Malignant transformation, such as ovarian squamous cell carcinoma (SCC) in ovarian mature cystic teratoma (OMCT), is a rare tumor. It exhibits a poor prognosis when diagnosed at advanced stages (1).

The gene mutations involved remain unclear, and the management of recurrent disease is still a challenge.

In recent years, immune checkpoint inhibitors (ICIs) have demonstrated great potential in treating a variety of cancers. To our knowledge, there is only one report in the literature of metastatic SCC arising from OMCT treated with an ICI (2). We herein report a recurrent case of ovarian SCC with a PIK3CA gene variation and immunohistochemical staining of programmed death-ligand 1 (PD-L1) >10%. This patient achieved clinical remission after platinum-based effective chemotherapy and programmed death 1 (PD-1) immunotherapy.

A 63-year-old woman (gravida 3, para 1) was referred to our hospital because of lower abdominal discomfort, and ultrasonography revealed an 8.7 * 8.0 cm heterogeneous adnexal mass in June 2018. The tumor markers were cancer antigen 125 (CA125) of 552.5 U/ml (<35) and SCC-associated antigen (Scc-Ag) of 9.4 ng/ml (<1.5). The human papillomavirus (HPV) screen of the cervix was negative before surgery. Due to the malignancy detected in frozen sections during the operation, laparoscopic hysterectomy plus bilateral salpingo-oophorectomy plus omentectomy plus pelvic lymph node dissection was performed. Postoperative pathologic examination indicated left OMCT with malignant transformation into moderately differentiated SCC. Metastases were not found in any other excised specimen. The stage was IC1 (cyst ruptured when taken out via vagina during operation) according to the International Federation of Gynecology and Obstetrics (FIGO) classification (3). Tumor markers decreased to normal after surgery. Three cycles of platinum-based chemotherapy (Taxol 175 mg/m² D1 and cisplatin 70 mg/m² D1, intravenously every 3 weeks) were given after surgery. Then, the patient received regular follow-up. The patient signed an informed consent that her data would be used for scientific purposes. The hospital’s ethics committee approved this study.

Malignant transformation occurs in 1%–2% of OMCTs, and the majority of these (80%) are SCCs (1). For those patients, prompt diagnosis and individualized treatment are crucial for a better prognosis. Sakuma (4) reported that optimal cytoreductive surgery can bring a mean survival of 14 months, and in suboptimal cases with advanced-stage disease, it is 7.8 months. The current recommendation of postoperative platinum-based chemotherapy in ovarian SCC is related to its activity in ovarian cancer and gynecological SCCs (5). However, to date, the appropriate treatment for patients with recurrent ovarian SCC is still a difficult problem.

This patient had a 7-month progression-free survival (PFS) with sirolimus used as a maintenance treatment after chemotherapy at the first recurrence, and at the second recurrence, she had a PFS of more than 17 months with PD-1 inhibitor therapy. To date, the survival time has been more than 41 months. For this case with a second recurrence, there are several key issues that should be thoroughly discussed. First, the operation may have played a pivotal role as the initial treatment, but its role in the second cytoreductive surgery is uncertain. Second, the cytogenetic abnormalities might precede histological changes, and the increased copy number of PIK3CA and immunohistochemical positive staining for PD-L1 may be correlated with poor PFS. Thus, these abnormalities could be potential therapeutic targets for ovarian SCC, especially ICIs.

There is a rationale for ICI treatment in the management of ovarian cancer. However, the efficacy remains limited with a response rate of 10%–15% (6, 7). This may be due to a low tumor mutational burden and low PD-L1 expression (7). PD-L1 expression has emerged as one of the biomarkers that could predict sensitivity to ICIs (8). There are no data regarding the prevalence of PD-L1 expression in ovarian SCC, but studies of SCC of other primary sites have shown PD-L1 positivity ranging from 33% to 59% in squamous non-small cell lung cancer to 83.7% in cervical cancer (2, 9). In this patient, positive tumor PD-L1 expression (>10%) may be correlated with the responsiveness of ICI therapy.

Several studies have shown that the malignant transformation of OMCTs may be associated with genetic mutations. OMCT-associated SCC has a much higher overall mutational burden and more copy number alterations than OMCT (10). The most frequently altered genes in ovarian SCC were TP53 (80%), PIK3CA (52%), and CDKN2A (44%) (11). PIK3CA is a key oncogene located on chromosome 3, and PIK3CA p.H1047L is a hotspot mutation that lies within the PI3K/PI4K domain of the PIK3CA protein. H1047L confers a gain-of-function effect on the PIK3CA protein, as indicated by the increased phosphorylation of Akt and Mek 1/2, growth factor-independent cell survival, and transformation in cell cultures (12, 13). Mutations of PIK3CA will cause the PI3K enzyme to be continuously activated (14). It has been reported that a key signaling target of PD-1-mediated inhibition is the PI3K–Akt pathway (15, 16), and PD-1 can block the activation of PI3K by recruiting SHP-2 (16).

The immune system plays a significant role in ovarian cancer outcomes. Overexpression of the immune checkpoint receptor PD-L1 can lead to inhibition of an effective antitumor immune response (17). It has been reported that humanized monoclonal antibodies targeting PD-1 confer durable antitumor activity with acceptable safety and toxicity in patients with advanced PD-L1-positive ovarian cancer (18). Wu (2) reported the first case of a patient with metastatic SCC arising from OMCT who was successfully treated with pembrolizumab after progressing through platinum-based combination chemotherapy. Here, we present the clinical experience of a woman with recurrent SCC who responded to treatment with chemotherapy and the PD-1 inhibitor.

Because of tumor heterogeneity, gene mutations, which are the basis of targeted therapy in carcinomas with the same histological type, vary from case to case. Currently, personalized cancer medicine has become increasingly important for the treatment of malignancies. In addition to surgery and chemotherapy, targeted therapy could also benefit refractory cases.

In conclusion, this study is the first report indicating measurable responses to combination chemotherapy with immunotherapy in “recurrent” ovarian SCC. When considered with the findings from previous studies, combination treatment, especially immunotherapy, may lead to improved results. Further studies are needed to confirm our preliminary observations.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

The hospital Peking Union Medical College Hospital (CAMS) ethics committee approved this study. The patient signed an informed consent that her data would be used for 40 scientific purposes.

XS: manuscript writing. MY: protocol development, manuscript revision, and final approval of the version to be published. YW, D-yC, and J-xY: manuscript revision. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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