Progressive pericardial effusion during chemotherapy for advanced Hodgkin lymphoma

A 48 year-old man, previously in excellent health, presented with several weeks of diffuse pruritus and night sweats as well as a cervical mass unresponsive to antibiotics. A biopsy of the supraclavicular lymph node demonstrated CD30-positive, CD15-negative classical Hodgkin lymphoma (HL), nodular sclerosing subtype (Fig. 1). There was a normal cardiac silhouette and widened mediastinum on a chest X-ray performed at that time (Fig. 2a,b). A staging positron emission tomography/computer tomography (PET/CT) revealed extensive FDG-avid cervical, supraclavicular, mediastinal as well as periportal adenopathy. There was no lymphoma in the bone marrow biopsy, confirming the diagnosis of stage IIIB disease according to Ann Arbor classification. The white blood cell count was 6.6 × 109/L, absolute lymphocyte count 900 × 106/L, hemoglobin 13.6 g/dL, erythrocyte sedimentation rate 37 mm/h and albumin 4.0 g/dL. The patient was offered treatment with standard ABVD chemotherapy for six cycles, with a plan for interim reassessment after two cycles. Lymph node biopsy demonstrating classical Hodgkin lymphoma with features of nodular sclerosis subtype: Reed-Sternberg cells (a) and lacunar and mummified cells (b), positive for CD30 (c), in the background of inflammatory cells including CD3-positive T-lymphocytes (d). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Images of (a) chest X-rays at the beginning and end of chemotherapy treatment, (b) initial staging PET/CT scan, showing a small, non-FDG-avid pericardial effusion and the malignant mediastinal adenopathy; (c) CT scan and a four-chamber echocardiographic projection after chemotherapy demonstrating enlarging effusion; (d) EKG tracing at the time of cardiology assessment. RV, right ventricle; LV, left ventricle; RA, right atrium; LA, left atrium. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] The patient had advanced HL with two negative prognostic factors based on the International Prognostic Score, corresponding to a 67% chance of 5-year freedom from progression of disease and overall survival of 81% [1]. Despite superior results in advanced HL reported in the HD9 study with dose-escalated BEACOPP, [2] its adoption has been hampered by high rates of infertility, infections, and secondary leukemias [3]. Recent data suggest attenuated difference between BEACOPP and ABVD if stem cell transplantation is planned for the minority of patients experiencing a relapse [4]. This area remains a subject of intense controversy. Moreover, evidence of complete response by PET/CT after two cycles of ABVD appears to confer excellent prognosis, even though decision-making based on such evaluation is still subject to prospective randomized trials. This paradigm underscores the focus on identifying the patients with good or poor outcomes with standard therapy rather than treating everyone with maximally aggressive protocols. Evaluation of cardiac function is recommended before administration of doxorubicin and the patient had an incidental negative stress echocardiogram 9 months before the lymphoma diagnosis, without evidence of decreased ventricular function or pericardial disease. Similarly, he had a normal pulmonary function test including diffusion lung capacity before receiving bleomycin. A complete clinical and radiographic response was confirmed at the time of 2-month interim restaging. There were no major side effects of chemotherapy except for Grade 2 neutropenia, aphtous ulcers, and toenail onchomycosis treated with oral terbinafine and nail avulsion. On the restaging PET/CT a moderate, circumferential pericardial effusion was noted, retrospectively present on the initial scan, without any fluorodeoxyglucose (FDG) activity in the pericardial sac. Since the patient had no respiratory or cardiovascular symptoms, therapy was continued as planned without interruption. During the last cycle of chemotherapy the patient reported transient bilateral swelling of the metacarpophalangeal joints and ankles. This was accompanied by a recurrent, atypical left-sided chest discomfort at rest and with exertion. There was no difference with position or respiration. He had no palpitations, dyspnea, dizziness, fever or night sweats, and no numbness or paresthesiae. No other musculoskeletal problems, recent travel, or tick bites were reported. Examination revealed normal vital signs with mild tachycardia (heart rate 89 beats per minute), no adenopathy or discernible edema in the hands, and only mild swelling of the ankles. Heart sounds were normal with no gallop, murmur, or rub. The symptoms subsided after a few days. Immediately after the last dose of chemotherapy, the lower extremity edema as well as cough and a steady left-sided chest discomfort recurred. The electrocardiogram (EKG) showed normal sinus rhythm at the rate of 84 beats per minute with a QRS interval of 90–110 msec (Fig. 2 d). There were no classic ST or T wave changes seen in acute pericarditis. There was no diagnostic low voltage or electrical alternans to suggest a large, hemodynamically significant pericardial effusion. Cardiac troponin and creatinine kinase were repeatedly normal. A 2D echocardiogram revealed a circumferential pericardial fluid measuring up to 19 mm at end diastole consistent with moderate to large pericardial effusion (Fig. 2 c). Early diastolic collapse of the right atrium was noted but no pericardial thickening or tamponade physiology. Chest X-ray confirmed enlargement of the transverse diameter of the heart with resolution of mediastinal adenopathy. The patient had a clinical syndrome of serositis with a progressive pericardial effusion. The electrocardiographic findings were non-specific. EKG findings in acute pericarditis include sinus tachycardia, focal or diffuse ST segment elevation, and/or PR segment depression with transient development of T-wave inversions. These changes may be mistaken for an acute myocardial infarction. Low-voltage QRS (defined as <5 mm in limb leads or <10 mm in anterior leads) may be noted when the pericardial effusion is large. Electrical alternans with beat-to-beat alteration of amplitude and axis of the QRS complex may indicate a large pericardial effusion and be associated with the clinical diagnosis of pericardial tamponade. The differential diagnosis of the effusion in our patient included infectious, inflammatory, and malignant causes. In particular, viral pericarditis exacerbating a pre-existing effusion was suspected. However, basic laboratory values, thyroid function, erythrocyte sedimentation rate and C-reactive protein, rheumatoid factor, antinuclear, anti-ds-DNA and other rheumatologic antibodies, as well as complement factors were normal. Tuberculin purified protein derivative skin test resulted in anergic response. Extensive serologic workup for Lyme disease, adenovirus, parovovirus B-19, Echo, Coxsackie, Herpes simplex, Epstein-Barr, and cytomegalovirus was unrevealing as well. The final restaging PET/CT showed sustained complete remission from HL with a markedly enlarged, uniformly distributed pericardial effusion 25 mm in thickness (compared with 11 mm on the initial and 16 mm on the interim CT), although no suspicious nodularities or FDG uptake in the area (Fig. 2b). A trial of therapy with ibuprofen 2,400 mg/day was undertaken under close clinical and echographic surveillance. There was no improvement in the persistent chest discomfort, leg swelling, or thickness of the effusion on reimaging. Colchicine 0.6 mg twice daily was added, without any clinical benefit after a total of 6 weeks of empiric therapy. The degree of edema and chest discomfort prevented the patient's return to work despite otherwise complete recovery from the cancer therapy. A diagnostic and therapeutic thoracoscopic biopsy with pericardial window creation was performed, with evacuation of a moderate amount of straw-colored fluid. The visualized pericardium appeared unremarkable during the procedure. The fluid cytology showed predominance of histiocytes and inconspicuous lymphocytes. The biopsy tissue did not contain any malignancy or infectious agents. It was felt that the patient had an idiopathic, progressive pericardial effusion exacerbated by serositis late in the course of chemotherapy. The leg edema and chest discomfort persisted for a few weeks following the surgery and then slowly dissipated with tapering doses of furosemide. Six months since completion of chemotherapy, the patient remains in remission from HL without any further symptoms or recurrent effusion, back at work full time. The occurrence of pericardial effusion in a patient with concomitant malignancy is quite alarming to oncologists due to concern for cardiac tamponade. Causes of effusion in this setting include not only direct neoplastic invasion but also radiation-related pericarditis, hypothyroidism, viral, mycobacterial infections, and other incidental etiologies. In the general population of patients presenting with symptomatic pericardial effusions, the proportion of malignant etiologies has decreased from 40% in the 1970's to 25% in the 1990's, mostly giving way to iatrogenic effusions resulting from cardiologic procedures [5]. In the series of oncology patients who underwent diagnostic drainage, the rates of truly malignant effusion are 38–58%, while the rest are at least pathologically benign [6, 7]. Pericardioscopy may have a higher yield for detection of neoplastic involvement compared with fluid cytology or pericardial window biopsy [8]. Additional molecular analysis may increase the diagnostic yield, but the cost-effectiveness of such testing and actual contribution to management is limited [9]. Therefore, a thorough communication with the cardiologist is necessary to assure mutual understanding of oncologic prognosis and treatment goals on one hand, and the risks of hemodynamic compromise on the other. The team approach helps make the important decision to evacuate the fluid or manage it conservatively. Lymphomas and other hematologic malignancies invade pericardium through direct infiltration or hematogenous spread. They may also be associated with inflammatory or autoimmune phenomena resulting in serous effusions. Unlike metastatic solid tumors, they may be curable with systemic chemotherapy, without a local intervention. In a comprehensive review of patients with acute leukemia and myelodysplastic syndrome, 20% had detectable effusions, although only 9% of these were classified as moderate or large and only 3% required drainage due to tamponade. The effusions were greatest at the time of detection and uniformly decreased during ongoing treatment [10]. Pericardial effusions in HL are extremely rare and usually reported in the context of prior thoracic irradiation or relapsed, refractory disease [11]. Malignant pericarditis can be a presenting manifestation in exceptional cases [12]. Nevertheless, in pediatric HL, 5% of patients, exclusively with nodular sclerosis subtype, had evidence of pericardial infiltration, although only two of 13 required fluid drainage and none demonstrated malignant cytology [13]. Invasion of pericardium has been described in HL almost exclusively with bulky disease exceeding one third of the thoracic diameter [14]. Interestingly, pericardial effusions are much more common (32%) in primary mediastinal large B-cell lymphoma [15]. This form of non-HL is characterized by extensive contiguous spread in the mediastinum and adjacent organs [16]. It shares many clinical, morphologic, and molecular features with nodular sclerosis HL, such as preponderance for younger patients, reactive fibrosis, and CD30-positivity. Both entities exhibit constitutive activation of NF-κB and JAK-STAT kinases as well as high levels of expression of cytokine pathways, TNF family members, and extracellular matrix elements [17]. Therefore, the presence of a pericardial effusion at diagnosis should raise the question of correct classification, which may occasionally prove difficult, particularly in cases of “gray-zone” lymphomas [18]. Some of the agents used in chemotherapy of lymphomas need to be considered as potential etiologic factors of pericardial effusions. Doxorubicin, aside from cumulative heart failure, may cause acute myopericarditis strongly correlating with troponin elevation. Attacks of chest pain during administration as well as sporadic, life-threatening pericarditis have been reported with bleomycin [19]. Pericarditis is also a dreaded late, dose-dependent complication of mediastinal irradiation, with a 10-year cumulative incidence of 9.5% in the past, although it is likely to decrease with the modern involved-field techniques [20]. The asymptomatic pericardial effusion in a patient with HL or another curable malignancy may create a decisional dilemma, particularly if it persists while the lymphoma unequivocally goes into remission during therapy. The majority of effusions in this setting are not malignant. An attempt at empiric anti-inflammatory therapy may be reasonable, as was done in our patient, particularly considering the association with diffuse joint serositis. The diagnostic and therapeutic pericardiocentesis is however recommended in large or symptomatic effusions [21]. Chronic idiopathic pericardial effusions may progress to a symptomatic stage with dyspnea and pleuritic chest pain, frequently with evidence of right atrial or right ventricular collapse. This reflects a continuum of hemodynamic changes ultimately culminating in tamponade [22]. Rarely, the effusive constrictive pericarditis may develop, sometimes despite drainage, and requires extensive surgical management with both visceral and parietal pericardial stripping [23]. Two-dimensional echocardiograms are useful in evaluating cardiodynamic physiology and appear to quantify the volume of effusions better than CT scans, which may be oversensitive in visualization of the fluid [24]. EKG findings may indicate acute pericarditis as etiology or suggest a large effusion with tamponade physiology and need to be recognized. Prospective studies show that most patients with large idiopathic effusions (over 20-mm thickness at end diastole) ultimately require pericardiectomy, since recurrence after pericardiocentesis is common and tamponade can develop unexpectedly after long periods of stabilization [25]. Based on our experience, in case of unexplained, progressive pericardial effusion during curative chemotherapy for HL a diagnostic and therapeutic drainage is also warranted, even though true neoplastic involvement may be rare.