DOI: https://doi.org/10.21203/rs.3.rs-1729801/v1
Background
Squamous cell carcinoma arising from mature cystic teratoma of the ovary (MCT-SCC) has a poor prognosis at advanced stages. Although the relationship between the homologous recombination deficiency (HRD) status and platinum-based chemotherapy sensitivity or poly (ADP ribose) polymerase (PARP) inhibitor efficacy in epithelial ovarian cancer has been demonstrated in clinical trials, the significance of the HRD status in MCT-SCC remains unclear.
Case presentation
A 73-year-old woman with no remarkable past medical history was referred to our hospital for a huge left ovarian tumor. Laparotomy was urgently performed due to tumor rupture. We performed total abdominal hysterectomy, bilateral salpingo-oophorectomy, and partial omentectomy. The ovarian tumor was strongly adherent to the surrounding pelvic organs and could not be completely resected. The postoperative diagnosis was stage IIIB MCT-SCC (pT3bNXM0) of the left ovary. After surgery, we conducted the myChoice CDx and microsatellite instability (MSI) tests. The genomic instability (GI) score of 87 was remarkably high, and there was no BRCA1/2 pathogenic mutation. In contrast, the MSI test was negative. After six courses of combination therapy with paclitaxel and carboplatin, the residual tumors had shrunk by 73% (target lesions: 85 mm to 23 mm) and SCC-Antigen levels decreased from 12.8 ng/ml postoperatively to 1.6 ng/ml at the end of the initial course of chemotherapy and remained in the normal range thereafter. We considered the complete removal of residual tumors feasible and performed interval debulking surgery (IDS). We performed residual tumor resection and pelvic and para-aortic lymphadenectomy, and the tumors were completely resected. Subsequently, the patient underwent two courses of the combination of paclitaxel, carboplatin, and bevacizumab, followed by maintenance therapy with olaparib and bevacizumab. Five months after IDS, no recurrence has been observed.
Conclusion
To the best of our knowledge, this is the first reported case of MCT-SCC with HRD-positive status. Although its frequency is unknown, platinum-based chemotherapy followed by maintenance therapy with oraparib and bevacizumab could be one of the promising treatment options for MCT-SCC.
The malignant transformation of mature cystic teratoma of the ovary is a rare condition, and it is considered to be squamous cell carcinoma (SCC) in 80% of cases. Stage II and higher cases of SCC arising from mature cystic teratoma of the ovary (MCT-SCC) have poor prognoses, and their five-year overall survival is < 50% [1, 2]. There is no standard treatment for MCT-SCC, and complete cytoreductive surgery, including hysterectomy, bilateral salpingo-oophorectomy, and lymphadenectomy followed by adjuvant platinum-based chemotherapy, which is considered effective [1–3].
Approximately 50% of cases of ovarian cancer involve a homologous recombination deficiency (HRD) due to alterations of homologous recombination repair (HRR) pathway genes [4]. The relationship between the HRD status and platinum-based chemotherapy sensitivity or poly (ADP ribose) polymerase (PARP) inhibitor efficacy in ovarian cancer has been demonstrated in previous clinical trials [5, 6]. The National Comprehensive Cancer Network (NCCN) guidelines recommend implementing BRCA and HRD testing in patients with recurrent or metastatic ovarian cancer [7]. However, the significance of the HRD status or homologous recombination repair pathway gene abnormalities in rare forms of ovarian cancer such as MCT-SCC is unclear.
Here, we present the case of a patient with advanced MCT-SCC and a remarkably high genomic instability (GI) score. The patient underwent maintenance therapy with olaparib and bevacizumab after platinum-based chemotherapy and two sessions of debulking surgery.
A 73-year-old multiparous woman with no remarkable past medical history visited her local physician with symptoms of low abdominal pain. A left ovarian tumor measuring approximately 15 cm was identified, and she was referred to our hospital for further examination and treatment. Computed tomography (CT) imaging revealed a left ovarian tumor with a solid part including fatty components and calcifications and the enlargement of para-aortic and pelvic lymph nodes. The blood squamous cell carcinoma antigen (SCC-Ag) level of 11.6 ng/ml was high. Based on these findings, she was suspected of having MCT-SCC. One week after the initial visit, she presented with increasing abdominal pain. Blood tests revealed elevated levels of inflammatory markers (white blood cell [WBC): 13,100 /ul, C-reactive protein (CRP) 16.83 mg/1), and CT imaging revealed that the tumor had shrunk to 10 cm in size with ascites extending into the upper abdomen (Fig. 1). Moreover, she was considered to have peritonitis due to tumor rupture, which necessitated an emergency exploratory laparotomy. Total abdominal hysterectomy, bilateral salpingo-oophorectomy, and partial omentectomy were performed. The left ovarian tumor measured 10 cm and had ruptured as diagnosed preoperatively, and the ensuing ascitic fluid cytology was positive. The left ovarian tumor was firmly adherent to the surrounding pelvic organs, and could not be completely resected. In addition, 5-mm-sized peritoneal disseminations remained on the surface of the rectum. The enlarged para-aortic lymph nodes measured approximately 1 cm. Postoperative histopathology revealed nonkeratinizing SCC with partially poorly differentiated SCC. The tumor contained hair follicles and was considered to be MCT-SCC. p53 overexpression was detected via immunostaining (Fig. 2). There was a 14-mm-sized omental disseminated metastasis. The postoperative diagnosis was stage IIIB ovarian cancer (pT3bNXM0). In addition, a 14 × 7-mm-sized endometrial cancerous mass was simultaneously detected. The endometrial cancer was stage IA and the histological diagnosis was grade 1 endometrioid carcinoma. After surgery, the myChoice CDx (Myriad Genetic Laboratories, Inc., Salt Lake City, United States) test and microsatellite instability (MSI) test (SRL, Tokyo, Japan) were performed using specimens from the nonkeratinizing SCC section of the primary tumor. The GI score of 87 was remarkably high, and there was no BRCA1/2 pathogenic mutation. Conversely, the MSI test was negative. Three weeks after surgery, the patient was placed on intravenous (IV) carboplatin AUC in six doses and paclitaxel (IV, 175 mg/m2). CT imaging after six courses showed that residual tumors had shrunk by 73% (target lesions: 85 mm to 23 mm; Fig. 3) and blood SCC-Ag levels decreased from 12.8 ng/ml postoperatively to 1.6 ng/ml at the end of one course of chemotherapy, and remained in the normal range thereafter. We considered the complete removal of residual tumors feasible and performed interval debulking surgery (IDS) six months after the first visit. Complete residual tumor resection was achieved by partially resecting the left ureter, and pelvic and para-aortic lymphadenectomy was also performed. The residual tumor contained nonkeratinizing SCC and the primary tumor, and chemotherapy-induced hyalinized stroma was widely observed. Metastatic SCC was also detected in a para-aortic lymph node. (Fig. 4). Since six weeks after IDS, the patient has received two courses of the combination of paclitaxel, carboplatin, and bevacizumab (IV, 15 mg/m2), followed by maintenance therapy with bevacizumab and oral olaparib (600 mg/day). Five months after IDS, no recurrence has been observed.
Although platinum-based chemotherapy shows some efficacy for MCT-SCC, the prognosis of advanced cases was poor [1, 2]. Clinical biomarkers that predict the efficacy of platinum-based chemotherapy for MCT-SCC have not been identified. Here, we presented the case of an MCT-SCC patient with a remarkably high GI score who was successfully treated with twice debulking surgeries, platinum-based therapy, and maintenance therapy with olaparib and bevacizumab. It has been reported that HRD, including the BRCA1/2 pathogenic mutation, may be an excellent biomarker for predicting the response to platinum-based chemotherapy and PARP inhibitors not only in ovarian cancer but also in breast, prostate, and pancreatic cancer [8]༎ Moreover, the significance of HR deficiency in SCC has been gradually elucidated, and the efficacy of PARP therapy has been tested in preclinical and clinical models for lung and head and neck SCC [9–11]. By contrast, bevacizumab maintenance therapy may be effective in MCT-SCC [12]. The combination of bevacizumab and olaparib demonstrated efficacy in a phase III trial for HRD-positive epithelial ovarian cancer [5]. This case suggests that the HRD status may be critical in determining the treatment strategy for MCT-SCC as well as other cancers.
In MCT-SCC, the frequency and mechanisms of HRD were unknown. MCT-SCC with BRCA1/2 pathogenic mutations has not been reported yet. The cause of the high GI score may be related to the molecular biological features of MCT-SCC. Recently, two comprehensive analyses have shown a characteristically high frequency of tumor suppressor protein P53 (TP53) pathogenic mutations in MCT-SCC, 20/25 (80%) and 7/8 (87.5%), respectively [13, 14]. In this case, the p53 mutation was suggested by immunostaining. TP53 mutations promote two types of genomic instability, which are chromosomal and amplification instability [15]. Recently, an association between TP53 mutations and the HRD status has been reported in several studies [16–18]. In MCT-SCC, TP53 wild-type patients have a poorer prognosis than TP53-mutant patients [13], which may also be related to the HRD status and chemotherapy sensitivity.
In the present case, the MSI test was negative; however, a mismatch repair deficiency was demonstrated in two of seven carcinomas arising from ovarian teratoma [19]. Furthermore, more than half of MCT-SCC cases demonstrated programmed death receptor-1 (PD-1) expression and high tumor-infiltrating CD8-positive lymphocyte counts, suggesting that immune checkpoint inhibitors may be effective for MCT-SCC [14]. At present, several cases have been reported in which pembrolizumab was effective for MCT-SCC [20, 21]. In recent studies, HRD is inversely correlated with MSI and is frequently identified in immunologically cold tumors [22, 23]. Therefore, a PARP inhibitor may be an attractive therapeutic option in patients who do not respond to the anti-PD-1 antibody. Further clarification of the association between the HRD status and molecular biological characteristics of MCT-SCC may provide more appropriate treatment options for MCT-SCC.
To the best of our knowledge, this is the first reported case of MCT-SCC with HRD-positive status. Although its frequency is unknown, platinum-based chemotherapy followed by maintenance therapy with olaparib and bevacizumab may be one of the promising treatment options for MCT-SCC. Future studies focused on the correlation of the HRD status with molecular characteristics of MCT-SCC and treatment efficacy should be carried out.
CT: Computed tomography
CRP: C-reactive protein
GI: Genomic instability
HRD: Homologous recombination deficiency
HRR: Homologous recombination repair
IDS: Interval debulking surgery
IV: Intravenously (IV)
MCT-SCC: Squamous cell carcinoma arising mature cystic teratoma of the ovary
MSI: Microsatellite instability
NCCN: National Comprehensive Cancer Network
PARP: Poly (ADP ribose) polymerase
PD-1: Programmed death receptor-1
SCC: Squamous cell carcinoma
TGOG: Taiwanese Gynecologic Oncology Group
TP53: Tumor suppressor protein P53
WBC: white blood cell
Ethics approval and consent to participate
This study was performed under the Declaration of Helsinki and was approved by the institutional ethics review board at Niigata Cancer Center (No 1148).
Consent for publication
Written informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Funding
This work was supported in part by JSPS KAKENHI grant number 21K16785 (Grant-in-Aid for Young Scientists for RT), the Takeda Grant for RT and the Kanzawa Grant for RT.
Acknowledgments
We thank Dr. Kosuke Yoshihara (Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences) for his clinical professional advice.