Atypia of undetermined significance (AUS), The International System (TIS) for reporting serous effusion cytopathology, (florid reactive mesothelial hyperplasia) in a case of liver cirrhosis.
Cytopathology:
- Moderate-high cellularity, with some flat sheet and loose two-dimensional clusters with scalloped border (clusters are not much crowded) and few dispersed single mesothelial cells
- Small papillary structures are seen (large compact tight papilla favours malignant nature of effusion)
- Centrally located round to ovoid nucleus and some with minor variation in location of nucleus (not eccentric location in majority of cells). Occasional cells with eccentric nuclei are seen.
- Occasional to few cells shows striking atypia (difficult to differentiate reactive from malignant) (moderate to marked atypia in a large number of cells and large number of such fragments favours malignant nature of process)
- Most of the cells have smooth nuclear membrane, finely granular chromatin and occasional small nucleoli. Few cells show nuclear membrane irregularity (more number of cells with irregular nuclear membrane, coarse chromatin and multiple nucleoli pointing towards malignant effusion)
- Few cells show cytoplasmic vacuoles (not useful for diagnosis)
- Cytoplasmic blebs are not seen
- Binucleation and multinucleation in mesothelial cells are seen (not useful for diagnosis)
- Cell size variation is less (marked variation favours malignant etiology).
- Slit-like spaces – “windows” formation is common in mesothelial cells but not specific findings ( it can be seen in adenocarcinoma)
- Cannibalism: Cell-in-cell engulfment is not specific findings for mesothelial cells ( it can be seen in adenocarcinoma)
- Many of the clusters show knobby/bumpy borders, common in mesothelial cells but not specific findings ( it can be seen in adenocarcinoma)
- some of the foci contain metachromatic fibrinous/collagenous core surrounded by mesothelial cells
- Mitotic figures are not helpful in the diagnosis
Points of Pathoclinics:
- Papillary structures formation, slightly increased N/C ratio and mild to moderate degree of nuclear hyperchromasia can be seen in a reactive mesothelial proliferation like in this case. But most of these papillary structures are loose, not crowded. Compare the nuclear features of cells in clusters with cells appearing in the background.
- Multinucleation is a common feature of reactive mesothelial but not specific for anything.
- Malignant effusion have high cellularity with three dimensional structures – spheres and morules with smooth outer border and abnormal nuclear features. Rest all other features are not useful for distinction of benign effusion from malignant effusion.
- Malignant cells are usually appears in tight and compact papillary, tubular and glandular structures with smooth outer borders
- Florid reactive mesothelial cells proliferation is commonly seen in liver parenchymal diseases like cirrhosis, renal failure, cardiac failure, pulmonary infarction, chronic infection, pancreatitis, radiation, peritoneal dialysis, collagen‐vascular diseases, ectopic pregnancy, tubo-ovarian abscess and chemotherapy. In these settings, clinical details are very important and pathologist should be less strict for rendering the diagnosis of reactive mesothelial proliferation.
- How macrophages look: macrophages are usually large in size, round -oval- or bean-shaped nuclei, fine chromatin (not coarse) , inconspicuous nucleoli and multi-vacuolated cytoplasm. N/C ratio is low.
- For metastatic carcinoma, focus on two distinct cell population – the malignant cells forms tight crowded clusters and three dimensional balls, along with background reactive mesothelial cells, mostly dispersed isolated or flat monolayer sheets.
- Cytological diagnosis of malignancy is straightforward if eye-catching abnormalities like marked pleomorphism, high nucleocytoplasmic ratio, hyperchromasia, irregular nuclear membrane, clumped, irregular chromatin and multiple nucleoli are present.
- Fluid cytology is not always diagnostic of neoplastic or non-neoplastic mesothelial cells or metastatic adenocarcinomas. Supports of clinical and radiological details solve many of these issues. In grey zone cytology, it is better to undercount the suspiciousness of malignancy rather than rendering the malignant diagnosis, especially in association with predisposing condition causing florid reactive mesothelial hyperplasia.
- Use of the International System (TIS) for reporting serous effusion cytopathology can reduce the interobserver variation, reduce misunderstanding among the pathologist as well as clinicians regarding the term used for diagnosis.
- CEA, Ber-Ep4, MOC-31, claudin-4 and B72.3 favours adenocarcinoma while calretinin, CK 5/6, D2-40 and WT1 favours mesothelial cell line.
- Stain for p53, EMA, E-cadherin, and Glut-1 comes positive in mesotheliomas and negative in reactive mesothelial proliferations
- Desmin positivity favours benign mesothelial proliferations and negative in malignant mesothelial proliferations
- Mesothelin is negative in reactive mesothelial cells and positive in malignant mesotheliomas. It is also positive in ovarian and pancreatic malignancy.
- Loss of BAP1 expression is a feature of malignant mesothelioma
- EMA positivity seen in adenocarcinoma, malignant mesothelioma and peritoneal inclusion like endometriosis or any gastrointestinal contaminant coming during any procedure. so evaluate with extra precaution. Cytoplasmic EMA positivity more favours adenocarcinoma, while thick/strong membranous EMA positivity along with cytoplasmic staining characteristically seen in malignant mesothelial cells, not in reactive mesothelial proliferation.