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Diffuse large B cell lymphoma with cardiac involvement: the importance of the multidisciplinary and multiparameter approach
Abstract
Lymphoma patients are at high risk of cardiovascular events due to anthracycline cardiotoxicity and, in rare cases, related to heart infiltration. The presence of cardiac masses adds further complexity to the management of lymphoma patients beyond myocardial chemotherapy-related toxicity, given possible unpredictable acute complications such as arrhythmias, atrioventricular block, myocardial ischemia, pericardial ef-fusion and cardiac tamponade. Here we describe the clinical presentation and successful multidisciplinary management of diffuse large B-cell lymphoma with multifocal cardiac involvement identified by total body 18 FDG positron emission tomography performed at disease staging.
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Background:
Advances in Lymphoma management have resulted in significant improvements in patient outcomes over the last 50 years. Despite these developments, cardiotoxicity from lymphoma treatments remains an important cause of mortality and morbidity in this cohort of patients. We outlined the most common cardiotoxicities associated with lymphoma treatments and their respective investigation and management strategies, including the role of cardiac pre-assessment and late effects monitoring.
Cardiac tumors are rare diseases with various imaging findings. However, differentiating cardiac
tumors based on imaging findings is challenging because of similarities in imaging features.
We present two cases of cardiac tumors, including primary cardiac lymphoma and cardiac metastasis,
in which the differential diagnosis was difficult.
Doxorubicin represents the mainstay in the upfront treatment of diffuse large B-cell lymphoma (DLBCL) patients. However, its administration is sometimes hampered by the coexistence of former comorbidities/cardiac issues, especially in the elderly population. Liposome encapsulated drug delivery systems have been adopted to reduce the exposure of normal tissues to the drug, both in solid cancers and lymphomas. Despite claims for lower toxicity, the efficacy of non-pegylated liposome doxorubicin (NPLD) in DLBCL, as compared to standard doxorubicin, has never been established. We systematically reviewed relevant literature of NPLD in lymphoma treatment. Adjusting for age/comorbidities, our metanalysis revealed that the use of combinations including NPLD (R-COMP) were non-inferior in terms of response, overall and progression-free survival to the standard of care (R-CHOP) in overlapping series of DLBCL patients. R-COMP may represent a safe and active option for elderly patients with DLBCL, or for those with some extent of cardiac impairment at baseline.
Objective
To summarize the clinical and pathological features of patients with cardiac lymphoma.
Methods
The general conditions, clinical features, pathological types, and prognostic indices of 37 patients with cardiac lymphoma treated in our hospital were analyzed.
Results
Among the 37 patients, only one had primary cardiac lymphoma, and the other 36 patients had secondary cardiac lymphoma. The cardiac manifestations were mainly chest tightness, shortness of breath, increased heart rates, and electrocardiographic abnormality caused by pericardial effusion, but myocardial enzyme levels were normal in all patients. Only three patients displayed solid heart-occupying manifestations. These lesions were mainly located in the right atrium, and the masses were all larger than 5 cm. The pathological type was diffuse large B cell lymphoma that did not arise from the germinal center in all three patients.
Conclusions
Cardiac lymphoma was mostly secondary, and pericardial effusion was the primary objective sign. Moreover, cardiac lymphoma was characterized by a high international prognostic index, late stage, and high rates of T and NK cell lymphoma. Most cases were accompanied by serous cavity effusion, extranodal involvement of important organs, elevated lactate dehydrogenase levels, hypoalbuminemia, and normal myocardial enzyme levels.
Lymphoma is one of the most common tumors with the risk of cardiac metastasis. The pattern of cardiac involvement is usually as focal masses. As early diagnosis of lymphoma plays a crucial role in its response to treatment and patient survival longevity, we report a rare case of cardiac lymphoma with diffuse cardiac involvement and acquired pulmonary stenosis. The patient was referred to our center for further evaluation because of dyspnea and systolic ejection murmur. In pericardial biopsy, T cell lymphoblastic lymphoma was reported. After a full course of chemotherapy and one-year follow up, symptoms had improved and echocardiography was normal except for small pericardial effusion.
<Learning objective: Early diagnosis of lymphoma plays a crucial role in its response to treatment and introducing atypical presentation form could be helpful for early diagnosis.
Purpose of review: Cardiac masses frequently present significant diagnostic and therapeutic clinical challenges and encompass a broad set of lesions that can be either neoplastic or non-neoplastic. We sought to provide an overview of cardiac tumors using a cardiac chamber prevalence approach and providing epidemiology, imaging, histopathology, diagnostic workup, treatment, and prognoses of cardiac tumors.
Recent findings: Cardiac tumors are rare but remain an important component of cardio-oncology practice. Over the past decade, the advances in imaging techniques have enabled a noninvasive diagnosis in many cases. Indeed, imaging modalities such as cardiac magnetic resonance, computed tomography, and positron emission tomography are important tools for diagnosing and characterizing the lesions. Although an epidemiological and multimodality imaging approach is useful, the definite diagnosis requires histologic examination in challenging scenarios, and histopathological characterization remains the diagnostic gold standard. A comprehensive clinical and multimodality imaging evaluation of cardiac tumors is fundamental to obtain a proper differential diagnosis, but histopathology is necessary to reach the final diagnosis and subsequent clinical management.
Cardiac involvement of malignant lymphoma is relatively common, although such a phenomenon has subclinical manifestations that are difficult to detect. We herein describe a patient with atrial fibrillation and sick sinus syndrome as the main symptoms. Computed tomography showed a mass in the right atrium extending into the superior vena cava (SVC). We implanted the patient with a leadless pacemaker. Transvenous biopsy revealed a diffuse large B-cell lymphoma. The patient was treated successfully with chemotherapy including rituximab. This case suggested that cardiac lymphoma may cause sick sinus syndrome, and leadless pacemaker implantation is a safe treatment option in patients with partial SVC obstruction.
Objectives
This study sought to assess the diagnostic accuracy of cardiac computed tomography (CT) and ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) with positron emission tomography/computed tomography (PET/CT) in defining the nature of cardiac masses.
Background
The diagnostic accuracy of cardiac CT and ¹⁸F-FDG PET/CT in identifying the nature of cardiac masses has been analyzed to date only in small samples.
Methods
Of 223 patients with echocardiographically diagnosed cardiac masses, a cohort of 60 cases who underwent cardiac CT and ¹⁸F-FDG PET/CT was selected. All masses had histological confirmation, except for a minority of thrombotic formations. For each mass, 8 morphological CT signs, standardized uptake value (SUVmax, SUVmean), metabolic tumor volume, and total lesion glycolysis in ¹⁸F-FDG PET were used as diagnostic markers.
Results
Irregular tumor margins, pericardial effusion, invasion, solid nature, mass diameter, CT contrast uptake, and pre-contrast characteristics were strongly associated with the malignant nature of masses. The coexistence of at least 5 CT signs perfectly identified malignant masses, whereas the detection of 3 or 4 CT signs did not accurately discriminate the masses’ nature. The mean SUVmax, SUVmean, metabolic tumor volume, and total lesion glycolysis values were significantly higher in malignant than in benign masses. The diagnostic accuracy of SUV, metabolic tumor volume, and total lesion glycolysis ¹⁸F-FDG PET/CT parameters was excellent in detecting malignant masses. Among patients with 3 or 4 pathological CT signs, the presence of at least 1 abnormal ¹⁸F-FDG PET/CT parameter significantly increased the identification of malignancies.
Conclusions
Cardiac CT is a powerful tool to diagnose cardiac masses as the number of abnormal signs was found to correlate with the lesions’ nature. Similarly, ¹⁸F-FDG PET/CT accurately identified malignant masses and contributed with additional valuable information in diagnostic uncertainties after cardiac CT. These imaging tools should be performed in specific clinical settings such as involvement of great vessels or for disease-staging purposes.
Advances in cancer therapeutics have led to dramatic improvements in survival, now inclusive of nearly 20 million patients and rising. However, cardiovascular toxicities associated with specific cancer therapeutics adversely affect the outcomes of patients with cancer. Advances in cardiovascular imaging have solidified the critical role for robust methods for detecting, monitoring, and prognosticating cardiac risk among patients with cancer. However, decentralized evaluations have led to a lack of consensus on the optimal uses of imaging in contemporary cancer treatment (eg, immunotherapy, targeted, or biological therapy) settings. Similarly, available isolated preclinical and clinical studies have provided incomplete insights into the effectiveness of multiple modalities for cardiovascular imaging in cancer care. The aims of this scientific statement are to define the current state of evidence for cardiovascular imaging in the cancer treatment and survivorship settings and to propose novel methodological approaches to inform the optimal application of cardiovascular imaging in future clinical trials and registries. We also propose an evidence-based integrated approach to the use of cardiovascular imaging in routine clinical settings. This scientific statement summarizes and clarifies available evidence while providing guidance on the optimal uses of multimodality cardiovascular imaging in the era of emerging anticancer therapies.
R-CHOP is the most commonly used regimen worldwide for the upfront treatment of diffuse large B-cell lymphoma (DLBCL). However, it is associated with significant cardiotoxicity, especially in older patients. The R-COMP regimen, with non-pegylated liposomal doxorubicin, may reduce the risk of cardiac events, but its efficacy has never been demonstrated in prospective trials. In this report, we describe the characteristics and outcome of DLBCL patients≥65 years prospectively enrolled in the Elderly Project by the Fondazione Italiana Linfomi and treated with full doses of R-CHOP or R-COMP per local practice. Starting from a dataset of 1163 cases, 383 (55%) were treated with R-CHOP and 308 (45%) with R-COMP. Patients treated with R-COMP were older (median age 76 vs 71 years), less frequently fit at simplified geriatric assessment (61% vs 88%, p<0.001), and also had a significantly higher frequency of baseline cardiac disorders (grade >1, 32% vs 8%, p<0.001). Nevertheless, 3-year progression-free survival (PFS) was 70% for R-CHOP and 64% for R-COMP (p=ns); 3-year overall survival was 77% for R-CHOP and 71% for R-COMP (p=ns). R-CHOP was associated with better PFS vs R-COMP only in the Elderly Prognostic Index (EPI) low-risk group. No differences between the two groups were observed in terms of interruption of treatment due to toxicities or in the rate of cardiac events (p=1.00). Our study suggests that R-COMP represents a potentially curative treatment for EPI intermediate-/high-risk older patients, even in the presence of a baseline cardiopathy. R-CHOP is confirmed as the standard therapy for patients at low risk.
Diffuse large B-cell lymphoma (DLBCL) is an aggressive but potentially curable disease and is most common in older people. Rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) is the standard of care for fit patients without cardiac contraindications. In each individual elderly patient the potential gains of treatment should be balanced against the risks of treatment related morbidity and mortality. A simplified comprehensive geriatric assessment or easily performed assessments such as gait speed and grip strength can be helpful to assess the fitness of an elderly patient. Pre-phase with corticosteroids, rigorous supportive care including G-CSF prophylaxis and careful monitoring can be important to prevent adverse events. In unfit elderly patients a dynamic dosing strategy is often applied. For very elderly patients (≥ 80 years) a dose reduced regimen (R-miniCHOP) is recommended. When anthracyclines are contraindicated, doxorubicin can be replaced by etoposide or gemcitabine. Most frail patients do not benefit from chemotherapy. Further progress can be expected from non-chemotherapy based therapies, such as bispecific antibodies, antibody-drug conjugates and immunomodulatory agents. This article provides an overview of first line treatment in elderly patients with DLBCL and our approach to the management of these challenging patients.
PURPOSE
To prospectively validate the use of a simplified geriatric assessment (sGA) at diagnosis and to integrate it into a prognostic score for older patients with diffuse large B-cell lymphoma (DLBCL).
METHODS
We conducted the prospective Elderly Project study on patients with DLBCL older than 64 years who underwent our Fondazione Italiana Linfomi original geriatric assessment (oGA) (age, Cumulative Illness Rating Scale for Geriatrics, activities of daily living, and instrumental activities of daily living) before treatment. Treatment choice was left to the physician's discretion. The primary end point was overall survival (OS) (ClinicalTrials.gov identifier: NCT02364050 ).
RESULTS
We analyzed 1,163 patients (median age 76 years), with a 3-year OS of 65% (95% CI, 62 to 68). Because at multivariate analysis on oGA, age > 80 years retained an independent correlation with OS, we also developed a new, simplified version of the GA (sGA) that classifies patients as fit (55%), unfit (28%), and frail (18%) with significantly different 3-year OS of 75%, 58%, and 43%, respectively. The sGA groups, International Prognostic Index, and hemoglobin levels were independent predictors of OS and were used to build the Elderly Prognostic Index (EPI). Three risk groups were identified: low (23%), intermediate (48%), and high (29%), with an estimated 3-year OS of 87% (95% CI, 81 to 91), 69% (95% CI, 63 to 73), and 42% (95% CI, 36 to 49), respectively. The EPI was validated using an independent external series of 328 cases.
CONCLUSION
The Elderly Project validates sGA as an objective tool to assess fitness status and defines the new EPI to predict OS of older patients with DLBCL.
Background:
Anthracycline-related heart failure is a leading cause of morbidity in survivors of adult-onset lymphoma. There is a paucity of information on screening for late-occurring preclinical disease, which, in turn, has limited guidelines for early detection and intervention. The objectives of this study were to examine the prevalence and risk of cardiac dysfunction, as measured by echocardiography (abnormal left ventricular systolic/diastolic function or strain), in lymphoma survivors who received treatment with anthracyclines and to evaluate the diagnostic yield of blood biomarkers in the asymptomatic setting.
Methods:
Lymphoma survivors who underwent hematopoietic cell transplantation (HCT) (n = 78) or received conventional therapy (non-HCT; n = 77) were compared with each other and with a group of matched controls (n = 51); the study was limited to lymphoma survivors who were >5 years from diagnosis.
Results:
At a median follow-up of 9.4 years after diagnosis, 1 in 5 (20.6 %) lymphoma survivors had cardiac dysfunction; the odds of having cardiac dysfunction were 6.6-fold greater (odds ratio [OR], 6.6; P = .01) among lymphoma survivors compared with matched controls. There was a dose-dependent risk of cardiac dysfunction according to the cumulative anthracycline dose (controls [referent group], 1-249 mg/m(2) [OR, 4.7; P = .05], and ≥250 mg/m(2) [OR, 7.6; P < .01]), but there was no difference in the prevalence of cardiac dysfunction between conventionally treated and HCT survivors. The diagnostic accuracy of cardiac blood biomarkers in the asymptomatic setting was quite poor.
Conclusions:
In these long-term survivors, there was a high rate of cardiac dysfunction that was independent of HCT status. The growing number of lymphoma survivors makes it imperative to identify reliable and cost-effective strategies to decrease the burden of heart failure in this population. Cancer 2017. © 2017 American Cancer Society.
The purpose of this phase 2, multicenter study was to determine the activity and safety of nonpegylated liposomal doxorubicin as part of "R-COMP" combination in patients with diffuse large B-cell lymphoma and coexisting cardiac disorders. The study was conducted using a Bayesian continuing assessment method using complete remission rate and rate of cardiac events as study endpoints. Between November 2009 and October 2011, 50 evaluable patients were enrolled (median age, 76 years). Median baseline left ventricular ejection fraction (LVEF) was 60%. Ischemic cardiopathy was the most frequent preexisting cardiac disorder (35%), followed by atrial fibrillation (15%), left ventricular hypertrophy (13%), and baseline LVEF <50% (12%). Based on the intent to treat analysis, overall response rate was 72%, including 28 patients in complete remission (complete remission rate, 56%), and 8 in partial remission (16%). At the end of treatment, grades 3 to 4 cardiac events were observed in 6 patients. No significant modifications from baseline values of LVEF were observed during treatment and follow-up. Nonpegylated liposomal doxorubicin instead of doxorubicin in the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen is a feasible option for patients with diffuse large B-cell lymphoma presenting with concomitant cardiac disorders.
Primary cardiac lymphoma (PCL) is a very rare disorder. Histologically, the majority of cases of PCL are diffuse B-cell lymphoma. PCL occurs more frequently in immunocompromised patients. Symptoms may vary according to the heart site involved. The most frequent cardiac clinical manifestations associated with PCL are pericardial effusion, heart failure, and atrioventricular block (AV-block). Diagnosis of PCL can be suggested by transesophageal echocardiography, computed tomography, and magnetic resonance imaging. However, cytologic examination of cardiac tumor or pericardial effusion is paramount for a definite diagnosis of this condition. Prognosis of PCL is poor with a median survival of 7months after initial diagnosis. Newer modalities including immunotherapy with rituximab or auto stem cell transplantation are promising in the treatment of this lethal condition.
Current literature suggests that the incidence of cardiac involvement by lymphoma as identified by autopsy varies widely, ranging from 8.7% to 20%. Historically, many cases might have been clinically undetected; however, improved imaging techniques increasingly identify cardiac involvement incidentally. In addition, newer agents resulting in improved cancer therapy outcomes might alter the prevalence and location of metastatic deposits to include more unusual disease sites, including intracardiac locations. We present 2 cases and a review of the literature.
Physiological fluorodeoxyglucose (FDG) uptake can obscure underlying disease or can even falsely suggest disease in patients undergoing whole-body positron emission tomography (PET) scanning for disease staging. Myocardial uptake in particular can present a problem because of its variability in fasting patients. Nonetheless, we present 2 cases in which FDG PET imaging was effective in identifying metastatic disease to the heart. In 1 case, an FDG PET scan revealed previously unsuspected myocardial metastases. In another case, FDG PET was useful in characterizing an intraatrial mass seen on anatomic imaging as a metabolically active lesion.
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