The use of CDKN2A deletion as a diagnostic marker for malignant mesothelioma in body cavity effusions.
BACKGROUND
The distinction between benign reactive mesothelial cells and malignant mesothelial cells in serous effusions is difficult and has an unusually high false negative rate. Unfortunately, there are no generally accepted markers to distinguish between benign reactive and malignant mesothelial cells. Homozygous deletion of CDKN2A is frequent in mesothelioma (present in > 70% of tumors). Therefore, detection of CDKN2A deletion by fluorescence in situ hybridization (FISH) was evaluated as an ancillary test in the cytologic diagnosis of malignant mesothelioma.


METHODS
Dual-color FISH for CDKN2A and chromosome 9 centromere was performed on cytolyt-fixed Thinprep slides from 6 cytologically suspicious and 7 cytologically positive effusions (all with histologically confirmed mesothelioma) and in 19 cytologically benign effusions (14 pleural effusions, 3 pericardial effusions, and 2 abdominal fluid specimens). Specimens containing > or = 15 nuclei that lacked signals for CDKN2A but showed at least 1 signal for chromosome 9 centromere were considered positive. In samples with negative cytology, the nuclei of at least 100 mesothelial cells were evaluated; whereas, in specimens with positive or suspicious cytology, counting nuclei was done only if < 15% of nuclei showed homozygous loss of CDKN2A.


RESULTS
Homozygous deletion was detected in mesothelial cells in six of seven specimens with positive cytology and in six of six specimens with suspicious cytology. Cytologically, there were numerous tumor cells in a single positive specimen without homozygous deletion. All 19 cytologically negative specimens were negative for CDKN2A deletion.


CONCLUSIONS
The detection of homozygous CDKN2A deletion by FISH would have been helpful in confirming a diagnosis of mesothelioma over reactive mesothelial cells in 12 of 13 samples with positive or suspicious cytology. Further studies on larger series of patients with suspicious cytology are needed to evaluate the validity and efficiency of this approach for improving the diagnostic accuracy of effusion cytology.
Illei
Peter B
PB
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Ladanyi
Marc
M
Rusch
Valerie W
VW
Zakowski
Maureen F
MF
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001202:Ascitic Fluid / Q000166:cytology; D005260:Female; D017353:Gene Deletion; D019942:Genes, p16; D005819:Genetic Markers; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008654:Mesothelioma / Q000175:diagnosis* / Q000235:genetics*; D008875:Middle Aged; D010490:Pericardial Effusion / Q000166:cytology; D010996:Pleural Effusion / Q000166:cytology; D012680:Sensitivity and Specificity
D005819:Genetic Markers