Serous cavities are lined by mesothelial cells and include the pleural, peritoneal, and pericardial spaces. Accumulation of fluid within these cavities may accompany congestive heart failure, hepatic cirrhosis, infection, inflammation, autoimmune disease, and malignancy. Distinguishing malignant from benign effusions is clinically important because a malignant effusion may represent the first manifestation of an underlying cancer, document recurrence, establish metastatic dissemination, alter tumour staging, and substantially influence prognosis and treatment. Cytological examination of effusion fluid is particularly attractive because thoracentesis, paracentesis, and pericardiocentesis are less invasive than tissue biopsy and can provide abundant material for morphology, cell-block preparation, immunocytochemistry, flow cytometry, and molecular testing. A definitive malignant cytological diagnosis can therefore avoid or appropriately direct more invasive procedures. Historically, terminology used for reporting serous-fluid cytology varied considerably among laboratories. Terms such as atypical, indeterminate, suspicious, and positive were applied inconsistently. The International System for Reporting Serous Fluid Cytopathology (TIS), developed through collaboration between the International Academy of Cytology and the American Society of Cytopathology, introduced five standardized categories: nondiagnostic (ND), negative for malignancy (NFM), atypia of undetermined significance (AUS), suspicious for malignancy (SFM), and malignant (MAL). The standardized framework is clinically useful because each category is associated with a different risk of malignancy (ROM). Nonetheless, conventional effusion cytology has imperfect sensitivity. Reactive mesothelial cells can mimic carcinoma, while poorly differentiated malignant cells may resemble reactive or inflammatory populations. Malignant cells may also be sparse, degenerated, trapped in fibrin, or absent from the sampled portion of fluid. Contemporary diagnostic evidence demonstrates that effusion cytology is generally highly specific but only moderately sensitive. The magnitude of sensitivity depends strongly on tumour biology; adenocarcinomas exfoliate readily, whereas mesothelioma and squamous-cell carcinoma are less reliably detected by cytology alone. These differences make clinical and radiological context essential when interpreting a negative specimen. The present systematic review was undertaken to evaluate contemporary evidence regarding the diagnostic utility of effusion cytology in malignant serous effusions, with particular attention to TIS category-specific ROM, diagnostic accuracy, site- and tumour-specific performance, cell blocks, immunocytochemistry, and methodological quality. 2. Aim and Objectives 2.1 Aim To systematically evaluate the diagnostic utility of effusion cytology in detecting malignant pleural, peritoneal, and pericardial effusions. 2.2 Objectives 1. To evaluate sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy. 2. To estimate and compare risk of malignancy across TIS categories. 3. To compare diagnostic performance across serous-fluid types and primary tumour types. 4. To identify major causes of false-negative, false-positive, and indeterminate cytological diagnoses. 5. To assess the incremental diagnostic value of cell-block preparation and immunocytochemistry. 6. To evaluate methodological quality of included studies using QUADAS-2.

3.1 Study Design and Reporting Framework This systematic review was structured according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement. Because the review evaluated diagnostic-test performance, methodological quality was assessed using QUADAS-2. No PROSPERO registration number is done for this manuscript. 3.2 Review Question 3.3 Information Sources and Search Period MEDLINE/PubMed, Embase, Scopus, Web of Science, and Google Scholar were considered in the structured search. Reference lists of relevant systematic reviews, meta-analyses, and TIS studies were also screened. The search window covered January 2020 through June 2026, thereby focusing on evidence published around or after introduction of TIS. 3.4 Search Strategy A representative search strategy combined terms for serous effusions, cytology, malignancy, diagnostic accuracy, and TIS. Database syntax was adapted as appropriate. (“serous effusion” OR “pleural effusion” OR “peritoneal effusion” OR “ascitic fluid” OR “pericardial effusion”) AND (“cytology” OR “cytopathology” OR “cell block”) AND (“malignancy” OR “malignant effusion” OR “diagnostic accuracy” OR “sensitivity” OR “specificity”) AND (“International System for Reporting Serous Fluid Cytopathology” OR “TIS”) 3.5 Eligibility Criteria Inclusion criteria I. Original studies evaluating pleural, peritoneal/ascitic, or pericardial cytology for malignant disease. II. Studies reporting TIS categories and/or category-specific ROM. III. Studies providing diagnostic-performance data or sufficient follow-up to establish malignant outcome. IV. Studies evaluating ancillary methods such as cell block or immunocytochemistry when directly relevant to malignant-effusion detection. V. Peer-reviewed full-text publications in adults or predominantly adult populations. Exclusion criteria i. Case reports, editorials, narrative reviews, and conference abstracts without extractable primary data. ii. Studies of non-serous fluids or cerebrospinal fluid. iii. Studies without an interpretable reference standard or follow-up for malignancy. iv. Purely experimental or technical studies without clinical diagnostic outcomes. v. Duplicate or overlapping cohorts without additional relevant data. 3.6 Data Extraction Extracted variables included author, year, country or setting, study design, sample size, effusion type, preparation method, TIS category distribution, ROM, sensitivity, specificity, PPV, NPV, diagnostic accuracy, reference standard, and use of ancillary investigations. 3.7 Diagnostic Thresholds Because TIS contains intermediate categories, three thresholds were considered when interpreting diagnostic-accuracy literature: (1) AUS, SFM, and MAL considered positive; (2) SFM and MAL considered positive; and (3) only MAL considered positive. Broadening the positive threshold generally increases sensitivity while reducing specificity. 3.8 Risk-of-Bias Assessment and Data Synthesis QUADAS-2 was used to evaluate patient selection, index-test conduct/interpretation, reference standard, and flow/timing. Retrospective recategorization, selective biopsy of suspicious cases, reliance on composite clinical follow-up, and exclusion of cases without verification were considered important sources of bias. A new pooled meta-analysis was not undertaken because robust contemporary meta-analyses were already available and substantial clinical heterogeneity existed across fluid type, tumour type, cytological preparation, TIS threshold, and reference standard. A structured narrative synthesis was therefore performed. 3.9 Study Selection and PRISMA 2020 Numerical Flow The review dataset contained 1,946 records identified through database searching and supplementary reference-list screening. After removal of 512 duplicate records, 1,434 titles and abstracts were screened. A total of 1,278 records were excluded at title/abstract level, leaving 156 full-text reports for eligibility assessment. Of these, 142 were excluded and 14 primary studies were included in the final qualitative synthesis. Full-text exclusions comprised wrong population or non-serous specimen (n=34), insufficient diagnostic or ROM outcomes (n=30), review/editorial/meta-analysis rather than a primary study (n=27), inadequate or non-comparable reference standard (n=21), duplicate or overlapping cohort (n=14), unavailable/incomplete full text (n=9), and other design-related exclusions (n=7).

Table 1. Diagnostic review framework Component Definition Population Patients with pleural, peritoneal/ascitic, or pericardial effusions. Index test Conventional cytology, cytospin, liquid-based cytology and/or cell-block cytology. Ancillary tests Immunocytochemistry, flow cytometry, or molecular testing where reported. Reference standard Histopathology, subsequent cytology, clinical/radiological follow-up, or confirmed malignancy according to the original study. Target condition Malignant involvement of a serous cavity. Outcomes Sensitivity, specificity, PPV, NPV, diagnostic accuracy, ROM, and diagnostic discordance. 4.1 Characteristics of Included Studies Fourteen primary studies were included in the focused qualitative synthesis. Most were retrospective institutional cohorts that reclassified archived effusion cytology according to TIS; one prospective oncology cohort and one ancillary cell-block/immunocytochemistry study were also included. Sample sizes ranged from 150 to 3,790 specimens. Table 2. Characteristics of included primary studies Study Setting Design Sample size Effusion type Key diagnostic findings Principal limitation Lobo et al., 2021 Portugal, oncology centre Retrospective TIS recategorization 2,323 Pleural, peritoneal, pericardial Specificity 100%; sensitivity ~61% for pleural/peritoneal; MAL ROM 100% Retrospective; verification not uniform Pinto et al., 2021 Portugal Paired pleural cytology-biopsy cohort 350 Pleural Sensitivity 60.3%; specificity 98.6%; MAL ROM 100% Biopsy-selected population Pergaris et al., 2021 Greece Retrospective TIS cohort 1,028 Pleural and peritoneal Pleural ROM: 0%, 5.3%, 33.3%, 93.3%, 100%; peritoneal MAL ROM 100% Composite follow-up reference Ahuja & Malviya, 2022 India Retrospective TIS cohort 1,300 Pleural, peritoneal, pericardial MAL ROM 100%; high diagnostic specificity across sites Histology available in selected cases Straccia et al., 2022 Italy Retrospective TIS cohort 3,790 Pleural, peritoneal, pericardial MAL ROM 100% in all sites; SFM ROM 93-100% Surgical follow-up incomplete Zhu et al., 2022 China, oncology centre Retrospective TIS cohort 3,633 Pleural, peritoneal, pericardial MAL ROM 100%; combined smear/LBC/cell block gave best sensitivity/accuracy High cancer prevalence; spectrum bias Sachan et al., 2023 India, oncology setting Prospective observational 555 416 peritoneal, 126 pleural, 13 pericardial Substantial interobserver agreement (k=0.717); MAL ROM 97-100% by site Single-centre prospective cohort Rajeswaran et al., 2023 India Retrospective TIS cohort 596 Pleural, peritoneal, pericardial ROM 10%, 4.4%, 19%, 83.3%, 100% Follow-up available for 395/596 Kala et al., 2023 India Retrospective TIS cohort 2,318 1,614 pleural, 612 peritoneal, 92 pericardial ROM 25%, 17.9%, 66.7%, 75.4%, 96.5% Retrospective; variable verification Yang et al., 2023 China Retrospective TIS cohort 2,103 1,199 pleural, 790 peritoneal, 114 pericardial ROM 50%, 24.9%, 36.8%, 89.0%, 100%; 1,342 cell blocks 776 lacked matched pathology for ROM analysis Batool et al., 2023 Pakistan Cross-sectional ancillary-technique study 150 78 pleural, 68 peritoneal, 4 pericardial Cytology+cell block+IHC sensitivity 92.31%, specificity 98.95% Small cohort; non-TIS diagnostic categories Maleki et al., 2024 USA Paired pleural cytology-biopsy cohort 223 Pleural Sensitivity 45%, specificity 97.7%, PPV 91.2%, NPV 77%; MAL ROM 100% Biopsy-selected, difficult-case spectrum Dogan et al., 2025 Türkiye Retrospective recategorization/interobserver study 3,501 Pleural, peritoneal, pericardial AUS ROM 27%; SFM ROM 49%; low agreement in intermediate categories Focused on atypical/SFM interpretation Kocherlakota et al., 2026 India Retrospective TIS cohort 1,447 Pleural, ascitic/peritoneal, pericardial MAL 13.4%; MAL ROM ~98.7%; high specificity and PPV Retrospective; verification-dependent ROM 4.2 QUADAS-2 Risk-of-Bias Assessment The dominant methodological concern was partial verification: histological or definitive clinical follow-up was more likely in cytologically atypical, suspicious, or malignant cases than in clearly negative cases. Retrospective recategorization and use of composite clinical follow-up were additional sources of bias. No study was judged high risk across all domains. Table 3. QUADAS-2 risk-of-bias assessment of included studies Study Patient selection Index test Reference standard Flow/timing Overall judgement Lobo et al., 2021 Moderate Low Moderate Moderate Moderate Pinto et al., 2021 Moderate Low Low Low-Moderate Low-Moderate Pergaris et al., 2021 Moderate Low Moderate Moderate Moderate Ahuja & Malviya, 2022 Moderate Low Low-Moderate Moderate Moderate Straccia et al., 2022 Moderate Low Moderate Moderate Moderate Zhu et al., 2022 Moderate Low Moderate Low-Moderate Moderate Sachan et al., 2023 Low-Moderate Low Moderate Low-Moderate Low-Moderate Rajeswaran et al., 2023 Moderate Low Moderate Moderate Moderate Kala et al., 2023 Moderate Low Moderate Moderate Moderate Yang et al., 2023 Moderate Low Low-Moderate Moderate Moderate Batool et al., 2023 Moderate Low Moderate Low Moderate Maleki et al., 2024 Moderate Low Low Low-Moderate Low-Moderate Dogan et al., 2025 Moderate Moderate Moderate Moderate Moderate Kocherlakota et al., 2026 Moderate Low Moderate Moderate Moderate Summary: 3 studies were judged low-to-moderate overall risk of bias and 11 were judged moderate risk. No study was assigned an overall high-risk judgement. The most common concerns were selective verification, retrospective design, and heterogeneity in the reference standard. 4.3 Pooled Risk of Malignancy Across TIS Categories A 2024 systematic review and meta-analysis of 16 eligible TIS studies reported pooled ROMs of 27% (95% CI 16-41%) for ND, 11% (95% CI 7-18%) for NFM, 49% (95% CI 37-61%) for AUS, 90% (95% CI 81-95%) for SFM, and 100% (95% CI 98-100%) for MAL. The progressive increase supports the construct validity and clinical usefulness of the five-tier TIS framework. Another contemporary review reported broadly similar ROM estimates, reinforcing that MAL is a strong rule-in category, whereas NFM cannot completely exclude malignancy. 4.4 Overall Diagnostic Accuracy A 2024 meta-analysis of 16 retrospective cross-sectional studies comprising 19,128 cases evaluated diagnostic accuracy at different TIS positivity thresholds. When AUS, SFM, and MAL were regarded as positive, pooled sensitivity was 77% (95% CI 68-84%) and specificity 95% (95% CI 93-97%). When SFM and MAL were considered positive, sensitivity was 57% (95% CI 49-65%) and specificity 100% (95% CI 99-100%). When only MAL was regarded as positive, sensitivity was 70% (95% CI 60-77%) and specificity 99% (95% CI 98-99%). These estimates demonstrate an important diagnostic trade-off: broadening the positive threshold increases sensitivity but reduces specificity. In routine practice, AUS and SFM are therefore better interpreted as risk-stratification categories rather than simple binary positive tests. 4.5 Pleural Effusions and Tumour-Specific Sensitivity A systematic review and meta-analysis of 36 studies involving 6,057 patients with malignant pleural effusion reported overall pleural-fluid cytology sensitivity of 58.2% (95% CI 52.5-63.9%), with substantial heterogeneity. Sensitivity was strongly dependent on primary tumour type. Pooled sensitivity was 83.6% for lung adenocarcinoma, 85.2% for ovarian carcinoma, 65.3% for breast carcinoma, 24.2% for pulmonary squamous-cell carcinoma, and 28.9% for mesothelioma. Consequently, a negative pleural-fluid cytology result should not delay tissue biopsy when mesothelioma or another poorly exfoliating tumour remains clinically likely. 4.6 Peritoneal and Ascitic Effusions Peritoneal cytology is important in gynaecological and gastrointestinal oncology. In the 3,790-specimen Straccia cohort, peritoneal ROM increased from 10.4% in NFM to 43.5% in AUS and reached 100% in both SFM and MAL. Pergaris et al. likewise reported peritoneal ROM of approximately 9% for NFM, 38.5% for AUS, 83.3% for SFM, and 100% for MAL. High malignant-cell yield in ovarian and other Müllerian carcinomas makes peritoneal fluid particularly suitable for cell-block immunophenotyping and, where sufficiently cellular, molecular analysis. 4.7 Pericardial Effusions Pericardial samples represented a smaller proportion of most cohorts but displayed the same general progression in ROM across categories. Straccia et al. reported ROM of 13.2% for NFM, 35% for AUS, and 100% for SFM and MAL in pericardial effusions. Because pericardial sample numbers are smaller, category-specific estimates are less precise than for pleural and peritoneal fluids. 4.8 Negative for Malignancy The pooled ROM of approximately 11% for NFM shows that a negative cytology result cannot definitively exclude malignant involvement. False-negative results may arise when tumour cells are not shed, are focally distributed, degenerate rapidly, are obscured by blood/inflammation, or are misinterpreted as reactive mesothelial cells. Persistently suspicious imaging, a known malignancy with unexplained recurrent effusion, or a tumour type with poor cytological sensitivity should prompt repeat sampling or tissue biopsy despite NFM cytology. 4.9 Atypia of Undetermined Significance AUS remains a diagnostically challenging category with pooled ROM around 49%. It should be reserved for specimens with atypical cells that cannot be confidently classified as reactive or malignant because of insufficient qualitative or quantitative features. Low cellularity, degenerative change, isolated atypical groups, and atypical mesothelial proliferation are common reasons for AUS. The wide ROM and interobserver variability reported in recent studies indicate that AUS requires strong clinicoradiological correlation and, where possible, repeat cytology, cell block, or ancillary testing. 4.10 Suspicious for Malignancy and Malignant Categories SFM carries a high pooled ROM of approximately 90% and is appropriate when morphology strongly suggests malignancy but is insufficient for a definitive MAL diagnosis because of scant cellularity, degeneration, or lack of confirmatory ancillary material. MAL is the most diagnostically reliable TIS category. Pooled ROM approaches 100%, and specificity is approximately 99-100% when MAL alone is regarded as a positive test. A definitive MAL diagnosis can confirm metastatic dissemination and may directly alter staging and management. 4.11 Role of Cell-Block Preparation and Immunocytochemistry Cell-block preparation preserves architecture, permits multiple sections, and provides material for immunocytochemistry and molecular testing. In the 3,633-case oncological cohort, simultaneous use of conventional smear, liquid-based preparation, and cell block produced the highest sensitivity, NPV, and diagnostic accuracy. Batool et al. evaluated 150 effusions and reported that combining cytology with cell block and immunohistochemistry increased diagnostic yield, reduced suspicious diagnoses from 38% to 4.7%, and achieved sensitivity of 92.31% and specificity of 98.95%. Common epithelial markers include BerEP4, MOC31, claudin-4, and pancytokeratin, whereas mesothelial lineage can be supported by calretinin, WT1, D2-40, and CK5/6. Site-specific panels may include TTF-1/Napsin A, PAX8/WT1, GATA3, CDX2, and SATB2 according to morphology and clinical context. 4.12 Causes of False-Negative and False-Positive Cytology False-negative diagnoses are the principal limitation of effusion cytology. Important causes include low tumour-cell shedding, sampling error, low cellularity, tumour-cell degeneration, blood or inflammatory obscuration, treatment-related change, and poor-exfoliating tumour types such as mesothelioma. False-positive diagnoses are uncommon because overall specificity is high. Florid reactive mesothelial proliferation is the most important mimic of malignancy; cell-block architecture, immunocytochemistry, and clinical context reduce this risk. Table 4. Pooled risk of malignancy according to TIS TIS category Pooled ROM 95% CI Nondiagnostic (ND) 27% 16-41% Negative for malignancy (NFM) 11% 7-18% Atypia of undetermined significance (AUS) 49% 37-61% Suspicious for malignancy (SFM) 90% 81-95% Malignant (MAL) 100% 98-100% Table 5. Tumour-specific sensitivity of pleural-fluid cytology Primary malignancy Pooled sensitivity Lung adenocarcinoma 83.6% Ovarian carcinoma 85.2% Breast carcinoma 65.3% Pulmonary squamous-cell carcinoma 24.2% Mesothelioma 28.9%

5.1 Principal Findings This systematic review confirms that effusion cytology is an effective rule-in test for malignant serous effusions because specificity is consistently very high, especially when a definitive MAL diagnosis is used as the positivity threshold. The principal weakness is incomplete sensitivity. Negative cytology cannot reliably rule out malignancy, and the clinical meaning of a negative result varies according to tumour biology, fluid type, and the pre-test probability of disease. 5.2 Clinical Value of TIS TIS has improved communication by replacing variable descriptive terminology with five diagnostic categories linked to progressively increasing malignancy risk. The pooled transition from approximately 11% ROM in NFM to 49% in AUS, 90% in SFM, and approximately 100% in MAL demonstrates useful risk stratification. The system also provides an audit framework for laboratories and facilitates comparison of results across institutions. 5.3 Importance of Tumour Biology Tumour-specific pleural-fluid sensitivity illustrates why cytology should not be interpreted in isolation. Adenocarcinomas often shed abundant malignant cells, whereas mesothelioma and squamous-cell carcinoma may yield few or no diagnostic cells. This biological difference explains why repeated negative cytology in suspected mesothelioma should prompt pleural biopsy rather than continued reliance on fluid cytology. 5.4 Indeterminate Categories AUS and SFM are not interchangeable. AUS carries an intermediate malignancy risk and should generally trigger repeat sampling, ancillary testing, or close clinicoradiological correlation. SFM has a substantially higher ROM and should be managed with a high index of suspicion. The low interobserver agreement reported in intermediate categories highlights the importance of explicit morphological criteria and cytopathologist experience. 5.5 Ancillary Testing Cell blocks transform an effusion specimen into a platform for immunocytochemistry and molecular diagnostics. This is particularly valuable when morphology alone cannot distinguish reactive mesothelial cells from metastatic carcinoma, when the primary site is unknown, or when predictive biomarkers are required. Immunocytochemical panels should be hypothesis-driven and selected according to morphology, sex, clinical history, and imaging. 5.6 Pre-analytical and Sampling Considerations Diagnostic accuracy begins before slide interpretation. Adequate volume, prompt transport, concentration of the cellular component, cytospin or liquid-based preparation, and routine cell-block preservation can increase yield. Repeat sampling may detect malignant cells missed initially, but persistent clinical suspicion should lead to tissue biopsy rather than indefinite repeated fluid cytology. 5.7 Clinical Implications A positive malignant effusion can establish metastatic disease and alter staging, prognosis, and treatment. Conversely, a negative result should be interpreted as a probability-modifying test rather than an absolute exclusion of disease. Multidisciplinary integration of cytology, imaging, clinical history, histology, and ancillary studies provides the safest diagnostic pathway. 6. Strengths of the Review 1. Use of PRISMA 2020 structure and explicit numerical study-selection flow. 2. Focus on contemporary TIS-based evidence and large institutional cohorts. 3. Inclusion of diagnostic accuracy, category-specific ROM, tumour-specific sensitivity, and ancillary techniques. 4. Formal QUADAS-2 risk-of-bias assessment. 5. Integration of evidence through August 2026, including recent 2025-2026 institutional studies. 7. Limitations Most included TIS studies were retrospective and reclassified archived specimens. Histological confirmation was incomplete and more likely in suspicious or malignant cases, creating partial verification bias. Reference standards varied and sometimes incorporated repeat cytology, clinical history, imaging, or follow-up rather than histology alone. Cancer-centre populations had higher disease prevalence than community cohorts, contributing to spectrum bias and variation in ROM. Preparation methods and availability of cell blocks, immunocytochemistry, and molecular testing differed among institutions. A de novo quantitative meta-analysis was not repeated because high-quality recent meta-analyses already provided pooled estimates and marked heterogeneity remained across primary tumour types and diagnostic thresholds. 8. Future Directions 1. Prospective multicentre validation using uniform TIS criteria and predefined reference standards. 2. Site-specific ROM estimates for pleural, peritoneal, and pericardial fluids. 3. Standardization of minimum fluid volume, processing, and routine cell-block protocols. 4. Improved reproducibility and management pathways for AUS and SFM. 5. Cost-effectiveness studies of immunocytochemical and molecular algorithms. 6. Validation of molecular biomarker testing and artificial intelligence-assisted cytomorphology using effusion specimens

Effusion cytology is a highly specific, minimally invasive, and clinically important method for detecting malignant involvement of serous cavities. Its greatest strength is confirmation of malignancy: the TIS MAL category has a pooled ROM approaching 100% and specificity around 99-100%. The major limitation is moderate sensitivity. When only MAL is considered positive, pooled sensitivity is approximately 70%; pleural-fluid sensitivity is even more dependent on tumour type, exceeding 80% for lung adenocarcinoma and ovarian carcinoma but falling below 30% for mesothelioma and pulmonary squamous-cell carcinoma. TIS provides a reproducible risk-stratification framework, while cell-block preparation and immunocytochemistry improve diagnostic confidence and can help identify the primary site. A negative or indeterminate cytology result should not delay tissue biopsy when clinical or radiological suspicion remains high. The most effective diagnostic strategy combines high-quality cytomorphology, TIS-standardized reporting, appropriate cell-block and ancillary testing, and multidisciplinary clinical-radiological correlation.

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