A 52-year-old woman presented at the emergency room (ER) in a regional hospital with progressive dyspnea, a dry cough and fatigue during several weeks despite taking oral antibiotics because of a suspected pneumonia. Three days prior to presentation she had experienced a severe dull thoracic and epigastric pain accompanied by nausea and vomiting that had resolved spontaneously. Besides taking ferrofumarate and cholecalciferol for iron-deficiency anemia and vitamin D deficiency, she had no previous medical history.
On presentation, physical examination revealed a regular tachycardia of 116 beats per minute (bpm), a blood pressure of 120/75 mmHg, an oxygen saturation of 100% while breathing ambient air, and a core temperature of 38.0 C (100.4 F). Cardiac, pulmonary, and abdominal examinations were unremarkable. There were no signs of deep venous thrombosis and the Wells-score was 4.5. The electrocardiogram (ECG) showed sinus tachycardia, normal electrical heart axis and normal PR- and QRS-intervals, but inverted T-waves in both antero- and inferolateral leads (Figure 1). A low hemoglobin level (5 mmol/L), elevated c-reactive protein (102 mg/ml), troponin-I (1036 ng/L, cut-off is <20) and NT-pro-BNP (366 ng/L, normally <100) levels were the most prominent abnormal laboratory results.
Computed tomography angiography of the thorax (CTA) ruled out pulmonary embolism, but demonstrated pericardial and pleural effusion. Subsequent transthoracic echocardiography (TTE) confirmed circumferential pericardial effusion of ~4.5 cm with signs of haemodynamic compromise (dilated and poor collapsing inferior caval vein, early systolic right atrial (RA) collapse and >25% respiratory variation in peak mitral E-wave). Urgent evacuation of ~1 L of hemorrhagic fluid after pericardiocentesis immediately ameliorated symptoms. Investigation of this pericardial fluid did not reveal a tuberculous, bacterial, viral, or malignant etiology. A respiratory viral panel by polymerase chain reaction (influenzas A and B and respiratory syncytial virus) and a serum HIV antibody test were negative. After recurrent pericardial effusion was ruled out 1 week later, she was discharged home. While unconfirmed, a discharge diagnosis of post-infectious/post-viral pneumonia related pericardial and pleural effusion was made.
Already 5 days later, she presented again with progressive dyspnea, coughing, and nausea. A further decrease in hemoglobin (4.7 mmol/L) was noted and TTE showed recurrent circumferential pericardial effusion (~3 cm) but now a dense structure suggesting thrombus in the pericardial sac (Figure 1). Coronary angiography (CAG) was performed after which coronary artery disease including dissection could be ruled out.
She was transferred to a tertiary university center and received a blood transfusion. Additional viral serology (adenovirus, coxsackievirus, echovirus, borrelia burgdorferi, cytomegalovirus, Epstein-Barr virus, and parvovirus), immunological testing (systemic lupus erythematosus, rheumatoid arthritis, vasculitis, complement screening, and M-protein), a tuberculosis test and blood culture analyses were normal. To re-assess the possibility of a malignant cause, a repeat CTA of the thorax and abdomen was performed. While macroscopic malignancies could be ruled out, the scan showed contrast extravasation into the pericardial space, suggesting active bleeding. After a multidisciplinary consultation between cardiologists and cardiothoracic surgeons, and given the observation that the patient remained hemodynamically stable, it was decided that urgent surgery was not yet indicated and that there was still sufficient time for additional diagnostic workup. On cine cardiac magnetic resonance imaging (CMR), left (LV) and right ventricular (RV) systolic function were preserved and pleural and pericardial effusion confirmed. During contraction, the LV apex remained remarkably "fixed" to the pericardium (Supplementary Video 1). On the delayed enhancement (DE) images, the high intra-pericardial signal again suggested contrast-extravasation into the pericardial sac, whereas an extensive, hypo-enhanced circumferential layer against the inner parietal pericardium suggested thrombus (Figure 1). No intramyocardial abnormalities were observed.
It was concluded that ongoing, albeit slow, intra-pericardial bleeding was present. Since other diagnostic clues were missing at this time, an initial post-viral and subsequent recurrent traumatic or reactive pericardial effusion after pericardiocentesis were still considered causative and urgent surgery was yet indicated.
Since focal bleeding from a traumatic ventricular lesion after initial pericardiocentesis could not be excluded, it was decided to first perform a limited thoracotomy via a left-sided submammary incision. After evacuating 2.5 L hemorrhagic pericardial fluid with thrombi, careful inspection did not reveal a focal bleeding site. Because of persistent bleeding, the incision was extended further but again no focal bleeding source was discernable. Instead, multiple active venous hemorrhages on the entire epicardium were visible and hemostasis was attempted by placing multiple fibrin sealant patches Tachosil (Baxter healthcare cooperation, Illinois, USA). In addition, multiple biopsies of the pericardium and pericardial fluid and thrombi were sent for pathological examination.
The patient was subsequently transferred to the intensive care unit (ICU), but went into cardiogenic shock the following day. TTE showed recurrent pericardial effusion with a thrombus compressing the RA. A conventional emergency sternotomy was carried out. After thrombus removal, again diffuse hemorrhages were observed and a single bleeding focus in the RA was sutured.
Unfortunately, within 3 days she had to be operated two more times to relief recurrent cardiac tamponade and a left-sided hemothorax. Repeatedly, extensive diffuse venous epicardial hemorrhages were found that were difficult to manage, causing her to remain hemodynamically unstable in the ICU. After 9 days, pathology of the pericardium revealed an epithelioid angiosarcoma. Given the disease extent and unfavorable prognosis, it was decided to refrain from additional aggressive therapy. She died the same day, 28 days after the initial presentation. A timeline is showcased in Figure 2.
After obtaining consent from relatives, gross autopsy revealed a diffusely thickened residual pericardium with an irregular surface with multiple thrombi and hemorrhages. The pericardium was extensively adhered to ribs, myocardium, ascending aorta, and aortic arch. A nodular epicardial surface was found with diffuse hemorrhages and thrombi. The heart was only minimally enlarged (419 [normal 233-403] g). Microscopy showed an atypical vascular proliferation with focal papillary structures consisting of large epithelioid cells with high amounts of eosinophilic cytoplasm. The nuclei of these epithelioid cells were pleomorphic and hyperchromatic with numerous, sometimes atypical, mitoses. Because these epithelioid cells stained positive for the immunohistochemical vascular markers ERG, CD31 and CD34 but not for CD68, HHV-8 and keratin markers CK AE1/AE3, CK 5/6, and CK7, a diagnosis of epithelioid angiosarcoma was made. The angiosarcoma was predominantly localized in the pericardium and epicardium without deeply infiltrating the myocardium leading to epicarditis and pericarditis. A single longitudinal thickened lesion was found at the RA appendage that had been surgically sutured. Microscopic evaluation of this lesion revealed transmural invasion of the angiosarcoma (Figure 3).
Additionally, lympho-vascular invasion with intracapillary tumor cells in the lungs (hemangiosis carcinomatosa) and focal invasion from the pericardium into the left lung was found, explaining the hemothorax.