The malignant transformation of mature ovarian teratomas is relatively rare in young adults, and the underlying pathogenesis is not completely understood. Several high-risk factors associated with this condition have been identified, including advanced age, large tumors, rapid tumor growth, and HPV infection [4]. The most frequently mutated genes are TP53, PIK3CA, TERT, and CDKN2A among patients experiencing the malignant transformation of teratomas [5,6,7]. Tamura et al. discovered that most MCT-SCCs (87.5%, 7/8) harbor at least one known oncogenic alteration in the PI3K–AKT–mTOR pathway, which is a potential target for numerous inhibitors [6]. Furthermore, recent studies have demonstrated that the inhibitory effect mediated by PD-1 is predominantly achieved through the PI3K-Akt signaling pathway, with PD-1 blocking PI3K activation through recruiting SHP-2 [7]. The results of genetic testing of six patients with ovarian-teratoma-associated squamous cell carcinoma revealed a high tumor mutational burden and elevated PD-L1 expression [5]. XCL1 may facilitate the interactions of PD-1 and PD-L1 within the tumor microenvironment, resulting in CD8 + T-cell dysfunction [6]. Such patients may benefit from immune checkpoint inhibitor therapy based on these findings, a hypothesis that is supported by several clinical case reports [7,8,9].

According to a previous review, only 1–2% of cases are diagnosed preoperatively, but this is based on data from 40 years ago, and it is thought that recent PET and MRI will be able to detect suspected cases with greater accuracy. Patients typically present with symptoms such as abdominal pain, abdominal distension, or palpable masses; a minority seek medical attention because of complications such as tumor torsion or rupture [10]. MRI and computed tomography (CT) are invaluable for preoperatively evaluating the malignant transformation of teratomas [4, 11]. Key MRI features indicative of malignant transformation include a thickened cystic wall, the presence of solid components, and enlargement of the surrounding tissues or peritoneal involvement. The characteristic CT findings include fat-containing components and enhanced solid areas. Patient 1 presented with a solid cystic mass and multiple enlarged lymph nodes in the retroperitoneum and at the lipid-fluid interface on MRI, consistent with the diagnosis of malignant teratoma, as described in the literature. Elevated levels of the serum tumor markers SCC, CA125, CA19-9, and CEA are frequently observed in patients with squamous cell carcinomas arising from teratomas [12]. In this study, the CA19-9 and CA125 levels of both patients were elevated. However, the absence of squamous cell carcinoma antigen measurements limited the interpretation of these findings. Malignant teratomas exhibit aggressive behavior and have poor prognoses and high mortality rates compared with epithelial tumors. The key prognostic factors include tumor stage, histologic grade, patient age, tumor size, presence of squamous cell carcinoma, CA125 levels, and extent of surgical resection [13, 14]. Li et al. reported that the five-year survival rates were 85.8%, 39.1%, 26.2%, and 0% for stages I, II, III, and IV disease among 435 patients, respectively [15].

Malignant teratoma transformation is typically treated following the protocols for epithelial or malignant germ cell tumors. Comprehensive surgical staging is recommended for early stage disease, whereas cytoreductive surgery is recommended for advanced stages [10]. The need for systematic lymphadenectomy remains a subject of considerable debate within the medical community [15, 16]. No standardized approach exists for postoperative adjuvant treatment, although adjuvant chemotherapy may improve the prognosis of patients with stage IB or higher disease [10]. Postoperative platinum-based combination chemotherapy is recommended for teratomas identified as squamous cell carcinomas given the efficacy of platinum-based chemotherapy in the treatment of various cancers, including gynecological squamous cell carcinomas [7]. The bleomycin + etoposide + cisplatin (BEP) regimen has also produced favorable outcomes [17]. However, the potential benefits of radiotherapy remain unclear and require further investigation [10].

Several critical issues emerged during this study that warrant an in-depth analysis. The first is the selection of the surgical approach. Both patients in this study demonstrated a strong preference for fertility preservation, rendering the feasibility of fertility-sparing surgical approaches a primary consideration in their treatment planning. The mortality rates do not substantially differ between fertility-preserving and radical surgery in patients with stage IA or IC disease, with successful pregnancies being reported [10, 15]. However, data on fertility-preserving surgery in patients with advanced-stage disease are limited. Peluso et al. reported a case of a young woman with stage IVB disease who underwent fertility-preserving surgery and was subsequently referred to a reproductive endocrinology department [18]. This study adhered to the NCCN guidelines on preserving the fertility of patients with germ cell tumors [15]. A fertility-preserving strategy was ultimately adopted for both patients following comprehensive evaluation and multidisciplinary discussions as well as considering the wishes of the patients and their families. Both patients postoperatively received GnRH-a therapy to protect ovarian function, and regular menstruation resumed in both patients after the discontinuation of the medication. Fertility preservation is crucial for women who have not yet given birth, although a consensus on the optimal treatment strategy for young patients has yet to be established. The second limitation relates to the selection of postoperative chemotherapy regimens: both patients were histologically diagnosed with squamous cell carcinoma. Platinum-based chemotherapy regimens were prioritized in this study on accordance with previous studies. However, recurrence and metastasis occurred during the course of chemotherapy in Patient 1, suggesting the occurrence of platinum resistance, although the precise mechanism of this resistance remains unclear. We hypothesized that this platinum resistance was associated with TP53 gene mutations based on the genetic test results of the patient. Although TP53 gene mutations in certain patients with ovarian cancer have been linked to platinum resistance and an increased risk of recurrence, not all TP53 mutations result in platinum resistance [19]. Therefore, further studies are required to validate these preliminary observations. The third limitation relates to the timing of immunotherapy intervention: two patients at different stages of the disease received immunotherapy at distinct time points, with favorable therapeutic outcomes in both. Recurrence and metastasis developed during postoperative chemotherapy in Patient 1; however, a complete response was achieved following the administration of PD-1 inhibitors. Patient 2 was diagnosed in the early stage of the disease. The risk of recurrence and metastasis remains high given the rarity of squamous cell carcinoma arising from teratomas, the high degree of malignancy, and the age of the patient. Early intervention may more effectively activate the host immune system, thereby suppressing tumor progression and preventing metastasis, as demonstrated by the increased use of immunotherapy in early stage tumor treatment. This study demonstrates that immunotherapy has the potential to improve the prognosis of early stage squamous cell carcinoma arising from teratomas. This study provides valuable data to support future immunotherapy research. Fourth, the potential applications of PARP inhibitors are highlighted. The test results for Patient 2 showed HRD positivity, providing a theoretical foundation for the use of PARP inhibitors (PARPis) in the event of subsequent recurrence or metastasis. PARPis are expected to be viable therapeutic options if disease progression occurs.

In conclusion, teratomas with malignant transformation are characterized by high recurrence rates, high mortality rates, and poor response to chemotherapy, which underscore the urgent need to explore new treatment strategies to improve patient survival. The results of this study demonstrate that combination immunotherapy can considerably improve patient prognosis without increasing the incidence of side effects. Immunotherapy can be considered as a therapeutic strategy in clinical decision making for advanced or recurrent cases, offering options for patients with this malignancy.