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Hershey, PA
Dr. Zander is Professor and Chair of the Department of Pathology, Penn State Milton S. Hershey Medical Center.
Correspondence to: Dani S. Zander, MD, Professor and Chair, Department of Pathology, Penn State Milton S. Hershey Medical Center, M.C. H083, PO Box 850, 500 University Dr, Hershey, PA 17033-0850; e-mail: dzander{at}hmc.psu.edu
Over the last several years, molecular technologies have come to occupy a portion of center stage in the evaluation of cytologic samples. These techniques have been particularly beneficial in the area of gynecologic cytology. The testing of liquid-based cervicovaginal cytology specimens for human papillomavirus has enhanced the effectiveness of the pap smear as a screening test for cervical malignancy and its precursor lesions, and has been recommended for most women 
30 years of age. This testing allows for the identification of patients who are at higher risk for cervical cancer and provides assistance to practitioners dealing with indeterminate cytology interpretations such as "atypical squamous cells of undetermined significance," which is a heterogeneous diagnostic category that includes examples of dysplasia, reactive changes, and atrophy.
Are we on the verge of parallel advances in the evaluation of bronchoscopic specimens? The accompanying article authored by Halling and colleagues (see page 694)1 would suggest that we are. These investigators compared the sensitivity and specificity of fluorescence in situ hybridization (FISH) and cytologic examination for the diagnosis of lung cancer in bronchial cytology samples. The FISH procedure was performed using a commercially available probe set (LAVysion; Abbott Molecular Inc; Des Plaines, IL) that was geared to detect alterations in chromosomal loci which are often affected in lung cancers. It includes locus-specific probes to chromosomes 5p15, 7p12 (EGFR), and 8q24 (C-MYC), and a centromeric probe to chromosome 6. Cytologic interpretation was provided by board-certified pathologists as part of a routine clinical evaluation. This study showed that for specimens obtained from both bronchial brushing and washing the sensitivities of FISH were higher than those of cytology, although the specificities of cytologic examination were slightly superior. For bronchial brushing specimens overall, the sensitivities of FISH and cytology were reported as 71% and 51%, respectively; for washings, 49% and 44%, respectively. In bronchial brushings, FISH was significantly more sensitive than cytology for the detection of non-small cell carcinomas as a group and for peripherally located tumors, while both techniques yielded similar sensitivities for small cell carcinomas and centrally located tumors. Combining FISH and morphologic evaluation enhanced the sensitivity of detection of multiple subsets of cases. The results described in this report are exciting and build on previous work that also supports enhanced diagnostic sensitivity when targeted FISH testing is added to the menu of testing performed on respiratory cytology samples.2345
Is the time right for FISH testing of bronchoscopic cytology samples to transition into more general use? If the answer to this question is in the affirmative, a number of additional questions must be answered. The appropriate clinical indications must be defined, as well as the limitations for applying this test and the potential pitfalls that may be encountered in sample acquisition and analysis. Quality control procedures will need to be put into place to ensure that the testing will produce accurate and reliable results.
Although the number of published investigations is small, available FISH probe sets appear to have a high sensitivity for the detection of some of the chromosomal changes associated with pulmonary carcinogenesis. Performance of this testing on patients who are suspected of harboring a lung cancer yields acceptable sensitivities, but if this testing is expanded to populations with a lower prevalence of lung cancer, then the positive predictive value is likely to decline and the risk of a false-positive result is likely to increase. False-positive FISH results (ie, a positive FISH result in the absence of a confirmatory surgical sample or transthoracic needle aspiration specimen that was positive for disease) were noted in four bronchial brushing samples and two washing samples in the current study.1 Two of these six samples came from patients with a previous diagnosis of lung cancer, one came from a patient with colon cancer metastatic to the liver and progressive pulmonary infiltrates, and three samples came from patients with no current or previous diagnosis of lung cancer and at least 6 months of follow-up. All six of these samples were interpreted as being negative for malignancy by cytologic examination. False-positive FISH results were also noted by Bubendorf et al4 in seven bronchial washing samples and two bronchial brushing samples that came from patients with common pneumonia, aspergillosis, cytomegalovirus pneumonia, tuberculosis, silicoanthracosis, and methotrexate-associated lung injury. As in the current study, none of these samples was interpreted as being malignant by cytologic examination.
While there are many potential explanations for these discrepancies between FISH and cytology results, the fact remains that the consequences of a false-positive result are potentially very significant. Most pathologists who review bronchoscopic cytology findings are very aware of this fact, and individuals may tend to categorize cases that are borderline, in terms of numbers of intact atypical cells or degrees of atypia, as being suspicious for malignancy. Will the addition of FISH-derived data into the diagnostic algorithm enable the classification of some morphologically borderline cases as malignant? Will the objective and relatively quantifiable data obtained by FISH serve as an advantageous complement to the pattern-based morphologic assessments of the eyes and brain, as was the case with flow cytometric analysis of lymphoproliferative processes? Although the data do not currently exist to answer these questions, the next few years will likely bring us more insight into the applications of this growing technology to the diagnosis of lung cancer.
Footnotes
The author has reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in the article.
References
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