Signet Ring Cell Carcinoma of the Stomach with Chylous Pleural Effusion: Laterality Shift and Fluid Composition Change

Abstract

Conventional white-light endoscopy (a) and narrow band imaging (b) reveal discoloration (yellow arrowheads), a finding suggestive of poorly differentiated early gastric cancer. [...]irregular microvascular structures and clearly demarcated lesion boundaries are observed on narrow band imaging, suggesting malignancy, like SRCC. Pathological findings. a Histological sections of a gastric biopsy stained with hematoxylin and eosin (H&E). (i) Low-power view (200x) showing overall tissue architecture and inflammatory infiltration. (ii) High-power view (400x) highlighting nuclear atypia, cytoplasmic changes, and possible signet ring cells. b Histological sections of a pleural biopsy stained with hematoxylin eosin (H&E). (i) Low-power view (200x) showing diffuse infiltration of tumor cells within fibrotic and adipose tissue. (ii) High-power view (400x) highlighting signet ring cells with mucin-filled cytoplasm and peripherally displaced nuclei, consistent with metastatic adenocarcinoma. Discussion Malignant pleural effusion is most commonly caused by lung cancer, followed by breast cancer, ovarian cancer, and lymphoma. There is one reported case in which untreated chylothorax changed in nature over time, suggesting that tumor progression into the intra-abdominal lymph nodes led to lymphatic obstruction and subsequent improvement of chylothorax [9]. Because a detailed evaluation

Introduction

Signet ring cell carcinoma (SRCC) of the stomach is an aggressive subtype of gastric adenocarcinoma characterized by early lymphatic invasion and a poor prognosis. Malignant pleural effusion is commonly associated with lung and breast cancers, with gastric cancer accounting for only approximately 5% of malignant pleural effusion cases [1, 2]. Chylous pleural effusion, or chylothorax, is a rare condition characterized by the accumulation of lymphatic fluid in the pleural cavity. It is usually caused by trauma or lymphatic disorders. Among malignancy-associated cases, lymphoma is the most common cause, while gastric cancer is an extremely rare source [3]. Diagnosis of chylothorax is based on milky pleural fluid appearance and elevated triglyceride levels and is typically linked to thoracic duct obstruction or invasion, leading to lymphatic backflow or rupture. SRCC is known for its strong tendency to invade lymphatics at an early stage, which theoretically increases the likelihood of chylothorax; however, reported cases remain very limited. Here, we report a unique case of gastric SRCC with chylous pleural effusion that evolved from bilateral to unilateral distribution and demonstrated a shift in pleural fluid characteristics. This presentation offers valuable insights into the diagnostic complexity and pathophysiology of lymphatic involvement in gastric cancer.

Case Report

A 66-year-old woman presented with pharyngodynia, general fatigue and mild dyspnea. On physical examination, diminished breath sounds were noted bilaterally, with no evidence of clubbing, cyanosis, or peripheral edema. No other significant systemic abnormalities were observed. Chest radiography and computed tomography (CT) revealed bilateral pleural effusion (Fig. 1a [i, ii]), and thoracentesis was performed. The pleural fluid was chylous, with an elevated triglyceride level of 1,074 mg/dL, leading to a diagnosis of chylothorax. Results of cytology and tuberculosis tests, including Ziehl-Neelsen staining and polymerase chain reaction, were negative. No obvious physical findings suggestive of collagen disease were observed, and various antibody tests, including rheumatoid factor and autoantibody tests, were negative. The pleural fluid carcinoembryonic antigen (CEA) level was 0.9 ng/mL, indicating no significant increase. Lymphoma was suspected, and flow cytometry was performed; however, no abnormalities were detected. The patient was treated with ampicillin/sulbactam (1.5 g intravenously every 8 h) for 7 days, leading to symptom resolution, and was subsequently followed up. The patient remained stable 1 month later (Fig. 1b [i, ii]). Additionally, the right pleural effusion showed improvement. However, 2 months after the initial presentation, the left-sided pleural effusion reaccumulated on CT and chest radiography. Repeat thoracentesis was performed (Fig. 1c [i, ii]), revealing a pale yellow fluid with a decreased triglyceride level of 22 mg/dL. The CEA level increased to 16 ng/mL. Cytological examination of the pleural fluid showed scattered malignant cells with signet ring morphology, characterized by intracellular mucin displacing the nuclei peripherally. The background consisted mainly of lymphocytes and mesothelial cells. These features supported the diagnosis of metastatic SRCC, thereby prompting upper gastrointestinal endoscopy to search for the primary tumor (Fig. 2a).

Fig. 1.

Chest computed tomography (CT) scans (upper row) and radiographs (lower row) taken during the initial visit and follow-up. a Chest CT scan (i) and radiograph (ii) at the initial visit show bilateral pleural effusion but no apparent abnormalities in the lung fields. b Chest CT scan (i) and the corresponding chest radiograph (ii) taken 1 month after the initial visit show that the left pleural effusion persisted but did not progress, and the right pleural effusion improved, with confirmation of decreased volume. No obvious abnormalities are observed in the lung parenchyma. c Chest CT scan (i) and the corresponding chest radiograph (ii) taken 2 months after the initial visit show a significant increase in the left pleural effusion, with a noticeable expansion in fluid volume. In contrast, there is no increase in the right pleural effusion with signs of continued improvement.

Fig. 2.

Upper gastrointestinal endoscopy, narrow band imaging, and thoracoscopic findings. Conventional white-light endoscopy (a) and narrow band imaging (b) reveal discoloration (yellow arrowheads), a finding suggestive of poorly differentiated early gastric cancer. Moreover, irregular microvascular structures and clearly demarcated lesion boundaries are observed on narrow band imaging, suggesting malignancy, like SRCC. Thoracoscopic findings reveal diffusely progressive lesions. c The blue arrow indicates the lung side, whereas the yellow arrowheads indicate the parietal pleura. Multiple irregular nodular lesions are visible on the parietal pleura, suggesting disseminated tumor involvement. d Extensively distributed whitish tumor lesions are present on the parietal pleura, strongly suggesting malignant pleural involvement.

Endoscopic examination revealed an area of pallor within a background of atrophic gastritis, raising the suspicion of early gastric cancer. Positron emission tomography (PET)-CT was conducted to identify the primary lesion, but no obvious primary tumor was detected, except for pleural dissemination (Fig. 3). Given this clinical discrepancy, thoracoscopy was performed (Fig. 2b). Thoracoscopic examination revealed diffusely thickened parietal pleura with redness and some whitish tissue, which was friable and prone to bleeding. A biopsy was performed at this site. Histopathological examination of both gastric and pleural biopsy specimens confirmed SRCC (Fig. 4a[i, ii], B[i, ii]). Genetic analysis revealed PD-L1 CPS 1–5, HER2 negativity, and CLDN18.2 positivity, all confirmed by immunohistochemistry.

Fig. 3.

Positron emission tomography-computed tomography revealing no primary lesions suspicious for malignancy other than the obvious pleural dissemination. The yellow arrow highlights the metastatic site.

Fig. 4.

Pathological findings. a Histological sections of a gastric biopsy stained with hematoxylin and eosin (H&E). (i) Low-power view (200x) showing overall tissue architecture and inflammatory infiltration. (ii) High-power view (400x) highlighting nuclear atypia, cytoplasmic changes, and possible signet ring cells. b Histological sections of a pleural biopsy stained with hematoxylin eosin (H&E). (i) Low-power view (200x) showing diffuse infiltration of tumor cells within fibrotic and adipose tissue. (ii) High-power view (400x) highlighting signet ring cells with mucin-filled cytoplasm and peripherally displaced nuclei, consistent with metastatic adenocarcinoma.

Chemotherapy Details

The patient underwent chemotherapy with capecitabine plus oxaliplatin (CapeOX).

Capecitabine: 1,000 mg/m² orally, twice daily for 14 days, followed by a 7-day rest period in a 21-day cycle.

Oxaliplatin: 130 mg/m² intravenous infusion on day 1 of each 21-day cycle.

Two cycles of CapeOX were administered.

This was followed by four cycles of CapeOX plus nivolumab.

Nivolumab: 360 mg intravenous infusion every 3 weeks (Q3W), added to the CapeOX regimen starting from the third cycle.

As the cancer progressed, bilateral pleural effusion became more prominent. Pleurodesis was performed; however, the patient passed away 4 months after diagnosis, just 2 weeks after undergoing pleurodesis. No autopsy was performed. CEA levels did not increase consistently throughout the clinical course, and tuberculosis culture results remained negative.

Discussion

Malignant pleural effusion is most commonly caused by lung cancer, followed by breast cancer, ovarian cancer, and lymphoma. Gastric cancer accounts for only approximately 5% of cases [1, 2]. The laterality of malignant pleural effusion varies depending on the malignancy type. Generally, malignant pleural effusion is unilateral, with bilateral pleural effusion reported in 10%–13% of cases [4]. In lung cancer, pleural effusion typically accumulates on the side of tumor development and may become bilateral as the disease progresses [5]. Bilateral pleural effusion has been reported in 43% of cases of gastric cancer [6]. Generally, bilateral pleural effusion does not immediately indicate malignancy; however, careful observation is required if disease progression is suspected.

Chylothorax was observed in this case. When chylothorax occurs without trauma, malignancy is suspected. Although lymphoma was initially suspected due to chylothorax, malignancy was also considered a major differential diagnosis.

Considering these factors, lymphoma and malignancy were strongly suspected in this case. However, cytology and flow cytometry results were negative. Given the low sensitivity of cytology, malignancy could not be definitively ruled out, requiring follow-up studies.

Reports of bilateral pleural effusion transforming into unilateral effusion are extremely rare, and this case provides significant insights for further discussion. Initially, the patient showed improvement, and the disappearance of chylothorax suggested idiopathic chylothorax. Even when chylous pleural effusion is present, heart failure is usually associated with transudative effusion. Additionally, echocardiographic findings indicated a low likelihood of heart failure.

However, during follow-up, there was an increase in the left pleural effusion, and SRCC was detected in it, necessitating a reevaluation of the patient’s disease status. The mechanism by which malignancies cause chylothorax is believed to involve external compression or infiltration of the thoracic duct by the tumor; this leads to ductal obstruction, increased intraductal pressure, expansion of collateral lymphatic vessels, dysfunction of lymphatic valves, and retrograde lymphatic flow. Eventually, the thoracic duct ruptures, allowing chyle to leak into the pleural cavity via the mediastinum [7, 8]. Although a definitive conclusion cannot be drawn, in this case, a reduction in lipid intake due to decreased appetite may have affected chyle composition. Alternatively, the initial lymphatic obstruction at a site relatively distant from the tumor may have led to the chylothorax; this condition subsequently disappeared due to further lymphatic infiltration by the tumor. There is one reported case in which untreated chylothorax changed in nature over time, suggesting that tumor progression into the intra-abdominal lymph nodes led to lymphatic obstruction and subsequent improvement of chylothorax [9].

Lower limb edema may also have been related to this process. Because a detailed evaluation of the right pleural effusion was not conducted, it remains speculative that both effusions may have been chylous. The persistence of the left pleural effusion was due to malignancy, and its increase paralleled the tumor progression.

A notable characteristic of this case was the persistently low serum CEA levels, even after the onset of pleural dissemination. Reports indicate that CEA levels do not always increase in SRCC due to its distinct tumor biology compared with that of conventional gastric adenocarcinoma [10]. This finding is consistent with the fact that SRCC has a low rate of CEA production, indicating that tumor markers may not always be effective for monitoring disease progression.

Additionally, in this case, early gastric cancer was suspected during endoscopic examination, but the actual diagnosis was advanced gastric cancer. This finding aligns with reports stating that SRCC may appear as early gastric cancer on endoscopy due to its subtle mucosal changes rather than forming a distinct mass, leading to a delayed diagnosis [11]. Given these misleading findings, it is crucial to perform biopsies even for minor atrophic mucosal changes. In this case, upper gastrointestinal endoscopy revealed minimal information; therefore, PET-CT was performed to confirm pleural uptake, followed by medical thoracoscopy. In pathological findings, SRCC was identified in both the gastric and pleural biopsies; however, the pleural biopsy exhibited clearer histopathological features with a higher tumor cell density. This aligns with previous reports indicating that SRCC often infiltrates the gastric mucosa diffusely, making mucosal biopsy diagnosis challenging, whereas metastatic lesions tend to display more distinct histological features [12, 13].

Yin et al. [12] reported a case where SRCC was difficult to diagnose from gastric biopsy but was more clearly identified in metastatic tissue. Similarly, Belkaïd et al. [13] found that metastatic lesions sometimes provide more definitive histopathological findings than primary sites. These findings support our case, where pleural biopsy provided a clearer diagnosis compared to gastric biopsy.

The prognosis of chylothorax associated with gastric cancer is generally poor, with a reported median survival of 3.9 months after diagnosis [3]. This poor prognosis is thought to be due to early lymphatic invasion and rapid systemic dissemination of SRCCs. In this case, CapeOX therapy was administered, and because HER2 and MSI were negative, nivolumab was administered. Recent studies have suggested that immunotherapy is effective in treating advanced gastric SRCC [14]. However, despite these treatments, the patient died within 4 months of disease onset, highlighting the need for more effective therapeutic strategies.

An important molecular finding in this case was CLDN18.2 positivity. CLDN18.2, a tight junction protein, is highly expressed in gastric adenocarcinoma, particularly SRCC. This molecule has gained attention as a novel therapeutic target [15], and the monoclonal antibody zolbetuximab that targets CLDN18.2 has shown promising results in clinical trials [16, 17]. Early molecular profiling may enable patients to benefit from personalized medicine.

Conclusion

This case is extremely intriguing as it demonstrates a shift from bilateral pleural effusion to unilateral effusion with changes in pleural fluid characteristics over time, a pattern that is rarely reported. Additionally, the lack of CEA elevation, despite pleural carcinomatosis, and the absence of significant findings on upper gastrointestinal endoscopy highlight the importance of thoracoscopy in the diagnostic process.

The atypical presentation observed in this case was likely due to the high metastatic potential of SRCC. Given the high expression of CLDN18.2 in SRCC and the potential of targeted therapies such as zolbetuximab, early detection through molecular profiling is crucial for improving treatment strategies and patient outcomes.

Statement of Ethics

The protocol for this study was reviewed and approved by the Institutional Review Board and Ethics Committee of the Japanese Red Cross Ise Hospital. Full name of the approving authority: Institutional Review Board and Ethics Committee of the Japanese Red Cross Ise Hospital. Approval No. ER2025-15. Institutional affiliation: Japanese Red Cross Ise Hospital, Japan. This study was conducted in accordance with the Declaration of Helsinki and the ethical guidelines established by the Ethics Committee. Since the patient was deceased at the time of submission, written informed consent for the publication of this case report and any accompanying images was obtained from the patient’s next of kin, in accordance with ethical guidelines. A copy of the signed consent form is available for confidential review by the Editor-in-Chief upon request. This case report has been prepared in accordance with the CARE guidelines, and the corresponding checklist is provided as supplementary material (for all online suppl. material, see https://doi.org/10.1159/000545958).

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

A.N. contributed significantly to the clinical management of the patient, study conception, and manuscript writing. T.K., K.I., H.N., and J.N. were also involved in the clinical practice. H.I. and S.K. contributed to pathological examination and case review. All authors reviewed the final draft of the manuscript and approved its submission.

References

1. Jovanovic D. Etiopathogenesis of malignant pleural effusion. AME Med J. 2021;6:28.

2. Gayen S. Malignant pleural effusion: presentation, diagnosis, and management. AmJMed. 2022;135(10): 1188–92.

3. Nagano N, Suzuki M, Tamura K, Kobayashi S, Kojima Y, Naka G,. Refractory chylothorax and lymphedema caused by advanced gastric cancer. Intern Med. 2019;58(21): 3143–8.

4. Jany B, Welte T. Pleural effusion in adults-etiology, diagnosis, and treatment. Dtsch Arztebl Int. 2019;116(21): 377–86.

5. Medenica M, Medenica M, Cosovic D. Pleural effusion in lung cancer: detection and treatment[internet]. Lung cancer- strategies for diagnosis and treatment. InTech;2018. Available from:

6. Liu Y, Du CX, Zhang HG.[Analysis of the prognosis of 111 patients with gastric cancer or adenocarcinoma of the esophagogastric junction combined with pleural or abdominal effusion]. Zhonghua Zhong Liu Za Zhi. 2013;35(9): 693–7.

7. Bhatnagar M, Fisher A, Ramsaroop S, Carter A, Pippard B. Chylothorax: pathophysiology, diagnosis, and management:acomprehensive review.JThorac Dis. 2024;16(2): 1645–61.

8. Teng CL, Li KW, Yu JT, Hsu SL, Wang RC, Hwang WL. Malignancy-associated chylothorax:a20-year study of 18 patients fromasingle institution. EurJCancer Care. 2012;21(5): 599–605.

9. Miyazaki S, Noda H, Morita T, Joman M, Okada M, Moriyama Y,.Acase of gastric cancer detected incidentally following to chylothorax, followed by change in the appearance of pleural effusion with cancer progression. Nihon Shokakibyo Gakkai Zasshi. 2007;104(9): 1359–64.

10. Kamio M, Yamada T, Sato K. Serum tumor markers in signet ring cell carcinoma of the stomach:aretrospective analysis. Gastric Cancer. 2020;23(4): 789–96.

11. Yamada T, Sato K, Nakamura Y. Signet ring cell carcinoma of the stomach mimicking chronic atrophic gastritis: diagnostic challenges. WorldJGastroenterol. 2021;27(4): 512–22.

12. Yin X, Li F, Ye H, Zhang G.Arare case of primary signet-ring cell carcinoma witharare endoscopic presentation. Gastrointest Endosc. 2025(25): S0016–5107.

13. Belkaïd S, Crumbach L, de Bernardi A, Darnis S, Bouquerel M, Neuhart A,. Gastric signet-ring cell adenocarcinoma masquerading as sarcoidosis. Lancet Oncol. 2024;25(4): e173.

14. Janjigian YY, Shitara K, Moehler M. Efficacy of nivolumab for advanced signet ring cell carcinoma:asubset analysis of the CheckMate 649 trial. Lancet Oncol. 2022;23(8): 1042–50.

15. Sahin U, Albers A, Brachvogel B. CLDN18.2 asatherapeutic target in gastric cancer: current status and future prospects. Gastroenterology. 2021;160(5): 1412–23.

16. Shitara K, Janjigian YY, Moehler M. Zolbetuximab in patients with CLDN18.2-positive gastric cancer:aphase III clinical trial.NEnglJMed. 2023;388(3): 134–45.

17. Yamaguchi K, Ohtsu A, Janjigian YY. CLDN18.2-targeted therapy for gastric cancer:asystematic review. Oncotarget. 2020;11(27): 2565–78.