Ovarian teratoid carcinosarcoma with a PIK3CA mutation: a case report and review of the literature

Ovarian teratoid carcinosarcoma involves an epithelial tumor of the Müllerian duct and an immature neuroepithelium, which is a characteristic of immature teratomas. Here, we describe the case of a 60-year-old woman who underwent surgery for a stage IC3 ovarian malignancy. The tumor showed a variety of histological features, including clear cell carcinoma, immature teratoma, and rhabdomyosarcoma, and a PIK3CA mutation was detected at the same locus in each. Two months after surgery and before the start of chemotherapy, multiple bone and liver metastases were found. Four courses of combination therapy with vincristine, actinomycin D and cyclophosphamide, the standard chemotherapy regimen for pediatric rhabdomyosarcoma, were administered, and a complete response was achieved. After a 2-month rest period, the patient developed recurrent peritoneal dissemination and underwent 6 courses of paclitaxel, carboplatin, and bevacizumab chemotherapy, resulting in a partial response. This is the eighth reported case of ovarian teratoid carcinosarcoma. This tumor has a very aggressive course, but initially responds to chemotherapy. However, survival over 5 years has not been reported, and elucidation of the pathogenesis and development of new treatment methods are needed. Supplementary Information The online version contains supplementary material available at 10.1007/s13691-022-00571-w.

Clear cell carcinoma, Immature neuroepithelial tumor, PIK3CA, Rhabdomyosarcoma, Teratoid carcinosarcoma

Tumors involving the Müllerian duct epithelium and immature neuroepithelium are referred to as teratoid carcinosarcomas and are very rare, with seven cases reported worldwide [1–7]. Here, we report the eighth case of a patient with teratoid carcinosarcoma of the ovary, and we review the literature. Case report The patient was a 60-year-old woman gravida 2, para 2 who reached menopause at age 48. She had no important family history. The patient was diagnosed with cervical intraepithelial neoplasia grade 2 (CIN2) at age 47 and attended follow-up every year. She was diagnosed with hypertension at age 55 and treated with amlodipine besylate. At age 60, the patient was diagnosed with deep vein thrombosis and treated with edoxaban tosylate hydrate. At a follow-up visit for CIN2, a mass of a neonatal head was found on the ventral side of the uterus. Ultrasonography revealed a 10-cm mass with a hyperechoic periphery, hypoechoic interior, and wall irregularity. Blood tests showed elevated LDH 367 U/l (reference: 124–222 U/l), CA125 974 U/ml (≤ 35 U/ml), and CA19-9 729 U/ml (≤ 37 U/ml). A heterogeneous mass was observed on T1- and T2-weighted MRI, with high signal areas on diffusion-weighted images (Fig. 1). Contrast-enhanced CT of the chest and abdomen showed no metastasis. A malignant tumor was suspected and laparotomy was performed. Bloody ascites was found in the abdominal cavity. A right ovarian tumor of 13 cm in size was found in the mesometrium. The tumor had spontaneously ruptured. Rapid intraoperative pathological diagnosis showed findings suspicious of clear cell carcinoma (CCC) of the ovary, and modified radical hysterectomy, bilateral salpingo-oophorectomy, pelvic and paraaortic lymphadenectomy, pelvic peritoneal stripping, and subtotal omentectomy were performed. Ascites cytology was positive, postoperative pathology showed no metastasis other than to the ovary, and the International Federation of Gynecology and Obstetrics (FIGO) stage was IC3. After obtaining a tentative pathological diagnosis, we decided to start chemotherapy 2 months later. However, CT and fluorodeoxyglucose–positron emission tomography prior to chemotherapy showed multiple liver and bone metastases (Fig. 1E). The AFP tumor marker level was 11 ng/ml (normal ≤ 10 ng/ml) and only germ cell tumor markers were mildly elevated (Fig. 2). After two courses of VAC therapy (vincristine 1.5 mg/m2, actinomycin D 0.045 mg/kg, cyclophosphamide 1200 mg/m2) as a regimen for rhabdomyosarcoma, the metastases had disappeared on imaging (Fig. 1F), complete response was achieved, and two more courses were added. AFP was not elevated after 2 months of treatment-free follow-up, but CA125 and CA19-9 were elevated. TC + Bev therapy (paclitaxel 175 mg/m2, carboplatin AUC6, bevacizumab 15 mg/m2) was administered for recurrence of peritoneal dissemination on the hepatic surface. Three months later, CT showed shrinkage of the peritoneal dissemination, and the response rate was 33%, indicating a partial response. However, 2 weeks after the sixth treatment, the patient died of a cerebral hemorrhage caused by worsening hypertension, which he considered a side effect of bevacizumab. Tumor histology showed glandular ducts, pale cytoplasm, and HNF1β-positive components of CCC, along with an immature neuroepithelium and an immature teratoma (IMT) grade 2 with hair, sebaceous glands and AFP-positive cells. In addition, there was a cluster of immature atypical cells with poor cell adhesion, which was cytokeratin (AE1/AE3)-negative and desmin- and myogenin-positive and had characteristics of rhabdomyosarcoma (Fig. 3). Immunohistochemistry results for this tumor are shown in Supplementary Table 1. The histopathological findings for this tumor clearly showed signs of CCC and IMT, and the initial diagnosis was a collision of two tumors that incidentally occurred simultaneously. However, in an expert consensus reached at a case conference held at the 51st Japanese Society of Gynecologic Pathology meeting (January 2020, Matsuyama, Japan), the tumor was diagnosed as teratoid carcinosarcoma of the ovary. Automated gene mutation analysis was performed to determine whether the tumors were monoclonal. Tumor tissues were collected by microdissection from 10-μm formalin-fixed paraffin-embedded (FFPE) sections of 2 cm2 at four sites with different histologies (CCC, mature component of teratoma, IMT, and rhabdomyosarcoma), and DNA was extracted with a QIAamp DNA FFPE Tissue Kit (Qiagen, Hilden, Germany). Targeted sequencing of mutation hotspots was performed using primers for PIK3CA exons 9 and 20 and KRAS exon 2, based on previous reports [8, 9]. Substitution of E545 with aspartic acid and a PIK3CA frameshift mutation at p.Ser553 were found in all four sites (Fig. 4A), but there were no mutations of H1047 of PIK3CA or G12 of KRAS. Thus, although the tumor components indicated a variety of tumor types, they were considered to be monoclonal due to the presence of the same mutations. Immunostaining for ARID1A was performed at three sites with malignant findings, and deletion of ARID1A was found in all of these sites (Fig. 4B).

Carcinosarcoma of the ovary is a rare disease that occurs in 5% of malignant ovarian tumors, is more common in postmenopausal women, and is characterized by formation of huge tumors [10]. Among these cases, malignant ovarian tumors consisting of Müllerian duct epithelial tumors and malignant germ cell tumors are rare, and are mostly endometrioid carcinomas and yolk sac tumors [11]. Ovarian teratoid carcinosarcoma is an even rarer tumor that involves an epithelial tumor of the Müllerian duct and an immature neuroepithelium, a component of IMT; only eight cases have been reported, including the case described here (Table 1). Our patient was initially diagnosed with collision carcinoma, which suggests that the disease is not well understood and many cases may be overlooked. A literature review was conducted in 2011 (6), but the clinical picture of ovarian teratoid carcinosarcoma remains unclear. Therefore, clinical and pathological aspects of the disease and its sensitivity to pharmacotherapy are described below. Table 1. | Author | Age | Symptoms | Elevated tumor marker | Tumor diameter (cm) | FIGO stagea | Müllerian epithelial component | Immature neuroepithelium | Other histological components | Chemotherapy | Prognosis | |---|---|---|---|---|---|---|---|---|---|---| | Ehrmann et al. [1] | 62 | Postmenopausal bleeding, ascites | CA125 AFP | 8 | IIIC | Serous carcinoma | + | SCC, ASC, CSA, RMS | CPA + ADM + CDDP, CDDP(IP) | Rec 4 m, DOD 2 y 3 m | | Tanimoto et al. [2] | 59 | Ascites | unknown | 20 | IV | Serous carcinoma | + | SCC, CSA | Unknown | Unknown | | Ohishi et al. [3] | 34 | Abdominal pain | CA125 AFP CA19-9 | 14 | IIIC | Endometrioid carcinoma, clear cell carcinoma | + | SCC, RMS, YST | Unknown | Rec 5 m, AWD 3 y 4 m | | Garcia-Galves et al. [4] | 69 | Abdominal pain, ascites | CA125 | 11 | IV | Endometrioid carcinoma, serous carcinoma | + | SCC, CAS, RMS, osteosarcoma, liposarcoma, YST | None | DOD 10 d (sepsis after surgery) | | Matsuura et al. [5] | 40 | Abdominal fullness | CA125 CA19-9 LDH | 20 | IIC | Endometrioid carcinoma | + | CAS, endometrial stromal sarcoma | PEP + ETP + CDDP, PTX + CBDCA, CPT-11 + CBDCA, DTX + CBDCA | Rec 1 y 4 m, DOD 3 y 10 m | | Nasser et al. [6] | 64 | Abdominal fullness | CA125 | 16 | IA | Serous carcinoma | + | None | None | NED 9 m | | Fox et al. [7] | 55 | Abdominal pain, low-grade fever, ascites | CA125 hCG LDH | 13 | IC3 | Endometrioid carcinoma | + | Embryonal carcinoma, dysgerminoma | IFM + PTX, GEM + CBDCA + Bev, nivolumab, BLM + ETP + CDDP | Rec 1 m, DOD 1 y 2 m (febrile neutropenia) | | This case | 60 | None | CA125 CA19-9 AFP LDH | 10 | IC3 | Clear cell carcinoma | + | RMS | VCR + ACT-D + CPA, PTX + CBDCA + Bev | Rec 2 m, DOD 1 y 3 m (cerebral hemorrhage) | SCC squamous cell carcinoma, ASC adenosquamous carcinoma, CAS chondrosarcoma, RMS rhabdomyosarcoma, YST yolk sac tumor, CPA cyclophosphamide, ADM adriamycin, CDDP cisplatin, CDDP (IP) intraperitoneal cisplatin, PEP peplomycin, ETP etoposide, PTX paclitaxel, CBDCA carboplatin, CPT-11 irinotecan, DTX docetaxel, IFM ifosfamide, GEM gemcitabine, Bev bevacizumab, BLM bleomycin, VCR vincristine, ACT-D actinomycin-D, Rec recurrence, DOD died of disease, AWD alive with disease, NED no evidence of disease aCases 1–6; FIGO 1988. Cases 7, 8; FIGO 2014 Germ cell tumors of the ovary are most commonly diagnosed in children and young adults, and are rare in postmenopausal women. However, 6 of the 8 reported cases of ovarian teratoid carcinosarcoma occurred in postmenopausal women. CA125, a marker for epithelial ovarian cancer, was elevated, as were tumor markers for germ cell tumors, such as AFP and hCG. The tumor size was > 10 cm in 7 patients, and 2 had tumors of 20 cm. All patients had immature neuroepithelium involvement, in accordance with the definition of teratoid carcinosarcoma, and the Müllerian epithelial component consisted of serous carcinoma (n = 3 cases), endometrioid carcinoma (n = 2), CCC (n = 1), and mixed type (n = 2). The E545K mutation in PIK3CA has been identified in teratoid carcinosarcoma [7]. In addition, since this tumor was associated with a component of CCC, the possibility of KRAS mutation was also considered [12]. Therefore, we investigated hot spot mutations of PIK3CA and KRAS and found the same PIK3CA mutation in different histological regions, confirming that the tumor was monoclonal (Fig. 4A). The analysis performed in this case is useful for investigating whether tumors with extremely heterogeneous histological findings, such as those observed in teratoid carcinosarcoma, are monoclonal or not. In addition, many tumors involving the yolk sac in the uterus or ovaries of women over 35 years of age are associated with endometriosis or carcinoma and have mutations of PTEN, PIK3CA, FGFR2 or CTNNB1, which are characteristic of endometrial cancer. The germ cell tumor component is considered to be of somatic cell origin [13]. In the present case, PIK3CA mutation and loss of ARID1A expression [12, 14], which are characteristics of CCC, were also found in the IMT component, suggesting that the germ cell tumor component was of somatic cell origin. Therefore, the fact that the same genetic mutation was found in different histological types was strongly suspected to be a possible driver mutation of cancer. The tumor in this case was stage I at the time of diagnosis, but recurred 2 months postoperatively with multiple metastases throughout the body. Similarly, another case had recurrence at 1 month after surgery [7]. Therefore, the tumor can be considered to be highly aggressive. No patient achieved a response beyond 1 year and 4 months without recurrence, and none survived beyond 3 years and 10 months. Chemotherapy was attempted in 3 cases, with some success in each patient. In some patients, chemotherapy was used in combination with surgery, but resulted in recurrence or death due to treatment-related complications. For our patient, we focused on the rhabdomyosarcoma component for initial chemotherapy. VAC therapy was administered based on treatment of rhabdomyosarcoma in children [15], and a complete response was achieved. Thereafter, there was no recurrence in common sites of rhabdomyosarcoma metastasis, such as lungs and bones, and no elevation of AFP, a marker for germ cell tumors; however, there was recurrence of peritoneal dissemination with CA125 and CA19-9 epithelial markers. Subsequently, a partial response was achieved with TC + Bev therapy, the standard therapy for epithelial tumors. Thus, teratoid carcinosarcoma appears to have a certain sensitivity to chemotherapeutic agents that are used in standard regimens for germ cell and epithelial malignancies of the ovary. The PIK3CA mutation was found in two cases, including our patient, and thus, targeting of the PIK3CA pathway may be of value. In conclusion, teratoid carcinosarcoma of the ovary is a very rare disease that may be overlooked due to incorrect diagnosis. The diverse histology of teratoid carcinoma makes it difficult to differentiate from collision carcinoma; however, mutational analysis of genes such as PIK3CA can be used to detect monoclonal tumors. Teratoid carcinoma responds well to chemotherapy, but has a very poor prognosis, and new treatment methods are needed. Supplementary Information Below is the link to the electronic supplementary material.

We thank Masanori Shiohara, MD, Suzuko Moritani, MD, PhD, and Ryoji Kushima, MD, PhD (Division of Diagnostic Pathology, Shiga University of Medical Science Hospital, Otsu, Japan) for immunohistochemical staining of ARID1A; and Keiko Yamanaka (Staff Member), Shigeaki Yamanaka (Chief Engineer), and Yoshihiro Mine (Technical Director) (Center for Instrumental Analysis, Kindai University Life Science Research Institute, Osaka, Japan) for DNA sequencing. Author contributions MA contributed to the study conception and design, and to draft writing. HT contributed to clinical data acquisition and draft revision. TO contributed to the pathological diagnosis and genetic analysis. HN and KM also contributed to clinical data acquisition. NM supervised the study and revised the draft. All authors approved the final manuscript. Funding This study was supported in part by the Japan Society for the Promotion of Science KAKENHI grant (18H02947; Grant-in-Aid for Scientific Research B) to NM. Declarations Conflict of interest Noriomi Matsumura is an outside director at TakaraBio Inc. The authors declare that they have no conflict of interest. Consent and ethical approval This case report was prepared with the consent of the patient and her family. The study was conducted in accordance with the 1975 Declaration of Helsinki. Footnotes Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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