AJTCCM VOL. 29 NO. 4 2023 171
Tuberculous pleural eusion (TPE) and malignant pleural eusion
(MPE) constitute the majority of exudative pleural effusions in
Malaysia.[1] Histopathological analysis is diagnostic for these
conditions,[2] while pleural uid cytology has a sensitivity of only
58.2% for MPE.[3] Clumps of tissue from chest drains are of diagnostic
value in the setting of cytology-conrmed MPE,[4] but the diagnostic
role of such macroscopic tissue in cytology-negative eusions remains
to be elucidated. In the present study, tissue termed pleural uid
residue (PFR) was obtained through direct ltration. e objectives
of the study were to determine: (i) histopathological correlation of
PFR with thoracoscopic pleural biopsy in diagnosing TPE and MPE;
and (ii) the cellularity, architecture and cytomorphology of PFR,
and whether immunohistochemical (IHC) staining was feasible. We
discuss the ndings in 18 cases.
This single-centre, prospective observational cohort study was
conducted on consecutive adult inpatients with cytology-negative
exudative pleural eusion who underwent medical thoracoscopy in
our respiratory unit from 6 September 2022 to 14 December 2022.
We excluded patients with bacterial empyema and those with a pre-
existing chest drain. A histopathological diagnosis of TPE in our setting
is dened as histological examination identifying granulomatous
inammation, or direct visualisation of acid-fast bacilli along with a
typical patient history.
During medical thoracoscopy, an initial volume of 500 mL of
pleural uid was suctioned aer trocar insertion, and the drain bottle
was removed for immediate ltering. e suctioned pleural uid was
extracted from the drain bottle and ltered through sterile 16-ply,
19 × 15 mesh size cotton gauze, which yielded PFR. e PFR was
gently rolled into a single mass, placed on a lter paper to air-dry for 2
minutes, and nally placed into a lter-paper envelope. is was then
xed in formalin and transported to the histopathology laboratory for
further processing and analysis. e act of rolling the ltered PFR into
a clump pays homage to the tissue coagulum clot cell block method of
transbronchial needle aspiration.[5]
Fig.1 compares the histopathological appearance of pleural tissue
obtained through pleural biopsy (A and B) and from PFR (C and
Pleural uid residue as a diagnostic tool for cytology-negative
malignant pleural eusion: A proof-of-concept study
L E Nyanti, MRCPI ; N-C Huan, FRCP; H Y Ramarmurty, MRCP; T Renganathan, MPath; M A bin Abdul Aziz, MPath;
J L Low, MBBS; K T Rosli, MRCPI; S Letcheminan, MRCP; M G Lansing, MRCP; K K Sivaraman Kannan, FRCP
Medical Department, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
larrynyan[email protected]du.my
Department of Respiratory Medicine, Queen Elizabeth Hospital, Kota Kinabalu, Malaysia
Pathology Department, Queen Elizabeth Hospital, Kota Kinabalu, Malaysia
Department of Respiratory Medicine, Queen Elizabeth Hospital, Kota Kinabalu, Malaysia
Medical Department, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
Department of Respiratory Medicine, Queen Elizabeth Hospital, Kota Kinabalu, Malaysia
Pleural uid residue, or macroscopic tissue, circulating freely in the pleural uid obtained through direct ltration, may carry diagnostic
histopathological information. We aimed to determine the histopathological concordance of pleural uid residue in diagnosing TPE and
MPE, compared with conventional pleural biopsy. is was a prospective cohort study of consecutive inpatients with cytology-negative
exudative eusion who underwent pleuroscopy and had their initial suctioned pleural uid ltered for residue samples. Pleural uid residue
demonstrated malignant cells in four out of seven cases of pleural biopsy-conrmed malignancy. Pleural uid residue has comparable
cytomorphology but reduced cellularity compared with pleural biopsy. No tuberculous histological features were present in the pleural uid
residue samples. In this preliminary study pleural uid residue provided histopathological information for malignant pleural eusion, but
no incremental diagnostic information for tuberculous eusion. However larger and more denitive studies are required to clarify these
ndings, and to explore the utility and suitability of pleural uid residue for mutational analysis
Keywords. Pleural uid residue, diagnostic accuracy, clump, malignant plural eusion.
Afr J Thoracic Crit Care Med 2023;29(4):e1149. https://doi.org/10.7196/AJTCCM.2023.v29i4.1149
Study synopsis
What this study adds. is study demonstrates the potential of pleural uid residue as a non-invasive diagnostic method for conrming
malignancy in cytology-negative exudative eusion.
Implications of the ndings. In resource-limited settings or patients contraindicated for pleural biopsy, pleural uid residue may provide
a viable diagnostic alternative; however, this observation needs further validation.
172 AJTCCM VOL. 29 NO. 4 2023
D). Of the 18 cases, 17 yielded conrmatory pleural biopsy samples
(Supplementary Table 1, available online at https://www.samedical.org/
le/2143). ere was positive correlation in 4 out of 7 MPEs (57.1%).
Six patients were diagnosed with adenocarcinoma, of whom 4 (66.7%)
had PFR consistent with malignancy; one did not have IHC staining.
One patient had squamous cell carcinoma on biopsy, but PFR only
demonstrated inammatory cells. Histological examination of PFR
revealed malignant columnar cells trapped within brin or blood clot,
either arranged in a glandular pattern or singly distributed (Fig.1D). e
cytomorphology of PFR and its feasibility for IHC staining are similar
to those of pleural biopsy samples, although PFR has less cellularity
and poorer architectural visualisation (Fig.1A andC). We did not do
mutational analysis.
Four patients had TPE on pleural biopsy, but their PFR demonstrated
only inammatory cells. Diagnoses of uraemic pleuritis (n=1) and
parapneumonic eusion (n=5) were made based on clinical history
and examination, combined with absence of features of tuberculosis on
pleural biopsy. e overall negative correlation was 6 out of6 PE/TPE
cases. Both PFR and thoracoscopic pleural biopsy were concordant in
terms of the presence of inammatory cells, but PFR added no further
In this proof-of-concept study, we demonstrated that PFR
contributes valuable histopathological information in the diagnosis
of cytology-negative malignant pleural effusion. Its fibrin-based
morphology is comparable to that of chest drain clumps previously
described.[4] PFR is morphologically comparable to pleural biopsy,
and immunohistochemical staining is feasible. Despite having less
cellularity, it is still theoretically sucient for mutational analysis.
In contrast to pleural fluid cytology, in which pleural fluid is
centrifuged to exclude any debris or sediments and subsequently
smeared for analysis, diagnostic information from PFR is obtained from
the debris found in pleural uid. PFR also diers from a cytology cell
block in that it does not require additives such as plasmaandthrombin
to enmesh the cellular material. Furthermore,PFR can be processed at
the patients bedside and immediately xed in formalin. is technique
could potentially negate the need for pleural biopsy in suspected
malignant pleural eusion, which would be particularly helpful in
patients who are not suciently stable formedical thoracoscopy, or
those who are far from a tertiary centre with the necessary equipment
to perform medical thoracoscopy.
It is likely that granulomas do not exist in TPE, as they are formed by
a lymphocyte-driven, macrophage-initiated immune reactionwhich
requires blood supply that is only present within the pleura.[6]
One would not expect to see acid-fast bacilli on histopathological
examination, given that tuberculous fluid is paucibacillary as a
resultof T-helper cell compartmentalisation and eective containment
of tuberculous bacilli.[2]
The present study is not without limitations. First, inconsistent
presence of PFR on ltration raises questions as to whether the ltration
method could be improved, or whether brin-containing residue is
uniformly formed in all kinds of malignant eusion; and if so, how
soon it forms. It is conceivable that a smaller mesh size could improve
PFR yield by capturing smaller residue, but this needs to be studied
further. Second, mutational analysis was not carried out. ird, the
potential role of PFR being ltered from newly inserted chest drains
was not explored in our study. Fourth, a small sample size and single-
centre setting reduces the generalisability of the ndings. Fih, the
usefulness of PFR for other types of malignancy is unproven, as only
adenocarcinoma was diagnosed in this study. ese limitations will be
addressed in a future pilot study.
PFR provides valuable diagnostic information to assist in the diagnosis
of malignant pleural eusion, but does not carry the histopathological
information necessary to diagnose pleural tuberculosis. Head-to-head
studies on the usefulness of PFR and cytology cell block may elucidate
PFRs diagnostic potential. Future studies are needed to explore its role
in patients with newly inserted chest drains or non-adenocarcinoma
malignancy, and its suitability for mutational analysis.
Declarations. Written informed consent was obtained from the patients
for publication of this article and the accompanying images. A copy of
the written consent is available upon request from the Editor-in-Chief of
this journal. is study was approved by the Medical Research & Ethics
Committee of Malaysia (NMRR ID-22-02491-IED).
Acknowledgements. None.
Author contributions. Conceptualization: LEN, HYR, NCH.
Methodology: LEN, HYR, NCH. Formal analysis: TR, MABAA.
Investigation: LEN, NCH, HYR, JLL, KTR, SL, MGL. Data curation:
JLL, LEN, MGL, KTR, NCH, HYR. Writing – Original dra: LEN, NCH,
HYR. Writing-Review and Editing: HYR, NCH, KKSK, TR, MABAA, SL.
Supervision: KKSK, HYR, NCH
Funding. None.
Conict of interest. None.
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Fig.1. Histopathological comparison between pleural tissue obtained
through pleural biopsy (A and B) and from PFR (C and D). Both samples
displayed strong and diuse immunoreactivity for TTF-1 (Aand C, 20×).
Under H&E staining, PFR demonstrated satisfactory cellularity, albeit
admixed with brin (D). Cytomorphological features were comparable and
characterised by malignant cells arranged in cords, nests and glandular
structures, with round to oval nuclei showing vesicular chromatin texture,
conspicuous nucleoli and a modest amount of eosinophilic cytoplasm
(B and D, H&E, 40×). (PFR = pleural uid residue; TTF-1 = thyroid
transcription factor-1; H&E = haematoxylin and eosin.)
AJTCCM VOL. 29 NO. 4 2023 173
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Submitted 5 June 2023. Accepted 10 September 2023. Published x November 2023.