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Hindawi Sarcoma Volume 2019, Article ID 1960593, 6 pages https://doi.org/10.1155/2019/1960593 Research Article Primary Cardiac Sarcoma: A Rare, Aggressive Malignancy with a High Propensity for Brain Metastases 1,2 3 1 4 Brittany L. Siontis, Lili Zhao, Monika Leja, Jonathan B. McHugh, 1,5 1 1 1 Maryann M. Shango, Laurence H. Baker, Scott M. Schuetze, and Rashmi Chugh Department of Internal Medicine, University of Michigan, 1500 E Medical Center Drive, Ann Arbor, MI 48109, USA Department of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55901, USA Department of Biostatistics, University of Michigan, 1415 Washington Heights M2541, SPHII, Ann Arbor, MI 48109, USA Department of Pathology, University of Michigan, 1500 E Medical Center Drive, Ann Arbor, MI 48109, USA Swedish Medical Center Cancer Institute, 21632 Highway 99, Edmonds, WA 98026, USA Correspondence should be addressed to Rashmi Chugh; rashmim@med.umich.edu Received 9 August 2018; Accepted 14 February 2019; Published 10 March 2019 Academic Editor: Akira Kawai Copyright © 2019 Brittany L. Siontis et al. *is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction. Primary cardiac sarcoma (PCS) has a poor prognosis compared to other sarcomas due to late presentation, challenging resection, incidence of metastases, and limited efficacy of systemic therapies. Methods. A medical record search engine was queried to identify patients diagnosed with PCS from 1992 to 2017 at the University of Michigan. Results. *irty-nine patients with PCS had a median age of 41 years (range 2–77). Common histologies were angiosarcoma (AS, 14), high-grade undifferentiated pleomorphic sarcoma (UPS, 10), and leiomyosarcoma (LMS, 5). Sites of origin were left atrium (18), right atrium (16), and pericardium (5). AS was the most common right-sided tumor; UPS was more common on the left. Eighteen patients presented with metastases involving lung (10), bone (7), liver (5), and brain (4). Twenty-five patients underwent resection, achieving 3 R resections. Patients received a median of 2 (1–6) systemic therapies. Median overall survival (OS) was 12.1 months (range 0–79). Median OS was 14.0 months and 8.2 months in patients who did or did not undergo resection, respectively (p � 0.018). Brain metastases occurred in 12 (31%) patients, 9 (75%) of whom had left heart tumors, at a median of 8.5 months (range 0–75) from diagnosis. Median OS was 5.6 months (range 0–30) after the diagnosis of brain metastases. Conclusions. PCS portends a poor prognosis, because of difficulty in obtaining complete resection of sarcoma, advanced stage at diagnosis, and high risk of brain metastases. Providers should be aware of the increased risk of brain metastases and consider brain imaging at diagnosis and follow-up. We present a case series of 39 patients with PCS in 1. Introduction attempt to characterize and better understand disease pre- Primary cardiac tumors are rare, with an overall incidence of sentation, location, treatment modalities, and overall sur- 0.001–0.02% [1]. Of these, 25% are malignant, most com- vival of patients with PCS. We highlight patterns of monly sarcomas. Consequently, the management of patients metastatic disease, histologic subtypes, and the barriers to with primary cardiac sarcomas (PCSs) is extrapolated from improvements in overall survival of PCS patients. small case series of afflicted patients and larger series of patients with sarcomas of different sites of origin but similar 2. Materials and Methods histologic subtypes. PCSs are distinct entities with many unique features coincident with their site of origin. As tu- 2.1. Patient Identification. *e University of Michigan mors are deep, visceral, and involve a critical organ, disease Electronic Medical Record Search Engine (EMERSE) was is often locally advanced impairing resection by the time searched using the terms “cardiac sarcoma” and “heart” plus symptoms develop. “sarcoma” to identify patients with a diagnosis of primary 2 Sarcoma Table 1: Patient demographics and disease characteristics. cardiac sarcoma treated at our institution between 1992 and 2017. Patients with sarcomas originating within the pul- No. of monary vasculature or great vessels were not included in this patients (%) analysis. Details regarding demographics, clinical pre- Male 13 (33) sentation, pathologic features, treatment protocols, and Female 26 (67) outcome were extracted from clinical records. All research Median tumor size in cm (range) 6.5 (1.7–16) was approved by the University of Michigan Institutional Median no. of total chemotherapy regimens 2 (range 1–6) Review Board (HUM00068553). Primary tumor location Right heart 16 (41) Left heart 18 (46) 2.2. Statistical Analysis. Descriptive statistics, such as me- Pericardium 5 (13) dian and range, were calculated for continuous variables, Histology and frequencies were presented for categorical variables. To Angiosarcoma 14 (36) compare two categorical variables, a frequency table was High-grade undifferentiated pleomorphic sarcoma 10 (26) Leiomyosarcoma 5 (13) created and analyzed using the chi-squared test or Fisher’s Intimal sarcoma 3 (8) exact test. Overall survival (OS) was estimated by the Fibrosarcoma 2 (4) Kaplan–Meier method and compared using the log-rank Other 5 (13) test. Statistical significance was defined as a two-sided p Metastatic disease present at diagnosis 18 (46) value<0.05. All analyses were conducted using SAS (version Sites of metastases 9.4, SAS Institute, Cary, NC). Lung 10 (55) Bone 7 (39) 3. Results Liver 5 (28) Brain 4 (22) 3.1. Demographics and Disease Characteristics. Pancreas 1 (5) *irty-nine patients with PCS presenting to the University of Adrenal 1 (5) Michigan between 1992 and 2017 were identified. Median Treatment Surgery 25 (58) age at diagnosis was 41 years. Patient demographics and brief R 3 (12) outline of disease characteristics are summarized in Table 1. R 9 (36) *e most common site of origin was the left heart. R 11 (44) All patients were symptomatic at time of diagnosis, most Unknown 2 (8) frequently with dyspnea (n � 29), chest pain (n � 8), cough Chemotherapy 28 (72) (n � 3), bilateral lower extremity edema (n � 3), and he- Radiation to cardiac tumor 3 (8) moptysis (n � 3). Twenty patients had evidence of peri- Median age in years (range) 41 (2–77) cardial effusion at diagnosis, including all 5 patients with pericardial tumors and 11/16 patients with right-sided tu- common histological variant was UPS (n � 6). Other his- mors. Twelve patients had evidence of tamponade at di- tological types included angiosarcoma (3), leiomyosarcoma agnosis, one of which had a left atrium (LA) tumor, 8 had (2), and fibrosarcoma (1). All patients with right-sided tu- right atrium (RA) tumors, and 3 had pericardial tumors. mors and brain metastases at diagnosis (n � 3) also had lung Eight patients had pulmonary hypertension at time of di- metastases. One patient had evidence of a right to left shunt agnosis. *ere were no clinically significant arrhythmias on echocardiogram as detected by a bubble study. present at diagnosis. Angiosarcoma was the most common tumor histology and was more commonly located on the right side of the 3.3. Surgery. Twenty-five patients (64%) underwent surgical heart (n � 11) and pericardium (n � 2, p< 0.0001) com- resection of their PCS. Eleven of the twenty-five (11/25, 44%) pared to other histologies. UPS (n � 8) and LMS (n � 4) patients had evidence of metastatic disease at diagnosis. An were the most commonly observed left-sided tumors R resection was obtained in only 3 patients (12%), all of (Figure 1). whom had left atrial tumors. Nine patients had R resections, 11 patients had R resections, and the surgical margin in 2 3.2. Metastases. Metastatic disease was present in 18/39 patients was unknown. Five patients with solitary brain (46%) of PCS patients at the time of diagnosis. *e distri- metastases underwent craniotomy as primary management bution of metastases at the time of disease diagnosis is listed of their metastatic disease. in Table 1. Twelve patients developed brain metastases, 4 of whom had brain metastases at initial diagnosis. All presented with 3.4. Radiation 2erapy. In total, 11 patients (26%) received neurologic symptoms. Median time from diagnosis of PCS radiation therapy. *ree patients had radiation to the pri- to diagnosis of brain metastases was 8.5 months (range 0– mary cardiac tumor, one to alleviate superior vena cava 75.8 months). Left-sided cardiac tumors were more com- syndrome and two to optimize clinical status prior to sys- monly associated with brain metastases (9/12, p � 0.01) temic chemotherapy. Eight patients received radiation compared to right-sided and pericardial tumors. *e most therapy to brain metastases (5 whole brain and 3 stereotactic Sarcoma 3 6% 7% 6% 6% 22% 6% 44% 11% 69% 6% 6% 11% Angiosarcoma Rhabdomyosarcoma HGUPS HG sarcoma Intimal Fibrosarcoma Extraskeletal osteosarcoma Spindle cell Angiosarcoma Leiomyosarcoma Leiomyosarcoma HGUPS (a) (b) FIGURE 1: Primary cardiac histology by tumor location. radiotherapy). Four patients received radiation therapy after diagnosis of brain metastases to death was 5.6 months (range resection of solitary brain metastases. Four patients received 0–30 months). radiation therapy alone for multifocal brain metastases. Two Survival di•erences were not statistically signi†cant of these patients received palliative radiation to symptomatic based on the presence of metastatic disease at diagnosis, lesions in the bone and lung. tumor location, or tumor histology because, in part, of our small sample size. 3.5. Systemic erapy. Twenty-eight patients (72%) received 4. Discussion chemotherapy, with a median of 2 regimens (range 1–6). We present our single-institution experience with primary Twenty-one patients (75%) who received chemotherapy had cardiac sarcoma with several notable †ndings: a high in- resection of their primary tumor. Two patients received cidence of metastatic disease to the brain as compared to neoadjuvant chemotherapy followed by resection, R , and sarcomas originating in other locations, pattern of meta- R . Figure 2 shows baseline (a) and posttreatment (b) im- static spread associated with location of sarcoma origin aging for a patient who received neoadjuvant chemotherapy within the heart, predilection of certain histologies to with good response, enabling subsequent resection. originate in the right versus left heart, and association of Most patients received systemic therapy with palliative multimodality therapy with improved patient survival de- intent. Seventeen patients (61%) received doxorubicin plus spite the lack of a standardized treatment approach. ifosfamide (AI) as †rst-line therapy with a mean of 5 cycles We found brain metastases occurred quickly and fre- (range 0.5–9). Ten patients received gemcitabine and quently in our PCS patients. ‘irty-one percent (12/39) of docetaxel (GT) as †rst (n 2) or second-line (n 8) therapy. our PCS patients developed brain metastases, compared to Eight patients received 3 or more lines of therapy. Other 1–8% in noncardiac sarcomas [2–7]. ‘is is close to the chemotherapy regimens frequently used in any line included estimated 10–30% prevalence of brain metastases in all paclitaxel (n 5), dacarbazine (n 3), and ifosfamide cancer patients [8]. ‘e median length of time from di- (n 3). agnosis to the development of brain metastases has been reported to be about 27 months in other soft tissue sarcomas 3.6. Survival. ‘e median OS for patients who underwent [2, 3, 6, 9, 10]. In our patient cohort, however, the median surgery was 14.0 months (range 1–79 months), compared to time from diagnosis of PCS to brain metastasis was 8.2 months (range 0–33 months; p 0.02) for patients who 8.5 months (range 0.3–75.8 months). ‘is may be secondary did not (Figure 3(a)). Patients who received chemotherapy to the intracardiac location of primary tumors, potentially lived longer compared to patients who did not with a median providing a more direct conduit from tumor to the brain via OS of 14.0 months versus 2.4 months, respectively the cardiac outžow tract, particularly in left-sided tumors. (p 0.0001, Figure 3(b)). Median OS for all patients was ‘ere are case reports of brain metastases developing in 12.1 months (range 0–79 months; Figure 3(c)). ‘ree pa- patients with angiosarcoma, HGPUS, and leiomyosarcoma tients were alive at the time of data assessment in October [3–5, 7, 9–16]. In our series, the most common histology to 2017, one diagnosed in 2015 and two diagnosed in 2016 metastasize to the brain was high-grade undi•erentiated (median follow-up time of 19 months). Median time from pleomorphic sarcoma (n 6). 4 Sarcoma (a) (b) Figure 2: Baseline cardiac MRI shows a large, heterogeneous mass in the pericardial space with a large e•usion and compression of the left atrium (a). Neoadjuvant chemotherapy with doxorubicin/ifosfamide ×12 cycles and gemcitabine/docetaxel ×6 cycles resulted in near complete response (b). 1.0 1.0 + Censored + Censored Logrank p = 0.0182 Logrank p < 0.0001 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0.0 0.0 N 14 0 N 7 0 Y 25 5 110 28 Y 5 110 0 20 40 60 80 100 0 20 40 60 80 100 Time Time (a) (b) 1.0 + Censored 0.8 0.6 0.4 0.2 0.0 At risk 39 5 1 1 0 0 20 40 60 80 100 Time (c) Figure 3: Overall Survival of cardiac sarcoma patients (n 39). Overall survival was signi†cantly improved with surgical resection of PCS (a) and chemotherapy administration (b). For all patients (c), median overall survival was 12.1 months (range 0–79 months). ‘e dashed curve represents surgery or chemotherapy and solid curve no intervention. ‘e prevalence of brain metastases in sarcoma is in- patients who lived longer than 12 months (22 pts), brain creasing due to prolonged survival from multimodal ther- metastases eventually developed in 9 (41%). Median OS for apies that have poor CNS penetration [17, 18]. In our our patients with brain metastases was 13.6 months, with a Survival probability Survival probability Survival probability Sarcoma 5 who undergo complete (R post-brain metastases median survival of 5.6 months. *is is ) resections without metastatic significantly shorter than reports of brain metastases in disease will relapse, highlighting the need for systemic sarcomas of all primary sites, which have a median of therapy [22, 26]. Although multimodal therapy for PCS 13.9 months from diagnosis to development of brain me- patients is associated with improved survival [20, 21, 26], tastases and overall and postmetastasis survival of 15 and the specific role of radiation and chemotherapy alone or in 9.2 months, respectively [3, 5]. combination in PCS has yet to be defined. A univariate *e management of brain metastases is largely de- analysis by Isambert et al. found that chemotherapy offered pendent on the number of lesions and patient performance a survival advantage only in patients who did not undergo status. Surgical intervention is considered with solitary primary cardiac tumor resection [24]. Abu Saleh et al. metastases, while radiation therapy is preferred for multi- reviewed the utility of neoadjuvant chemotherapy in the focal disease or in patients with marginal performance management of right-sided cardiac tumors in 44 patients status. Metastasectomy of brain metastases is reported to [27]. In their cohort, 73% of patients received neoadjuvant result in increased post-brain metastases survival to about chemotherapy consisting of doxorubicin and ifosfamide. 9 months, compared with 2.7 months for those who did not *ere was a significant improvement in median overall receive surgical intervention [3]. In our cohort, one patient survival in patients who achieved a complete (R ) versus R 0 1 underwent metastasectomy alone with a post-brain metas- resection, 53.5 months and 9.5 months, and those who tases survival of 12 months. In our cohort, 4 patients re- received neoadjuvant chemotherapy versus primary sur- ceived radiation therapy for brain metastases with a median gery, 20 versus 9.5 months, respectively. *e authors post-brain metastases survival of 8 months. Four patients conclude that neoadjuvant chemotherapy improves the underwent surgical resection followed by radiation with a ability to achieve complete resection and thus translates post-brain metastases survival of 5.5 months. Since most into improved survival. However, the ability to deliver patients had received chemotherapy by the time they de- neoadjuvant chemotherapy relies on accurate preresection velop brain metastases, the role of chemotherapy in brain diagnosis. Given the rarity of these tumors and clear metastases remain unclear [5, 16]. benefits to multimodality therapies, it is imperative to Surgical resection is the preferred management for employ a multidisciplinary team approach. *e creation of localized sarcomas. As compared to other sarcomas, PCS a multispecialty, multi-institution cardiac tumor board in patients are more likely to have advanced stage or in- which our institution participates enhances the ability for operable primary tumor at presentation. Barriers to cross-discipline discussions to optimally manage these complete resection include anatomic location and de- challenging tumors. clining performance status due to tumor at presentation. In our patient cohort, those who received chemo- Given the difficulty in achieving complete resection with therapy alone and those who underwent surgical resection cardiac tumors, autotransplantation has been explored to and received systemic chemotherapy had a survival ad- allow for complete resection and optimal reconstruction. vantage (p � 0.039) compared to those who did not receive Ramlawi et al. reported on their institutional experience chemotherapy. Given the retrospective nature of this with cardiac transplant in 34 patients with left-sided car- study, it is important to note that patients who receive diac tumors [19]. In their series, 26 patients had primary chemotherapy generally have better performance status cardiac sarcomas. In those with malignant tumors, 1- and and organ function, which likely impacted the survival 2-year survival was 46% and 28%, respectively. While the advantage noted with chemotherapy. Local disease con- authors conclude cardiac autotransplantation to be feasible trol, resulting in improved cardiac function, likely results and safe for complex left-sided tumors, this should only be in better performance status and ability to tolerate ag- considered in certain individuals and performed at expe- gressive therapies. rienced specialty centers. Nearly 50% of our patients had evidence of metastatic 5. Conclusions disease at time of presentation, which is higher than the reported 20–30% in several case series [20–23]. In our pa- Primary cardiac sarcomas are rare, confer increased risk of tient cohort, metastatic disease at presentation did not brain metastases, are associated with shorter survival du- impact survival compared with those with localized disease ration, and have a higher disease-specific mortality com- (14 months versus 10 months, p � 0.12, respectively), while pared to soft tissue sarcomas arising in extracardiac sites. surgical resection did (p � 0.02), highlighting the impor- Increased mortality may be due to the difficulty with tance of local disease control. *is survival benefit of re- complete resection and high disease and symptom burden at section has been noted in other reports of PCS and is presentation, making aggressive multimodal therapy diffi- independent of the presence of metastatic disease [24]. *is cult. Multidisciplinary care incorporating surgery, radiation, may be due to the preservation of cardiac function as heart and systemic therapy when appropriate constitutes ideal failure has been described as the most common cause of management. Based on our findings, we recommend brain death of PCS patients [25]. Furthermore, improved cardiac imaging at the time of primary cardiac sarcoma diagnosis function ultimately aids in ability to administer systemic given the incidence of brain metastases. Furthermore, our therapy, specifically an anthracycline. results suggest a role for aggressive multimodal therapy Surgery alone, however, is not enough to prevent pri- including resection and systemic therapy, even in the mary tumor recurrence or distant metastases. Most patients metastatic setting, to improve outcomes. 6 Sarcoma heart: case report,” Arquivos de Neuro-Psiquiatria, vol. 59, Data Availability no. 3-B, pp. 793–796, 2001. [16] A. Ogose, T. Morita, T. 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