cncy21246
TRANSCRIPT
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Pericardial Fluid Cytology: An Analysis of 128 Specimens
Over a 6-Year Period
Ema A. Dragoescu, MD and Lina Liu, MD
BACKGROUND: Pericardial fluid (PF) accumulates through various mechanisms and cytology is part of the workup to deter-
mine the specific etiology, primarily to rule in or rule out malignancy. To the best of the authors’ knowledge, the current study
is the largest systematic evaluation of PF cytology performed to date. METHODS: PF specimens collected over 6 years were
retrieved. Clinical history, laboratory, cytologic, and pericardial biopsy results were recorded. RESULTS: A total of 128 PF
specimens were obtained from 113 patients (56 males and 57 females), representing 4.5% of all fluids. Of these, 95 cases
(74.2%) were benign, 2 (1.6%) had ‘‘severely atypical cells, ’’ and 31 cases (24.2%) were malignant. The most common
etiologies for benign PF specimens were neoplasm (23.1%), idiopathic (19%), infection (14.7%), and connective tissue dis-
ease (12.6%). The most common neoplasm producing malignant PF was lung carcinoma, both in males (75%) and females
(52.2%), with adenocarcinoma being the most common type (72.2%). In females, breast carcinoma was the second most
common neoplasm (39.1%). Approximately 87.1% of patients with malignant PF specimens had a prior history of malig-
nancy and approximately 32.7% underwent a concomitant pericardial biopsy. The false-negative rate for cytology was
14.7% (hematologic malignancies [2 cases], metastatic sarcoma [1 case], and sarcoidosis [1 case] not detected) and that
for pericardial biopsy was 40% (metastatic carcinoma [4 cases] not detected). CONCLUSIONS: PF specimens are uncom-
mon. A specific interpretation is rendered in approximately 98.4% of cases. Lung carcinoma is the most common tumor to
produce malignant PF in both males and females. Approximately 87.1% of patients with malignant PF have a known
history of malignancy. Although cytology is superior to pericardial biopsy in diagnosing metastatic carcinoma, other
tumors may go undetected in the PF. Cancer (Cancer Cytopathol) 2013;121:242-51. VC 2013 American Cancer Society.
KEY WORDS: pericardial, fluid, etiology, cytology, malignant.
INTRODUCTION
Cytologic evaluation is just one aspect of the overall workup of pericardial fluid (PF), which, together withgeneral chemical analysis and microbiology cultures, has as its main purpose the determination of the etiol-ogy of the PF. To rule in or rule out malignancy is the main contribution of the cytologic evaluation in thelaboratory workup of PF. Several well-known conditions can produce a pericardial effusion such as infec-tion, malignancy, connective tissue disease, pericardial injury, metabolic causes, heart disease, or idiopathiccauses.1-6 Each effusion is treated based on the specific etiology and hemodynamic stability of the patient.7
With knowledge of the specific cause that triggered the accumulation of the pericardial effusion, clinicianscan tailor the treatment to target that specific cause or simply provide supportive measures.
Although systematic evaluation of pleural and peritoneal fluid cytology is abundant in the literature,8-10
large series focusing on PF cytology are surprisingly sparse.11,12 There are several reasons for this discrepancy.
Received: May 24, 2012; Revised: August 14, 2012; Accepted: August 24, 2012
Published online January 29, 2013 in Wiley Online Library (wileyonlinelibrary.com)
DOI: 10.1002/cncy.21246, wileyonlinelibrary.com
Corresponding author: Ema A. Dragoescu, MD, Department of Pathology, Virginia Commonwealth University Health System, 1200 East Marshall St,
PO Box 980662, Richmond, VA 23298-0662; Fax: (804) 828-8733; [email protected]
Department of Pathology, Virginia Commonwealth University Health System, Richmond, Virginia.
Presented in part at the 59th American Society of Cytopathology Annual Meeting; November 4-8, 2011; Baltimore, MD.
We thank Mrs. Patricia R. Strong, Director of the Writing Center and Assistant Professor at the University College at Virginia Commonwealth
University in Richmond for her critical review of the article and useful suggestions.
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First, pericardial effusions are uncommon in the cytology
laboratory compared with the other 2 types of effusions.
Unless the PF is accumulated in a large amount or pro-
duces hemodynamic compromise (ie, cardiac tampon-
ade), the effusion is usually not tapped.1,13 Patients with
small amounts of pericardial effusion can be completely
asymptomatic.1 In addition, if a patient has a concomitant
pleural and pericardial effusion, the pleural effusion is
preferentially tapped unless there is hemodynamic com-
promise. Therefore, the collection of a large number of PF
cytology cases for a systematic analysis is difficult to ac-
complish. However, with an appropriate sample, conclu-
sions specific to PF cytology can be drawn. A systematic
review of the literature revealed only 2 series focused on
PF cytology, both of which were published > 15 years
ago.11,12 To the best of our knowledge, the current study
of 128 cases collected over 6 years is the largest series pub-
lished in the literature to date, allowing us to gain insight
into the specifics of PF cytology.
The objective of the current study was to analyze a
large cohort of PF specimens from a single institution to
determine the etiology of the effusions, the diagnostic use-
fulness of cytology evaluation, how the cytologic results
correlate with pericardial biopsy, and the usefulness of
immunohistochemical stains in the workup of cases. To
provide a useful interpretation of the PF, it is necessary for
practicing cytopathologists to know the most common
conditions that can lead to PF accumulation and how
cytologic evaluation can contribute in distinguishing
between them.
MATERIALS AND METHODS
PF specimens collected between January 2005 and De-
cember 2010 were retrieved through a computerized
search. The specimens had been collected through ultra-
sound or fluoroscopic-guided pericardiocentesis or at the
time of pericardial window. Standard analysis of PF at the
time of collection included general chemistry (glucose,
protein, and lactate dehydrogenase levels), microbiology
(aerobic and anaerobic cultures, acid-fast bacilli stain,
mycobacterial culture, and fungal culture), and cytologic
evaluation. Each specimen was received fresh in the cytol-
ogy laboratory. If the specimens were cloudy, turbid, or
bloody, a total of 10 mL from each specimen was poured
off into a centrifuge tube and saline was added to bring
the specimen up to 45 mL. Specimens with a clear appear-
ance on visual inspection were used in their entirety.
Specimens were centrifuged for 15 minutes at 1500 revo-
lutions per minute. A drop from the sediment was placed
in the cytospin chamber. One Diff-Quik–stained and 3
Papanicolaou-stained cytospin slides were prepared for
each specimen and a cell block also was prepared when
excess PF was available. Immunohistochemical stains
were performed on the cell block in selected cases. PF cy-
tology cases were originally reviewed, interpreted, and
reported by different cytopathologists at the time of col-
lection and initial diagnosis. Cases with a malignant cyto-
logic diagnosis were reviewed retrospectively by both
authors. Clinical history, laboratory and radiologic
results, the original cytologic diagnosis, and all pertinent
histologic diagnoses, if available, were recorded. In cases
with concomitant pericardial biopsy, false-positive and
false-negative rates were calculated using standard statisti-
cal methods.
RESULTS
A total of 128 PF specimens were obtained from 113
patients (56 males and 57 females) who ranged in age from
6 years to 85 years (mean, 52.6 years). PF samples com-
prised 4.5% of fluid specimens processed at our institution
during the study period (1292 pleural and 1396 peritoneal
fluid specimens). The amount of PF fluid received ranged
from< 1 mL to 1150 mL (mean, 61.0 mL).
The cytologic microscopic interpretation was
recorded into 3 general categories: ‘‘benign’’ (ie, no malig-
nant cells identified), ‘‘severely atypical cells present, ’’
and ‘‘malignant cells present.’’ For each category, a more
detailed description was included in the diagnosis that
specifically stated the types of cells present. For example,
the description for the benign category (‘‘no malignant
cells identified’’) usually stated the presence of reactive
mesothelial cells, acute and chronic inflammatory cells,
and/or blood. For the malignant cases, tumor type and/or
favored primary tumor site were stated based on the
clinical history, prior pathology information, or
immunohistochemical stains performed on the cell block.
Cases recorded as ‘‘severely atypical cells present’’ were
paucicellular, comprised of rare cells with atypical cyto-
logical features, and a definitive diagnosis (benign vs ma-
lignant) could not be rendered.
The vast majority of PF specimens (95 cases;
74.2%) were classified as benign, negative for malignancy.
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In only 2 cases (1.6%) was a cytologic interpretation of
‘‘severely atypical cells present’’ rendered, and malignant
cells were present in the PF specimen in 31 cases (24.2%).
PF Specimens With Benign
Cytologic Interpretation
There were 95 PF specimens with a benign cytologic
interpretation collected from 83 patients. Duplicate sam-
ples resulted from 7 patients who underwent repeated
cytologic evaluation of PF draining from the pigtail cathe-
ter placed at the time of the initial pericardiocentesis
(5 patients with 2 PF specimens and 2 patients with 3 PF
specimens) and 3 patients had chronic recurrent effusion
accumulated at an interval of 3 months to 4 months. The
interpretation did not change with repeated cytologic
evaluations of the PF. There was a wide range of etiologies
for the benign effusions (Table 1), as detailed below.
Neoplasms
It is interesting to note that neoplasms represented
the most common cause of benign pericardial effusions at
the study institution (23.1%). The vast majority of these
cases were from patients with a prior or concurrent history
of malignancy for which they received systemic chemo-
therapy and radiotherapy to the chest (77.2%). For exam-
ple, 9 patients (41%) had advanced stage primary lung
carcinoma, with small cell carcinoma being the most com-
mon primary lung carcinoma associated with a benign
pericardial effusion while receiving treatment. Another 5
patients (22.7%) had a prior history of malignancy diag-
nosed elsewhere in the body that resulted in metastases to
the lung and/or mediastinal lymph nodes that were
treated with palliative radiotherapy to the chest. Three
patients (13.5%) had a prior history of a treated malig-
nancy in the chest area (esophageal and breast carcinoma
and mediastinal yolk sac tumor) in which the disease was
locally controlled with no direct involvement of the
pericardium, and the PF was considered to be due to treat-
ment effect.
In a minority of patients with a history of neoplasia
(18.3%) the PF accumulated through other mechanisms
that were not directly related to chemotherapy and/or
radiotherapy. For example, in 1 patient with multiple
myeloma, the disease involved the mediastinum and sub-
sequent pericardial biopsy confirmed direct pericardial
involvement, whereas in the other patient with multiple
myeloma the effusion was considered to be the result of
uremia secondary to renal involvement by multiple
myeloma. In the patient with acute myeloid leukemia, the
hemorrhagic pericardial effusion was considered to be due
to thrombocytopenia.
Primary malignant tumors of the pericardium were
very uncommon, with only 1 case of primary cardiac lym-
phoma involving the pericardium reported in the current
study (4.5%). The patient in this case had a benign
TABLE 1. Etiology of 95 PF Specimens With aBenign Cytologic Interpretation
EtiologyTotal No.of Cases
Neoplasms (no. of cases; % of total) 22 (23.1%)
Neoplasm in patients undergoing chemotherapy and/or
RT (17 cases; 77.2%)
Primary lung carcinoma (9; 41%)
Small cell carcinoma (5)
Adenocarcinoma (3)
Squamous cell carcinoma (1)
Metastases to lung/mediastinal lymph nodes (5; 22.7%)
Soft tissue sarcoma (1)
Rectal adenocarcinoma (1)
Appendiceal adenocarcinoma (1)
Renal cell carcinoma (1)
Oropharyngeal squamous cell carcinoma (1)
Mediastinal yolk sac tumor (1; 4.5%)
Esophageal carcinoma (1; 4.5%)
Breast carcinoma (1; 4.5%)
Other mechanisms (4 cases; 18.3%)
Multiple myeloma (2)
Chronic lymphocytic leukemia (1)
Acute myeloid leukemia (1)
Primary cardiac lymphoma (1; 4.5%)
Idiopathic 18 (19%)
Infections 14 (14.7%)
Connective tissue diseases 12 (12.6%)
Systemic lupus erythematosus (8)
Scleroderma (3)
Sjogren syndrome (1)
Pericardial injury syndromes 8 (8.4%)
Trauma to chest (4)
Stab wound (2)
Gunshot wound (1)
Motor vehicle accident (1)
Recent acute myocardial infarction (2)
Pericardiotomy for closure of patent foramen ovale (1)
Perforated ventricle after pacer placement (1)
Metabolic causes 6 (6.3%)
Uremia (5)
Hypothyroidism (1)
Medication induced 6 (6.3%)
Minoxidil (3)
Tacrolimus (3)
Sarcoidosis 2 (2.1%)
Hypereosinophilic syndrome 1 (1.2%)
Multifactorial 6 (6.3%)
Abbreviations: PF, pericardial fluid; RT, radiotherapy.
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pericardial effusion and no ancillary studies were per-
formed. However, the concomitant pericardial biopsy
demonstrated the presence of a follicular lymphoma,
which was confirmed by immunohistochemical studies
and fluorescence in situ hybridization for t(14;18).
Of the 22 benign PF specimens associated with a
neoplasm, 9 of the patients underwent a concomitant per-
icardial biopsy (40.9%). Six cases had a negative result on
the pericardial biopsy (2 primary lung adenocarcinomas,
1 metastatic rectal adenocarcinoma, 1 metastatic renal cell
carcinoma [RCC], 1 metastatic oropharyngeal squamous
cell carcinoma, and 1 esophageal carcinoma). Three cases
had a positive pericardial biopsy (1 case each of metastatic
soft tissue sarcoma, primary cardiac lymphoma, and mul-
tiple myeloma).
Idiopathic
The second largest group of patients with benign PF
specimens is represented by those with idiopathic cases
(19%), in whom no cause for the effusion could be identi-
fied based on the clinical history or comorbid conditions,
or from routine evaluation of the fluid.
Infections
Infections represented the third most common cause
of benign PF specimens (14.7% of all benign PFs), with
the vast majority (71.4%) being bacterial in nature.
Table 2 summarizes the various bacteria identified from
PF cultures and/or blood cultures. The least common
etiologies noted were viral and atypical mycobacteria.
Viral serologies were not performed routinely, except in
immunocompromised patients. Two patients (14.3%)
were identified as having elevated serum titers for
Coxsackie virus type A. Both of these patients were immu-
nosuppressed; 1 patient had acute myelogenous leukemia
and was status post-bone marrow transplant, and the
other patient was an 8-year-old child with hemophago-
cytic lymphohistiocytosis. Mycobacterial infections were
uncommon in the current series as a cause for PF (14.3%
of all infectious PFs), with none being produced by Myco-
bacterium tuberculosis. One patient was a 57-year-old
female with chronic neutropenia of unknown etiology
who was diagnosed with Mycobacterium kansasii by cul-
ture from a mediastinal lymph node biopsy performed at
an outside hospital, and by respiratory culture performed
at the study institution. The second patient was a 37-year-
old man with an untreated human immunodeficiency
virus infection who had disseminated Mycobacterium
avium complex diagnosed from blood culture and bone
marrow biopsy examination.
Other Conditions
The other etiologies of benign PFs at the study insti-
tution were connective tissue diseases (12.6%), pericardial
injury syndromes (8.4%), metabolic causes (6.3%), medi-
cation (6.3%), sarcoidosis (2.1%), and hypereosinophilic
syndrome (1.2%), which are well known in the literature
to be associated with a pericardial effusion. The unusual
case of a patient who was status post-liver transplant (with
TABLE 2. Etiology of 14 Infectious PF Specimens
Etiologic Organism(No. of Cases and % of All Infectious PFs)
PFCultures
BloodCultures Comments
Bacterial (71.4%)
Vancomycin-resistant Enterococcus (2) þ þMethicillin-resistant Staphylococcus aureus (1) - þ Intravenous drug use with endocarditis
Methicillin-sensitive Staphylococcus aureus (1) þ þ Septic shock
Staphylococcus spp. coagulase negative (2) þ NA
Escherichia coli (1) þ NA
Klebsiella oxytoca (1) þ NA
Gram-positive cocci (Gemella spp.) (1) þ NA
Presumed bacterial, specific organism not identified (1) - - Mediastinal abscess in a patient with uncontrolled diabetes mellitusa
Viral (14.3%) - NA Elevated serum titers
Coxsackie virus (2)
Atypical mycobacteria (14.3%)
Mycobacterium avium complex (1) NA þ Disseminated infection in untreated HIV-positive patient
Mycobacterium kansasii (1) - NA Large mediastinal lymphadenopathy
Abbreviations: þ, positive; �, negative; HIV, human immunodeficiency virus; NA, not applicable; PF, pericardial fluids; spp, species.aThe patient had a white blood cell count of 20,800/mL and pneumomediastinum. Antibiotic therapy was initiated and thoracoscopy was performed to drain
the empyema a few days prior to the development of the pericardial effusion.
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3 PFs collected days apart) in whom the fluid accumula-
tion was attributed to treatment with tacrolimus, because
the dose of tacrolimus was increased just 3 weeks before
the development of symptoms of pericardial effusion,
should be noted.
Multifactorial
Six patients (6.3%) presented with several comorbid
conditions simultaneously, each of which could have been
responsible for the PF; however, not one stood out as
being the main cause of fluid accumulation. The associa-
tion of comorbid conditions included uremia, treatment
with minoxidil, receipt of radiotherapy for lung carci-
noma 4 years prior, infection, hypothyroidism, or unde-
termined rheumatologic condition.
Despite the long list of conditions that led to the
pericardial effusion in these cases, all benign PFs had simi-
lar, fairly nonspecific findings on cytologic examination.
Specifically, the PFs contained mesothelial cells, which
were usually reactive in nature, with a variable mixture of
acute and chronic inflammatory cells and macrophages.
In addition, hemorrhagic PFs contained hemosiderin-
laden macrophages and numerous red blood cells. The
mesothelial cells were easily recognized as such, with no
need to perform confirmatory immunohistochemical
stains on the cell block. Nine of the 14 infectious PFs
(64.3%) demonstrated abundant acute fibrinopurulent
exudate.
Cytologic Interpretation of PF Specimens
With ‘‘Severely Atypical Cells’’
In 2 cases (1.6%), a cytologic interpretation of ‘‘severely
atypical cells present’’ was rendered. One case was that of
a 67-year-old man with a lung mass who presented with
cardiac tamponade. The PF demonstrated rare clusters of
atypical cells and no further workup was performed on
the cell block material. A fine-needle aspiration of a right
posterior cervical lymph node performed 1 day later indi-
cated metastatic small cell carcinoma. The second case
was that of a 45-year-old female with no known history of
malignancy who also presented with cardiac tamponade.
Rare groups of atypical cells were noted in the PF; how-
ever, no further ancillary studies were performed on the
cell block. Two months later, the patient presented
with enlarging pleural and peritoneal effusions which
demonstrated a metastatic adenocarcinoma. However, no
primary tumor site was identified.
PF Specimens With a Malignant Cytologic
Interpretation
There were 31 PF specimens with a malignant cytologic
interpretation that were collected from 28 patients
(Table 3). Four patients (1 male and 3 females) had
repeated PF cytology at a 1-day interval because of contin-
uous drainage from the pigtail catheter. The interpreta-
tion did not change with repeated cytologic evaluations of
the PF.
All malignant PF cases, with the exception of 1 case,
were due to a very short list of metastatic carcinomas
(those of the lung, breast, pancreas, and gynecologic
tract), as indicated in Table 3. There were no cases of ma-
lignant mesothelioma involving the pericardium.
It is interesting to note that malignant PF specimens
were more common in females, who represented 74.2%
of patients with malignant effusions. This was due pri-
marily to cases of lung carcinoma, which represented >
50% of the malignant PF specimens detected in females.
In fact, lung carcinoma was the most common primary
carcinoma that produced pericardial metastases in both
males and females (6 cases in males [75.0%] and 12 cases
in females [52.3%]). The most common type of lung car-
cinoma metastatic to the pericardium in both males and
females was adenocarcinoma (13 cases, representing
72.2% of all lung carcinomas). In males, metastatic pan-
creatic adenocarcinoma was a distant second (1 case;
TABLE 3. Distribution of the Primary Site in 31Malignant PF Specimens, Separated by Gender
Primary Site
Males(8 Cases;25.8%)
Females(23 Cases;
74.2%)
Lung 6 (75.0%) 12 (52.3%)
Adenocarcinoma 5 8
Non-small cell carcinoma, NOS — 3
Large cell neuroendocrine
carcinoma
— 1
Small cell carcinoma 1 —
Breast — 9 (39.1%)
Pancreas 1 (12.5%) —
Uterine serous carcinoma — 1 (4.3%)
Diffuse large B-cell lymphoma — 1 (4.3%)
Adenocarcinoma of
unknown primary tumor
1 (12.5%) —
Abbreviations: NOS, not otherwise specified; PF, pericardial fluid.
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12.5%), whereas in females, the breast was the second
most common site of metastatic carcinoma (9 cases;
39.1%). The only nonepithelial malignant neoplasm
involving the PF was a case of diffuse large B-cell malig-
nant lymphoma (4.3%).
In the vast majority of cases (87.1%), patients had a
known, pathologically proven, prior history of malignancy,
specifically lung, breast, uterine, and pancreatic carcinoma.
Only 4 patients (12.9%) had no documented, pathologi-
cally proven prior history of malignancy at the time of PF
cytology; however, 2 of these patients were known to have
a lung mass based on the imaging studies performed at the
time of PF collection. One patient diagnosed with diffuse
large B-cell lymphoma had newly diagnosed human
immunodeficiency virus infection with diffuse lymphade-
nopathy, fever, and weight loss. The fourth patient had
multiple lung nodules as well as liver and bone metastases
with no clear primary tumor site identified.
Cytological evaluation of the PF specimens revealed
3 distinct morphologic patterns in the case of metastatic
carcinomas.
One pattern consisted of cellular specimens with
malignant cells arranged either in 3-dimensional groups
with a depth of focus or dispersed as single cells, or a com-
bination of these 2 patterns. The cytoplasm of malignant
cells ranged from scant to moderate, and was usually
vacuolated. Characteristically, tumor cell nuclei were
markedly enlarged when compared with the benign meso-
thelial cells and displayed significant pleomorphism, with
coarse chromatin, irregular nuclear membranes, and visi-
ble nucleoli (Fig. 1). This pattern was the most common,
being present in all cases of metastatic lung carcinoma
(with the exception of small cell carcinoma), pancreatic
adenocarcinoma, uterine serous carcinoma, adenocarci-
noma of unknown primary tumor, and 44.4% of meta-
static breast carcinoma cases.
The second pattern was recognized in only slightly
more than one-half of metastatic breast carcinoma cases
(55.6%) and was comprised of cellular specimens with
malignant cells arranged in 3-dimensional groups with a
sharply demarcated ‘‘community border’’ or tubular/
duct-like arrangements. Single, discohesive cells were not
the predominant feature (Fig. 2). Another characteristic
of this pattern was the marked uniformity of the tumor
cells with minimal nuclear pleomorphism. In addition,
the tumor cell nuclei were not enlarged when compared
with the benign mesothelial cells, but they had dark,
coarse nuclear chromatin (Fig. 3).
The only case of metastatic small cell carcinoma in
the current study had a pattern that at low power mim-
icked a benign lymphocytic effusion because the tumor
cells were predominantly arranged singly or in very small
aggregates (2-10 cells) (Fig. 4). However, at higher
FIGURE 1. Metastatic lung adenocarcinoma is shown. Malig-
nant cells are arranged in groups or dispersed as single cells.
Characteristically, tumor cells have markedly enlarged and
pleomorphic nuclei with coarse, dark chromatin when
compared with the benign mesothelial cells (Papanicolaou
stain, � 600).
FIGURE 2. Metastatic breast carcinoma is shown, demon-
strating a cellular specimen with numerous 3-dimensional co-
hesive clusters of malignant cells. Note the tubular/duct-like
arrangement of the malignant cells within the clusters (Papa-
nicolaou stain, � 100).
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magnification, nuclear molding was appreciated in the
small cellular aggregates. The tumor cells appeared nearly
as ‘‘naked nuclei’’ because they barely had any visible cyto-
plasm. Another distinctive feature noted at higher magni-
fication was variability in nuclear size and chromatin
consistency ranging from small, apoptotic bodies with
dark, smudged chromatin to larger nuclei with crisper
chromatin details. Nevertheless, the size of the tumor cell
nuclei was smaller than that of the nuclei of mesothelial
cells (Fig. 5).
Although most commonly encountered, the first
morphologic pattern is nonspecific in suggesting a pri-
mary tumor site on morphologic grounds alone. This is in
contrast with the other 2 patterns, which, when recog-
nized, are very helpful in recognizing metastatic breast
carcinoma or small cell carcinoma, respectively.
In addition to routine cytology, immunohistochem-
ical stains were performed in 12 cases (38.7%). It appears
that the immunohistochemical stains were performed pri-
marily to confirm the presence of malignant cells and to
distinguish them from the reactive mesothelial cells rather
than to identify the primary tumor site. The antibodies
used included classic adenocarcinoma (MOC-31,
BerEP4, and B72.3), mesothelial (calretinin, cytokeratin
5/6 [CK5/6], and Wilms Tumor-1 [WT-1]) markers
with the addition of more specific markers depending on
the clinical history (eg, thyroid transcription factor 1
[TTF-1], cancer antigen 19-9 [CA 19-9], estrogen and
progesterone receptors, BRST-2, human epidermal
growth factor receptor 2 [HER2] neu, and p63).
Correlation of PF Cytology With
Pericardial Biopsy
Twenty-seven patients with benign PF cytology (corre-
sponding to 33 PF specimens) had a concomitant
FIGURE 3. Metastatic breast carcinoma is shown. At a higher
magnification, tumor cells are noted to be uniform with
minimal pleomorphism, although the nuclear chromatin is
distinctly dark and coarse (Papanicolaou stain, � 400).
FIGURE 4. Metastatic small cell carcinoma is shown. At a
lower magnification, this pattern mimics a benign lympho-
cytic effusion because the tumor cells scattered in the
background as single cells may be confused with inflamma-
tory cells (Papanicolaou stain, � 40).
FIGURE 5. Metastatic small cell carcinoma is shown. However,
at a higher magnification, one can appreciate a morphologic
spectrum ranging from small apoptotic bodies to larger cells
that are nearly devoid of cytoplasm and with nuclear molding
(Papanicolaou stain, � 1000).
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pericardial biopsy performed at the time of pericardial
window (23.9%). Four patients (14.8%) had a false-neg-
ative cytologic interpretation because the pericardial bi-
opsy demonstrated the presence of a specific condition
such as metastatic soft tissue sarcoma to the mediasti-
num with direct involvement of the pericardium, multi-
ple myeloma involving the mediastinum with secondary
involvement of the pericardium, primary cardiac follicu-
lar lymphoma, and nonnecrotizing granulomas consist-
ent with sarcoidosis.
The 2 patients with severely atypical cells in their PF
specimens did not undergo a pericardial biopsy.
Ten patients with malignant PF cytology (corre-
sponding to 12 PF specimens) underwent a concomitant
pericardial biopsy (8.8%). Four patients (40%) had a
false-negative pericardial biopsy result demonstrating
nonspecific chronic pericarditis, although the PF cytology
identified metastatic carcinoma. In 1 patient (10%), a few
severely atypical cells were present in the pericardial bi-
opsy but could not be characterized further because they
were not present on deeper levels. In the 5 patients with
positive pericardial biopsy (50%), the cytologic diagnosis
was confirmed.
Overall, the performance of PF cytology in detecting
malignancy was found to be better than that of pericardial
biopsy, with a sensitivity of 71% and a specificity of
100% (compared with 64% sensitivity and 85% specific-
ity for the pericardial biopsy).
DISCUSSION
To the best of our knowledge, the current study of 128
PFs specimens is the largest series focusing on PF cytology
published to date in the literature.11,12 Our experience is
that the vast majority of cases (98.4%) can be easily classi-
fied as either benign or malignant. Cases with a noncom-
mittal diagnosis of ‘‘atypical cells, suspicious’’ are very
uncommon, in general due to the limited number of cells
present on the cytospin slides and cell block.
It was intriguing to observe in the current series that
the most common cause of pericardial effusion at the
study institution was malignancy, which can produce
both benign (23.1%) and malignant (24.2%) PF speci-
mens. The mechanisms that lead to PF accumulation in
the face of malignancy are multiple, including treatment
effect (in particular chest radiotherapy), direct extension
of the tumor to the pericardium, hematogenous and
lymphangitic tumor spread to the pericardium, or other
consequences of the malignant process (eg, uremia,
thrombocytopenia).13
With regard to malignant PF specimens, we were
able to make several interesting observations that to the
best of our knowledge have not been mentioned in previ-
ous studies.11,12
In the current study, malignant PF specimens were
found to be more common in females (74.2% of all
malignant effusions). It is interesting to note that this
finding is actually due to metastatic lung carcinoma, not
breast carcinoma as one may presume.
Lung carcinoma is by far the most common malig-
nancy that is metastatic to the pericardium in both males
(75.0%) and females (52.3%), with adenocarcinoma
being the most common histologic type encountered
(72.2%).
Metastatic breast carcinoma to the pericardium
appears to never be the first manifestation of the disease,
because all of the 9 patients in the current study with ma-
lignant PF due to breast carcinoma were known to have
this disease.
Malignant PF is rarely the first manifestation of the
disease. In the vast majority of malignant PF specimens
(87.1%), patients had a known, pathologically proven his-
tory of malignancy.
In the current study, various other etiologic condi-
tions were identified in the benign PF specimens in
addition to neoplasia, which is in keeping with prior liter-
ature.3,5,11,12,14 However, although the etiologic spec-
trum of benign PF is broad, the cytologic findings are
limited and nonspecific. Reactive mesothelial cells in be-
nign PF specimens are usually recognized as such from the
routine preparations without the need for confirmatory
immunohistochemical stains. Typically, reactive mesothe-
lial cells in benign effusions are present as single cells or
small 3-dimensional groups with a scalloped, knobby con-
tour and demonstrate a spectrum of morphological
changes. They have a round-to-oval shape with a moder-
ate amount of cytoplasm with prominent borders with a
‘‘lacy skirt’’ periphery; a slit-like space called a ‘‘window’’
forms between 2 adjacent cells due to the presence of sur-
face slender microvilli. The cytoplasm has a biphasic
staining pattern with a denser endoplasm and a more
lucent, clear ectoplasm. Nuclei are typically round-to-oval
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and centrally located, with finely distributed nuclear chro-
matin; binucleated and multinucleated cells can be noted
in benign effusions.15,16
Conversely, malignant mesothelial cells appear as 3-
dimensional cell balls (or morules), which are crowded
cellular groups of various sizes and shapes in which the
nuclei are overlapped and individual cellular details are
difficult to appreciate. The lobulated contour of these cell
balls is a clue toward their mesothelial origin. Another
characteristic feature is the presence of giant atypical me-
sothelial cells. These are isolated, multinucleated giant
cells with significant nuclear atypia, in which the nuclear-
to-cytoplasmic ratio is low. This is due to the presence of
abundant cytoplasm with the characteristics of mesothelial
cells cytoplasm, that is an optically dense central portion
and clear periphery.15-17
The presence of other cytologic elements in addition
to the reactive mesothelial cells, such as macrophages or
mixed acute inflammatory infiltrate, does not provide any
clues to the specific etiology of the benign effusion. One
exception to this observation is represented by the pres-
ence of abundant acute fibrinopurulent exudate in 64.3%
of bacterial infections.
The distinction between reactive mesothelial cells and
malignant cells is usually straightforward. Three distinct
cytomorphologic patterns are recognized in PF specimens
involved with metastatic carcinoma. It is worth highlight-
ing the pattern of small, single malignant cells observed in
cases of metastatic lobular carcinoma of the breast and
small cell carcinoma.16 This pattern is difficult to recognize
and the malignant cells can be overlooked, especially if the
prior history of malignancy is not known.10 In both situa-
tions, a single file or linear arrangement of molded tumor
cells can be noted. The malignant cells of lobular carci-
noma of the breast also have an eccentrically placed nucleus
and small cytoplasmic vacuoles.16,18
In the case of malignant PF specimens, immunohis-
tochemical stains are typically needed to confirm the pres-
ence of malignant cells through classic adenocarcinoma
and mesothelial markers, rather than to determine the pri-
mary tumor site.19-21 This approach is justified by the
finding that approximately 93.5% of malignant PF speci-
mens had either a pathologically proven, known history of
malignancy or a potential primary tumor site identified
through imaging studies (ie, a lung mass in 2 patients) at
the time of PF cytologic examination.
Repeated cytologic evaluations occurred in 14
patients (12.4%), involving both benign and malignant
PF specimens, and yielded similar interpretations. Analo-
gous results were obtained by Wiener et al in their study.12
Repeated cytologic examinations to increase the probabil-
ity of detecting malignancy are not necessary in the
workup of PF specimens.22
It appears that cytology alone was considered suf-
ficient for pathologic evaluation in the majority of
cases, with only one-third of patients (32.7%) under-
going a concomitant pericardial biopsy. Cytologic eval-
uation was found to correlate well with pericardial
biopsy. The rate of false-negative results for cytology
was 14.7% in the current study. Cases not identified
through cytology included hematologic malignancies,
metastatic sarcoma, and sarcoidosis involving the peri-
cardium. This discrepancy could be due to the fact
that the effusion is produced through an exudative
mechanism but the malignant cells and/or granulomas
do not actually shed as easily into the accumulated
fluid as carcinoma cells. Conversely, pericardial biopsy
had a 40% false-negative rate, indicating nonspecific
chronic pericarditis changes when the PF cytology
demonstrated metastatic carcinoma. This could be due
to sampling error, because the biopsy represents
a smaller portion of the pericardium. It appears that a
combination of PF cytology and pericardial biopsy, if
clinically feasible to obtain, would yield a better sensi-
tivity in diagnosing malignancy.
PFs appear to be unusual in a cytology laboratory,
because they represented a mere 4.5% of all body cavity
fluids at the study institution. The cytologic evaluation of
these specimens is not very different from that of other
fluids (pleural or peritoneal) in terms of cytomorphology
and the need for immunohistochemical stains. However,
there are very specific conditions that produce PF accu-
mulation. Our main role as cytopathologists examining
PF specimens is to identify the malignant cases, keeping
in mind that some tumors (sarcomas, hematologic malig-
nancies) may go undetected in the PF. Conversely, cytol-
ogy is superior to pericardial biopsy in diagnosing
metastatic carcinomas.
FUNDING SUPPORT
No specific funding was disclosed.
Original Article
250 Cancer Cytopathology May 2013
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CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
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