Cncy21246

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.

242 Cancer Cytopathology May 2013

Original Article

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.

Pericardial Fluid Cytology/Dragoescu and Liu

Cancer Cytopathology May 2013 243

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.


Original Article

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.



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.

Original Article


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).



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).

Original Article


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



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


CONFLICT OF INTEREST DISCLOSURES

The authors made no disclosures.

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