Successful Management of Malignant Pericarditis Using Nivolumab for Metastatic Esophageal Squamous Cell Carcinoma

Abstract

Esophageal cancer is a malignant disease with a poor prognosis and is one of the most common causes of cardiac metastasis. Malignant pericarditis may cause the repetitive accumulation of pericardial effusion, which can occasionally pose a clinical challenge. We herein report a case of malignant pericarditis in a patient with metastatic esophageal squamous cell carcinoma with cardiac tamponade, which was successfully managed with single pericardial drainage and systemic nivolumab monotherapy. This is the first case report to suggest that systemic therapy with nivolumab is a promising option for the management of malignant pericarditis.

Introduction

Neoplastic cardiac tamponade is a rare condition that occurs in patients with advanced-stage cancer, commonly in those with lung, breast, gastric, and esophageal cancer, as well as lymphoma/leukemia (1). An autopsy case series revealed that 1.4-10% of patients with cancer had metastatic pericarditis, while another autopsy case series of patients with esophageal cancer identified cardiac metastasis at a frequency of 12% (2-4). The manifestation of cardiac tamponade and the management of metastatic pericarditis can be a critical problem in some patients with esophageal cancer.

The drainage maneuver is widely used to manage pericardial effusion. However, the reaccumulation rate is 45-70% with only a single drainage; therefore, treatment is crucial to prevent the reaccumulation in this population (5,6). Pericardiodesis is one promising treatment method, and injection of sclerosing or anticancer agents into the pericardial cavity has been reported to be effective in reaccumulation prevention (7-9). However, pericardiodesis is highly invasive, with concerns about adverse events such as chest pain, a fever, short-term infection, and cardiac diastolic failure in the long term (10). In terms of invasiveness and side effects, management using systemic anticancer agents can be optional; however, reports of the effectiveness of such treatment are currently limited (8). Furthermore, nivolumab, a human monoclonal immunoglobulin G4 antibody targeting programmed cell death protein 1 (PD-1), is currently a key drug in the treatment of esophageal cancer; however, to our knowledge, no study has reported the successful management of malignant pericarditis using immune checkpoint inhibitors (11).

We herein report a case of malignant pericarditis in a patient with metastatic esophageal squamous carcinoma that was successfully managed with nivolumab.

Case Report

A 52-year-old man who had been diagnosed with metastatic esophageal squamous carcinoma (cT2N3M1) 23 months previously received 6 courses of cisplatin (CDDP)/5-fluorouracil (5-FU) therapy as palliative chemotherapy (12). He had achieved complete response 17 months prior and had continued to receive maintenance S-1 monotherapy (tegafur, 5-chloro-2,4-dihydropyrimidine, and potassium oxonate) up to the hospital admission date, with careful surveillance using computed tomography (CT) and esophagogastroduodenoscopy. Five months before admission, CT revealed no evidence of recurrence but showed mild pericardial hypertrophy without pericardial effusion (Fig. 1a). One week before admission, he complained of chest discomfort, and three days before admission, he complained of chest pain. One day before admission, he developed acute dyspnea and was transferred to our hospital.

Figure 1.

Changes in pericardial effusion and epicardial nodule size. (a) Five months before the onset of cardiac tamponade. Orange arrows indicate pericardial metastasis. (b) The onset of cardiac tamponade accompanied by heart failure. (c) Before initiating systematic nivolumab monotherapy. (d) Day 28 after commencement of nivolumab monotherapy. (e) Week 11 after commencement of nivolumab monotherapy. Red arrows, pericardial effusion; orange arrows, epicardial nodules.

On admission, he complained of dyspnea, and his vital signs were as follows: body temperature, 36.5°C; heart rate, 120 beats/minute; respiratory rate, 21 breaths/minute; blood pressure, 102/88 mmHg; and SpO₂ 98% (O₂ 10 L). A physical examination revealed jugular venous distention and the absence of heart murmurs upon chest auscultation, which were suggestive of Beck's triad (13). Echocardiography findings indicated considerable pericardial effusion and right ventricular diastolic collapse, with no apparent wall motion asynergy. However, a detailed assessment of the valve, systolic, and diastolic function could not be performed due to the patient's unstable vital signs. Electrocardiography revealed no ST elevation, and laboratory test findings showed notable elevation of aminotransferase [aspartate aminotransferase (AST), 1,017 U/L; alanine aminotransferase (ALT), 1,126 U/L], lactate dehydrogenase (LDH, 1,115 U/L), creatinine levels (2.81 mg/dL), and N-terminal prohormone of brain natriuretic peptide (NT-proBNP, 1,920 pg/mL) levels. Creatine kinase (CK, 215 U/L), creatine phosphokinase-MB (CKMB) (6 U/L), cardiac troponin T (0.0087 ng/mL), and the coagulation system parameters were almost within normal limits. Plain chest CT revealed prominent pericardial effusion (Fig. 1b) and mediastinum and hilar lymphadenopathy.

After consultation with the cardiology department, emergent pericardial drainage was performed, and 620 mL of bloody pericardial effusion was drained (8). After drainage, his cardiorespiratory condition and laboratory test results improved drastically (AST level, 41 U/L; ALT level, 303 U/L; LDH level, 251 U/L; creatinine level, 0.75 mg/dL). Blood culture results were negative. The patient was discharged from our hospital on day 8 of admission. A pathological examination of the pericardial effusion revealed squamous cell carcinoma, and cell block immunohistochemistry demonstrated positive staining for EpCAM (MOC31) and p40 antibodies, suggestive of an esophageal origin (Fig. 2) (14,15). Based on these results, a diagnosis of recurrent pericardial metastasis originating from esophageal squamous carcinoma was made (8).

Figure 2.

Histological findings of cell block from pericardial effusion. (a) Hematoxylin and Eosin staining. (b) Results of an immunohistochemical analysis showing staining for EpCAM (MOC31). (c) Results of an immunohistochemical analysis showing staining for p40.

Sixteen days after hospital discharge, nivolumab monotherapy (480 mg per body every 4 weeks) was initiated as second-line palliative chemotherapy (11). At day 28 and week 11 of therapy, contrast chest CT revealed a marked reduction in pericardial effusion and epicardial nodule size [long diameter reduced from 29.3 to 18.5 and 11.2 mm; short diameter reduced from 15.9 to 10.8 and 4.0 mm, respectively, compared with the diameter measurements pre- and postnivolumab monotherapy at day 28 and week 11 (Fig. 1c-e)]. Mediastinum and hilar lymphadenopathy also responded. The treatment effect was rated as partial response according to the criteria of the original clinical trial (11). The patient reported that his chest discomfort was alleviated and that he would continue treatment as long as it was effective.

Discussion

We herein report a patient with esophageal cancer in whom metastatic pericarditis was successfully managed with single pericardial drainage and systemic nivolumab monotherapy. Management with systemic chemotherapy can be less invasive than management with pericardiodesis. Furthermore, this case suggests that immune checkpoint inhibitors can be promising for managing malignant pericarditis.

Cardiac tamponade is a life-threatening condition, and early detection of pericardial effusion is critical. The accumulation of pericardial effusion is known to be slow, but once the stretch reaches its limit, the cardiac chamber becomes compressed, leading to the sudden onset of symptoms (16). Esophageal cancer is the fourth-most common cancer, accounting for 6% of all primary metastatic cardiac tumors, and the incidence of cardiac tamponade among patients with esophageal cancer has been reported to be 0.01% (1,3). Lymph fluid flow from the heart is thought to be blocked by mediastinal lymph node metastases, and metastasis occurs retrogradely along the lymphatic vessel (17,18). In our patient, the risk of cardiac metastasis was relatively high because prominent metastases were observed in the mediastinal lymph nodes before complete response was achieved. Furthermore, the pericardial thickening observed five months before admission might have indicated metastatic pericarditis, although no pericardial effusion was observed (Fig. 1a). In patients with esophageal cancer with mediastinal lymph node metastasis, careful surveillance of pericarditis findings other than pericardial effusion is crucial.

Reports on systemic treatment for malignant pericarditis are limited in the literature. While several reports have demonstrated the effectiveness of systemic chemotherapy, our study is the first report, to our knowledge, of successful management using an immune checkpoint inhibitor (19,20). To date, no standardized management strategy for malignant pericarditis has been established, and it is difficult to conduct a randomized controlled trial due to its low incidence (8). The further accumulation of practical data (e.g., nationwide registry data research) is warranted to clarify the comparative benefits and risks between invasive and noninvasive treatment methods and the content of anticancer agents (e.g. chemotherapy versus immune checkpoint inhibitors) (21).

Conclusion

Systemic therapy with nivolumab is a promising option for the management of metastatic pericarditis of esophageal origin. Further clinical research is warranted to identify the most promising treatment strategy for this population.

The authors state that they have no Conflict of Interest (COI).