Latest Review Date: November 2024

Category: Surgery                                                                 

POLICY:

The use of confocal laser endomicroscopy is considered investigational.

DESCRIPTION OF PROCEDURE OR SERVICE:

Confocal laser endomicroscopy (CLE), also known as confocal fluorescent endomicroscopy and optical endomicroscopy, allows in vivo microscopic imaging of cells during endoscopy. Confocal laser endomicroscopy CLE is proposed for a variety of purposes, especially as a real-time alternative to biopsy/polypectomy and histopathologic analysis during colonoscopy and for targeting areas to undergo biopsy in individuals with inflammatory bowel disease or Barrett esophagus.

The process of CLE involves light from a low-power laser illuminates 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, two types of CLE systems have been cleared by the U.S. Food and Drug Administration (FDA). 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 systematic 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 (see Medical Policy # 494- Chromoendoscopy as an Adjunct to Colonoscopy), which are primarily intended to improve the sensitivity of colonoscopy, CLE is unique in that it is designed to characterize the cellular structure of lesions immediately. Confocal laser endomicroscopy 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 overlooked 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 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. The American Gastroenterological Association 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 the standardization of systems for classifying lesions viewed with CLE devices. Although there is not currently an internationally accepted classification system for colorectal lesions, two systems have been developed that have been used in a number of studies conducted in different countries. These include 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 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.

KEY POINTS:

The most recent literature review was updated through October 7, 2024.   

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 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 (eg, 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 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 theSeattle protocol randomized biopsies was 5%. Additionally, dysplasia prevalence was 4% with Seattle protocol randomizedbiopsies 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 (eg , 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.

Practice Guidelines and Position Statements

American Society for Gastrointestinal Endoscopy

The American Society for Gastrointestinal Endoscopy (2006; reaffirmed in 2011) published guidelines on the role of endoscopy in the surveillance of premalignant conditions of the upper gastrointestinal (GI) tract. Regarding the use of confocal endoscopy as an adjunct to white-light endoscopy, the guidelines stated that this technique is “still in development.”

In 2019, the ASGE published a guideline on screening and surveillance of Barrett esophagus (BE) which recommends against routine use of confocal laser endomicroscopy (CLE) compared with white-light endoscopy with Seattle protocol biopsy sampling in patients with BE undergoing surveillance. An older guideline from the Society (2012) on the role of endoscopy in BE and other premalignant conditions of the esophagus stated the following:

“Adjuncts to white-light endoscopy used to improve the sensitivity for the detection of BE and dysplastic BE include chromoendoscopy, electrical enhanced imaging, magnification, and confocal endoscopy.”

In 2014, the ASGE published a technology status evaluation on CLE. It concluded that CLE is an emerging technology with the potential to improve patient care. However, before it can be widely accepted, further studies are needed in the following areas:

1. “[T]he applicability and practicality of CLE, especially in community settings…...Although current studies of CLE seem promising, these have primarily been in academic centers, and their generalizability in nonacademic practices is unknown."
2. The “learning curve of CLE image interpretation, use of CLE devices, and additional time needed to perform the procedure….”
3. The clinical efficacy of the technology … compared with other available advanced imaging technologies….”
4. Improvements in CLE imaging and image interpretation….”

The ASGE published guidelines on the role of endoscopy in benign pancreatic disease in 2015 and stated that "confocal endomicroscopy is an emerging technology that may prove useful for the evaluation of indeterminate pancreatic strictures." Similarly, in the ASGE's 2016 guidelines on the role of endoscopy in the diagnosis and treatment of cystic pancreatic neoplasms, they acknowledged that CLE was an emerging technique for pancreatic lesion evaluation, but made no formal recommendations regarding its use.

American Gastroenterological Association

In 2011, the American Gastroenterological Association (AGA) published a position statement on the management of BE. The statement included the following recommendations on endoscopic surveillance of BE (see Table 1).

Table 1. Recommendations on Endoscopic Surveillance of Barrett Esophagus

LOR: level of recommendation; QOE: quality of evidence.

In 2016, the AGA published a clinical practice update expert review on the diagnosis and management of low-grade dysplasia in BE. Regarding the use of other advanced endoscopic imaging techniques, the guideline stated that the use of confocal laser endomicroscopy "cannot be recommended in the routine clinical management" of patients undergoing surveillance.

In 2022, the AGA published a clinical practice update on new technology for surveillance and screening in BE. The article makes the following best practice advice statement relevant to screening and surveillance for BE:

• "Screening and surveillance endoscopic examination should be performed using high-definition white light endoscopy and virtual chromoendoscopy, with endoscopists spending adequate time inspecting the Barrett’s segment."
• "Advanced imaging technologies such as endomicroscopy may be used as adjunctive techniques to identify dysplasia."

While the article did summarize data in support of innovative screening technologies such as CLE, the panelists noted that: "the use of these techniques was not required for a high-quality exam and the data to date did not support its routine use." However, the panelists also noted that "these technologies were promising and carried potential benefits in select cases and currently might be best utilized in expert centers."

U.S. Preventive Services Task Force Recommendations

The U.S. Preventive Services Task Force recommendations on colorectal cancer screening do not mention CLE.

KEY WORDS:

Confocal laser endomicroscopy, confocal fluorescent endomicroscopy, Optical endomicroscopy, Pentax Confocal Laser System, Cellvizio, CLE, CranioFlex Confocal Miniprobe

APPROVED BY GOVERNING BODIES:

Two confocal laser endomicroscopy (CLE) devices have been cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process.

Cellvizio® (Mauna Kea Technologies) is a confocal microscopy device with a fiber optic probe (ie, 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.

Confocal Video Colonoscope (Pentax Medical) is an endoscopy-based CLE system. The EC-38 70 CILK system, cleared by the FDA in 2004, is used with a Pentax Video Processor and with a Pentax Confocal Laser System. According to the FDA, the device is intended to provide optical and microscopic visualization of and therapeutic access to the lower gastrointestinal tract. FDA product code: GCJ/FDF (endoscope and accessories). This device is no longer commercially available from the manufacturer.

Table 2. Endomicroscopy Devices Cleared by the U.S. Food and Drug Administration

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits. Group-specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply.

FEP:  Special benefit consideration may apply. Refer to member’s benefit plan. 

CURRENT CODING: 

CPT Codes:

*NOTE: Code 88375 cannot be reported in conjunction with codes 43206, 43252, 0397T

REFERENCES:

1. American Society for Gastrointestinal Endoscopy Technology Committee. Confocal laser endomicroscopy. Available online at: www.asge.org/uploadedFiles/Publications_and_Products/Practice_Guidelines/confocal.pdf.

2. American Society for Gastrointestinal Endoscopy. The role of endoscopy in the surveillance of premalignant conditions of the upper GI tract. www.guideline.gov. 
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33. Liem EIML, Freund JE, Savci-Heijink CD, et al. Validation of Confocal Laser Endomicroscopy Features of Bladder Cancer:The Next Step Towards Real-time Histologic Grading. Eur Urol Focus. Jan 15 2020; 6(1): 81-87.
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36. Liu J, Li M, Li Z, et al. Learning curve and interobserver agreement of confocal laser endomicroscopy for detecting precancerous or early-stage esophageal squamous cancer. PLoS One. 2014; 9(6): e99089.
37. Liu JJ, Droller MJ, Liao JC. New optical imaging technologies for bladder cancer: considerations and perspectives. J Urol 2012; 188(2):361-8.
38. Liu T, Zheng H, Gong W, et al. The accuracy of confocal laser endomicroscopy, narrow band imaging, and chromoendoscopy for the detection of atrophic gastritis. J Clin Gastroenterol. May-Jun 2015; 49(5):379-386.
39. Martinek J, Kollar M, Krajciova J, et al. Confocal laser endomicroscopy in diagnosing indeterminate biliary strictures and pancreatic lesions a prospective pilot study. Rozhl Chir. 2020; 99(6): 258-265.
40. Mi J, Han X, Wang R, et al. Diagnostic accuracy of probe-based confocal laser endomicroscopy and tissue sampling by endoscopic retrograde cholangiopancreatography in indeterminate biliary strictures: a meta-analysis. Sci Rep. May 04 2022; 12(1): 7257.
41. Moore C, Mehta V, Ma X, et al. Interobserver agreement of confocal laser endomicroscopy for detection of head and neck neoplasia. Laryngoscope. Mar 2016;126(3):632-637.
42. Muthusamy VR, Wani S, Gyawali CP, et al. AGA Clinical Practice Update on New Technology and Innovation forSurveillance and Screening in Barrett's Esophagus: Expert Review. Clin Gastroenterol Hepatol. Dec 2022; 20(12): 2696-2706.e1.
43. Muthusamy VR, Chandrasekhara V, Acosta RD, et al. The role of endoscopy in the diagnosis and treatment of cysticpancreatic neoplasms. Gastrointest Endosc. Jul 2016; 84(1): 1-9.
44. Nakaoka K, Hashimoto S, Kawabe N, et al. Probe-based confocal laser endomicroscopy for the diagnosis of pancreatic ductal structures. J Gastroenterol Hepatol. Jan 2021; 36(1): 118-124.
45. Napoleon B, Lemaistre AI, Pujol B, et al. In vivo characterization of pancreatic cystic lesions by needle-based confocal laser endomicroscopy (nCLE): proposition of a comprehensive nCLE classification confirmed by an external retrospective evaluation. Surg Endosc. Oct 1 2015.
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47. Nathan CA, Kaskas NM, Ma X, et al. Confocal Laser Endomicroscopy in the Detection of Head and Neck Precancerous Lesions. Otolaryngol Head Neck Surg. Jul 2014; 151 (1): 73-80.
48. Neumann H, Vieth M, Atreya R, et al. Prospective evaluation of the learning curve of confocal laser endomicroscopy inpatients with IBD. Histol Histopathol. Jul 2011; 26(7): 867-72.
49. Park CH, Kim H, Jo JH et al. Role of probe-based confocal laser endomicroscopy-targeted biopsy in the molecular and histopathological study of gastric cancer. J. Gastroenterol. Hepatol., Jan 2019;34(1): 84-91. 
50. Qian W, Bai T, Wang H, et al. Meta-analysis of confocal laser endomicroscopy for the diagnosis of gastric neoplasia and adenocarcinoma. J Dig Dis. Jun 2016; 17(6):366-376.
51. Qumseya B, Sultan S, Bain P, et al. ASGE guideline on screening and surveillance of Barrett's esophagus. Gastrointest Endosc. Sep 2019; 90(3): 335-359.e2.
52. Richardson C, Colavita P, Dunst C, et al. Real-time diagnosis of Barrett's esophagus: a prospective, multicenter study comparing confocal laser endomicroscopy with conventional histology for the identification of intestinal metaplasia in new users. Surg Endosc. May 2019; 33(5): 1585-1591.
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POLICY HISTORY:

Medical Policy Panel, January 2013

Medical Policy Group, January 2013 (3):  New policy

Medical Policy Administration Committee, February 2013

Available for comment February 21 through April 7, 2013

Medical Policy Group, December 2013: 2014 Coding Update – Code #43206 removed ‘rigid’ & added ‘transoral’: Code 43252 – removed ‘Upper gastrointestinal endoscopy including esophagus, stomach, and either the duodenum and/or jejunum as appropriate;’; added Esophagogastroduodenoscopy, flexible, transoral:– Effective 1/1/14

Medical Policy Panel, January 2014

Medical Policy Group, January 2014 (3):  Updates to Key Points and References; no change in policy statement

Medical Policy Panel, January 2015

Medical Policy Group, January 2015 (4): Updates to Key Points and References; no change in policy statement. Added CPT code 88375 to current Coding section

Medical Policy Group, November 2015: 2016 Annual Coding Update. Added CPT code 0397T to Current coding.

Medical Policy Panel, November 2015

Medical Policy Group, December 2015 (4): Updates to Key Points and References. No change to policy statement.

Medical Policy Panel, November 2016

Medical Policy Group, January 2017 (4): Updates to Description, Key Points, Approved by Governing Bodies, Key Words & References; No change to policy statement.

Medical Policy Panel, November 2017

Medical Policy Group, December 2017 (4):  Updates to Key Points and References. No change to policy statement.

Medical Policy Panel, November 2018

Medical Policy Group, December 2018 (4): Updates to Key Points, Approved by Governing Bodies, and References. Key Word added: CranioFlex™ Confocal Miniprobe. No changes in policy statement.

Medical Policy Panel, November 2019

Medical Policy Group, December 2019 (5): Updates to Description, Key Points, Approved by Governing Bodies, Practice Guidelines and Position Statements, and References. No changes to Policy Statement.

Medical Policy Panel, November 2020

Medical Policy Group, November 2020 (4): Updates to Description, Key Points, Approved by Governing Bodies, and References.  No change to policy statement.

Medical Policy Panel, November 2021

Medical Policy Group, November 2021 (5): Updates to Description, Key Points, Practice Guidelines and Position Statements, and References. Policy Statement updated to remove “not medically necessary,” no change to policy intent.

Medical Policy Panel, November 2022

Medical Policy Group, November 2022 (5): Updates to Description, Key Points, Approved by Governing Bodies, Practice Guidelines and Position Statements, and References. No change to Policy Statement.

Medical Policy Panel, November 2023

Medical Policy Group, November 2023 (11): Updates to Key Points, Current Coding, Benefit Application, and References. Added 0397T to the note in the Current Coding section. No change to Policy Statement.

Medical Policy Panel, November 2024

Medical Policy Group, November 2024 (11): Updates to Description to replace the word “patients” with the word “individuals”, and Key Points. No change to policy intent.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.