Somatically derived ovarian yolk sac tumor in a postmenopausal woman: A case report of durable remission with personalized chemotherapy.

A 74-year-old woman (G2P2) presented with a two-month history of early satiety, bloating, and left lower quadrant pain. Her medical history includes type 2 diabetes, hypertension, and obesity (BMI 38.5 kg/m 2 ). Menarche was at age 11, with regular menses, and menopause at 52. Her father was diagnosed with prostate cancer at 57 and her maternal grandmother had breast cancer at 77. A contrast-enhanced CT of the abdomen and pelvis revealed a predominately cystic mass measuring 21.1 x 18.0 x 21.5 cm, with areas of mural nodularity and enhancing septations. The mass extended directly into an umbilical hernia, where a discrete 1.7 cm nodule was identified. No metastatic disease or lymphadenopathy was noted ( Fig. 1 ). Serum tumor markers showed a baseline CA125 113.5 U/mL, CA19-9 17.47 U/mL, and CEA 42.7 U/ML. Baseline germ cell tumor markers were not collected. Fig. 1 CT Imaging of pelvic mass with umbilical involvement (a) axial view and (b) sagittal view. CT Imaging of pelvic mass with umbilical involvement (a) axial view and (b) sagittal view. She underwent a midline total abdominal hysterectomy, bilateral salpingo-oophorectomy (TAH BSO), and staging, including omentectomy, peritoneal biopsies, pelvic washings, and removal of the umbilical hernia nodule during laparotomy. A 25 cm ovarian mass was identified, along with 900 cc of straw-colored ascites. No residual disease remained at the end of her surgery.

Vinita Popat: Writing – review & editing, Writing – original draft, Data curation, Conceptualization. Adam Rucker: Writing – review & editing, Data curation. Joseph W. Carlson: Writing – review & editing, Data curation. Aimee Keegan: Writing – review & editing, Data curation. Lorna Rodriguez-Rodriguez: Writing – review & editing, Conceptualization.

Partially funded by Fridman Markel Funds.

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

The final pathology of the left tube, ovary, and umbilical nodule showed high-grade carcinoma, most consistent with a somatically derived yolk sac tumor ( Fig. 2 ). The right fallopian tube was positive for a tubal intraepithelial lesion. No malignancy was identified in the other specimens. Fig. 2 Surgical Pathology. (a) Somatic differentiation of yolk sac tumor (b) Yolk sac tumor with hyaline globules (c) Glypican-3 IHC staining (d) SALL-4 IHC staining. Surgical Pathology. (a) Somatic differentiation of yolk sac tumor (b) Yolk sac tumor with hyaline globules (c) Glypican-3 IHC staining (d) SALL-4 IHC staining. On IHC staining, the ovarian tumor was positive for p53 (mutated pattern), Glypican-3, SALL-4, and CDX2, and was negative for PAX8 and WT1. The left fallopian tube showed a p53 mutated pattern in both the tubal epithelium and tumor, with PAX8 in the tubal epithelium alone. The right fallopian tube epithelium also stained positive for p53 mutated pattern. The umbilical nodule stained diffusely positive for p53 and focally positive for PAX8.

After multidisciplinary tumor board review, the decision was made to treat the patient with etoposide & cisplatin (EP) chemotherapy. Bleomycin was deferred due to patient frailty. She received 20 mg/m 2 of cisplatin and 100 mg/m 2 of etoposide daily for five days every 21 days. Serial measurements of CA-125, CEA, and alpha-fetoprotein (AFP) tumor markers were obtained before and after each cycle of treatment. A baseline AFP level was not obtained before surgery, but her postoperative AFP level was elevated at 35.3 ng/mL (normal < 8 ng/mL). After the first two chemotherapy cycles, the patient’s AFP levels decreased during treatment but rose significantly three days before cycles #2 and #3 ( Fig. 3 ). This suggested that the 21-day interval between treatments was too long. As a result, cycle #3 of EP treatment was administered differently, as if patient was receiving only the EP aspect of the gestational trophoblastic neoplasm treatment, EMA-EP (etoposide, methotrexate, dactinomycin, and cisplatin), with plans to administer treatment every 14 days ( Aminimoghaddam et al., 2018 ). Fig. 3 Adjustments to dosing strategy following trends in AFP levels. (a) Change in AFP and Ca-125 levels throughout course of chemotherapy (b) Chemotherapy dosing and adjustments. Adjustments to dosing strategy following trends in AFP levels. (a) Change in AFP and Ca-125 levels throughout course of chemotherapy (b) Chemotherapy dosing and adjustments. In cycle #3, the patient received etoposide 100 mg/m 2 on days 1 and 2, followed by 80 mg/m 2 of cisplatin and 100 mg/m 2 of etoposide on day 8. Cycle #4 was administered two weeks later, with 100 mg/m 2 of etoposide day 1, and 50 mg/m 2 of cisplatin on day 8. Etoposide was withheld on day 2 and day 8 of cycle #4 due to persistent thrombocytopenia after day 1. Between cycle #3 and #4, the AFP level normalized, and the CA-125 level remained low. Imaging at this time showed no evidence of ongoing malignancy. During the patient’s chemotherapy course, she received GCSF support with the last two cycles. As the patient had no clinical evidence of disease, chemotherapy was discontinued after cycle #4. Surveillance consisted of serial examinations, imaging studies, and tumor marker assessments every 3 months for the first two years, followed by every 6 month assessments for an additional 3 years, now with annual follow up assessments. She has remained disease-free for over five years without any further treatment.

Ovarian yolk sac tumors (YSTs) in postmenopausal women are exceptionally rare, with fewer than 100 cases reported ( Wang et al., 2018 ). These tumors often originate from the somatic differentiation of epithelial ovarian neoplasms and are historically associated with a poor prognosis, particularly in advanced stages ( Bassi et al., 2022 ). Postmenopausal women more often present with advanced-stage disease and have poorer outcomes than younger patients, even when disease stage is comparable ( Wang et al., 2018 ). This case highlights a unique and favorable outcome in a patient with stage IIIB disease with a five-year remission following tailored chemotherapy. Somatically derived yolk sac tumors (SD-YSTs) are distinct from traditional germ cell yolk sac tumors (GC-YSTs) in their pathogenesis, demographics, and tumor biology. GC-YSTs arise from primordial germ cells in in young, reproductive-age women, while, SD-YSTs arise from germ cell differentiation of endometriosis or epithelial ovarian tumors, such as high-grade serous carcinoma, and predominantly affect postmenopausal women ( Skala et al., 2020 , McNamee et al., 2016 ). Both share histopathological features, including Schiller-Duval bodies and elevated expression of markers like alpha-fetoprotein (AFP), SALL-4 and Glypican-3. However, SD-YSTs often exhibit additional epithelial differentiation and may express markers like CK7 and PAX8, which are typically absent in GC-YSTs. These differences highlight the importance of accurate immunohistochemical profiling for diagnosis. McNamee et. al theorized SD-YSTs develop through a process of neometaplasia/retrodifferentiation of epithelial neoplasms, resulting in germ cell components within an otherwise epithelial malignancy ( McNamee et al., 2016 ). This may explain cases of YSTs arising from non-ovarian sites like the bladder, colon, and vulva ( Collins et al., 2022 , Murakami et al., 2020 , Kolin et al., 2022 ). Consistent with the molecular profiles described by Skala et al., which demonstrated that ovarian tumors with yolk sac differentiation often harbor somatic mutations such as TP53 and PI3K/AKT pathway alterations, our patient’s tumor was TMB-low with TP53 (H179Y) and AKT2 mutations, supporting a somatically derived yolk sac tumor arising in the setting of high-grade carcinoma 7 . Typically, GC-YSTs respond more favorably to standard germ cell tumor chemotherapy regimens, whereas SD-YSTs often exhibit chemoresistance, possibly contributing to poorer outcomes in postmenopausal women. While the distinct pathogenesis and clinical characteristics of SD-YSTs and GC-YSTs are crucial for diagnosis, effective treatment strategies rely on a nuanced understanding of their shared and divergent biological behaviors. GC-YSTs are successfully treated with a combination of bleomycin, etoposide, and cisplatin (BEP). However, for in SD-YSTs, there is insufficient evidence to recommend a specific treatment modality ( Williams et al., 1994 ). Most providers have historically utilized BEP in treatment of this rare subset of tumors, and all documented treatments incorporated platinum, highlighting the significance of platinum in targeting both epithelial and germ cell tumor components. In this patient's case, due to her older age and frailty, bleomycin was deferred. Because of thrombocytopenia, cisplatin was dose reduced in cycle #3 and further dose-reduced in cycle #4. Etoposide was also dose reduced in cycle #4 for this reason. Despite dose reductions, her treatment successfully achieved disease remission. We modified the chemotherapy schedule based on tumor marker kinetics. In response to rising AFPs levels, we decreased the interval between chemotherapy cycles (every 14 days instead of every 21 days), rather than increasing dosages or changing drugs. Serial AFP measurements provided an early and reliable indication of treatment efficacy. Given AFP's half-life of approximately six days, weekly monitoring allowed timely treatment adjustments. Intensifying the frequency of chemotherapy rather than the dose proved pivotal to achieve durable disease control ( Walhof et al., 1988 ). While accelerated (q2-week) BEP regimens have demonstrated efficacy in male germ cell tumors with G-CSF support to maintain dose intensity, our patient’s frailty and AFP kinetics prompted us to shorten the treatment interval as an individualized, biomarker-driven approach rather than a guideline-based modification ( Grimison et al., 2014 ). In addition, this patient’s AFP normalization by day 21 is consistent with prior findings that an early AFP decline is an independent prognostic factor ( De la Motte et al., 2016 ). This approach aligns with emerging evidence suggesting intensified therapy for high-risk patients whose tumor markers do not decline according to expected trajectories ( Sessa et al., 2020 ). This case demonstrates that somatically derived YST, though traditionally linked with dismal outcomes, can achieve remission with personalized treatment strategies and omitting bleomycin. It highlights the potential for platinum-based regimens, coupled with real-time biomarker-driven adjustments, to overcome resistance and improve survival even in advanced disease. Further studies are needed to establish standardized treatment protocols for somatically derived YSTs, particularly in older and frail patients. This case highlights the promise of individualized chemotherapy regimens in improving outcomes for this rare malignancy.

Malignant germ cell tumors of the ovary account for 2–3 % of all ovarian tumors ( Dunn et al., 2018 ). Ovarian yolk sac tumors (YSTs), the second most common types of malignant ovarian germ cell tumor, predominantly affect premenopausal patients, with 92 % of cases occurring in individuals under 50 ( de La Motte, xxxx , Nasioudis et al., 2017 ). The incidence of YSTs in postmenopausal women is low and is often associated with advanced-stage disease (stages III-IV) ( Nasioudis et al., 2017 ). In postmenopausal patients, YSTs can arise from a somatic differentiation of epithelial ovarian neoplasms, occasionally making them challenging to differentiate from primary germ cell tumors. As somatically derived yolk sac tumors (SD-YSTs) were only recently characterized in the literature in 2016, their clinical presentation and optimal management remain areas of active investigation. The prognosis for postmenopausal YSTs is poor, with a five-year overall survival of only 30.6 % (n = 36) ( Nasioudis et al., 2017 ). We present a case report of a patient with stage IIIB somatically derived yolk sac tumor successfully treated with personalized chemotherapy, who remains in remission after five years.

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.