A case report of gastroesophageal adenocarcinoma with yolk sac tumor differentiation in a pregnant patient

Introduction

Gastroesophageal adenocarcinomas with yolk sac tumor differentiation are exceedingly rare. Yolk sac tumors are germ cell tumors which largely arise in the gonads as primary tumors or as a part of mixed germ cell tumors (1). While they are predominantly gonadal, approximately 5% of yolk sac tumors occur in extragonadal sites. These sites typically include midline locations, such as the mediastinum, retroperitoneum, and the central nervous system (1).

Approximately 60% of yolk sac tumors present in a pure form while 40% present with mixed germ cell tumors (2). There have only been a limited number of cases reported of gastroesophageal adenocarcinomas dedifferentiating into a yolk sac component in either mixed or pure forms (3).

Yolk sac tumors typically present with an aggressive clinical course. Most patients, unfortunately, have widespread metastases at the time of diagnosis, making curative treatment challenging (4).

In this report, we present a rare case of gastroesophageal adenocarcinoma with yolk sac tumor differentiation with liver and lung metastasis who withstood multiple systemic treatment regimens given her young age and lack of other comorbidities. We present this article in accordance with the CARE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-622/rc).

Case presentation

A 22-year-old female gravida 1 para 0 at 29 weeks and 1 day of gestation with a past medical history significant for iron deficiency anemia and type 1 von Willebrand disease presented with right upper quadrant abdominal pain, nausea, vomiting, fatigue, and melena ongoing for several weeks. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Verbal informed consent was obtained from the patient for the publication of this case report and accompanying images before she passed away.

Given her ongoing clinical symptoms and initial laboratory studies concerning for anemia requiring multiple iron and packed red blood cell transfusions, there was high suspicion for gastrointestinal blood loss. However, an endoscopy was not initially pursued given her gravid state.

Laboratory studies on arrival were significant for hemoglobin (Hgb) of 9.2 g/dL, total bilirubin of 0.8 mg/dL, aspartate aminotransferase (AST) 132 U/L, alanine aminotransferase (ALT) of 48 U/L, alkaline phosphatase (ALP) of 558 U/L, lipase of 177 U/L. Magnetic resonance imaging (MRI) of the liver revealed multiple intrahepatic masses throughout the right and left hepatic lobe and a left upper quadrant mass possibly arising from the pancreatic tail (Figure 1A,1B). Computed tomography (CT) of the chest revealed bilateral pulmonary nodules concerning for metastatic disease. Subsequent tumor makers revealed a cancer antigen 19-9 (CA19-9) of 1,395 U/mL and an alpha-fetoprotein (AFP) of 303,000 ng/mL. A liver biopsy was performed and initially read as a high-grade neuroendocrine carcinoma. She underwent an emergent cesarean section at 30 weeks and 2 days due to fetal distress. Given her sharp climb in total bilirubin and liver enzymes, she was treated with one cycle of inpatient carboplatin dosed at an area under the curve of 5 and etoposide dose reduced to 50 mg/m² on days 1 through 3 with subsequent improvement in her transaminitis. During treatment, her hepatic mass biopsy slides were in the process of being reviewed by pathology at John Hopkin’s University and discovered to be a malignant neoplasm with yolk sac tumor differentiation (pure or mixed) or a somatic carcinoma with divergent YST differentiation [Figure 2A; Table 1: (I)]. She was then transitioned to bleomycin 30 units weekly with etoposide and cisplatin on days 1 through 5 of 21-day cycle [bleomycin, etoposide, and cisplatin (BEP)] for a total of five cycles with anticipated curative intent.

Figure 1 Magnetic resonance imaging of abdomen demonstrating (A) extensive intrahepatic masses and (B) a heterogenous mass within the left upper quadrant measuring 6.9 cm × 5.8 cm.

Figure 2 Pathology images of liver, gastroesophageal, and lung nodule biopsies with immunohistochemical staining patterns. (A) Liver core biopsy, malignant neoplasm with yolk sac differentiation (HE staining; magnification: 40×); (B-D) gastroesophageal mass biopsy, adenocarcinoma with yolk sac tumor differentiation (HE staining; magnification: B, 40×; C, 40×; D, 100×); (E) immunohistochemical stain positive for CK7 on gastroesophageal biopsy (magnification: 40×); (F) immunohistochemical stain focally positive for SALL4 on gastroesophageal biopsy (magnification: 40×); (G,H) lung nodule core biopsy, poorly differentiated adenocarcinoma with yolk sac tumor differentiation (HE staining; magnification: G, 40×; H, 100×). HE, hematoxylin and eosin.

Next generation sequencing of the liver biopsy revealed a tumor protein 53 (TP53) mutation and cyclin E1 (CCNE1) amplification. She reported a family history of breast cancer in two maternal great aunts and pancreatic cancer in her maternal great grandmother. Genetic testing was performed with a panel of 70 genes and returned negative for any pathogenic variants. She had no prior smoking history or significant alcohol use. She had no known predisposing risk factors for malignancy.

A few months later, the patient underwent an esophagogastroduodenoscopy with endoscopic ultrasound (EUS) [esophagogastroduodenoscopy (EGD) with EUS]. The EGD revealed a tumor at the distal esophagus extending down to the level of the gastroesophageal junction (GEJ) becoming more necrotic as it went towards the gastric cardia. EUS revealed areas of hypoechoic changes in the left lobe of the liver, likely representing the known tumor burden of the liver. Biopsies of the tumor from the GEJ revealed p16-positive, microsatellite stable, human epidermal growth factor receptor 2 (HER2)-negative adenocarcinoma with yolk sac tumor differentiation, representing her primary tumor site (Figure 2B-2D). The tumor was positive for epithelial markers of gastrointestinal origin with foci of cells positive for SALL4, a marker with high specificity for yolk sac tumor [Figure 2E,2F; Table 1: (II)]. She was started on fluorouracil 2,800 mg/m², leucovorin 30 mg, oxaliplatin 85 mg/m² (FOLFOX), and nivolumab 240 mg every 2 weeks and underwent five cycles but was then switched to paclitaxel 80 mg/m² with ramucirumab 8 mg/kg due to progression of her disease. She later developed dyspnea and interval imaging was consistent with pneumonitis likely from her first dose of paclitaxel. She was then switched to nab-paclitaxel 125 mg/m² with ramucirumab. However, given worsening of her ground-glass opacities, taxanes were no longer considered.

Her interim chest imaging also revealed that her multifocal bilateral pulmonary nodules had increased in size. She underwent a CT-guided biopsy of a 12-millimeter lesion in the right upper lobe of the lung, in which pathology exhibited a poorly differentiated adenocarcinoma consistent with metastasis from the previously diagnosed gastroesophageal primary with yolk sac tumor differentiation [Figure 2G,2H; Table 1: (III)].

She was started on vinblastine 0.11 mg/kg, ifosfamide 1,200 mg/m² with mesna, and cisplatin 16 mg/m² (VeIP) every 4 weeks for four cycles, which was poorly tolerated given she was heavily pre-treated. She ultimately elected to go on hospice while on single agent irinotecan and passed 18 months after her initial presentation.

Discussion

Gastroesophageal adenocarcinomas with yolk sac tumor differentiation are extremely rare and comprise less than 0.1% of cancers of the region (5). Upper gastrointestinal carcinomas with YST differentiation typically have a poor prognosis due to widespread metastases at the time of diagnosis. The origin of yolk sac tumors arising in the gastrointestinal tract remains unclear. The main hypothesis is that YSTs derive from migrating germ cells during embryogenesis similar to other extragonadal germ cell tumors (5). This hypothesis has been suggested as pure YSTs in the stomach have been reported (5). Adenocarcinomas can also de-differentiate to embryonal ectoderm at the cellular level. However, there are several case reports that suggest that the adenocarcinoma components of the tumor heterogeneously transform to YSTs through aberrant differentiation, as was likely the case in our patient (6-9).

Schrader et al. describe a case of a gastrointestinal adenocarcinoma with differentiation into a choriocarcinoma. In their case, the patient underwent multiple biopsies to determine the final diagnosis and optimal treatment regimen. Biopsy of a GEJ mass revealed poorly differentiated adenocarcinoma while biopsy of the liver demonstrated poorly differentiated carcinoma and beta-human chorionic gonadotropin (β-hCG) staining cells consistent with non-gestational choriocarcinoma. Based on the histologic findings, their patient was treated with fluorouracil, leucovorin, and oxaliplatin (10). Kafka et al. describe a case of a patient with retroperitoneal lymphadenopathy as well as elevated AFP and β-hCG, which were not elevated in our patient due to her malignant process but rather her gravid state. Biopsy of the retroperitoneal lymph node revealed a poorly differentiated adenocarcinoma that was positive for CK7 and CK20 and negative for TTF-1 consistent with a gastrointestinal primary. An EGD revealed a locally advanced gastric cancer. Additional histopathologic testing revealed a poorly differentiated mixed-type gastric adenocarcinoma with trophoblastic tumor cell proliferations and the expression of β-hCG and HER2 overexpression and the patient was treated with capecitabine, oxaliplatin, and trastuzumab (11). These cases underscore the importance of a thorough evaluation for the primary tumor when pathology results are discordant with clinical findings.

Histologically, YSTs may have one or more morphologic patterns including reticular, microcystic, polyvesicular, alveolar-glandular, myxomatous, papillary, hepatoid, glandular, solid or tubular patterns. The distinguishing finding includes Schiller-Duval bodies, which are perivascular formations comprised of round or elongated fibrovascular cores with surrounding primitive columnar or cuboidal cells (6). Clinical diagnosis includes initially checking serum AFP levels as it is often produced by YST cells although it is a non-specific marker that can be elevated in gastrointestinal tumors, including hepatocellular carcinoma and gastric carcinoma (5).

The prognosis of patients diagnosed with gastric carcinomas with YST differentiation is generally poor given that most patients have widespread metastases at the time of diagnosis. Unfortunately, most patients expire within one year of diagnosis (5). Regimens including cisplatin, vinblastine, bleomycin, and etoposide can be used according to established germ cell cytotoxic regimens but have not been shown to improve long term survival (5). Chemotherapies for typical gastric adenocarcinomas can be utilized, especially if there is a strong suspicion that the primary adenocarcinoma components heterogeneously transformed to a YST (5).

Conclusions

Given our patient presented with metastatic disease during the third trimester of gestation and responded, albeit short-lived, each time to multi-agent therapy, including drugs from most classes of traditional cytotoxic therapies, as well as immunotherapy and vascular endothelial growth factor receptor 2 antibody blockade, she defied prognostic predictions based on what was quoted in the limited literature (Figure 3).

Figure 3 Chronological timeline of clinical course. Timeline illustrating the patient’s clinical course from initial presentation during pregnancy through diagnostic clarification, multimodal systemic therapy, and disease progression. This case highlights the diagnostic complexity of gastroesophageal adenocarcinoma with yolk sac tumor differentiation and the aggressive clinical course despite sequential cytotoxic and targeted therapies. AFP, alpha-fetoprotein; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BEP, bleomycin, etoposide, cisplatin; CA19-9, cancer antigen 19-9; CT, computed tomography; EGD, esophagogastroduodenoscopy; EUS, endoscopic ultrasound; FOLFOX, fluorouracil, leucovorin, oxaliplatin; GEJ, gastroesophageal junction; Hgb, hemoglobin; MRI, magnetic resonance imaging; VeIP, vinblastine, ifosfamide, cisplatin.

This case contributes to the limited existing literature on gastrointestinal adenocarcinomas with YST differentiation, emphasizing the utmost importance of early diagnosis and effective treatment for this aggressive malignancy. It hopes to shed light on a better understanding of the pathophysiology, diagnosis, and management options of this rare condition and optimistically provide data to aid in extending survival rates.

Acknowledgments

We would like to thank Dr. Eugene Alexandrin, Dr. Jillian Grau, and Dr. Lisa Dwyer-Joyce from the Department of Pathology and Laboratory Medicine at Lehigh Valley Health Network-Jefferson Health for their contribution to reviewing and analyzing the pathology to establish the correct diagnosis and for providing the histologic images for this article.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-622/rc

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-622/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-622/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Verbal informed consent was obtained from the patient for the publication of this case report and accompanying images before she passed away.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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