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Molecular Predictive Factors for Progression of High-Grade Preinvasive Bronchial Lesions

¹ Clinique Pneumologique and Groupe LITIS–Quantif EA 4108, Rouen University Hospital, and Faculté de Médecine-Pharmacie, Rouen France; ² INSERM U.614, Faculté de Médecine-Pharmacie, Rouen, France; and ³ Service d'Anatomie et Cytologie Pathologiques, and Laboratoire de Génétique Somatique des Tumeurs, Rouen University Hospital, Rouen, France

Correspondence and requests for reprints should be addressed to Luc Thiberville, M.D., Clinique Pneumologique, Hôpital Charles Nicolle–CHU de Rouen, 1 rue de Germont, 76031 Rouen Cedex, France. E-mail: luc.thiberville{at}univ-rouen.fr

Rationale: The outcome of precancerous bronchial lesions is not well known, and their management is subject to controversy. Many molecular alterations are present in preinvasive lesions, but none has been assessed to predict the evolution of the lesions.

Objectives: To analyze the outcome of high-grade precancerous lesions according to their molecular profile.

Methods: Twenty-three severe dysplasia and 31 carcinoma in situ (CIS) lesions in 37 patients were monitored using repeated autofluorescence bronchoscopy over a 12-year period. Microdissection and polymerase chain reaction analysis were performed on paraffin tissue sections to assess loss of heterozygosity (LOH) and microsatellite instability on chromosome 3p, 5q, and 9p. Histology and molecular status at baseline were compared between 7 lesions that became invasive, 11 that relapsed after treatment, 17 that were eradicated with local treatment, and 19 that spontaneously regressed.

Measurements and Main Results: Ninety-four percent of lesions that progressed or relapsed were CIS at baseline, whereas 79% of spontaneously regressing lesions were severe dysplasia (P < 0.0001). 3p and 9p LOH was more frequent in CIS than in severe dysplasia (P = 0.03). In the whole group of lesions as well as in the CIS group, 3p LOH was strongly associated with progression (P < 0.0001 and P = 0.02, respectively). Microsatellite instability was not associated with the outcome of the lesions. A therapeutic strategy based on the presence of 3p or 9p LOH would have led to overtreatment of six lesions but would have missed only 1 among the 18 progressing lesions.

Conclusions: Baseline histology and 3p LOH analysis appear to be useful in predicting the outcome of high-grade precancerous lesions.

Key Words: precancerous conditions • gene deletion • follow-up studies • bronchoscopy • disease progression

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject There is no known predictive factor distinguishing precancerous bronchial lesions that will progress from the ones that will regress. Several molecular abnormalities are found in precancerous lesions with an increasing rate during the cancerization process. What This Study Adds to the Field Carcinoma in situ histology and chromosome 3p deletion are significantly associated with the long-term progression of high-grade lesions on follow-up.