Fluorescence in situ hybridization in the definitive diagnosis of malignant mesothelioma in effusion cytology.
BACKGROUND
Distinction of malignant mesothelioma (MM) from reactive mesothelial cells (RM) in effusions is notoriously difficult. The aim of our study was to test chromosomal aberrations detected by fluorescence in situ hybridization (FISH) in the diagnosis of MM in effusion cytology and to explore the potential role of p16, p14, and p15 gene methylation as an alternative mechanism of tumor suppressor gene inactivation.


METHODS
Fifty-two effusions of biopsy-proven MM and 28 benign effusions were retrospectively analyzed by multitarget FISH assay for aberrations of chromosomes 3, 7, 17, and 9p21. In case of a negative result, the corresponding MM biopsy specimen was analyzed. Methylation-specific polymerase chain reaction (MSP) for p16, p14, and p15 was performed on FISH-negative MM biopsy specimens.


RESULTS
Seventy-nine percent of effusions with biopsy-proven MM had chromosomal aberrations, with loss of 9p21 as the most common finding. All benign effusions were FISH negative. Sensitivity, specificity, and positive and negative predictive values for detection of MM by FISH were 79%, 100%, 100%, and 72%, respectively. Six of nine FISH-negative effusions with biopsy-proven MM were also FISH negative in the MM biopsy specimens. Four of five FISH-negative biopsy specimens showed promoter methylation in p16 and p14 as compared with one of 12 benign controls.


CONCLUSIONS
FISH is a sensitive and highly specific method for the definitive diagnosis of MM in effusion cytology. In the subset of FISH-negative MM, tumor suppressor genes on the chromosomal region 9p21 are often inactivated by promoter methylation.
Institute for Pathology, University Hospital Basel, Schönbeinstrasse 40, 4031 Basel, Switzerland. ssavic@uhbs.ch
Spasenija
S
Savic
Noreli
N
Franco
Bruno
B
Grilli
Audrey de Vito
Ade V
Barascud
Michelle
M
Herzog
Beata
B
Bode
Heinz
H
Loosli
Peter
P
Spieler
René
R
Schönegg
Inti
I
Zlobec
Douglas P
DP
Clark
James G
JG
Herman
Lukas
L
Bubendorf
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D004273:DNA, Neoplasm / Q000032:analysis; D003937:Diagnosis, Differential; D005260:Female; D019942:Genes, p16; D006801:Humans; D017404:In Situ Hybridization, Fluorescence / Q000379:methods*; D008297:Male; D008654:Mesothelioma / Q000235:genetics / Q000473:pathology*; D008875:Middle Aged; D010996:Pleural Effusion / Q000175:diagnosis; D016066:Pleural Effusion, Malignant / Q000235:genetics / Q000473:pathology*; D016133:Polymerase Chain Reaction; D012189:Retrospective Studies
D004273:DNA, Neoplasm