery disease
  204. Research progress on autophagy and its roles in sepsis induced organ injury
  205. Neuronutrition in autism spectrum disorders
  206. Pumilio 2 in neural development, function, and specific neurological disorders
  207. Antibiotic prescribing patterns in general dental practice- a scoping review
  208. Clinical and medico-legal reflections on non-invasive prenatal testing
  209. Smartphone use and back pain: a narrative review of postural pathologies
  210. Targeting endothelial oxidative stress in hypertension
  211. Exploring links between acne and metabolic syndrome: a narrative review
  212. Case Reports
  213. Delayed graft function after renal transplantation
  214. Semaglutide treatment for type 2 diabetes in a patient with chronic myeloid leukemia: A case report and review of the literature
  215. Diverse electrophysiological demyelinating features in a late-onset glycogen storage disease type IIIa case
  216. Giant right atrial hemangioma presenting with ascites: A case report
  217. Laser excision of a large granular cell tumor of the vocal cord with subglottic extension: A case report
  218. EsoFLIP-assisted dilation for dysphagia in systemic sclerosis: Highlighting the role of multimodal esophageal evaluation
  219. Molecular hydrogen-rhodiola as an adjuvant therapy for ischemic stroke in internal carotid artery occlusion: A case report
  220. Coronary artery anomalies: A case of the “malignant” left coronary artery and its surgical management
  221. Combined VAT and retroperitoneoscopy for pleural empyema due to nephro-pleuric fistula in xanthogranulomatous pyelonephritis
  222. A rare case of Opalski syndrome with a suspected multiple sclerosis etiology
  223. Newly diagnosed B-cell acute lymphoblastic leukemia demonstrating localized bone marrow infiltration exclusively in the lower extremities
  224. Rapid Communication
  225. Biological properties of valve materials using RGD and EC
  226. A single oral administration of flavanols enhances short-term memory in mice along with increased brain-derived neurotrophic factor
  227. Repeat influenza incidence across two consecutive influenza seasons
  228. Letter to the Editor
  229. Role of enhanced external counterpulsation in long COVID
  230. Expression of Concern
  231. Expression of concern “A ceRNA network mediated by LINC00475 in papillary thyroid carcinoma”
  232. Expression of concern “Notoginsenoside R1 alleviates spinal cord injury through the miR-301a/KLF7 axis to activate Wnt/β-catenin pathway”
  233. Expression of concern “circ_0020123 promotes cell proliferation and migration in lung adenocarcinoma via PDZD8”
  234. Corrigendum
  235. Corrigendum to “Empagliflozin improves aortic injury in obese mice by regulating fatty acid metabolism”
  236. Corrigendum to “Comparing the therapeutic efficacy of endoscopic minimally invasive surgery and traditional surgery for early-stage breast cancer: A meta-analysis”
  237. Corrigendum to “The progress of autoimmune hepatitis research and future challenges”
  238. Retraction
  239. Retraction of “miR-654-5p promotes gastric cancer progression via the GPRIN1/NF-κB pathway”
  240. Retraction of: “LncRNA CASC15 inhibition relieves renal fibrosis in diabetic nephropathy through downregulating SP-A by sponging to miR-424”
  241. Retraction of: “SCARA5 inhibits oral squamous cell carcinoma via inactivating the STAT3 and PI3K/AKT signaling pathways”
  242. Special Issue Advancements in oncology: bridging clinical and experimental research - Part II
  243. Unveiling novel biomarkers for platinum chemoresistance in ovarian cancer
  244. Lathyrol affects the expression of AR and PSA and inhibits the malignant behavior of RCC cells
  245. The era of increasing cancer survivorship: Trends in fertility preservation, medico-legal implications, and ethical challenges
  246. Bone scintigraphy and positron emission tomography in the early diagnosis of MRONJ
  247. Meta-analysis of clinical efficacy and safety of immunotherapy combined with chemotherapy in non-small cell lung cancer
  248. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part IV
  249. Exploration of mRNA-modifying METTL3 oncogene as momentous prognostic biomarker responsible for colorectal cancer development
  250. Special Issue The evolving saga of RNAs from bench to bedside - Part III
  251. Interaction and verification of ferroptosis-related RNAs Rela and Stat3 in promoting sepsis-associated acute kidney injury
  252. The mRNA MOXD1: Link to oxidative stress and prognostic significance in gastric cancer
  253. Special Issue Exploring the biological mechanism of human diseases based on MultiOmics Technology - Part II
  254. Dynamic changes in lactate-related genes in microglia and their role in immune cell interactions after ischemic stroke
  255. A prognostic model correlated with fatty acid metabolism in Ewing’s sarcoma based on bioinformatics analysis
  256. Red cell distribution width predicts early kidney injury: A NHANES cross-sectional study
  257. Special Issue Diabetes mellitus: pathophysiology, complications & treatment
  258. Nutritional risk assessment and nutritional support in children with congenital diabetes during surgery
  259. Correlation of the differential expressions of RANK, RANKL, and OPG with obesity in the elderly population in Xinjiang
  260. A discussion on the application of fluorescence micro-optical sectioning tomography in the research of cognitive dysfunction in diabetes
  261. A review of brain research on T2DM-related cognitive dysfunction
  262. Metformin and estrogen modulation in LABC with T2DM: A 36-month randomized trial
  263. Special Issue Innovative Biomarker Discovery and Precision Medicine in Cancer Diagnostics
  264. CircASH1L-mediated tumor progression in triple-negative breast cancer: PI3K/AKT pathway mechanisms
Heruntergeladen am 5.2.2026 von https://www.degruyterbrill.com/document/doi/10.1515/med-2025-1325/html
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