Cytology of Pleural Fluid as a

Diagnostic Challenge
Paavo Pääkkö, MD, PhD
Chief Physician and Head of the Department
Department of Pathology,
Oulu University Hospital, Finland
Oulu University Hospital
 General overview of cytology of
pleural effusions
! Exfoliative cytological examination of pleural effusions
common method for determining whether effusion is
benign or malignant
! Effusions subdivided into transudates and exudates
depending on the protein content
! Transudates result from alterations in hydrostatic or
oncotic pressure, often due to systemic factors, e.g.
congestive heart failure
! Exudates result from pathological processes localized
to the serosal membranes => higher protein content
and cellularity increased compared to transudates, e.g.
infections
Utility and limitations of cytology of
pleural effusions
! Cells exfoliated into effusion fluid can be examined as
cytology smears, liquid-based preparations, cytospin
preparations, or cell blocks
! Most of the exudates benign
! The absence of malignant cells does not rule out
malignancy
! Only 30-40 % of malignant mesotheliomas, and 60-70
% of cancers metastatic to the pleura diagnosed by
exfoliative cytology
 Cytology vs. histology
! Exfoliative cytology has of limited usefulness in
diagnosing malignant mesothelioma
! Benign reactive mesothelial cells may have features that
mimic malignancy, and malignant mesotheliomas may
be cytologically bland
! Without evidence of invasion of underlying tissues,
diagnosis of mesothelioma on cytologic grounds maybe
difficult
! Sarcomatous mesotheliomas typically do not shed cells
into effusion
 Cytological features of malignancy
! Cancer cells as individual cells, sheets of cohesive cells,
and three-dimensional spherical clusters, called morulae
! Papillary or acinar structures
! Usually the number of malignant cells high, rarely a few
! Presence of psammoma bodies
! Enlarged cells with enlarged nuclei, coarse chromatin,
prominent nucleoli
! Mitoses, atypical mitoses, and necrotic debris
 Reactive atypia of mesothelial cells
! Benign mesothelial cells exfoliate easily and
display a spectrum of reactive changes from
minimal reactive change to highly atypical
reactive change, mimicking malignancy
! Reactive mesothelial cells shed as invidual cells,
in clusters or sheets, with adjacent cells
separated from one another by spaces referred
to as ”windows”
 Cytological features of reactive
mesothelial cells
! Nuclei round or oval with distict nuclear membranes,
chromatin vesicular or finely granular, and cytoplasm
adundant and darkly-stained
! Peripheral cytoplasm stains darker than central
cytoplasm, and microvilli around the periphery result in
fuzzy rim or border
! Binucleation or multinucleation frequent
! Cytoplasmic vacuoles may compress the nucleus,
suggesting the signet ring cells of adenocarcinoma
Reactive mesothelial cells
 Cytological features of malignant
mesothelioma
! Malignant mesotheliomas cause <1 % of
malignant pleural effusions, and only epithelial
malignant mesotheliomas likely exfoliate cells
into effusion fluids
! Malignant mesothelioma cells lack the significant
degree of cytological pleomorphism
! Cells arranged in sheets, clusters, morulae or
papillary structures
 Hints for correct interpretation
! Atypical reactive mesothelial cells blend with cells with lesser
degrees of reactive atypia within a benign effusion, giving the
impression of one population of cells
! In cases of malignancy, reactive mesothelial cells and malignant
cells often appear as two separate and distinct population of cells
! It is necessary to first determine if cells in a fluid are truly
malignant before secondarily determining the type of malignancy
! Immunohistochemical confirmation that atypical cells are
mesothelial in origin does not help to distinguish between
reactive mesothelial cell proliferation and mesothelioma
 Case 1
! 60-year old man
! Exposed to asbestos
! Hydrothorax and pleural plaques
! Cytological specimen taken from pleural cavity
 Calretinin

CK 5/6

CK7

EMA
 Conclusion from Case 1

! Strong suspicion for malignancy, fitting rather

for malignant mesothelioma than metastatic
adenocarcinoma
! The diagnosis of malignant mesothelioma was
later confirmed by histological sample
 Calretinin

WT1

EMA
 Case 2
! 76-year old male
! Suspicion for lung malignancy
! Hydrothorax
! An aspiration from left pleural cavity performed,
and cytological analyses requested
 TTF-1

CK 7

CK 5/6
EMA

E-Cadherin

Calretinin
 Conclusion from Case 2

! Strong suspicion for a metastatic carcinoma

! TTF-1 positivity suggests for pulmonary origin
of the carcinoma
 Case 3

! 76-year old female

! Breast carcinoma operated 6 years ago
! Fluid in the pleural cavity and both lungs
contain tumour infiltrations
! Pleural cytology requested
 PAN-CK

CK 5/6 Estrogen receptor

 Connclusion from Case 3

! Strong suspicion for a metastatic carcinoma

! Estrogen receptor-positivity suggests for a
metastatic breast carcinoma
 Case 4
! 76-year old male
! Laryngeal squamous cell carcinoma operated
1993
! COPD
! Heavy smoker
! Abundant fluid in the left pleural cavity
 CK 7 CK 7

TTF-1

Calretinin

CK 5/6
 Conclusion from Case 4

! Mild suspicion for a malignancy, origin of which

possibly in the lungs
! In addition, the cell population contained
atypical mesothelial cell proliferation
 Summary and conclusions
! Most of the exudates benign
! The absence of malignant cells does not rule out
malignancy
! Malignant mesotheliomas cause <1 % of malignant
pleural effusions, and only epithelial malignant
mesotheliomas likely exfoliate cells into effusion fluids
! It is necessary to first determine if cells in a fluid are
truly malignant before secondarily determining the type
of malignancy
! Immunohistochemistry of histological sections from a
cell block may help to determine the type of malignancy