Medical policy: Confocal Laser Endomicroscopy

Policy number: MP 2.093

Effective date: 2/1/2026

Policy

Use of confocal laser endomicroscopy is considered investigational. There is insufficient evidence to support a general conclusion concerning the health outcomes or benefits associated with this procedure.

Cross-reference:
MP 1.118 Endoscopic radiofrequency ablation or cryoablation for Barrett's esophagus

Product variations

This policy is only applicable to certain programs and products administered by Capital Blue Cross and subject to benefit variations. Please see additional information below.

FEP PPO - Refer to FEP Medical Policy Manual.

Description/Background

Confocal laser endomicroscopy (CLE), also known as confocal fluorescent endomicroscopy and optical endomicroscopy, allows in vivo microscopic imaging of the mucosal epithelium during endoscopy. The process uses light from a low-power laser to illuminate tissue and, subsequently, the same lens detects light reflected from the tissue through a pinhole. The term confocal refers to having both illumination and collection systems in the same focal plane. Light reflected and scattered at other geometric angles that is not reflected through the pinhole is excluded from detection, which dramatically increases the special resolution of CLE images.

To date, 2 CLE systems have been cleared by the U.S. Food and Drug Administration. One is an endoscope-based system in which a confocal probe is incorporated onto the tip of a conventional endoscope. The other is a probe-based system; the probe is placed through the biopsy channel of a conventional endoscope. The depth of view is up to 250 µm with the endoscopic system and about 120 µm with the probe-based system. A limited area can be examined; no more than 700 µm in the endoscopic-based system and less with the probe-based system. As pointed out in systemic reviews, the limited viewing area emphasizes the need for careful conventional endoscopy to target the areas for evaluation. Both CLE systems are optimized using a contrast agent. The most widely used agent is intravenous fluorescein, which is FDA-approved for ophthalmologic imaging of blood vessels when used with a laser scanning ophthalmoscope.

Unlike techniques such as chromoendoscopy which are primarily intended to improve the sensitivity of colonoscopy, CLE is unique in that it is designed to immediately characterize the cellular structure of lesions. CLE can thus potentially be used to make a diagnosis of polyp histology, particularly in association with screening or surveillance colonoscopy, which could allow for small hyperplastic lesions to be left in place rather than removed and sent for histologic evaluation. Using CLE would reduce risks associated with biopsy and reduce the number of biopsies and histologic evaluations.

Another potential application of CLE technology is targeting areas for biopsy in individuals with Barrett esophagus (BE) undergoing surveillance endoscopy. CLE would be proposed as an alternative to the current standard approach, recommended by the American Gastroenterological Association, which is that individuals with Barrett esophagus who do not have dysplasia undergo endoscopic surveillance every 3 to 5 years. AGA has further recommended that random 4-quadrant biopsies every 2 cm be taken with white-light endoscopy in individuals without known dysplasia.

Other potential uses of CLE under investigation include better diagnosis and differentiation of conditions such as gastric metaplasia, lung cancer, and bladder cancer.

As noted, limitations of CLE systems include a limited viewing area and depth of view. Another issue is standardization of systems for classifying lesions viewed with CLE devices. Although there is not currently an internationally accepted classification system for colorectal lesions, 2 systems have been developed that have been used in a number of studies conducted in different countries. These are the Mainz criteria for endoscopy-based CLE devices and the Miami classification system for probe-based CLE devices. Lesion classification systems are less developed for non–gastrointestinal lesions viewed by CLE devices, e.g., those in the lung or bladder. Another challenge is the learning curve for obtaining high-quality images and classifying lesions. Several recent studies, however, have found that the ability to acquire high-quality images and interpret them accurately can be learned relatively quickly; these studies were specific to colorectal applications of CLE.

Regulatory status

Two CLE devices have been cleared for marketing by the FDA through the 510(k) process.

Cellvizio^® (Mauna Kea Technologies) is a confocal microscopy device with a fiber optic probe (i.e., a probe-based CLE system). The device consists of a laser scanning unit, proprietary software, a flat-panel display, and miniaturized fiber optic probes. The F-600 system, cleared by the FDA in 2006, can be used with any standard endoscope with a working channel of at least 2.8 mm. According to the FDA, the device is intended for imaging the internal microstructure of tissues in the anatomic tract (gastrointestinal or respiratory) that are accessed by an endoscope. The 100 series version of the system (F400-v2) was cleared by the FDA in 2015 for imaging the internal microstructure of tissues and for visualization of body cavities, organs, and canals during endoscopic and laparoscopic surgery, and has been approved for use with several miniprobes for specific indications. Confocal Miniprobes™ approved for use with the Cellvizio 100 series that are particularly relevant to this review include the GastroFlex™ and ColoFlex™ (for imaging of anatomical tracts, ie, gastrointestinal systems, accessed by an endoscope or endoscopic accessories), and the CranioFlex™ (for visualization within the central nervous system during cranial diagnostic and therapeutic procedures such as tumor biopsy and resection). In 2020, the Cellvizio 100 series system received extended FDA approval to allow for use of fluorescein sodium as a contrast agent for visualization of blood flow for all of its approved indications. Later in 2020, the Cellvizio I.V.E. system with Confocal Miniprobes was approved by the FDA as a newer version of the previously approved 100 series system, designed to reduce the system footprint and improve device usability. The 2 devices are otherwise equivalent and are approved for the same indications. In 2022, the Cellvizio 100 series system F800 model received extended FDA approval to allow for use of indocyanine green (ICG) and pafolacianine as contrast agents. Intravenous administration of ICG is used to perform fluorescence angiography and interstitial administration of ICG is used to perform fluorescence imaging and visualization of the lymphatic system. Intravenous administration of pafolacianine is used to perform fluorescence imaging of tissues. FDA product codes: GCJ, GWG, OWN.

Rationale

Summary of evidence

For individuals who have suspected or known colorectal lesions who receive confocal laser endomicroscopy (CLE) as an adjunct to colonoscopy, the evidence includes multiple diagnostic accuracy studies. Relevant outcomes are overall survival (OS), disease-specific survival, test validity, and resource utilization. In 3 published systematic reviews, pooled estimates of the overall sensitivity of CLE ranged from 81% to 94%, and pooled estimates of the specificity ranged from 88% to 95%. It is uncertain whether the accuracy is sufficiently high to replace biopsy/polypectomy and histopathologic analysis. Moreover, issues remain concerning the use of this technology in clinical practice (e.g., the learning curve, interpretation of lesions). The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have Barrett esophagus (BE) who are undergoing surveillance and receive CLE with targeted biopsy, the evidence includes several randomized-controlled trials (RCTs) and meta-analyses. Relevant outcomes are OS, disease-specific survival, test validity, and resource utilization. Evidence from RCTs has suggested that CLE has similar or higher sensitivity than standard endoscopy for identifying areas of dysplasia. However, a 2014 meta- analysis found that the pooled sensitivity, specificity, and negative predictive value (NPV) of available studies were not sufficiently high to replace the standard surveillance protocol. In a 2022 meta-analysis, the absolute increase in neoplasia detection using CLE compared with the Seattle protocol randomized biopsies was 5%. Additionally, dysplasia prevalence was 4% with Seattle protocol randomized biopsies and 9% with CLE. National guidelines continue to recommend 4-quadrant random biopsies for patients with BE undergoing surveillance. One RCT, which compared high-definition white-light endoscopy with high-definition white-light endoscopy plus CLE, was stopped early because an interim analysis did not find a between-group difference in outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have gastrointestinal lesions and have had endoscopic treatment who receive CLE to assess the adequacy of endoscopic treatment, the evidence includes a systematic review that includes a single RCT and 2 prospective, nonrandomized studies. Relevant outcomes are OS, disease-specific survival, test validity, and resource utilization. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have a suspicion of a condition diagnosed by identification and biopsy of lesions (e.g., lung, bladder, or gastric cancer) who receive CLE, the evidence mainly consists of a small number of diagnostic accuracy studies. Relevant outcomes are OS, disease-specific survival, test validity, and resource utilization. There is limited evidence on the diagnostic accuracy of CLE for these other indications. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Definitions

N/A

Disclaimer

Capital Blue Cross’ medical policies are used to determine coverage for specific medical technologies, procedures, equipment, and services. These medical policies do not constitute medical advice and are subject to change as required by law or applicable clinical evidence from independent treatment guidelines. Treating providers are solely responsible for medical advice and treatment of members. These polices are not a guarantee of coverage or payment. Payment of claims is subject to a determination regarding the member’s benefit program and eligibility on the date of service, and a determination that the services are medically necessary and appropriate. Final processing of a claim is based upon the terms of contract that applies to the members’ benefit program, including benefit limitations and exclusions. If a provider or a member has a question concerning this medical policy, please contact Capital Blue Cross’ Provider Services or Member Services.

Coding information

Note: This list of codes may not be all-inclusive, and codes are subject to change at any time. The identification of a code in this section does not denote coverage as coverage is determined by the terms of member benefit information. In addition, not all covered services are eligible for separate reimbursement.

Investigational, therefore not covered:

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