ABSTRACT
Case Study
In early 2010, Mrs. Y., a 58-year-old Japanese woman, underwent a routine mammogram
that revealed left focal asymmetry. A biopsy demonstrated invasive ductal carcinoma,
and she was referred to surgery. She underwent a lumpectomy and left axilla sentinel
lymph node biopsy. Pathology confirmed an invasive ductal adenocarcinoma, moderately
differentiated, 1.2 cm, estrogen receptor (ER)/progesterone receptor (PR) negative,
and HER2/neu negative with negative surgical margins. Three left axillary sentinel
lymph nodes showed no evidence of disease.
Mrs. Y. was diagnosed with stage I T1cN0Mx breast cancer. Her oncologist estimated
that she had a 25% 10-year risk of relapse and a 13% 10-year risk of mortality, with
an estimated 35% mortality benefit conferred by adjuvant therapy. Although it was
recognized that triple-negative breast cancer confers a worse prognosis (Foulkes,
Smith, & Reis-Filho, 2010), no available prognostic calculators considered hormone
receptor status; the oncologist’s projections were overly optimistic. In a recent
retrospective study in triple-negative breast cancer patients, (Hernandez-Aya et al.
(2011) found a 5-year mortality rate of 16% for T1N0 patients and a 5-year relapse
of 26% in these patients, similar to what Mrs. Y.’s oncologist had estimated for 10
years.
The oncologist recommended adjuvant therapy, and Mrs. Y. received four cycles of adjuvant
docetaxel and cyclophosphamide followed by radiation therapy to the tumor bed and
left breast. Her treatment followed the course recommended by the National Comprehensive
Cancer Network Guidelines at that time (Carlson et al., 2009). She completed therapy
in October 2010 without having experienced any dose reductions, delays, or complications.
Mrs. Y. continued to show no evidence of disease until early 2013, when she developed
left neck and arm swelling. Computed tomography (CT) scan of the neck and thorax revealed
a left supraclavicular mass compressing the left internal jugular and subclavian veins
and enlarged cervical lymph nodes. A biopsy of the supraclavicular mass confirmed
metastatic breast cancer. CT scan of the abdomen and pelvis showed no other sites
of disease. She was treated with involved-field irradiation (16 Gy) to the sites of
tumor recurrence and then was lost to follow-up.
Six months following completion of irradiation, Mrs. Y. presented to the emergency
department (ED) with dyspnea. On review of systems, she reported a 3-month history
of a progressive cough and a 3-week history of hoarseness with progressive shortness
of breath (SOB) and difficulty speaking. Upon physical examination, her voice was
hoarse, breath sounds were clear to auscultation, and there were palpable left supraclavicular
nodes. She did not have muffled heart sounds, elevated jugular venous pressure (JVP),
or pulsus paradoxus. In the ED, her vital signs were blood pressure (BP) 129/85, pulse
89, oxygen saturation 98%, and respirations 16. An electrocardiogram (ECG) revealed
sinus rhythm with borderline T-wave abnormalities in diffuse leads and a heart rate
of 94. Her troponin I level was zero. A CT angiogram revealed a moderate-sized pericardial
effusion (Figure 1) and supraclavicular and mediastinal lymphadenopathy with no evidence
of a pulmonary embolus. Ultrasound confirmed a moderate pericardial effusion with
no evidence of tamponade.
Figure 1
CT pulmonary embolus study showing pericardial effusion measuring 19.27 mm in this
plane.
Overnight, Mrs. Y.’s SOB remained stable but her BP dropped to 70/49, which improved
to 80/62 in response to a normal saline bolus. An ECG revealed sinus rhythm with partial
resolution of the T-wave abnormalities and a heart rate of 65. Systolic blood pressure
remained below 90 for several hours despite fluid boluses; by morning her BP had improved
to 93/63. Echocardiography (echo) revealed a moderate-sized circumferential pericardial
effusion with mild diastolic right atrium/right ventricle collapse, a dilated inferior
vena cava, and mild mitral valve inflow variation with respiration, consistent with
mild hemodynamic compromise. Left ventricle size and systolic function were normal.
Based on the echo findings, newly elevated JVP, and ongoing hypotension, Mrs. Y. was
diagnosed with cardiac tamponade and suspected malignant pericardial effusion. Cardiology
performed a diagnostic and therapeutic echo-guided pericardiocentesis and removed
260 mL of a bloody turbid fluid. A drain was left in, but it removed only 10 mL of
fluid overnight and was removed the next day. Mrs. Y. had almost immediate relief
of her dyspnea, and by day 3 she reported that she felt "a hundred times better" than
she had at admission. She was discharged later that day after repeat echo showed a
stable small pericardial effusion. Cytology of the pericardial fluid ultimately revealed
metastatic adenocarcinoma consistent with the original breast cancer diagnosis.
ARTICLE
The pericardium surrounds the heart and the great blood vessels and is composed of
a thin visceral membrane, a fibrous parietal membrane, and the pericardial space between
the membranes, which normally contains less than 50 mL of an ultrafiltrate of plasma
known as pericardial fluid (Hoit, 2011; Braunwald, 2012). The parietal membrane is
composed primarily of collagen and elastin fibers, which gives the membrane some elasticity
(Braunwald, 2012). As a result of this elasticity, the normal pericardium has a nonlinear
pressure-volume curve. Small pericardial fluid volume changes do not generally result
in any change in pericardial pressure, but a large sudden increase in pericardial
volume can cause a steep change in pericardial pressure, leading to tamponade (Imazio
& Adler, 2013).
With a slowly enlarging pericardial effusion, the pericardial membranes stretch to
accommodate the growing fluid volume without any significant change in the pericardial
pressure until the limit of pericardial membrane stretch is reached. When pericardial
fluid volume increases beyond the limit of membrane stretch, cardiac tamponade results
(Imazio & Adler, 2013). Surprisingly, although the pericardium has many normal functions
(Table 1 ), there are no significant consequences if the pericardium is removed or
congenitally absent (Hoit, 2011; (Braunwald, 2012).
Table 1
Functions of the Pericardium
Etiology of Pericardial Effusions
Pericardial effusions can be idiopathic, infectious (most commonly viral), cardiac,
autoimmune, medication-induced, radiation-induced, traumatic, metabolic, malignant,
or the result of other causes (Imazio & Adler, 2013). The most common cause in cancer
patients is a malignant effusion from lung or breast cancer (Lestuzzi, 2010; Pawlak-Cieślik
et al., 2012), but nonmalignant etiologies (thoracic radiation, infection, autoimmune
process, and medication) and other cancers (other solid tumors, hematologic malignancies,
Hodgkin lymphoma, and non-Hodgkin lymphoma) can also cause effusions (Maisch, Ristić,
& Pankuweit, 2010). Chemotherapeutic agents that can cause pericardial effusion include
cyclophosphamide, cytarabine, dasatinib (Sprycel), doxorubicin, gemcitabine, and other
cardiotoxic agents (Svoboda, 2010).
Symptoms and Exam Findings
Effusions that develop quickly are the most likely to cause symptoms and physical
exam findings (Seferović et al., 2013; Burazor, Imazio, Markel, & Adler, 2013). Dyspnea
is the most common symptom in malignant pericardial effusion (Svoboda, 2010). Other
symptoms include pleuritic chest discomfort, cough, fatigue, hoarseness from recurrent
laryngeal nerve compression, and hiccups from phrenic nerve compression, with syncope
being particularly concerning for tamponade (Borlaug, DeCamp, & Gangadharan, 2013;
Refaat & Katz, 2011).
Pericardial effusions can be difficult to diagnose because clinical findings have
poor sensitivity; tachycardia may be the only sign (Pawlak-Cieślik et al., 2012).
The classic physical exam findings that are concerning for tamponade are collectively
referred to as Beck’s triad: hypotension (often with a narrow pulse pressure), tachycardia,
and muffled heart sounds. Beck’s triad was initially described for acute tamponade,
which develops over minutes to hours; it is rarely seen in cancer patients with malignant
pericardial effusions, who tend to develop subacute tamponade over days to weeks (Argulian,
Herzog, Halpern, & Messerlin, 2012; (Borlaug et al., 2013; Imazio & Adler, 2013).
Other signs of tamponade include elevated JVP and pulsus paradoxus (Refaat & Katz,
2011). Pulsus paradoxus above 10 mm Hg has been reported to be the most sensitive
physical finding for tamponade but still only has a sensitivity of 82%, followed by
tachycardia and elevated JVP, with sensitivities of 77% and 76%, respectively (Sherbino,
2009).
Diagnostic Workup
Given that dyspnea is the most common symptom, a chest x-ray is often the first study
obtained. An enlarged cardiac silhouette with clear lungs (the "water bottle sign,"
as shown in Figure 2) is the classic finding in pericardial effusion, and concomitant
pleural effusion is common in malignant pericardial effusions (Hoit, 2013a). The patient’s
ECG may be normal, or it can demonstrate low QRS voltage, nonspecific ST- or T-wave
changes, or electromechanical dissociation (agonal phase; Svoboda, 2010). Low QRS
voltage is indicative of cardiac tamponade, but its absence does not rule out tamponade
(Seferović et al., 2013). Low QRS voltage is most commonly associated with tamponade
caused by a malignant pericardial effusion and usually resolves within a week of pericardiocentesis
(Oliver et al., 2002). Elevated troponin I and creatine kinase myoglobin levels are
commonly seen but appear to have no prognostic implication (Imazio et al., 2013).
Figure 2
Water bottle sign on chest x-ray (Hellerhoff, 2010).
Echo is the diagnostic standard, as it is the most useful imaging study for determining
the presence, size, location, and hemodynamic effect of a pericardial effusion (Hoit,
2011). Although a CT of the thorax is generally not a good modality for determining
the severity of an effusion, both CT and magnetic resonance imaging (MRI) may be superior
to echo for determining the amount and distribution of pericardial fluid and whether
an effusion is hemorrhagic or loculated (Bogaert & Francone, 2013). Cardiac chamber
collapse on echo typically occurs before clinical hemodynamic failure (Mallemat &
Tewelde, 2013). Echo findings consistent with cardiac tamponade include collapse of
the right atrium at end diastole and the right ventricle in early diastole, reciprocal
changes in left and right ventricular volumes with respiration, increased respiratory
variation of mitral and tricuspid valve inflow velocities, and inferior vena cava
(IVC) dilatation with less than a 50% reduction in IVC diameter during inspiration
(Hoit, 2013b). See Table 2 for a list of key elements in diagnosing malignant pericardial
effusion.
Table 2
Diagnosing Malignant Pericardial Effusion
Initial Management
In 2004, the Task Force on the Diagnosis and Management of Pericardial Diseases of
the European Society of Cardiology published guidelines for the management of pericardial
effusion (Maisch et al., 2004). Although there are many articles that specifically
address pericardial effusions in patients with cancer, there have been no randomized
controlled trials or prospective intervention trials (Burazor et al., 2013). Treatment
of pericardial effusion secondary to malignant disease requires consideration of the
patient’s prognosis from the underlying malignancy, the availability of local expertise,
and the cardiovascular and medical status of the patient (Imazio & Adler, 2013). Stable
patients without evidence of tamponade can be managed with careful monitoring, serial
echo studies, avoidance of volume depletion, and therapy aimed at the underlying cause
of the pericardial effusion (Borlaug et al., 2013), regardless of effusion size (Mallemat
& Tewelde, 2013).
Patients with evidence of tamponade who are hypovolemic should be given volume resuscitation
if systolic BP is below 100 mmHg (Sagristà-Sauleda, Angel, Sambola, & Permanyer-Miralda,
2008). In tamponade, there is a significant increase in the pericardial pressure,
and the central venous pressure must be kept higher than the pericardial pressure
in order for the heart to fill. If volume resuscitation results in hemodynamic improvement,
such patients may be observed closely without urgent need for pericardiocentesis (Hoit,
2013b). In patients with cancer, pericardiocentesis is indicated for symptomatic cardiac
tamponade and for high suspicion of tuberculous or infectious etiology (Maisch et
al., 2013; Sagristà-Sauleda et al., 2011).
In general, pericardial effusion drainage should be considered if the echo demonstrates
chamber collapse and the patient is symptomatic; drainage is not necessarily indicated
for echocardiographic right atrial collapse in an asymptomatic patient (Hoit, 2011;
Maisch, Ristić, Seferovic, & Tsang, 2011). Furthermore, pericardiocentesis is associated
with risk and will not always resolve symptoms (Mallemat & Tewelde, 2013). Major complications
of pericardiocentesis in a large study (1,127 procedures) occurred in 1.2% of echo-guided
cases and included heart chamber laceration requiring surgery, pneumothorax, ventricular
tachycardia, and bacteremia (Tsang et al., 2002). Minor complications requiring monitoring
but no intervention occurred in 3.5% of echo-guided cases and included transient heart
chamber entrance and small pneumothorax (Tsang et al., 2002).
If pericardiocentesis is required, different approaches can be used (Table 3). Pericardiocentesis
may be followed by catheter placement for ongoing fluid removal until the rate of
fluid return is less than 20 to 30 mL over 24 hours (Imazio, Spodick, Brucato, Tinchero,
& Adler, 2010). The risk of recurrence of pericardial effusion is significantly reduced
when pericardiocentesis is followed by extended catheter drainage, with 6-month recurrence
rates of 14% vs. 27% with and without extended drainage (Tsang et al., 2002). However,
it is important to note that only 33% of the sample in this study had a malignant
pericardial effusion, and malignancy was independently correlated with increased risk
of effusion recurrence (Tsang et al., 2002). Repeat echo should be performed after
pericardiocentesis to confirm adequate fluid removal and to detect early recurrent
fluid accumulation (Cheitlin et al., 2003).
Table 3
Techniques for the Management of Malignant Pericardial Effusion
The most helpful pericardial fluid studies are cytology, Gram stain, and bacterial/fungal
cultures, although negative cytology is not sufficient to exclude malignancy (Maisch
et al., 2011). In immunocompromised patients, polymerase chain reaction studies for
viruses can be helpful, such as cytomegalovirus in transplant patients (Maisch et
al., 2011). Protein, lactate dehydrogenase, glucose, and cell count have not been
shown to be diagnostically helpful because they do not reliably distinguish malignant
from benign pericardial effusions (Karatolios, Pankuweit, & Maisch, 2013).
There is significant controversy regarding the best time for consideration of surgical
rather than percutaneous decompression of pericardial effusions in patients with malignancy.
It is well documented that pericardial effusions have a higher risk of recurrence
after pericardiocentesis compared with surgical interventions, with recurrence rates
as high as 90% in patients with malignancy (Refaat & Katz, 2011). Although surgical
interventions result in increased discomfort and morbidity compared with pericardiocentesis
(Svoboda, 2010), for a patient who experiences multiple symptomatic recurrences of
a malignant pericardial effusion, a surgical decompression may result in overall improvement
in quality of life with more time outside the hospital despite the initial increase
in morbidity. A variety of surgical options exist, some of which can create a pericardial
window to allow ongoing drainage to the pleural or peritoneal space (Table 3).
Prevention of Recurrence
The guidelines of the European Society of Cardiology include the following options
to prevent recurrence of malignant pericardial effusions: systemic antineoplastic
treatment, intrapericardial instillation of sclerosing or cytotoxic agents, percutaneous
balloon pericardiotomy, surgical subxiphoid pericardiotomy or pleuropericardiotomy,
and radiation therapy (Maisch et al., 2004). Although anti-inflammatory medications
have been shown to be very useful in inflammatory pericardial effusions, they have
little utility in malignant effusions (Imazio & Adler, 2013). The standard recommendation
is systemic chemotherapy to control the cause of the malignant effusion (Lestuzzi,
2010; Maisch et al., 2004; Refaat & Katz, 2011). Instillation of sclerosing agents
has been shown to have little impact on effusion reaccumulation or survival (Kunitoh
et al., 2009). Percutaneous balloon cardiotomy is less invasive than surgical interventions
and has a good success rate (Maisch et al., 2011). The various surgical options outlined
in Table 3 have a lower rate of effusion recurrence than do percutaneous interventions,
but they incur higher morbidity. Radiation therapy was used historically to control
malignant pericardial disease (Cham, Freiman, Carstens, & Chu, 1975), but it is no
longer favored, as it can also cause pericardial effusions (Svoboda, 2010).
Intrapericardial instillation of cisplatin is favored in some centers, with a reported
response rate of 93%, a response duration of 3 months, and greater efficacy in lung
cancer vs. breast cancer (Maisch et al., 2010). Intrapericardial instillation of thiotepa
has been used in breast cancer with good effect (Burazor et al., 2013). Although a
retrospective review showed significant improvement in outcomes for patients treated
with both intrapericardial and systemic chemotherapy (Lestuzzi et al., 2011), the
use of such practices has not been widely adopted due to the potential for pain caused
by introduction of the agents and concern for later development of constrictive pericarditis
(Borlaug et al., 2013).
Prognostic Implications
Development of a symptomatic pericardial effusion in a patient with a malignancy confers
a poor prognosis, with a median survival time of 2 to 5 months from the time of detection
(Dequanter, Lothaire, Berghmans, & Sculier, 2008;). Prognosis may be slightly better
in the subset of patients with negative cytology (Neragi-Miandoab et al., 2008), hematologic
rather than solid malignancies (Svoboda, 2010), and breast rather than lung or other
solid tumors (Kim et al., 2010). Leukemic pericardial effusions have been shown to
be relatively frequent (20%) but generally asymptomatic and small, with a large retrospective
review showing that only 3% of such pericardial effusions required intervention (Sampat
et al., 2010).
Case Discussion and Update
After the pericardiocentesis, Mrs. Y. began systemic chemotherapy as recommended.
She had no further issues related to the pericardial effusion in the 5 months after
the pericardiocentesis, although her metastatic breast cancer continued to progress.
Repeat CT imaging showed only a small residual effusion (Figure 3).
Figure 3
CT thorax done 2 months after peri - cardiocentesis showing minimal residual pericar
- dial effusion.
Mrs. Y.’s case is somewhat unusual in that she became symptomatic with a relatively
small effusion. In slowly accumulating effusions (the typical pattern in malignancy),
patients are rarely symptomatic with an effusion size less than 500 mL (Schoen & Mitchell,
2010) and may remain asymptomatic until 2,000 mL or more has accumulated (Hoit, 2013a).
However, symptoms are a result not only of effusion size, but also of the rate of
fluid accumulation relative to pericardial stretch and how effectively the heart compensates
for the reduced heart chamber size (Saito et al., 2008).
Mrs. Y.’s symptoms were typical, as she presented with shortness of breath, the most
common symptom, and subsequently developed hypotension. Her rapid improvement with
pericardiocentesis is also typical although not universal. Mrs. Y. had multiple risk
factors for pericardial effusion, including metastatic breast cancer, history of thoracic
radiation, and treatment with cyclophosphamide. Given that these risk factors are
present for the majority of patients with metastatic breast cancer, it is important
for advanced practitioners to have a high index of suspicion for pericardial effusion
in addition to malignant pleural effusion and pulmonary embolus when such patients
present with shortness of breath.
Considerations for Advanced Practitioners
Pericardial effusion should be suspected in any patient with a malignancy and any
of the following symptoms: dyspnea or pleuritic chest pain, new radiographic cardiomegaly
without pulmonary congestion, unexplained persistent fever, presence of an isolated
left pleural effusion, or hemodynamic deterioration of unknown etiology (Hoit, 2013b).
The most common malignancies causing pericardial effusion are breast and lung cancer,
followed by Hodgkin lymphoma, non-Hodgkin lymphoma, and leukemia (Lestuzzi, 2010).
Consequently, it is especially important for advanced practitioners to have a high
index of suspicion in a patient with one of these malignancies presenting with shortness
of breath. Radiation-induced pericardial effusion may occur during the radiation therapy
itself or up to 20 years after therapy (Lee, Finch, & Mahmud, 2013), and a history
of thoracic radiation therapy should further increase the suspicion of pericardial
effusion.
A patient with a moderate pericardial effusion may be minimally symptomatic and may
have no specific physical exam findings and a normal ECG. If a pericardial effusion
is within the differential diagnosis for the reasons outlined here, echocardiography
is the most specific and clinically important diagnostic tool, as it can provide evidence
of cardiac compromise prior to the development of overt tamponade. In pericardial
effusions that develop slowly and do not cause hemodynamic compromise, systemic chemotherapy
is often a better option than invasive intervention. Any patient who develops symptomatic
tamponade from a malignant pericardial effusion needs intervention for the effusion,
preferably with pericardiocentesis followed by systemic chemotherapy, if these interventions
are aligned with the patient’s goals of care. For recurrent symptomatic malignant
pericardial effusions, a surgical intervention may, after the initial postsurgical
recovery period, improve quality of life and reduce hospital stays.