Microscopic examination of cytospins (Figures 1-2) and cell block section (Figure 3) revealed abundant papillary fragments of atypical epithelioid cells. The papillary structures contained collagenous cores. The atypical cells displayed small, round nuclei and moderate amounts of cytoplasm. There are macrophages in the background. Immunohistochemical stains performed on the cell block demonstrated the atypical cells were positive for calretinin (Figure 4) and D2-40 (Figure 5), with loss of BAP-1 expression (Figure 6). They are negative for TTF-1, GATA-3, PAX-8, CDX2, and NKX3.1. Notably, the patient had a history of occupational exposure of possible asbestos as a retired plumber. Based on these findings, a diagnosis of mesothelioma was made. Two weeks later, a repeat pleural fluid cytology with a concurrent right pleural biopsy yielded consistent cytomorphology and similar immunoprofile.
Questions:
- Which immunohistochemical marker is most likely positive in mesothelioma and negative in metastatic adenocarcinoma?
- CEA
- TTF-1
- Calretinin
- Ber-EP4
- MOC-31
- Which genetic alteration is most commonly associated with mesothelioma?
- EGFR mutation
- BAP1 loss
- KRAS mutation
- BRCA1 amplification
- TP53 mutation
- Which of the following is a characteristic feature of mesothelioma on cytology?
- Cells in large clusters with nuclear molding
- Single cells with a high nuclear-to-cytoplasmic ratio
- Papillary clusters with cytoplasmic “windows”
- Small round blue cells with scant cytoplasm
- Pleomorphic epithelioid cells
Answers:
Question 1: Correct Answer is C.
C. Calretinin is a calcium-binding protein that is strongly expressed in mesothelioma. It is a reliable marker for mesothelial differentiation and helps distinguish mesothelioma from adenocarcinoma.
A. CEA (carcinoembryonic antigen) is positive in adenocarcinomas, especially of lung and gastrointestinal origin, but negative in mesothelioma.
B. TTF-1 (thyroid transcription factor-1) is highly specific for lung adenocarcinomas and thyroid carcinomas.
D. Ber-EP4 is a marker for epithelial lineage. It is positive in adenocarcinomas but not in mesothelioma.
E. MOC-31 is a marker for epithelial lineage. It marks epithelial tumors but not mesothelioma.
Question 2: Correct Answer is B.
B. BAP1 (BRCA1-associated protein 1) loss is a common mutation in mesothelioma. Loss of BAP1 contributes to tumorigenesis by impairing DNA repair and cell cycle regulation.
A. EGFR mutation is associated with lung adenocarcinoma but not with mesothelioma.
C. KRAS mutation can be seen in lung, colorectal and pancreatic cancers but is not typical for mesothelioma.
D. BRCA1 amplification is linked to breast and ovarian cancers.
E. TP53 mutation is common in various cancers but not a hallmark of mesothelioma.
Question 3: Correct Answer is C.
C. Due to the mesothelial origin, mesothelioma cells in effusion cytology often form cohesive, three-dimensional clusters with clear spaces or "windows" between them. These windows are formed by the slender microvilli that cover the surface of mesothelial cells. The cytoplasm is typically abundant and dense.
A. Nuclear molding is more characteristic of small cell carcinoma.
B. Single cells with a high nuclear-to-cytoplasmic ratio are typical of poorly differentiated carcinomas, neuroendocrine or hematopoietic neoplasms.
D. Small round blue cells with scant cytoplasm are seen in small round blue cell tumors such as lymphoma, neuroblastoma, et al, but not mesothelioma.
E. Mesothelioma cells can be pleomorphic, but usually have bland cytology.
References:
1. Mastromarino MG, Lenzini A, Aprile V, Alì G, Bacchin D, Korasidis S, Ambrogi MC, Lucchi M. New Insights in Pleural Mesothelioma Classification Update: Diagnostic Traps and Prognostic Implications. Diagnostics (Basel). 2022 Nov 22;12(12):2905. doi: 10.3390/diagnostics12122905. PMID: 36552912; PMCID: PMC9776784.
2. Brcic L, Kern I. Clinical significance of histologic subtyping of malignant pleural mesothelioma. Transl Lung Cancer Res. 2020 Jun;9(3):924-933. doi: 10.21037/tlcr.2020.03.38. PMID: 32676358; PMCID: PMC7354152.
3. Louw A, Lee YCG, Acott N, Creaney J, Van Vliet C, Chai SM. Diagnostic utility of BAP1 for malignant pleural mesothelioma in pleural fluid specimens with atypical morphology. Cytopathology. 2022; 33: 84–92.
4. Cigognetti M, Lonardi S, Fisogni S, Balzarini P, Pellegrini V, Tironi A, Bercich L, Bugatti M, Rossi G, Murer B, Barbareschi M, Giuliani S, Cavazza A, Marchetti G, Vermi W, Facchetti F. BAP1 (BRCA1-associated protein 1) is a highly specific marker for differentiating mesothelioma from reactive mesothelial proliferations. Mod Pathol. 2015 Aug;28(8):1043-57. doi: 10.1038/modpathol.2015.65. Epub 2015 May 29. PMID: 26022455.