CLE in diagnosing pleural malignancies, a comparison with pathology

Novel optical imaging techniques such as confocal laser endomicroscopy (CLE)
have emerged in recent years as techniques that actually enable in vivo
real-time microscopic analysis of malignancies of the GI-tract and lung cancer
(1,2,3). Through recent advances the probe became small enough to fit through a
biopsy needle and can be used during CT-guided (3) and endosonographic guided
biopsies (EUS-FNA)(1,2). Since the first trimester of 2016 our research group
in the AMC is performing needle based CLE for lung cancer (Clin trial gov
NCT02689050), with promising results7. As a result, expansion of this
innovative technique to other intra-thoracic malignancies during biopsy
procedures seems a logical next step. Patients with intra-thoracic malignancies
often require invasive procedures such as bronchoscopy, thoracoscopy,
mediastinoscopy trans thoracic needle aspiration or surgical exploration to
obtain a diagnosis. Intra thoracic malignancies encompass lung cancers,
thymomas and malignant pleural mesothelioma. These tumors often present with
pleural thickening, unilateral pleural effusion, mediastinal enlargement or a
peripheral located mass in the lungs. Tissue collection of the suspected
pleural thickening is required to assess a diagnosis and differentiate between
the tumor types, to classify and to stage in a proper manner. To date, the
different biopsy methods, such as CT-guided pleural biopsy, mediastinal biopsy,
endosonography and thoracoscopy have their limitations in diagnosing these
malignancies. Sampling errors frequently occur resulting in the common
histological finding of *non-specific pleuritic/fibrosis*, which presents a
great uncertainty for clinicians and patients.11 Novel microscopic imaging
techniques such as CLE seem to be capable of distinguishing areas of fibrosis
from malignant tumors involved in lung cancer14, however data in other
intra-thoracic malignancies are lacking. Therefore the aim of this study is to
investigate whether CLE can:
1. Provide real time information of the biopsy location during diagnostic
biopsies in patients with suspected pleural lesions encompassing mesothelioma,
thymoma and other tumors
2. Improve the diagnostic yield of tissue-biopsies.

To describe criteria on CLE-imaging of different entities (thoracic wall/
pleura/ fibrosis/ mediastinum) compared to histology.

This is a multi-center (NKI and AMC), investigator-initiated, observational
study. A maximum of 20 patients with (a strong suspicion of) an intra-thoracic
malignancy are enrolled. All of the enrolled patients have an indication for
tissue collection (by transthoracic CT/US- guided biopsy, E(B)US,
mediastinoscopy or thoracoscopic guided biopsy).

A participating patient will not benefit from this study. However the results
of this study may benefit the diagnostic procedure of future intra thoracic
(mesothelioma) diagnostics and may improve quality of life of future patients,
by lowering the number of biopsies. The procedure of needle based CLE combined
with endosonographic- and transthoracic- tissue biopsy have proved to be safe
and provides real time information on a microscopic level regarding tissue
architecture3,4,7,16. There is little burden related to study participation:
during a conventional biopsy procedure (e.g. endosconographic-, transthoracic-
or thoracoscopic biopsy), optical CLE with the use of a light beam will be
performed by fitting the CLE probe through the biopsy needle and bringing it in
perpendicular contact with the tissue. This is followed by conventional biopsy
of the tissue (routine work up) at the same site as the CLE measurements,
without the need for additional biopsies for research purposes. Estimated
prolonged procedure time due to imaging is 5 (for transthoracic approaches,
under local anesthesia) to 10 minutes (for EUS and thoracoscopy approaches,
with propofol-sedation or general anesthesia). Adverse events are not expected,
based on our own CLE experience in patients with interstitial lung diseases
(Clintrial.gov identifier NCT02689102, NL54612-018-15), lung cancer and
sarcoidosis (Clintrial.gov identifier)(Clinicaltrial.gov identifier NCT
NCT02689050, protocol nr NL54612-018-15), and the data of previous studies
where CT-guided transthoracic biopsies combined with CLE was reported to be
safe, easy to perform and little time-consuming, without adverse events related
to CLE. In conclusion, to our opinion the burden and risks associated with the
additional optical technique measurements are neglectible.