Role for immunotherapy in pretreated, recurrent, metastatic squamous cell carcinoma arising from mature cystic teratoma

1. Background

Mature cystic teratomas (MCTs) are the most common ovarian germ cell tumor, representing 10–20 % of all ovarian neoplasms and up to 60 % of benign ovarian neoplasms (Black et al., 2015). MCTs arise from a single germ cell undergoing asexual parthenogenesis resulting in three mature germ cell layers with 46XX karyotype. MCTs are most common in women in their fourth decade of life, typically range from 5 to 10 cm in size at time of initial diagnosis and are largely benign. However, in < 2 % of cases there can be malignant transformation arising from one or multiple individual components. While malignant transformation can result in a wide variety of de novo tumor histology, up to 80 % of these transformations differentiate as squamous cell carcinoma (SCCa) (Li et al., 2019). Pelvic ultrasound is frequently utilized in the diagnosis and characterization of MCTs, with a unique finding – the Rokitansky protuberance – highly specific for this tumor. This protuberance represents the echogenic interfaces of fat, hair, and tissue, and appears as a characteristic hyperechoic nodule. The Rokitansky protuberance is the most common site of malignant transformation within MCTs (Hackethal et al., 2008). There are several factors that increase the likelihood of malignant transformation within an MCT – such as size > 10 cm or age > 50 years old – as well as findings such as elevated serum tumor markers or presence of hypercalcemia which might signal transformation has already occurred (Comerci et al., 1994). First line treatment of malignancy arising within MCTs is complete surgical cytoreduction. Specific data guiding necessity of, or type and duration of adjuvant treatment, is highly limited and no definitive consensus currently exists. Moreover, different histology may represent divergent driver events and likely represent biologically distinct entities with unique mutational profiles. Regarding SCCa, adjuvant treatment for advanced or metastatic disease is extrapolated from guidelines for epithelial ovarian cancer and typically includes platinum-based chemotherapy. However, for recurrent or refractory disease, evidence guiding treatment decisions is limited to small case series and case reports. Alkylating agents such as doxorubicin have shown possible survival benefit; however, patient populations are small and heterogenous, limiting reliability of findings. Due to the rarity of this pathology, secondary therapy is not well-defined (Hackethal et al., 2008, Ayhan et al., 2000). Given evolving experience and increasingly successful utilization of immune checkpoint blockade in treatment of SCCa of the cervix and vulva, and highly constrained availability of quality data guiding later-line therapy for pre-treated metastatic SCCa of the ovary, we sought to explore the role of immunotherapy in this setting.

2. Case report

A 41-year-old premenopausal Hispanic female presented to the emergency department in February 2021 with acute complaints of severe lower abdominal pain, nausea, vomiting, and fatigue. Her abdominal and bimanual pelvic exam revealed a palpable, firm mass extending from the pelvis to the level of the umbilicus. Computed topography (CT) of her abdomen and pelvis showed an 8.5 × 10.6 × 10.3 cm heterogenous mass in the right pelvis with a Rokitansky nodule consistent with a mature cystic teratoma. There was also soft tissue filling of the left gonadal vein concerning for vascular invasion, multiple enlarged retroperitoneal lymph nodes, and concern for carcinomatosis (Fig. 1A, Fig. 1B). Imaging of the chest was negative for definitive metastatic disease. CA-125 was elevated to 179.9 U/mL and CEA 7.3 ng/mL, while other tumor markers were not elevated. Labs were notable for leukocytosis of 26,000, total calcium of 14.4 mg/dL, and ionized calcium of 7.4 mg/dL, concerning for a leukemoid reaction and hypercalcemia of malignancy. She was medically stabilized and underwent exploratory laparotomy, modified radical hysterectomy, bilateral salpingo-oophorectomy, omentectomy, resection of abdominal wall mass, left pelvic lymph node dissection, resection of left infundibulopelvic ligament and radical tumor debulking, with residual tumor in the suprarenal para-aortic lymph node bed at the left renal hilum. Surgical pathology confirmed moderately differentiated squamous cell carcinoma arising from mature cystic teratoma of the ovary measuring 18 cm with tumor extending into the uterine corpus invading serosa, myometrium and adjacent fibroadipose tissue, with metastatic disease found directly extending within the left IP ligament, para-aortic nodal tissue, omentum, and abdominal wall. Immunohistochemistry within the primary tumor revealed diffuse positive staining for p40, with HPV independence demonstrated with negative p16 and lack of HPV in-situ hybridization, and the cervix was notably without pathologic abnormality. The specimens were also tested for programmed death ligand 1 (PD-L1), which demonstrated a combined positive score (CPS) > 5 % (Fig. 2a, Fig. 2b, Fig. 2c, Fig. 2d). In the post-operative period, the patient recovered well and the hypercalcemia resolved. She underwent germline panel genetic testing with no significant mutations identified. Ultimately, the patient was diagnosed with stage IIIC moderately differentiated squamous cell carcinoma arising from right ovarian mature cystic teratoma with residual disease.

Fig. 1A.

Pre-operative mass with extension along gonadal vein.

Fig. 1B.

Pre-operative para-aortic lymph nodes near left renal hilum.

Fig. 2a.

Arrow 1 showing ovarian capsule, arrow 2 showing malignant transformation.

Fig. 2b.

Medium power view shows nests and sheets of tumor cells with arrow to focal necrosis.

Fig. 2c.

High power view of keratin pearls characteristic of squamous cell carcinoma.

Fig. 2d.

P40 immunostaining diffusely positive, signifying squamous carcinoma.

Due to the rarity of disease and lack of well-defined treatment protocols, the patient was discussed at multidisciplinary tumor board to discuss options and gain consensus expert opinions from gynecologic oncology, radiation oncology, diagnostic radiology, genetics, and gynecologic pathology divisions. The decision was made to offer adjuvant chemotherapy with carboplatin, paclitaxel, and bevacizumab every 3 weeks for 6 cycles. Despite this, after receiving 6 cycles of systemic chemotherapy, CA 125 was noted to be rising from 26 to 56, and surveillance CT of the chest, abdomen, and pelvis revealed a markedly enlarged left periaortic lymph node abutting the left adrenal gland and renal hilum (4.8 × 4.5 cm, previously 2.2 cm, Fig. 3A), slightly enlarging right retrocrural lymph node (1.1 cm, previously 0.9 cm), and a new soft tissue mass adjacent to left external iliac vessels (2.2 × 1.9 cm), consistent with primary platinum-refractory progression of disease (Fig. 3B). The patient was again presented at multidisciplinary tumor board and, given the inability to safely dose radiation due to location of the disease, based on the significant PD-L1 positivity of the primary tumor the decision was made to transition therapy to single agent pembrolizumab 200 mg every 3 weeks. Assessment of treatment response on initial scans showed slight enlargement of target lesions (+9%, iRECIST stable disease), however this was followed by a partial response (−32 % in target lesions) which developed during the first 9 months of treatment, followed by prolonged and ongoing stable disease and normalization of CA 125 (Fig. 3C). The patient presently remains on therapy, completing 25 cycles over 18 months of continuous treatment with no cycle delays. The patient has tolerated treatment very well, with the only treatment-related adverse effect arising after 6 cycles of pembrolizumab – a mild grade 2 hypothyroidism well-controlled with oral levothyroxine replacement. She has resumed normal activities of daily living without assistance, has a good quality of life, and maintains an excellent functional status while remaining on active therapy.

Fig. 3A.

Initial lymphatic disease prior to therapy.

Fig. 3B.

New lymphatic metastases while undergoing initial therapy signifying progression of disease.

Fig. 3C.

Reduction of disease while on pembrolizumab.

3. Discussion

Malignant transformation with MCTs is a rare phenomenon with a wide array of possible histology potentially arising from any of the three germ layers. Squamous cell carcinoma of the ovary is the most common malignant transformation of the MCT; however, this is most frequently ovary-confined disease and is most often cured with surgical resection. There is scant literature on the management of these tumors, particularly outside of stage I disease and/or frontline therapy, and the limited available case studies suggest managing them similarly to the more common epithelial ovarian malignancies. In these case studies, the patients are generally managed with platinum-based chemotherapy, but patients with progressive disease have a very poor prognosis (Tehranian et al., 2021). Additionally, in contrast to treatment for SCCa in other locations, the role of radiation therapy is less well-defined and not been shown to improve survival (Hackethal et al., 2008). Furthermore, published data is sparse regarding post-progression therapies and very poor response rates and survival are reported.

Along with cytoreductive surgery, combination chemotherapy with carboplatin and paclitaxel has shown to be effective in treating squamous cell carcinoma arising from MCTs and has shown improved survival in patients with advanced disease (Hackethal et al., 2008). There is also evidence that bevacizumab along with platinum-based chemotherapy has improved survival in advanced and recurrent ovarian cancer patients (Tewari et al., 2019, Aghajanian et al., 2012). In at least one case study, bevacizumab in combination with platinum-based therapy was successful in managing squamous cell carcinoma arising from MCT (Fukase et al., 2020). Given the lack of high-quality data specific for advanced SCCa arising from MCT, the decision was made to proceed with carboplatin, paclitaxel, and bevacizumab as adjuvant chemotherapy based on established treatments for stage III epithelial ovarian cancer with residual disease. The patient failed this initial therapy, having rapid progression of disease while on active treatment after six cycles, consistent with a primary platinum-refractory disease.

Our patient’s immunohistochemistry evaluation showed PD-L1 in 2 % of tumor cells and in 10 % of tumor associated immune cells, giving a combined positive score (CPS) > 5 %. Programmed cell death protein 1 (PD1) is a checkpoint protein that regulates immune response, and the expression of its ligand, PD-L1 allows for tumor cells to evade the host immune response to tumor cells. Pembrolizumab is a humanized IgG4 monoclonal anti-PD1 antibody that modulates the immune response to more effectively prevent immune evasion by tumor cells. It has received broad FDA approval to treat a variety of malignancies, including melanoma and non-small cell lung cancer, and phase II/III clinical trials have also demonstrated success – as monotherapy or in combination – in treating gynecologic malignancies (Makker et al., 2022, O'Malley et al., 2022, Colombo et al., 2021). The majority of phase I/II/III trials have yet to demonstrate efficacy or survival advantage for immunotherapy in the treatment of ovarian cancer, regardless of PD-1/PD-L1 status, in the frontline (i.e. JAVELIN 100, GOG 3015, INEOV), recurrent (KEYNOTE 100), or resistant settings (i.e. JAVELIN 200, GY-003) (Chardin and Leary, 2021). Generally, HPV-negative malignancies have been excluded from clinical trials of immunotherapy, and in the limited data available, primarily related to HPV negative head and neck cancer, the response to treatment and efficacy has been limited. One recent non-randomized single arm phase II trial showed that a combination of pembrolizumab, bevacizumab, and oral metronomic cyclophosphamide was safe and well-tolerated in recurrent ovarian cancer, and objective response rates were impressive at 43 % among platinum resistant participants. However, progression free survival was similar to other therapies in the platinum resistant setting at 7.6 months (Zsiros et al., 2021). Among the sparsely available experience utilizing immunotherapy in cases of SCCa arising within MCT, a Chinese case report described treatment with camrelizumab (a PD-1 inhibitor) in combination with the multi-tyrosine kinase inhibitor anlotinib. In this case, treatment was poorly tolerated and subsequently discontinued due to severe toxicity and gastrointestinal bleeding (Li et al., 2021). Our patient was placed on Pembrolizumab as monotherapy due to a positive CPS score, and she remains on active treatment with prolonged stability of disease for>18 months. This is the first English-language report of a patient with recurrent, platinum-refractory SCCa arising within MCT of the ovary to be treated with single agent pembrolizumab with durable, favorable treatment course and maintained quality of life.

4. Conclusion

Malignancy arising from MCTs is a rare disease and there is limited data available on treatment. The established treatments have generally poor outcomes (Hackethal et al., 2008), and experience is highly limited in providing post-progressive treatment. The approach of utilizing the patient’s immunohistochemical profile to provide targeted treatment, in this case immune checkpoint blockade using Pembrolizumab, resulted in durable disease control with good quality of life. This case demonstrates that there is a potential role for Pembrolizumab therapy in patients presenting with PD-L1 positive progressive SCCa arising within MCT of the ovary.

CRediT authorship contribution statement

Carson C. Edwards: Investigation, Writing – original draft, Writing – review & editing, Visualization. Steven Blaine Holloway: Conceptualization, Validation, Writing – review & editing, Visualization, Supervision. Shalini Sethi: Writing – review & editing, Visualization. Jayanthi S. Lea: Validation, Writing – review & editing, Supervision, Project administration.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.