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Primary Cardiac Angiosarcoma

Authors' Perspective Following Synthesis of Available Literature

Doherty, Deb, PT, PhD1; Arena, Sara, PT, DScPT2; Claucherty, Emma, PT, DPT3; Moore, Sheena, PT, DPT3

doi: 10.1097/01.REO.0000000000000147
PERSPECTIVE PAPER
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Why are malignant primary cardiac tumors so rare? Is it because of the specialized cardiac muscle cells or the large number of mitochondria per cell? Is it because cardiac muscle is the most aerobic organ of the body and its myocardial capillary density is at a 1:1 ratio, which is 10-fold higher than that of the skeletal muscle? There is overwhelming evidence regarding the benefits of aerobic exercise in prevention of many types of cancer and their associated sequelae. However, there appears to be an evidence gap that needs to be filled. Is there a link between the rare occurrence of primary cardiac cancers in terms of the oxygenation of cardiac muscle tissue and the benefits of aerobic exercise that could provide a new area of research for the primary prevention of cancer? Discussion of these questions was the impetus for the authors to conduct a literature search and then synthesize the review findings. This perspective aims to explore currently available knowledge and gaps in available evidence to understand areas in which physical therapists may impact the varied levels of preventive intervention on primary malignant cardiac cancers. The 35 presenting symptoms and medical history reported in the literature may provide a basis for correlation with other genetic and epigenetic factors to explore along our journey for answers. The physical therapy profession is well positioned to promote healthy behaviors and provide patient education to reduce risk factors and prevent and treat noncommunicable diseases consistent with a biopsychosocial paradigm.

1Associate Professor, Oakland University, Rochester, MI

2Assistant Professor, Oakland University, Rochester, MI

3Oakland University, Rochester, MI

Correspondence: Deb Doherty, PT, PhD, 3154 HHB, Oakland University, Human Health Bldg, 433 Meadow Brook Rd, Rochester, MI 48309 (doherty@oakland.edu).

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.rehabonc.com).

The authors declare no conflicts of interest.

Why are malignant primary cardiac tumors so rare? Is it because of the specialized cardiac muscle cells that make up the heart? Is it because the cardiac muscle cells have the largest number of mitochondria per cell? Is it because cardiac muscle is the most aerobic organ of the body and its myocardial capillary density is at a 1:1 ratio, which is 10-fold higher than that of the skeletal muscle?1 How does oxidative stress play a role in primary cardiac tumor malignancy? It is known that oxygenation of cardiac muscle differs physiologically from both skeletal muscle and vascularization of the organ bodies. For example, the resting blood flow of myocardial muscle tissue is 10 times higher than that of skeletal muscle.1 The authors posit that the physiologic differences in the oxygenation as well as preventing, decreasing, and/or managing associated oxidative stresses of the varied tissues with exercise may provide carcinogenic protection within the highly vascular cardiac muscle.2

There is overwhelming evidence regarding the benefits of aerobic exercise in primary, secondary, and tertiary prevention of many types of cancer and their associated sequelae.3 However, there appears to be a large evidence gap that needs to be filled. Is there a link between the rare occurrence of primary cardiac cancers in terms of the oxygenation of cardiac muscle tissue and the benefits of aerobic exercise that could provide a new area of research for the primary prevention of cancer? All mainstream physical therapy prevention strategies, inclusive of education and interventions for moderate amounts of physical activity, nutrition consumption, stress reduction, sleep habits, and smoking cessation, have been identified as strategies to decrease oxidative stress.3 However, it is not known whether there is a correlation between the rare occurrence of primary cardiac cancers and the aforementioned prevention strategies.

Because no one resource provided these answers, discussion of these questions was the impetus for the authors to conduct a literature search and then synthesize these review findings. Identifying factors that contribute to decreased incidents of malignant cardiac tumors may be of benefit to physical therapists (PTs) who provide care to individuals with cancer diagnoses in other body systems, with the ultimate goal of decreasing cancer-specific mortality.

In an effort to unpack the complex issue of malignant cardiac tumors, this perspective aims to explore evidence already available in the literature. While the authors hope to extract items relevant to a PT practice, this review is intended to be the first in a series of investigations that provide a basis for future research that explains the rarity of malignancy in cardiac tissues.

The authors completed a literature search that identified a huge cross section of cardiac cancer types, including primary, metastatic, age-stratified, and extra-cardiac tumors. It became apparent that each had varied physiologic and treatment constructs. Because angiosarcoma has the highest occurrence of malignant primary cardiac tumors in adults, the authors narrowed their focus to this diagnosis. Let us explore the synthesis from the available literature.

Primary cardiac tumors are a rare pathology with an incidence rate of 0.0017% to 0.03%.4 Approximately 25% of primary cardiac tumors are malignant. The most common type of malignant cardiac tumor is angiosarcoma, a primary malignant cardiac tumor originating from endothelial cells.4 It is an aggressive neoplasm that has a high rate of local recurrence and systemic metastasis.5 Primary cardiac angiosarcoma (PCA) is most commonly found in the right atrium with presenting symptoms that mimic those of congestive heart failure. PCA is often overlooked in the differential diagnosis process due to its rarity of occurrence.5 Furthermore, the infrequency of this condition has made it difficult to standardize medical therapies.5 While surgical intervention is the standard contemporary method for treating PCA, a combination of chemotherapy and radiation is used as an adjunct therapy. Despite these interventions, long-term prognosis remains poor and most individuals are deceased within months of diagnosis.5 Currently, there is a paucity of evidence regarding causation, cause, risk factors, and an individual's preexisting health status prior to a PCA diagnosis.

Because of the low occurrence of PCA, the profession's understanding of this condition lacks volume and detail. This is specifically evident in regard to a variety of risk factors including epigenetic, preemptive risk reduction, and prior physical activity levels that limit the ability to provide care aimed toward thwarting malignant cell conversion. This literature synthesis describes characteristics, lifestyle risk factors, and physical activity levels of individuals with a diagnosis of PCA identified by an exhaustive literature review to determine possible trends and/or correlations.

Cochrane Library, CINAHL, PubMed, and EMBASE databases were employed in the query using the key terms “primary cardiac tumors” and “primary heart neoplasms.” The available evidence was collected between May and September 2015 (Figure 1) and then cross analyzed following an unsystematic narrative review process, as described by Green et al.6 Initial inclusion (English Language, primary cardiac tumors) resulted in 1224 articles. With the addition of exclusion criteria (animal research, pediatric or <18 years of age, non-English language, tumor metastasis to heart), 636 articles remained. Secondary analyses led to classification of these articles into 3 categories: benign, malignant, and other, inclusive of multiple types of tumors, extra-cardiac tumors, and imaging or surgical technique. Finally, 67 articles were identified that pertained solely to PCA or presented and categorized it separately from other diagnosis (Figure 2).

Fig. 1

Fig. 1

Fig. 2

Fig. 2

To ensure thorough review and analyses of the literature, A Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)7 template was modified (including identification of patient demographics—age, gender, and race) and implemented to evaluate features relevant to each document (see the Addendum, Supplemental Digital Content 1, http://links.lww.com/REHABONC/A7). Each article was evaluated by 2 investigators. Previous medical history and relevant lifestyle risk factors, inclusive of nutritional considerations, body mass index (BMI), drug use, sleep patterns, socioeconomic status, stress levels, prior physical activity levels, and environmental exposures, were recorded.8 These risk factors are considered an essential component of assessment, referral, and intervention for every patient's health and wellness regardless of disease or injury. Bezner8 describe the health-promoting behaviors considered standard practice for PTs. Thus, it is imperative that in analyzing evidence for practice, the health and wellness behaviors of each patient are included and analyzed. This inclusion aims to educate health care professionals about the need for more comprehensive evaluation and treatment considerations. Diagnostic and prognostic information, inclusive of presenting symptoms, histology reports, metastasis, medical intervention, physical therapy intervention, and survival, was recorded for each individual case presented within a citation.

Sixty-seven articles pertaining to PCA met the inclusion criteria. Evidence was provided in various research formats, including 43 case studies,4,9,10–49 12 case series,50–61 7 literature reviews,62–68 and 5 narrative reviews.5,69–72 Sixty-six subjects identified in the articles met the diagnostic criteria for malignant PCA. Males were diagnosed 1.25 times more frequently than females, with the greatest prevalence in the fourth decade of life for both genders (Figure 3). Race was reported for 5 subjects, including 2 individuals identified as African American and 3 individuals identified as White.4,10,11

Fig. 3

Fig. 3

Medical history was reported in 7 cases4,12–15,49 and included abdominal pain,4 dyspnea,12 chronic rheumatic heart disease,13 chronic atrial fibrillation,13 moderate aortic regurgitation,13 mixed mitral valve disease,13 persistent atypical syncope,13 chest pain,14 recurrent pericardial effusions,15 recurrent chest pain upon exertion,12 and shortness of breath.49 Lifestyle risk factors included smoking tobacco reported in 2 cases9,16 and consumption of alcohol (amount not specified) in 2 cases.9,15 It is notable that nutritional considerations, BMI, sleep patterns, socioeconomic status, stress levels, prior physical activity levels, and environmental exposures were not reported.

A total of 35 presenting symptoms from either the primary tumor or a metastasis at initial diagnosis were recorded in 56 of the cases (Table 1). The 4 most common presenting symptoms were dyspnea (n = 22), chest pain (n = 18), breathlessness (n = 10), and pericardial effusion (n = 10). The authors recognize that the symptoms identified in this review of cases are not unique to the diagnosis of a PCA. Given the rarity of this diagnosis, it is understandable that symptoms may favor a differential diagnosis of more common ailments. However, unsuccessful remediation of symptoms after appropriate medical intervention should give health care providers justification to conduct appropriate testing to rule out this diagnosis.

TABLE 1

TABLE 1

Histologic reporting was included for 13 individuals,* whereas metastases were reported among 24 individuals. The most common metastatic sites include the lung (n = 16), the liver (n = 11), the pericardium (n = 10), the brain (n = 6), the bone (n = 5), and the pleura (n = 4). PCA was most commonly medically managed with surgery (n = 38), followed by chemotherapy (n = 23), radiation therapy (n = 14), heart transplantation (n = 2), and an antitubercular regimen (n = 1). Five individuals refused medical interventions, and medical intervention provided was absent from 12 cases.

Physical therapy intervention for cough and right anterior chest pain prior to diagnosis was reported in 1 case. The individual was reported to be under the care of a PT for 2 weeks; however, no description regarding the frequency, duration, or type of interventions provided was available. It was noted that the cough was resolved, but the chest pain became pleuritic in nature after the physical therapy intervention and a 2-week course of antibiotic medication.17

Inconsistencies in follow-up times and number of follow-up visits led to variability in the survival status reporting available to the investigators. Of the 32 cases for which longevity was available, medical follow-up ranged from 4 to 32 months. Thirteen patients were reportedly still living at that time, whereas 19 were reported as deceased. Because of these inconsistencies in follow-up reporting, correlations between survival, lifestyle risk factors, and physical activity levels could not be analyzed.

A review of case studies and series describing individuals with a diagnosis of PCA revealed a paucity of evidence with regard to possible risk factors. In addition, documentation specific to the effect of physical therapy during various stages of treatment or a correlation between physical activity and tumor development was not present. Lack of evidence regarding prevention strategies, inclusive of prior physical activity levels, limited the authors' ability to garner whether care thwarted malignant cell conversion in this population. Further research with intention toward capturing this data is warranted to improve prevention and early detection efforts.

In agreement with current literature, this review indicated a higher incidence of PCA diagnosis in males than in females.16 The results also indicated that the highest rate of diagnosis occurred in the fourth to fifth decades of life, which paralleled the current accepted demographic of PCA.5 Race was reported only in 5 cases, thereby limiting diagnostic patterns for this variable. Furthermore, this literature review did not reveal a comprehensive historical description of the individual with a diagnosis of PCA. This includes details of the medical history, lifestyle risk factors that include physical activity, or diagnostic/prognostic data.

Standardization for reporting of these data in future case series and reports may provide sufficient data to achieve this review's purpose of identifying trends and correlations. In addition, an understanding of potential characteristics or variables that may contribute to an increased risk of developing this form of cancer would be beneficial. Specifically, smoking tobacco is a widely accepted risk factor for various types of cancer but it is still unknown whether it is a risk factor for PCA. Furthermore, strong evidence exists for an association of obesity with the following cancer types: endometrial, esophageal adenocarcinoma, colorectal, postmenopausal breast, prostate, and renal.73 Underlying mechanisms linking obesity to the development of cancer include chronic inflammation, oxidative stress, cross talk between tumor cells and surrounding adipocytes, migrating adipose stromal cells, obesity-induced hypoxia, shared genetic susceptibility, and functional defeat of the immune function.73 While it can be hypothesized that vascular tissue cells, such as cardiac endothelial cells, are susceptible to these adverse effects preceding cancer development, the absence of data in the reported case histories cannot yet support this suggestion.

The findings of this literature review generated incomplete evidence or description of the role of a PT in the prevention or treatment of PCA. To the authors' knowledge, this is the first literature review attempting to seek correlation between lifestyle factors and the presence of PCA. Physical therapy is the professional authority that synthesizes examination and evaluation to provide evidence-based interventions with the purpose of optimizing movement to improve the human experience.74 Therefore, understanding signs, symptoms, and common risk factors that may be modified prior to disease onset will save lives. A component of the physical therapy examination and evaluation process involves the assessment of patient exercise tolerance, health promotion and wellness risk factors, and functional activities of daily living.8 This type of assessment places PTs at the forefront for identifying symptoms such as dyspnea, chest pain, and fatigue, as well as the effects of these symptoms on quality of life. Unfortunately, these symptoms are not unique to PCA. Thus, differential diagnosis is not possible using these factors alone. Because of the rarity of the disease and the poor outcomes reported in the literature, which may be due to late-stage diagnosis and limited treatment options, PT referrals are scarce. With this review, the authors seek to provide 2 avenues for awareness among health care providers and opportunities for increased intervention. First, information gleaned from this review may provide PTs with increased knowledge to share within the profession. Second, this review suggests a potential for further education about the benefits of physical therapy in both prehabilitation and rehabilitation.

Because surgical intervention was the most common medical intervention provided to individuals with a diagnosis of PCA, pre- and postoperative exercise should be considered. While there is limited evidence related to the benefits of exercise training specific to this diagnosis, it has been reported in common malignancies. For example, Jones et al75 completed a single group study of 25 individuals with suspected operable lung cancer. Exercise consisted of 5 endurance cycle ergometry sessions per week at varying intensities. Participants underwent cardiopulmonary exercise testing, Six-Minute Walk Test, and pulmonary function testing at baseline, immediately before, and 30 days after surgical resection. Analyses indicated that presurgical exercise capacity decreased postsurgery but did not decrease beyond baseline values. The researchers concluded that prehabilitation was beneficial in improving cardiorespiratory fitness prior to pulmonary tumor resection. This evidence leads to the following question: “Could prehabilitation for pulmonary tumor translate to benefits for PCA?”

Published research that included comprehensive lifestyle risk factors and physical activity data was limited. Sadly, the questions that initiated the authors' desire to examine the literature are unable to be answered or even considered with the evidence currently available in the scientific community. Further research to capture causative factors, medical history, prediagnosis lifestyle, and risk factors among individuals with PCA is warranted to improve prevention and early detection efforts. Prospective studies with an emphasis on the effect of a PT's role in prehabilitation, secondary prevention, postoperative recovery, and symptoms management necessitate further investigation.

This specific investigation review revealed a paucity of evidence regarding characteristics, lifestyle risk factors, or physical activity levels of individuals with a diagnosis of PCA. The authors' quest to understand whether muscle physiology may be a contributor to the rarity of primary malignant cardiac tumor is just beginning. Furthermore, the literature was limited with regard to case histories inclusive of lifestyle and behavior risk factors that would be amenable to physical therapy prevention strategies. The authors' aspire to initiate dialogue within the physical therapy profession as well as within the health care community about the need for more evidence regarding the factors that may be contributing to the rare occurrence of primary cardiac tumors. The 35 presenting symptoms and past medical history reported in this literature are certainly not exclusive to PCA but may provide a basis for correlation with other genetic and epigenetic factors to explore along our journey for answers. The physical therapy profession is well positioned to promote healthy behaviors and to provide patient education that reduce risk factors and prevent and treat noncommunicable diseases consistent with a biopsychosocial paradigm.8

The authors aspire to continue examination of rare cancers that may exhibit unique characteristics in partnership and in parallel to other researchers with similar scholarly ambitions. Continued efforts are warranted to examine both unique characteristics of cardiac muscle physiology and cancer risk factors that may be amenable to PT prevention strategies and interventions.

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ACKNOWLEDGMENTS

The authors thank Dr Julia Rodriguez, for her mentorship in conducting the literature review and in securing the articles for analysis, and Sherry Wynn Purdue, for her editorial assistance.

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Keywords:

malignant heart tumor; primary cardiac neoplasm

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