Cardiac Tamponade in Patients With Breast Cancer: A Systematic Review

Cardiac tamponade is a rare presentation in breast cancer and may be associated with poor prognosis. In this article, we reviewed the characteristics and survival outcomes of patients with breast cancer who developed cardiac tamponade. Three databases (PubMed, EMBASE and SCOPUS) were searched for relevant articles published from 1978 to 2022 and 16 articles were identified comprising 64 cases. The median age of the cases was 52 years. Cardiac tamponade was diagnosed with echocardiogram or computerized tomography of the chest or both in 91.9%, 1.6% and 6.5% of the cases, respectively. Cytology of the pericardial fluid was done in 90.5% of the cases while biopsy in addition to cytology was done in 9.5% of cases. Tamponade was proven to be malignant in 97.4% of the cases. The initial treatment for tamponade was pericardiocentesis. Adjunct therapies ranged from the insertion of a pericardial window, pericardiectomy, radiotherapy and chemotherapy. The median time from the first treatment of breast cancer to the onset of tamponade was 24 months while the median survival following diagnosis of tamponade was 13 months. There was no significant correlation (spearman rank-sum correlation coefficient= 0.35, p = 0.165) between time to tamponade (interval time from the first diagnosis of breast cancer and the onset of cardiac tamponade) and survival. Cardiac tamponade may adversely affect survival in patients with breast cancer. Early diagnosis with echocardiogram and cytology may guide management and expectations. Further observational studies are needed to determine the predictors of cardiac tamponade and optimal treatment in patients with breast cancer.


Introduction And Background
Cardiac tamponade is a rare presentation in breast cancer with a reported prevalence of less than 1% [1][2][3][4]. It results from acute or chronic pericardial effusion which impairs diastolic filling and venous return to the heart. This ultimately reduces cardiac output, leading to cardiogenic shock and death. Cardiac tamponade in breast cancer is an emergency that requires early detection and prompt management based on available evidence.
Pericardial effusion leading to cardiac tamponade in breast cancer may be due to direct involvement or metastatic spread of the underlying malignancy to the pericardium, the effects of radiation or systemic antineoplastic therapies. The onset of cardiac tamponade may impact negatively the outcomes of breast cancer [4]. Due to the rarity of cardiac tamponade in breast cancer, studies are restricted to mostly case reports and case series with varying findings. We performed a systematic review of the available literature to explore the characteristics and survival outcomes in patients with breast cancer who develop cardiac tamponade.
(primary), human subjects, and extractable data. The exclusion criteria included pericardial effusion without cardiac tamponade, co-existing primary cancers, other cancers with metastases to the breast presenting with cardiac tamponade, articles in any other language apart from English, animal subjects, non-extractable data, and post-mortem diagnosis of breast cancer and/or cardiac tamponade.
Two authors independently selected eligible articles based on the inclusion and exclusion criteria. This was done in two stages: screening the titles and abstracts of the articles for relevance and then, examination of the full texts of the relevant articles to determine those that met the inclusion criteria. Articles that did not meet these criteria were excluded. A third author resolved disagreements between the two authors involved in this process.

Data extraction
The following data were extracted from each article: first author and year of publication, country, the number of patients, study design, gender, age (years), the diagnostic tool for cardiac tamponade, laterality of breast cancer, histology of breast cancer, malignant or benign tamponade, time to tamponade, treatment for tamponade, re-accumulation of pericardial effusion, survival time (months), and vital status at the end of follow-up. Time to tamponade was defined as the interval time from the first treatment of breast cancer to cardiac tamponade, and survival time was defined as the time from the first treatment of cardiac tamponade to the date of death or last follow-up.

Quality assessment
The quality of each one of the eligible 16 articles was assessed by two authors using the tool and approach suggested by Murad et al. [6]. A third author resolved disagreements in judgment. The tool was proposed for assessing the quality and possible risk of bias of studies used in the systematic review of case reports/case series. It evaluates studies in four domains: selection, ascertainment, causality, and reporting. The domain of ascertainment and causality have two and four sub-groups respectively. This makes up a total of eight items in the tool.
For this systematic review, each domain was assigned one (1) point. For domains that have sub-groups, their assigned weighted score (1) was divided by the number of sub-groups. A zero point was assigned to an item if the answer is in negative. Three items in the causality domain (questions of other alternative causes that may explain the observation ruled out, challenge/rechallenge phenomenon, and presence of dose-response effect) were excluded due to their irrelevance to this present systematic review resulting in a final assessment tool presented in Table 5. Based on this, the following grading system was used to determine the quality: 0 -2 (low quality), 3 (moderate quality) and 4 (good quality).

Statistical analyses
All statistical analyses were conducted using Microsoft Excel (Profession plus 2016, USA). Patient-level data were extracted from the studies, and all analyses were based on available cases. All variables were converted to a uniform scale of measurement, for example, survival time in years was converted to months. Categorical variables were presented with frequency and percentages, while continuous variables were presented with median and ranges. A spearman rank-sum correlation was used to assess the relationship between time to tamponade, and survival time after treatment of cardiac tamponade. Statistical significance was determined at p < 0.05.

Literature search results
Our literature search yielded 962 articles ( Figure 1) with a total of 765 articles after removing duplicates. Initial screening of the studies by title and abstract resulted in 47 articles for full-text review while a final total of 16 articles was obtained after satisfying the set-out criteria for qualitative and quantitative analysis.

Quality assessment results
The quality of the included studies and the domains in which each study was deficient in quality are shown in Table 6. Ten of the studies had good or moderate quality while the remaining 6 were rated low.

Study overview
Sixteen studies ( Table 1) published from a period of 1978 and 2022, with a total of 64 patients with breast cancer and cardiac tamponade were included in this systematic review. Of these, five studies were from the United States, two from the United Kingdom, eight were from Asia, and one from Europe. Regarding the study designs, 11 were case reports, one was a case series, and four were cohort studies.

Demographic and baseline characteristics of study participants
The demographic and clinical characteristics of the study participants are shown in

Intervention and outcomes
The different intervention measures used in the management of the cardiac tamponade and the clinical outcomes are shown in

Discussion
To the best of our knowledge, this is the first systematic review that examined the characteristics and survival outcomes of patients with breast cancer who develop cardiac tamponade. All the cases were females. Breast cancer is about 100 times more common in females than in males [19]. We found that cardiac tamponade was more frequently described with left breast cancer than the right breast. Breast cancer occurs more commonly on the left breast than the right and has more aggressive biologic characteristics with worse outcomes than the latter [20][21][22][23].
In this study, cardiac tamponade was more frequently associated with invasive ductal carcinoma of the breast compared to other histologic types. Invasive ductal carcinoma is the most common histological type of breast cancer [24,25]. The aggressive nature of this type of breast cancer and the anatomic proximity of the breast to the heart partly explain why it commonly metastasizes to the pericardium. For the studies that reported the immunohistochemistry status in our review, most of the cases in our review were hormone receptor-positive (either estrogen receptor [ER] or progesterone receptor [PR] or both) and Her-2 receptor negative; this should expectedly, as shown by some studies [26][27][28], mean a less aggressive tumor type, reduced recurrence including effusion and a relatively good prognosis. However, other studies have demonstrated that a negative ER or PR receptor status alone in breast cancer is associated with more aggressiveness, recurrence and poorer prognosis [29][30][31].
From our review, the most frequent diagnostic method for cardiac tamponade was an echocardiogram. This is a relatively inexpensive, non-invasive tool that can be done at the bedside and does not carry the risk of radiation like computerized tomography. Typical echocardiographic features suggestive of the onset of cardiac tamponade are early diastolic right ventricular (RV) collapse, right atrium and left atrium collapse, and phasic respiratory changes in the RV and left ventricle [32]. Though an echocardiogram remains the choice imaging in the diagnosis of tamponade, there are situations where a CT scan of the chest has more advantages. Patients with obesity have reduced acoustic windows making echocardiography technically difficult; in these patients, a CT scan of the chest is preferred due to its ability to acquire high-quality motion-free images of the pericardium [33]. Also, a CT scan has a larger field of view which provides an assessment of the whole chest, making it possible to detect conditions that may mimic pericardial effusion such as massive pleural effusion, pericardial masses or other mediastinal diseases [33].
Our review found that the most common diagnostic tool for the pathology of tamponade was cytology which is consistent with findings in the literature [34]. Cytology may have been done more frequently compared to biopsy because the pericardium is more difficult to biopsy compared to other mesothelial sites such as the pleura and peritoneal [35]. Furthermore, Karpathiou et al. [36] suggested that cancer cells tend to float freely in the pericardial cavity in contrast to pleural metastases, which tend to be more invasive of the pleura; hence, easier to obtain cytology of the free-floating cancer cells. More importantly, cytology has been reported to have a higher cancer detection rate of malignant pericardial effusion compared to biopsy [34]. These reasons may explain why cytology of pericardial effusion is more frequently performed resulting in more reported cases of pathologic diagnosis of pericardial effusion and tamponade with cytology than biopsy. However, a combination of both cancer detection methods (cytology and biopsy) may improve the diagnostic accuracy of the pathology of pericardial cells [37]. The presence of neoplastic cells in pericardial effusion has been found to be associated with poor prognosis [38][39][40].
The initial treatment of cardiac tamponade was pericardiocentesis in all the included studies in our review [1][2][3][4][7][8][9][10][11][12][13][14][15][16][17][18]; in some cases, this was enough to treat the tamponade. However, others received adjunct therapies such as surgery (pericardial window or pericardiectomy) or chemotherapy (local intra-pericardial instillation or systemic). There has been an ongoing debate as regards which treatments are most effective. Some advocate a combination of pericardiocentesis and intrapericardial instillation of sclerosing agents because they found the recurrence rate of pericardial effusion lower in their study compared to other studies where the patients were treated with pericardiocentesis alone [41]. Reynolds et al. [42] suggested that pericardiocentesis should be followed by systemic chemotherapy for malignant pericardial effusion in patients with breast cancer because this method was deemed to achieve local control of pericardial effusion and improve survival. However, according to Bishiniotis et al. [1], a combination of pericardiocentesis, local instillation of sclerosing agents and systemic adjuvant therapy achieves satisfactory survival outcomes. Some of the local intra-pericardial therapy that has been described in the literature include tetracycline, thiotepa, cisplatin, bleomycin, atabrine hydrochloride and sclerotherapy [1,2,4,9,12,14,16,38]. Other authors adopted a more aggressive approach by creating a pericardial window (pericardiectomy) in addition to pericardiocentesis and chemotherapy which they argue provides better survival [2]. Nevertheless, some authors hold the opinion that patients with malignant cardiac tamponade managed conservatively had a longer symptom-free interval than those who had surgical interventions such as the pericardial window in other studies [43].
From the aforementioned, it is clear that there is currently no agreement on the optimal adjunct therapy in the management of cardiac tamponade in breast cancer after an initial pericardiocentesis. As pointed out by Press et al. [44], due to the lack of controlled trials and large observational studies in this area, it is difficult to make definite conclusions on the optimal adjunct treatment due to different histologic types of cancer, lack of uniformity in defining clinical response, and concurrent therapy in many of these patients.
The median survival time of patients with cardiac tamponade was 13 months in our study; this seems better than what was reported in lung cancer, which is the commonest cause of cardiac tamponade [44][45][46][47]. Mortality in our review was largely unrelated to re-accumulation of pericardial effusion or recurrence of cardiac tamponade. We also did not find any significant association between time to tamponade and survival. This may suggest that other factors such as tumor burden and underlying comorbidities may play a role in the survival outcomes of these patients. More observational studies are needed to determine the predictors of survival in this population of patients.
Our study does have some limitations. Firstly, the publications in the literature on this subject comprise primarily case reports and case series, with few cohort studies. Case reports and case series are subject to the risk of selection and publication biases since positive findings tend to be more commonly published than negative ones. In addition, our review included a relatively small number of cases due to the rarity of cardiac tamponade in breast cancer. Therefore, the general application of our findings may be difficult and should be interpreted cautiously.
Despite these limitations, a systematic review of the case reports and case series, with the few observational studies, was important to summarize the available data on cardiac tamponade in patients with breast cancer to provide insight into the characteristics and survival of this specific patient population. More observational studies are needed to establish the predictors, survival, and optimal therapy of cardiac tamponade in breast cancer which will assist in making evidence-based decisions in managing such patients.

Conclusions
Cardiac tamponade though rare, may adversely affect survival in patients with breast cancer. Early diagnosis with echocardiogram and cytology may guide management and expectations. More observational studies are needed to establish the predictors, survival, and optimal therapy of cardiac tamponade in breast cancer which will assist in making evidence-based decisions in managing such patients.

Selection
Does the patient(s) represent(s) the whole experience of the investigator (center) or is the selection method unclear to the extent that other patients with a similar presentation may not have been reported? (1 point)

Ascertainment
Was the exposure adequately ascertained? (0.5 points) Was the outcome adequately ascertained? (0.5 points) Causality Was follow-up long enough for outcomes to occur? (1 point)

Reporting
Is the case(s) described with sufficient details to allow other investigators to replicate the research or to allow practitioners to make inferences related to their own practice? (1 point)

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.