Mature teratomas (MT) are common benign germ cell tumors composed of well-differentiated tissues from three embryonic layers [1]. Ovarian MTs, particularly the mature cystic subtype (MCT), represent 95% of all teratomas and 10%–20% of all ovarian neoplasms [2]. While typically benign, these tumors can rarely give rise to secondary somatic malignancies, posing significant clinical and prognostic challenges.

Somatic neoplasms arising in mature teratomas (SN-MT), often termed “somatic malignant transformation,” occur in 1%–2% of cases [3]. Despite their rarity, increased risk is associated with advanced patient age, larger tumor size, and prolonged duration of the tumor. While the majority of somatic neoplasms that develop from mature teratomas are malignant, benign or borderline neoplasms have also been documented on occasion. Squamous cell carcinoma (SCC) is the most frequently reported subtype. Other entities include adenocarcinoma, sarcomas (particularly rhabdomyosarcoma), neuroendocrine tumors, melanoma, and rare hematologic malignancies [4].

The pathogenesis of SN-MT remains unclear, with proposed mechanisms including chronic inflammation and genetic instability. Molecular studies suggest roles for TP53 and PIK3CA alterations, though it remains uncertain whether these events originate from benign tissue or secondary malignant clones [5, 6]. Clinically, SN-MT typically presents with nonspecific symptoms like abdominal pain or pelvic masses. While serum markers like SCC antigen and CEA may be elevated in specific cases, they offer limited diagnostic utility [7, 8]. Consequently, preoperative differentiation remains difficult, necessitating histopathological confirmation.

Malignant transformation in mature teratomas is characterized by the presence of invasive malignancy within a background of benign teratomatous tissue [9, 10]. Malignant areas often demonstrate stromal invasion, desmoplastic reactions, marked cytologic atypia, increased mitotic activity, and necrosis. Because these lesions are frequently focal and heterogeneously distributed, small malignant foci may be missed during routine sampling. Therefore, extensive and systematic gross sampling, particularly of the solid areas, mural thickening, necrosis, and hemorrhage, is essential. Immunohistochemistry is critical for distinguishing malignancies arising in mature teratomas from primary or metastatic ovarian malignancies [11–13].

Prognosis depends on histologic subtype, stage, and surgical success, with radical surgery serving as the cornerstone of therapy [14, 15]. Adjuvant treatments should be individualized based on the somatic component rather than conventional germ cell regimens. Given that current evidence is largely limited to small series, the true frequency and prognostic determinants of SN-MT remain poorly defined [16, 17]. This study aims to determine the frequency of SN-MT and compare clinicopathological features across various histologic subtypes.

A total of 385 women with histologically confirmed mature teratomas were included. The incidence of benign and malignant somatic neoplasms originating from mature teratomas was found to be 3.1% (n = 12). The frequency of malignant transformation from mature teratomas was found to be 2.07% (n = 8). The histological spectrum was heterogeneous, comprising both benign and malignant entities. Benign tumors identified in MTs included paraganglioma (16.6%), choroid plexus papilloma (8.3%), and adnexal tumor (8.3%), while malignant tumors included squamous cell carcinoma (SCC) (33.3%), glioblastoma (8.3%), anaplastic astrocytoma (8.3%), adult-type granulosa cell tumor (8.3%), and mixed carcinoma (8.3%).

Among the 373 MT cases (96.9%) without somatic neoplasia, the mean age was 37.75 ± 14.18 years (range, 13–83 years). The tumors were located in the right (48.2%), left (45.6%), and bilateral (6.2%) ovaries. The mean tumor diameter was 6.67 ± 3.32 cm (range, 1.5–17). On gross examination, 77.7% were cystic, and 22.3% were solid–cystic.

The mean age of the SN-MT group was 43.0 ± 18.27 years (range, 20–73 years). Tumors were located in the right ovary in 75% of the cases and in the left ovary in 25% of the cases. It was observed that none of the SN-MT cases was bilateral. The mean tumor diameter was 9.45 ± 4.22 cm (range, 3.5–15). Grossly, 83.3% of the SN-MT cases showed mixed solid–cystic components, whereas only two cases (16.7%) were purely cystic (Table 1).

There was no significant difference between the MT and SN-MT groups in terms of age (p = 0.390) or the proportion of patients aged <45 years versus ≥45 years (p = 0.333). Tumor laterality (right/left/bilateral) did not differ significantly between the groups (p = 0.170). When tumor size was analyzed by laterality, left-sided tumors differed significantly between the groups (p = 0.006), with larger tumors in the SN-MT group; right-sided tumors did not differ significantly (p = 0.243). Gross cut-surface characteristics differed markedly between the groups (p < 0.0001). MTs were predominantly cystic, whereas SN-MTs were predominantly mixed solid–cystic (Table 2).

Preoperative serum CA 125 was available for 274 patients, CA 19-9 for 251, and CEA for 191 patients, respectively. No significant differences were observed between the MT and SN-MT groups for CA 125, CA 19-9, or CEA (all p = 0.99). The marker levels are summarized in Table 3.

Intraoperative frozen section evaluation was performed in 7/12 SN-MT cases (58.3%). Frozen sections were reported as benign in 4 cases and malignant in 3 cases. Among those reported as malignant, the final diagnoses included SCC (n = 2) and mixed carcinoma (n = 1). Among the frozen section–benign cases, final pathology revealed glioblastoma, anaplastic astrocytoma, and SCC, indicating false-negative frozen section results. In five SN-MT cases where intraoperative frozen sections were not performed, microscopic evaluation of permanent sections revealed the development of choroid plexus papilloma, paraganglioma, skin adnexal tumor, and adult-type granulosa cell tumor. Intraoperative frozen section results, individual surgical and medical treatment plans for 12 SN-MT patients are reported in Table 4.

Among the benign neoplasms arising within mature teratomas, paraganglioma was characterized by the classic “Zellballen” nesting pattern of tumor cells separated by a delicate fibrovascular stroma (Figure 2A); immunohistochemically, these cells demonstrated moderate cytoplasmic synaptophysin expression (Figure 2B). The choroid plexus papilloma cases exhibited a complex papillary architecture lined by uniform epithelial cells (Figure 2C), which showed strong S100 protein positivity along the epithelial lining (Figure 2D). Additionally, adnexal skin appendage tumors were identified by their well-differentiated follicular or sebaceous structures closely associated with the ectodermal components of the teratoma.

Within the malignant category, the tumors followed diverse lineages. SCC displayed sheets and nests of atypical squamous cells infiltrating the stroma, prominent keratin pearl formation, and extensive intercellular bridges, alongside diffuse nuclear p63 positivity. Adult-type granulosa cell tumors showed prominent trabecular, insular, and microfollicular growth patterns (Figure 3A), the latter containing numerous pathognomonic Call-Exner bodies; the neoplastic cells presented cuboidal-to-polygonal morphology with scant cytoplasm and characteristic pale, angulated, and grooved nuclei (Figure 3B), accompanied by diffuse cytoplasmic positivity for inhibin (Figure 3C) and calretinin.

Among the neuroepithelial malignancies, glioblastoma displayed high-grade features, including markedly increased cellularity, prominent nuclear atypia, frequent atypical mitoses, and areas of necrosis with pseudopalisading (Figures 4A,B) Immunohistochemically, the tumor cells showed diffuse GFAP positivity (Figure 4C), retained nuclear ATRX expression (Figure 4D), strong nuclear p53 overexpression (Figure 4E), and a remarkably high Ki-67 proliferation index (Figure 4F). In contrast, anaplastic astrocytoma presented as a glial proliferation adjacent to mature teratoma epithelia, exhibiting moderate pleomorphism without necrosis or prominent proliferative activity (Figures 5A,B). Structurally, these cells revealed diffuse GFAP positivity (Figure 5C), loss of nuclear ATRX (Figure 5D), strong mutant IDH-1 (IDH1-R132H) immunoreactivity (Figure 5E), and a low Ki-67 index (5%) (Figure 5F).

The mixed carcinoma case comprised three distinct malignant components. The first component consisted of infiltrative nests of atypical keratinized and non-keratinized squamous cells showing p40 positivity (Figure 6A). Adjacent to these areas, a high-grade adenocarcinoma component was identified in a necrotic background, characterized by pleomorphic cells with papillary architecture and p53 overexpression (Figure 6B). The intimate juxtaposition and transition between the squamous cell carcinoma and high-grade adenocarcinoma components were clearly demonstrated (Figure 6C). Finally, a small focus of mucinous adenocarcinoma was present, composed of pleomorphic cells with prominent nucleoli and abundant vacuolated cytoplasm, showing positivity for MUC1 and MUC2 immunostains (Figure 6D). Notably, p53 demonstrated a wild-type expression pattern in both the squamous and mucinous adenocarcinoma. components. In the MT group, cystectomy was performed in 60.5% of the patients, USO in 20%, and TAH + BSO in 19.5%. The SN-MT group underwent Total Abdominal Hysterectomy + Bilateral Salpingo-Oophorectomy (TAH + BSO) in 41.7% of the patients, unilateral salpingo-oophorectomy (USO) in 41.7%, and cystectomy in 16.6%. Of the eight cases exhibiting malignant transformation, four were diagnosed following TAH + BSO, while the remaining four were diagnosed via unilateral/bilateral ovarian cystectomy. According to the 8th edition of the American Joint Committee on Cancer (AJCC) staging system, the distribution was as follows: Stage I (n = 5) and Stage III (n = 3). The clinicopathological and surgical characteristics of the SN-MT cases are detailed in Table 4.

At diagnosis, para-aortic lymph node metastasis was detected only in the mixed carcinoma case; at 31 months, the patient developed right adrenal metastasis. The adrenal metastasis was confirmed to be of ovarian origin, as whole-body PET-CT imaging demonstrated no other primary tumour focus, thereby excluding a synchronous or metachronous secondary malignancy. The SN-MT group was followed for a mean of 80.3 ± 6.13 months (range, 50-132).

In the present study, we evaluated the frequency and clinicopathological characteristics of somatic neoplasms arising in mature teratomas in a large cohort over an extended study period. The incidence of malignant transformation was 2.07%, which falls within the reported range of 0.17%–5.5% in the literature, although it is higher than the 0.54% rate reported by Neville et al. [18]. This difference may be related to the long study period, systematic archival review, and detailed re-evaluation of surgical specimens, which likely improved detection sensitivity, particularly for rare histological variants and focal lesions.

The histological spectrum in our cohort was heterogeneous, comprising both benign and malignant entities. Squamous cell carcinoma (SCC) was the most frequent subtype, accounting for approximately one-third of cases, consistent with previous studies [18–20]. This predominance is biologically plausible given the frequent squamous differentiation within mature teratomas. Rare entities, including paraganglioma, adult-type granulosa cell tumor, and central nervous system-type tumors, further highlight the broad differentiation potential and histological diversity of these lesions.

From a histogenetic perspective, mature teratomas (MTs) and adult granulosa cell tumors (AGCTs) arise from distinct embryological lineages [21]. Their coexistence in the same ovary is rare, with fewer than 15 cases reported [22, 23] The most widely accepted explanation is the collision tumor theory, although alternative hypotheses, including divergent differentiation, have also been proposed [21]. Molecular studies, particularly FOXL2 mutation analysis, support the independent origin of AGCTs [24, 25]. In our case, the synchronous presentation of AGCT and MT in the right ovary of a 50-year-old patient represents a rare entity. Morphologically, a 2.2 cm solid area located within the wall of a 5 cm MT exhibited classic AGCT features, characterized by uniform cells displaying microfollicular/insular patterns and nuclear grooves (coffee-bean nuclei); this diagnosis was confirmed by diffuse immunohistochemical positivity for inhibin and calretinin. Although molecular analysis for FOXL2 mutation could not be performed due to institutional limitations, the distinct histological demarcation between the two components, the absence of a transitional differentiation zone, and their entirely different embryological lineages rule out the possibility of a mixed/combined tumor. These findings strongly support that our case represents a pathological model of a “collision tumor,” characterized by the coincidental coexistence of two independent neoplasms.

The occurrence of glial neoplasms within mature cystic teratomas is exceptionally rare and is considered within the spectrum of monodermal teratomas. Although neuroectodermal differentiation is relatively common in mature teratomas, malignant transformation into high-grade astrocytic tumors is extremely uncommon. Clinically, these aggressive secondary malignancies typically affect young women, presenting primarily with non-specific abdominal pain and signs of mass effect [26]. From a diagnostic and macro-morphological perspective, evaluating these specimens carries inherent difficulties; because the astrocytic component arises directly within the background of an ovarian germ cell tumor framework, precisely measuring or isolating the exact boundaries and size of the astrocytoma can often be highly challenging [27]. This underscores the critical importance of extensive sampling and a comprehensive IHC panel to prevent diagnostic pitfalls. In our glioblastoma case, the diagnosis was supported by diffuse GFAP positivity, ATRX retention, p53 overexpression, a high Ki-67 proliferation index, and IDH1 (R132H) negativity, consistent with an IDH-wildtype phenotype. However, given the limited number of reported cases, the molecular profile of ovarian glioblastomas remains incompletely defined.

While some studies have suggested advanced age as a risk factor for somatic malignant transformation, others have failed to demonstrate it as an independent predictor [28]. In the present analysis, no significant differences were observed in age when assessed as a continuous variable or when stratified by a 45-year threshold. However, the broader age distribution observed in the SN-MT group indicates a need for more in-depth clinical and pathological evaluation of older patients.

Tumor size and macroscopic features appear to be important indicators of somatic neoplastic transformation [29]. In our study, SN-MTs were significantly larger and more frequently demonstrated mixed solid–cystic architecture compared with MTs. The presence of solid areas, mural nodules, or necrosis should therefore raise suspicion for malignant transformation and prompt extensive sampling.

No statistically significant difference was observed between the MT and SN-MT groups in terms of tumor location. Although right-sided tumors were significantly more frequent in the SN-MT group, this finding should be interpreted with extreme caution due to the limited sample size of our cohort. This distribution reflects a random variation specific to small sample sizes rather than a clear biological mechanism. Similarly, the absence of somatic neoplasia in bilateral mature teratomas in our cohort should not be generalized and is likely due to the limited number of cases.

Serum tumor markers (CA 125, CA 19-9, and CEA) showed no significant difference between groups, consistent with previous reports indicating limited diagnostic value in predicting somatic transformation [30].

Although intraoperative frozen section analysis was performed in only a limited number of cases (n = 7) in our cohort, our descriptive observations highlight the inherent diagnostic challenges associated with these lesions. In our small subset, the presence of focal and heterogeneous malignant components appeared to contribute to the difficulty of intraoperative assessment. While no definitive statistical conclusions can be drawn due to this sample size limitation, our experience suggests that careful procurement of samples, specifically targeting the solid components of the mass during intraoperative frozen section, may help minimize diagnostic pitfalls. Likewise, during gross evaluation of mature teratomas, meticulous and comprehensive sampling of heterogeneous areas remains a critical practice to facilitate the identification of potential SN-MT areas.

Malignant transformation was identified in eight patients, four of whom were diagnosed after TAH + BSO and four after USO. The preference for more radical surgical approaches in SN-MT cases reflects the impact of suspicion of malignancy on surgical decision-making [31]. Despite the favourable outcomes observed in the majority of cases, particularly in patients with early-stage and completely resected tumors, advanced-stage patients demonstrated a need for chemotherapy.

Finally, several methodological limitations are acknowledged. The retrospective design inherently limits the data completeness and uniformity of measurements. An incomplete assessment of serum tumor markers may reduce the statistical power. The relatively small number of SN-MT cases constrained detailed subtype-specific analyses and generalizability. The lack of molecular and genetic investigations has limited mechanistic and prognostic interpretations. Nevertheless, the systematic pathological re-evaluation of all cases by expert pathologists, the long follow-up period, and the large overall cohort strengthened the significance of our findings. Future multicenter prospective studies incorporating molecular profiling are warranted to elucidate the biology of somatic neoplasms that arise in mature teratomas.

In conclusion, this study demonstrated that somatic neoplasms arising in mature teratomas represent a rare but highly heterogeneous clinicopathological entity. Larger tumor size and presence of solid components are the most reliable features associated with somatic neoplastic transformation. Our findings contribute to increased diagnostic awareness among pathologists and clinicians, and provide practical insights for the early recognition of this uncommon but clinically significant phenomenon. Further large-scale, multicenter, prospective studies are essential to validate these observations and facilitate the development of standardized diagnostic and therapeutic algorithms.