Pulmonary Diseases Unit, Department of Internal Medicine, Immunoallergic and Respiratory Diseases, Azienda Ospedaliero-Universitaria “Ospedali Riuniti,” Ancona, Italy
Reprints: Stefano Gasparini, MD, SOD Pneumologia, Azienda Ospedaliero-Universitaria “Ospedali Riuniti,” Via Conca, 71, 60020 Ancona, Italy (e-mail: email@example.com).
There is no conflict of interest.
Transbronchial needle aspiration (TBNA) is a technique that has greatly expanded the diagnostic capabilities of flexible bronchoscopy, allowing sampling from lesions located outside the airways and from the hilar and mediastinal lymph nodes. This method, which can be performed in a traditional manner on the basis of computed tomography scan images or under the guidance of endobronchial ultrasound-TBNA, is widely used for the staging of lung cancer and for the diagnosis of mediastinal pathologies. Even though transbronchial needles specifically designed for obtaining tissue cores suitable for histologic examination have been commercially available since 1985,1,2 the real advantage of using these needles is not well defined. The majority of bronchoscopists do not use histology needles routinely. It is generally believed that histology needles should be used only when a pathology other than lung cancer is suspected, such as granulomatous diseases or lymphoma, which may require histologic assessment for better diagnosis.
Two main questions should be addressed and discussed on this topic.
The first is, are histology needles able to provide a better diagnostic yield in comparison with cytology needles?
It is surprising to observe that more than 25 years after the introduction of flexible TBNA and despite numerous types of needles available on the market, there is just one controlled prospective study comparing different kinds of needles (histology versus cytology). In this study, Shenk et al3 performed TBNA on 64 patients initially using a 22-gauge cytology needle and subsequently, during the same bronchoscopic procedure, a 19-gauge histology needle inserted at the identical point. The histology needle was significantly more sensitive than the 22-gauge needle (85.5% vs. 52.7%), and in 20 of their patients the 19-gauge needle was exclusively diagnostic. Histology needles may provide both tissue fragments fixed in formalin for histologic evaluation and a sample that can be processed for cytologic analysis (flush solution or smear on a slide). From the study by Shenk et al,3 it seems that the cytologic and histologic evaluation of the samples obtained by the histology needle is complementary, as sensitivity improves from 63.6% (only cytology) and 78.2% (only histology) to 85.5% if both histologic and cytologic material are examined. It could be hypothesized that the higher sensitivity of histology needles is mainly related to the larger size of the needle, with enhanced suction capability, and to the presence of an inner 21-gauge needle, which acts as a stylet and prevents plugging and contamination of the needle with the material coming from the mucosa and the tracheobronchial wall. However, more recently, Stratakos et al,4 using a 19-gauge histology needle in 77 patients and processing the material obtained for both histologic and cytologic evaluation, showed that the histologic examination provided a 35% increase in the diagnostic yield over cytology only. Even if there is a doubt that the cytologic sample obtained by a histology needle, after the removal of tissue fragments, may be of lower quality in comparison with the sample obtained by a cytology needle, the data support the fact that histologic evaluation provides better sensitivity in comparison with cytologic assessment.4 More comparative, prospective, large studies are necessary to substantiate the findings. However, on the basis of the actual evidence provided by these 2 studies, the answer to the first question is that histology needles seem to have better sensitivity in comparison with cytology needles and that they should be used more extensively in the routine bronchoscopic activity, irrespective of the suspect diagnosis.
The second, and probably the more jugular, question is, are TBNA histology samples better than cytologic samples in identifying the histologic subtypes of lung cancer?
Until recently, the distinction between small-cell lung cancer (SCLC) and non-SCLC (NSCLC) has been considered sufficient for therapeutic purposes, as similar chemotherapy protocols were used in all cases of NSCLC. Currently, most cytopathologists are able to correctly distinguish SCLC from NSCLC on the basis of cytologic samples, and, indeed, 75% of lung cancers are diagnosed based on cytology alone.5 Recently, the advent of new chemotherapeutic agents with different activity on the specific subtypes of NSCLC and the introduction of personalized treatments according to the histology require more effort to carefully identify the histology of the tumor. Is it just an issue related to the size of the sample, that is, cytology versus histology? The distinction between poorly differentiated squamous cell carcinoma and adenocarcinoma can be difficult on both the cytologic and histologic samples,6 especially in small-size biopsies such as those that can be obtained through bronchoscopy. Cytologic and histologic interpretation of specimens obtained simultaneously match in 75% to 85% of cases and, in the remaining cases, biopsy or cytology alone is diagnostic in equal number.5 In my experience, in 193 patients affected by centrally located lung cancer, from whom cytologic (TBNA) and histologic (biopsy forceps) samples were obtained, histology was unable to identify the subtype of the tumor in 12.3% of the cases and cytology in 17.6%, without any significant statistical difference (Gasparini S, Ferretti M; unpublished data).
In the January issue of this Journal, Hermens et al7 report their experience with TBNA using histology needles. The investigators compared the results of histology with those of cytology in 50 patients affected by mediastinal lymph node enlargement. Two pathologists reviewed all specimens independently. In 86% of the cases histology and cytology provided the same diagnosis, whereas in 7 patients (14%) histologic evaluation modified the diagnosis. In 4 patients with lung cancer, a different type of carcinoma was found in the histology samples with respect to the diagnosis obtained by cytology alone. However, some discrepancies in the definition of histology were observed even in the histologic evaluation made by the 2 pathologists involved with the study. As underlined by the same investigators, the major limitation of this interesting study is that immunohistochemical staining was not used. As histologic distinction between the different types of lung carcinoma may be difficult, both in small biopsy specimens or in cytologic specimens, pathologists frequently use ancillary techniques, among which immunohistochemistry has gained wide acceptance.6 The use of a panel of immunohistochemical markers, such as thyroid transcription factor-1, p63, cytokeratin 7, high-molecular-weight cytokeratins, and neuroendocrinal markers, may allow distinction between SCLC, adenocarcinoma, and squamous cell carcinoma in a large percentage of cases. It would be interesting to know whether the same variability between histology and cytology would have been found in the study of Hermens et al7 if they had used an immunohistochemical panel. In the era of target-specific chemotherapy in lung cancer, it would be desirable to make immunohistochemical markers a routinely used technique in the management of specimens obtained during bronchoscopy.
This question is likely to become more complex with the advent of new molecular techniques that can provide more useful information for lung cancer treatment. Epidermal growth factor mutation, vascular endothelial growth factor pathways, and kRAS mutation are just some of the molecular markers that can be relevant for therapeutic and prognostic purposes. These molecular assessments can also be evaluated from cytologic samples, using the proper treatment of the sample (eg, cell blocks).8–10
In conclusion, Hermens et al should be congratulated for their effort to better qualify the nature of the mediastinal lymph nodes using histology needles during their TBNA procedures. The use of histology needles may increase the sensitivity of TBNA. However, the real issue in the bronchoscopic diagnosis of lung cancer is not histology versus cytology. The real issue is to have a skilled cytopathologist who is cognizant of the significance of sample interpretation from a prognostic and therapeutic point of view in the new era of lung cancer personalized chemotherapy. He or she should be able to obtain as much information as possible by the bronchoscopic sampling with regard to the histology and molecular pathways of the tumor. This can be achieved by creating teams in which interventional pulmonologists, oncologists, and cytopathologists work together to obtain the best results from the sampling techniques and from the retrieved material, whether histologic or cytologic.
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7. Hermens FHW, Limonard GJM, Hoevenaars BM, et al. Diagnostic value of histology compared with cytology in transbronchial aspiration samples obtained by histology needle. J Bronchol Intervent Pulmonol. 2010;17:19–21.
8. Savic S, Tapia C, Grilli B, et al. Comprehensive epidermal growth factor receptor gene analysis from cytological specimens of non-small-cell lung cancer. Br J Cancer. 2008;15:154–160.
9. Mohamed S, Yasufuku K, Nakajima T, et al. Analysis of cell cycle-related proteins in mediastinal lymph nodes of patients with N2-NSCLC obtained by EBUS-TBNA: relevance to chemotherapy response. Thorax. 2008;63:642–647.
10. Nakajima T, Yasufuku K, Suzuki M, et al. Assessment of epidermal growth factor receptor mutation by endobronchial ultrasound-guided transbronchial needle aspiration. Chest. 2007;132:597–602.
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