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The International System for Reporting Serous Fluid Cytopathology
University of Wisconsin School of Medicine and Public Health
Conflict of Interest
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Educational Objectives
History: Bethesda ‐ GYN
Bethesda
System
For Reporting Cervical Cytology 2014
M.E. Sherman, et al.The Bethesda Interobserver Reproducibility Study (BIRST):, Cancer. 111 (2007) 15–25.
D.F. Kurtycz, et al; Bethesda Interobserver Reproducibility Study-2 (BIRST-2Sy): Bethesda 2014, JASC. 6 (2017) 131–144.
History: Bethesda ‐ Thyroid
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History: Paris System ‐ Urinary
History: Milan System ‐ Salivary
History: Milan System ‐ Salivary
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Other Systems
All the systems seek definition of terms, standardization of terminology and restriction of atypical and suspicious categories
Beginnings of TIS
Why This System?
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Initial Survey
Survey Results
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Survey Results
Survey Results
Survey Results: Ancillary
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Proposed Diagnostic Categories
Proposed Diagnostic Categories
Risk of Malignancy
Diagnostic Category % ROMb (SE)c
Non-Diagnostic (ND) 17% (± 8.9%)
Negative for Malignancy (NFM) 21% (± 0.3%)
Atypia of Undetermined Significance (AUS) 66% (± 10.6%)
Suspicious for Malignancy (SFM) 82% (± 4.8%)
Malignant (MAL) 99% (± 0.1%)d-g
Farahani SJ, Baloch Z. Are we ready to develop a tiered scheme for the effusion cytology? A comprehensive review and analysis of the literature. Diag Cytopathol. Vol. 47, No.11, Nov. 2019. p.1145-1159. b= Risk of Malignancy, c= SE=Standard Error
A meta-analysis of 34,941 samples
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Monograph Structure
Monograph Production
Non‐Diagnostic (ND)
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Adequacy
Rooper LM, Ali SZ, Olson MT. A minimum fluid volume of 75 mL is needed to ensure adequacy in a pleural effusion:a retrospective analysis of 2540 cases. Cancer Cytopathol. 2014;122(9):657-665.
Adequacy
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0 20 40 60 80 100
Sensitivity
Volume of Fluid
Volume vs Positivity
Adequacy
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0 20 40 60 80 100
Sensitivity
Volume of Fluid
Volume vs Positivity
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Adequacy
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0 20 40 60 80 100
Sensitivity
Volume of Fluid
Volume vs Positivity
Bronchoscopy-Guided Transtracheal and Transbronchial (Wang) FNA, H. B. Xie, R. Cornwell,, J Grossman, H.D.Hoerl, and D Kurtycz, M.D., Diag Cyto. October 2002, Vol. 27, No. 5, p. 276-281
Non‐Diagnostic
a. An abscess is diagnostic. It gives information about a condition and the sample is suitable for culture
b. A hemolyzed sample or degenerate sample does not provide much information.
c. Degenerate Geimsad. Papanicolaou prep
with air drying
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Negative for Malignancy (NFM)
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Negative for Malignancy (NFM)
Microvilli on Mesotheial cells
https://pathresidents.com/usapathology/em-handbook/diagn-organelles-section/organelle-pages/cell-processes.html
Normal microvilli keep mesothelial cells apart, but cells are connected to one another by desmosomes
Negative for Malignancy (NFM)
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Immunocytochemical studies, clinical and radiographic correlations required.
Effusions
AdequateInadequate
Expected cellular findings (mesothelial cells, some inflammatory cells) Unexpected cellular and non-cellular findings
In regard to volume and distribution:
Dx. Negative for malignancy(NFM)
Mostly mesothelial cells arranged singly and/or in small clusters. No cellular atypia. Some histiocytes, lymphocytes, neutrophils
Increased volume and/or cell distribution:
Predominantly mesothelial cells (single and/or numerous
clusters)
Dx. NFM
Dx. Mesothelioma
Predominantly histiocytes(often appearing like a “second
cell population”)Dx. NFM
Predominantly lymphocytesDx. NFM
Dx. Lymphoma
Predominantly or increased eosinophils
Predominantly neutrophils Dx. NFM
Dx. NFM
Second (malignant) cell population
Single cells Dx. Melanoma, lymphoma, breast (lobular) ca, sarcoma
Small clusters Dx. AdenoCa, breast, lung, small cell carcinoma
Large clusters Dx. AdenoCa, ovarian, pancreatic
Psammoma bodies
Collagen balls
Asbestos bodies
LE cells
Necrosis, spindle and giant cells
Detached ciliary tufts
Dx. NFM
Dx. NFM
Dx. NFM
Dx. NFM
Dx. NFM
Dx. NFM
Infectious organisms Dx. NFM
Figure 1. Algorithmic Approach to Serous Effusion. NFM - Negative for malignancy – E. Wojcik
Atypia of Undetermined Significance (AUS)
Atypia of Undetermined Significance (AUS)
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Atypia of Undetermined Significance (AUS)
Atypia of Undetermined Significance (AUS)
Atypia of Undetermined Significance (AUS)
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Suspicious For Malignancy (SFM)
Suspicious For Malignancy (SFM)
Adenocarcinoma?
Suspicious For Malignancy (SFM)
Lobularcarcinoma?
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Malignant
Malignant (P)
Malignant (P)
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Mesothelioma
Mesothelioma
Not‐Mesothelioma
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Mesothelioma
Loss of BAP-1 in mesothelial Cells
Malignant (M)
Malignant (M)
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Ancillary Techniques
Table 8.2.Testing predictive mutations, other alterations in malignant effusions (common examples), and principal molecular techniques with reference r
Gene Tumor type Targeted treatment Status
EGFR NSCLC EGFR TKIs FDA approvedBRAF (p.V600E) NSCLC, melanoma BRAF inhibitors FDA approvedKRAS (p.G12C) NSCLC AMG 510 EmergingHER2/ERBB2 NSCLC anti-HER2 EmergingMETex14 NSCLC MET Inhibitors EmergingBRCA1/2 Ovarian, breast & prostate cancer PARP inhibitors FDA approvedSTK11/LKB1 NSCLC Immune checkpoint inhibitors EmergingMSI all tumor types Immune checkpoint inhibitors FDA approvedTMB Different tumor types Immune checkpoint inhibitors Emerging
Gene Tumor type Targeted treatment Status
EGFR (p.T790M, p.C797S)NSCLC later generation EGFR TKIs FDA approvedALK NSCLC later generation ALK TKIs EmergingROS1 NSCLC later generation ROS1 TKIs EmergingNTRK NSCLC later generation NTRK TKIs EmergingSTK11/LKB1 NSCLC Immune checkpoint inhibitors Emerging
Reference range LODall the mutations in the analyzed gene regions 10%-20%only hotspot mutations 1%-5%only hotspot mutations 0,1%-1%all the mutations in the analyzed gene regions 0,01%-5%
Abbreviations: ALK: anaplastic lymphoma kinase; BRAF: V-Raf Murine Sarcoma Viral Oncogene Homolog B1; BRCA1/2: Breast Cancer Type 1/2 Susc
Sanger SequencingRT-PCRdPCRNGS
Primary driver mutations
Resistance mutations
Molecular techniques
Ancillary Techniques
A) PD-L1 in malignant effusion of NSCLC. Cell block section. membranous PD-L1 staining in all tumor cells and weakly positive macrophages in the background.
B) Diffuse staining of tumor cells, smear
C) PD-L1 negative tumor cells and an adjacent macrophage serving as a positive internal control.
D) Heterogenous PD-L1 staining.
Ancillary Techniques
FISH analysis using UroVysion multi-probe FISH assay (increased copy numbers of chromosomes 3 (red), 7(green) und and 17 (aqua), and homozygous loss of 9p21 signals (gold). Note some benign cells with retained 9p21 signals
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Diagnostic categories & clinical management
Questions
Questions
Rodriguez EF et al. Molecular Alterations in Patients with Pulmonary Adenocarcinoma Presenting with Malignant Pleural Effusion at the First Diagnosis. Acta Cytologica.2017;61(3):214-222.
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Questions
Questions
Malkhasyan KA et al. The clinical characteristics of melanoma with BRAF V600R mutation: a case series study. Melanoma Res. doi: 10.1097/CMR.0000000000000630. [Epub ahead of print] 2019 Jul 11.
Questions
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Questions
Edmond Cibas, Barbara Ducatman. Cytology Diagnostic Principles and clinical correlates. Chapter 4. Pleural, pericardial, and peritoneal fluids, page 142. Fourth edition. Elsevier
Questions
Questions
Edmond Cibas, Barbara Ducatman. Cytology Diagnostic Principles and clinical correlates. Chapter 4. Pleural, pericardial, and peritoneal fluids, page 142. Fourth edition. Elsevier
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Chapters
Peritoneal Washings
Cytopreparation
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Quality Management
Pathophysiology
Final Thoughts
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