Description of Procedure or Service

Description

The esophagus is a long tube that serves to connect the mouth to the stomach. Although the esophagus is primarily a connecting organ, it experiences significant chemical and mechanical trauma. The esophagus has mechanisms and structures to withstand this damage, but molecular injury is common. Both serological and genetic markers have been suggested to identify, diagnose, or assess risk in the esophagus.

Eosinophilic esophagitis (EoE) is one such condition, as its nonspecific symptoms (pain, issues swallowing, vomiting, and so on) may be accompanied by inflammatory markers in the esophagus. Similarly, esophageal cancer is characterized by several nonspecific symptoms, while a predecessor condition, Barrett’s esophagus (BE), may have no clinical symptoms at all.

For guidance concerning Tumor Mutational Burden Testing (TMB) and/or Microsatellite instability (MSI) analysis please refer to the AHS-M2178 Microsatellite Instability and Tumor Mutational Burden Testing policy.

Related Policies

Genetic Testing for Germline Variants of the RET Proto-Oncogene AHS-M2078

Microsatellite Instability and Tumor Mutational Burden Testing AHS-M2178

***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician.

Policy

BCBSNC will provide coverage for esophageal pathology testing when it is determined to be medically necessary because the medical criteria and guidelines shown below are met.

Benefits Application

This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore, member benefit language should be reviewed before applying the terms of this medical policy. 

When Esophageal Pathology Testing is covered

1. For individuals who have been newly diagnosed with cancer of the esophagus or esophagogastric junction (EGJ), reimbursement is allowed for mismatch repair (MMR) analysis by immunohistochemistry (IHC). 
2. For individuals who have been diagnosed with locally advanced, recurrent, or metastatic cancer of the esophagus or EGJ and for whom PD-1 inhibitor treatment is being considered, reimbursement is allowed for tumor analysis of PD-L1 expression by IHC. 
3. For individuals who have been diagnosed with inoperable locally advanced, recurrent, or metastatic adenocarcinoma of the esophagus or EGJ and for whom trastuzumab or an approved biologic or biosimilar drug to trastuzumab is being considered for first-line therapy, reimbursement is allowed for HER2 overexpression testing by IHC, fluorescence in situ hybridization (FISH), or other in situ hybridization (ISH) methodology.
4. For individuals diagnosed with unresectable locally advanced, recurrent, or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or EGJ and for whom one of the following drugs is being considered as a second-line therapy, the corresponding gene testing is considered medically necessary: 
   1. Entrectinib, larotrectinib or repotrectinib: NTRK1/2/3 gene fusion.
   2. Selpercatinib: RET gene fusion.
   3. Dabrafenib or trametinib: BRAF V600E mutation.

When Esophageal Pathology Testing is not covered

1. The use of genetic testing, (e.g., molecular panel tests, gene expression profiling) to diagnose or monitor an individual with eosinophilic esophagitis (EoE) or to assess the risk of an individual developing EoE is considered not medically necessary. 
2. Reimbursement is not allowed for wide-area transepithelial sampling (WATS) for the diagnosis and evaluation of Barrett’s esophagus, low-grade esophageal dysplasia, or high-grade esophageal dysplasia. 
3. Reimbursement is not allowed for assessing for risk of Barrett’s esophagus and/or esophageal, including esophagogastric junction, cancer using a molecular classifier (e.g., TissueCypher^® Barrett's Esophagus Assay).
4. Epigenetic analysis for the likelihood for Barrett’s esophagus, esophageal, or esophagogastric junction cancer (e.g., methylation analysis, EsoGuard) is considered not medically necessary. 
5. To diagnose, assess, or monitor eosinophilic esophagitis (EoE), the Esophageal String Test is considered investigational. 
6. For esophageal and esophagogastric junction cancers, cell-free tumor DNA/circulating tumor DNA (cfDNA/ctDNA) testing is considered not medically necessary. 

Note: For two or more gene tests being run on the same platform, please refer to AHS-R2162 Laboratory Procedures Medical Policy.

Policy Guidelines

Background

The esophagus is a long tube that connects the mouth to the stomach. Its primary function is to transport food from the mouth to the stomach. However, this organ is often exposed to difficult conditions, from abrasive food to the acidic conditions of the stomach. Although mechanisms are in place to protect against injury (namely the tough squamous cells), it is common to see injury or disease in the esophagus.

Many serological and genetic markers have been proposed as tools to assist in evaluation of esophageal pathology. Eosinophilic esophagitis (EoE), Barrett’s esophagus (BE), and esophageal cancer are typically diagnosed with histological analysis from endoscopic biopsy, but biopsies frequently require careful consideration and resources to perform properly. For these reasons, serum and genetic markers have been suggested as noninvasive markers for esophageal pathologies.

Eosinophilic Esophagitis (EoE)

Eosinophilic esophagitis (EoE) is marked by the presence of eosinophils in the esophagus. Eosinophils are typically associated with mitigating inflammation but are not normally found in the esophagus. EoE is represented by a broad set of clinical symptoms, such as difficulty swallowing, chest, or abdominal pain, and feeding dysfunction. Diagnosis is established through endoscopy with biopsies to confirm eosinophilia. The current diagnostic criteria set the cutoff for eosinophilia at ≥15 eosinophils per high-power field, (60 eosinophils per mm²) although this figure has been heavily discussed.

Proprietary Testing- EoE

Laboratory tests have been suggested as a noninvasive adjunct for EoE. Serum IgE will be elevated in up to 60% of EoE patients, as allergies have a strong association with EoE. Many other markers, such as eotaxin-3, major basic protein-1, tryptase, chemokines, and serum eosinophil count, have all been suggested to assist in evaluation of EoE. Immune system factors may also contribute to pathology. Since eosinophils are not normally found in the esophagus, their presence in the esophagus may suggest an underlying issue with the immune system. Various interleukins, mast cells, and T cells have all been proposed as contributing to pathogenesis, but the exact pathway and mechanisms are not completely understood. Genetic features have also been used for EoE evaluation. Twin studies and family histories have indicated a role for genetics in EoE. Several genes have also been identified as potential risk factors, such as CAPN14 (an interleukin-13 regulator), TSLP (a basophil regulator), and CCL26 (promotes eosinophil movement into esophagus).

Wen, et al. (2013) developed a diagnostic gene expression panel (“EDP”) for EoE. The authors identified candidate genes using two cohorts of EoE and control patients, then validated these genes with a separate cohort of 194 patients (91 active EoE, 57 control, 34 ambiguous, 12 reflux). The panel was found to identify EoE patients at 96% sensitivity and 98% specificity. The authors also noted that the panel could separate patients in remission from unaffected patients.

Shoda, et al. (2018) used an “EoE Diagnostic Panel” (EDP) to further classify EoE cases by histologic, endoscopic, and molecular features. The EDP consisted of 95 esophageal transcripts purported to identify EoE among both unaffected patients and patients with other conditions. A total of 185 biopsies were studied. The authors identified three clear subtypes of EoE; subtype 1 with a normal-appearing esophagus and mild molecular changes, subtype 2 with an inflammatory and steroid-responsive phenotype, and subtype 3 with a “narrow-caliber” esophagus and severe molecular alterations. These findings were replicated in a 100-biopsy sample.

Tests are commercially available for EoE. Noninvasive tests (as an alternative to endoscopy) have been recently popular. The Esophageal String Test is one such alternative. The patient swallows a gelatin-coated capsule with a string wrapped inside. Once the capsule is in the patient’s stomach, the gelatin dissolves, allowing the capsule to pass through. The string itself is used to collect samples from the patient’s esophagus and is easily removed from the patient. From there, the sample is analyzed for several biomarkers (major basic protein-1, eotaxins 2 and 3, and so on) to provide a probability% (a trademarked “EoEscore”) of esophageal inflammation.

Barrett’s Esophagus (BE)

Barrett’s esophagus (BE) is a condition in which the normal squamous tissue lining the esophagus is replaced by metaplastic columnar epithelium. This new epithelium contains gastric features and is typically caused by chronic gastroesophageal reflux disease (GERD). This condition predisposes to esophageal cancer. When noxious substances (gastric acid, bile, et al) are exposed to the squamous esophageal tissue, the damage is usually repaired through regeneration of these squamous cells. In BE cases, this damage is repaired not through creation of new squamous cells, but through metaplastic columnar cells. The exact reason for this is unknown. Although these metaplastic cells are more resistant to reflux-based damage than the normal squamous cells, these cells frequently show the oxidative DNA damage that is typical of cancer. Mutations in the p53 tumor suppressor gene appear to be the catalyst for cancers, as acquisition of this mutation in conjunction with the replication of the genome is conducive to carcinogenesis.

Vollmer (2019) performed a review assessing incidence of adenocarcinoma detected during surveillance of BE. The author identified 55 studies encompassing 61371 total patients. Of the 61371 total patients, 1106 developed adenocarcinoma. Overall, the author found that the model created from the studies “predicted the per-person probability of developing cancer in five years of complete follow-up is approximately 0.0012.” Variables affecting this probability included mean time of follow-up, definition of Barrett metaplasia, and fraction of patients followed up for at least five years.

Proprietary Testing- BE

Proprietary tests are commercially available for assessment of BE, usually to evaluate risk (BE progression to cancer, risk of BE itself, and such). For example, TissueCypher proposes to predict likelihood of progression from BE to esophageal cancer. The test measures nine protein biomarkers that represent morphological and cellular changes (p53, p16, AMACR, CD68, COX2, HER2, K20, HIF1-alpha, CD45RO). These biomarkers are quantified and converted to a risk score (1-10) and probability of progression.

Esoguard, by Lucid Diagnostics, is an esophageal DNA test which analyzes 31 methylated biomarkers in the diagnosis of non-dysplastic Barrett’s esophagus and adenocarcinoma. The assay uses next generation sequencing to examine individual DNA molecules for the presence or absence of cytosine methylation with a 90% specificity and 90% sensitivity.

Finally, a proprietary imaging system, WATS^3D, is commercially available. This imaging system samples from a wider area, as opposed to only taking focal samples in a traditional biopsy. This technology also provides a 3-dimensional image of the sampled area. This technology purports to provide more precise sampling than the traditional 4-quadrant biopsies, claiming an increased detection rate of BE and other dysplasias. “WATS^3D increased the overall detection of esophageal dysplasia by 242% and Barrett’s by 153%.”

Esophageal Cancer

Esophageal cancers are largely divided into two groups: squamous cell carcinomas (SCCs) and adenocarcinomas (EAC). SCCs usually begin in the middle of the esophagus, whereas EACs often originate near the gastroesophageal junction. Both share several risk factors, such as smoking. Due to the numerous environmental risk factors for both types of cancer, it is difficult to ascertain the true impact of genetic factors. These cancers are primarily diagnosed through histologic examination, usually obtained through endoscopy.

Advancements have been in the molecular characterization of both types of cancer. TP53 mutations are the most common mutation seen in both types of cancer. Other frequently mutated genes in adenocarcinoma include ELMO1 and DOCK2 (enhance cell motility), ARID1A, SMARCA4 and ARID2 (chromatin remodelers), and SPG20 (traffics growth factor receptors). BE, as the precursor to adenocarcinomas, includes certain similarities in genetic mutations but at a less severe rate. Further, the rate of overlap tended to increase with higher degree of dysplasia.

Squamous cell carcinoma mutations tend to be in genes associated with specific cellular pathways. Genes in ubiquitous pathways, such as EGFR, NOTCH3, and RB, are frequently mutated in SCC. The molecular profile of esophageal SCC tends to align more with other squamous cell cancers (such as head and neck cancers) rather than EAC. Numerous gene expression studies have been performed to further classify molecular subtypes of esophageal cancer. Gene expression profiles may have utility in assessing response to treatment, prognosis, or risk assessment.

Historically, Carcinoembryonic Antigen (CEA) has been used as the serum cancer marker in the diagnosis of esophageal cancer, as CEA levels have been shown to be significantly higher in these patients. The sensitivity (8-70%), specificity (57-100%), and positive likelihood ratio (5.94) of CEA means that patients with EC have a 6-fold higher chance of having higher CEA levels. Other markers include squamous cell cancer antigen (SCC-Ag) and cytokeratin 21-1 fragment (CYFRA21-1). The sensitivity and specificity Cyfra21–1 ranged from 36% to 63% and from 89% to 100%, respectively, with patients having a 12-fold higher chance of having EC. The sensitivity and specificity of SCC-Ag ranged from 13% to 64% and from 91% to 100%, respectively, whereas its PLR was 7.66.

Li, et al. (2019) investigated potential biomarkers for lymph node metastasis for esophageal squamous cell carcinoma. Six studies encompassing 70 patients were included. The authors identified nine biomarkers and four cellular mechanisms that influence lymph node metastasis. From there, they identified three biomarkers with broader influence on prognosis of disease, PTEN, STMN1, and TNFAIP8. The authors suggested that those three biomarkers should be researched further.

Plum, et al. (2019) evaluated HER2 overexpression’s impact on prognosis of esophageal adenocarcinoma (EAC). A total of 428 EAC patients that underwent a “transthoracic thoraco-abdominal esophagectomy” were included. The authors identified 44 patients with HER2 positivity (IHC score 3+ or 2+ with gene amplification). This cohort was found to have a better overall survival (OS, 70.1 months vs 24.6 months), along with better histology, absence of lymphatic metastases, and lower tumor stages. The authors also noted a similarity in results to a large 2012 study.

Frankell, et al. (2019) examined the molecular landscape of esophageal adenocarcinoma (EAC). The authors assessed 551 genomically characterized EACs. A total of 77 driver genes and “21 non-coding driver elements” were identified. The authors also found an average of 4.4 driver events per tumor. A three-way association was found, between hyper-mutation, Wnt signaling, and loss of immune signaling genes. Finally, the authors also identified “sensitizing events” (events causing a tumor to be more susceptible to a therapy) to CD4/6 inhibitors in over half of the EAC cases studied.

Clinical Utility and Validity

Ackerman, et al. (2019) evaluated the ability of the 1-hour Esophageal String Test to distinguish between active eosinophilic esophagitis (EoE), inactive eosinophilic esophagitis, and normal esophagi. A total of 134 patients (62 active EoE, 37 inactive EoE, 35 normal) were included. The authors found that eotaxin 3 measured from both EST samples and the control biopsy extracts to be the best marker for distinguishing active EoE from inactive EoE (by both sensitivity and specificity). Addition of major basic protein 1 (MBP-1) improved sensitivity by 0.039 (0.652 to 0.693) and specificity by 0.014 (0.261 to 0.275) across all patients.

Hao, et al. (2019) performed a cost-effectiveness analysis of an “adenocarcinoma risk prediction multi-biomarker assay” (TissueCypher’s Barrett’s Esophagus Assay). A hypothetical cohort of 10000 patients with BE diagnoses (including non-dysplastic intestinal metaplasia [NBDE], indefinite for dysplasia [IND], and low-grade dysplasia [LGD]) was created. A Markov decision model was used to compare BE management costs between assay use and the standard-of-care (SOC). A surveillance interval of five years was used. Low-risk patients were found to have a 16.6% reduction in endoscopies. High-risk patients were found to have a 58.4% increase in endoscopic treatments (compared to the SOC arm), leading to a death total of 111 for the assay arm compared to 204 in the SOC arm (a 45.6% reduction). Overall, the authors calculated the incremental cost-effectiveness ratio (ICER) to be $52,483/quality-adjusted life-year (QALY), and they found that “the probability of the Assay being cost-effective compared to the SOC was 57.3% at the $100,000/QALY acceptability threshold.”

Eluri, et al. (2018) aimed to validate a genomic panel intended to represent tumor mutational load (TML). Previously, the authors evaluated a panel of ten genomic loci from which a TML score was calculated. This mean TML was found to be significantly higher in 23 BE patients that had progressed to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) as compared to 46 that had not progressed. The area under the curve in this prior study was found to be 0.95 at a mutational load (ML) cutoff of one (on a scale of 1-10). In the present study, 159 subjects were included. Cases had “baseline nondysplastic BE (NDBE) and developed HGD/EAC ≥ 2 years later.” 58 subjects were progressors and 101 were nonprogressors. The authors identified no difference in mean ML in pre-progression tissue in both cohorts (ML = 0.73 ± 0.69 vs. ML = 0.74 ± 0.61). The area under the curve at the cutoff of ML 1 was only 0.50, and the authors concluded that the “utility of the ML to stratify BE patients for risk of progression was not confirmed in this study.”

Trindade, et al. (2019) evaluated tumor mutational load’s ability to “risk-stratify those that may progress from non-dysplastic BE to dysplastic disease. A total of 28 patients were included, and ML levels were compared between those that progressed to dysplasia and those who had not. Eight total patients progressed to dysplasia (6 low-grade, 2 high-grade), and seven of these patients had “some level” of genomic stability detected (ML ≥.5 on a scale of one to 10). Ten of the 20 patients that did not progress to dysplasia had “no” ML level. The authors also noted that at an ML of ≥1.5, the risk of progression to high-grade dysplasia was 33%, with a sensitivity of 100% and specificity of 85%. The authors concluded “that ML may be able to risk-stratify progression to high-grade dysplasia in BE-IND. Larger studies are needed to confirm these findings.”

Moinova, et al. (2018) evaluated the ability of two DNA methylation signatures to detect BE. Methylation signatures of the VIM and CCNA1 loci were evaluated in 173 patients with or without BE. CCNA1 methylation was found to have an area under the curve of 0.95 for distinguishing BE-related dysplasia compared to normal esophagi. When the data for VIM methylation was added, the resulting sensitivity was 95%, and the resulting specificity was 91%. These findings were replicated in a validation cohort of 86 patients, with the combination of methylation markers detecting BE metaplasia at 90.3% sensitivity and 91.7% specificity.

Critchley-Thorne, et al. (2016) validated a pathology panel to predict progression of BE to esophageal cancer. The authors identified 15 potential biomarkers, which were evaluated in both training and validation sets. This “classifier” separated patients into three different risk classes: low, intermediate, and high in the training set of 183. The authors calculated the hazard ratio of intermediate to low risk at 4.19 and high to low at 14.73. In the validation set (n = 183), the concordance index (an estimation of area under the curve) of the 15-factor classifier was 0.772, the best of the amounts tested (3, 6, 9, 12, 15, 17). The authors also noted that this classifier provided independent prognostic information that were out performed predictions based on other clinicopathological factors, such as segment length, age, and p53 overexpression.

Another multicenter study investigated the use of WATS^3D with either random or targeted FB in the detection of esophageal dysplasia (ED). A total of 12,899 patients were enrolled in the study, and WATS^3D detected an additional 213 cases of ED beyond the initial 88 cases identified by FB, representing an increase of 242%. Regarding screening for BE, WATS increased the overall detection by 153% (from 13.1% to 33% of the individuals enrolled). The authors noted that the order of testing (e.g., FB or WATS) did not impact the results. The authors conclude, “In this study, comprised of the largest series of patients evaluated with WATS, adjunctive use of the technique with targeted and random FB markedly improved the detection of both ED and BE. These results underscore the shortcomings of FB in detecting BE-associated neoplasia, which can potentially impact the management and clinical outcomes of these patients.”

A study into the cost-effectiveness of WATS^3D testing as an adjunct to the standard-of-care forceps biopsy (FB) used a reference case of a 60-year-old individual with GERD to see the number of screens needed to avert one cancer and one cancer-related death as well as to calculate the QALYs as measured in 2019 U.S. dollars. With this as a reference case, 320 – 337 individuals would need to be screened using WATS^3D to avert one cancer, and 328 – 367 individuals would be required to avert one death. The additional cost associated with WATS^3D was $1219, but an additional 0.017 QALYs were produced, resulting in an ICER of $71395/QALY. The authors concluded that screening for BE in certain GERD patients “is more cost-effective when WATS^3D is used adjunctively to the Seattle protocol than with the Seattle protocol alone.”

One study compared the use of the WATS^3D technology to standard forceps biopsy. A total of 117 individuals with a history of Barrett’s esophagus with dysplasia had both techniques performed. For the biopsy, a four-quadrant biopsy quadrant protocol was performed every 1 – 2 cm. Evaluation of the biopsy and the WATS^3D technique was performed by separate pathologists, blinded to each other’s results. Moreover, “Brush biopsy [WATS^3D] added an additional 16 position cases increasing the yield of dysplasia detection by 42% (95% CI: 20.7 – 72.7). The number needed to test (NNT) to detect one additional case of dysplasia was 9.4 (95% CI: 6.4 – 17.7).” The authors of the study noted that no statistical difference was evident between medical centers, the type of forceps used, or between sampling every 1 cm versus every 2 cm. They conclude, “These data suggest that computer-assisted brush biopsy is a useful adjunct to standard endoscopic surveillance regimens for the identification of dysplasia in Barrett’s esophagus.”

Another multicenter prospective trial of 4203 patients studied the use of WATS^3D as an adjunct to four-quadrant random forceps biopsy in detecting Barrett’s esophagus and esophageal dysplasia. FB alone detected 594 cases of BE, and the addition of WATS^3D detected an additional 493 cases, an increase of 83%. Likewise, WATS^3D detected an increase of 88.5% of low-grade dysplasia (LGD). The authors concluded that “Adjunctive use of WATS to FB significantly improves the detection of both BE and ED. Sampling effort, an inherent limitation associated with screening and surveillance, can be improved with WATS allowing better informed decisions to be made about the management and subsequent treatment of these patients” These findings support the earlier study by Johanson and colleagues. In their study of 1266 patients being screened for BE and ED, they noted an overall increase of 39.8% in the detection of BE when WATS^3D (brush biopsy or BB) was used as an adjunct to FB. They also report that the number of patients needed to test to obtain a positive BE result was 8.7. Interestingly, specifically for patients with GERD, the addition of WATS^3D resulted in an even higher increase in the detection of BE (by 70.5%).

Vennalaganti, et al. (2018) published a randomized trial at 16 different medical centers (n = 160 patients) compared the order of testing (WATS3D followed by biopsy sampling versus biopsy sampling followed by WATS3D) to detect high-grade dysplasia/esophageal adenocarcinoma (HGD/EAC). The authors also stated secondary aims of determining the amount of additional time required for WATS3D and the ability of each procedure to separately detect neoplasia. The order of the procedures was not statistically relevant. The use of WATS3D as an adjunct to biopsy did result in a 14.4% absolute increase in the number of HGD/EAC cases detected. The authors noted that WATS3D, on average, adds 4.5 minutes to the total procedure time. They conclude that “Results of this multicenter, prospective, randomized trial demonstrate that the use of WATS in a referral BE population increases the detection of HGD/EAC.”

Diehl, et al. (2021) studied the impact of TissueCypher BE assay on clinical decisions in the management of BE patients. TissueCypher was ordered for 60 patients with BE and the impact of the test was assessed. TissueCypher results impacted 55.0 % of management decisions, resulting in either upstaging or downstaging of treatment. The authors note that "In 21.7% of patients, the test upstaged the management approach, resulting in endoscopic eradication therapy or shorter surveillance interval. The test downstaged the management approach in 33.4 % of patients, leading to surveillance rather than EET. In the subset of patients whose management plan was changed, upstaging was associated with a high-risk TissueCypher result, and downstaging was associated with a low-risk result." The authors conclude that TissueCypher will help target EET for high risk patients and reduce unneeded procedures in low-risk patients.

Wechsler, et al. (2021) studied the clinical utility of noninvasive biomarkers to identify EoE in children and predict esophageal eosinophilia. Blood/urine was collected from 183 children and several biomarkers were measured including Absolute eosinophil count (AEC), plasma eosinophil-derived neurotoxin (EDN), eosinophil cationic protein (ECP), major basic protein-1 (MBP-1), galectin-10 (CLC/GAL-10), Eotaxin-2 and Eotaxin-3, and urine osteopontin (OPN) and matrix metalloproteinase-9 (MMP-9). According to the results, all plasma and urine biomarkers were in increased in EoE. A panel that included all the other biomarkers was superior to measuring only AEC alone. AEC, CLC/GAL-10, ECP, and MBP-1 were significantly decreased in patients with esophageal eosinophil counts <15/hpf in response to treatment. AEC combined with MBP-1 best predicted the esophageal eosinophil counts. The authors conclude that eosinophil-associated proteins along with AEC are superior to AEC alone in distinguishing EoE and predicting eosinophil counts.

Guidelines and Recommendations

United European Gastroenterology (UEG), The European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), the European Academy of Allergy and Clinical Immunology (EAACI), and the European Society of Eosinophilic Oesophagitis (EUREOS)

These joint guidelines were published by a task force of 21 physicians and researchers for eosinophilic esophagitis (EoE). In it, they note that noninvasive biomarkers (inflammatory factors, total IgE, chemokines, tryptase, et al) are “not accurate” to diagnose or monitor EoE. They remark that absolute serum eosinophil count fared best in correlating with severity of disease but had a diagnostic accuracy of 0.754. The guidelines state that histology is necessary for monitoring. The String Test was also mentioned as having good preliminary results but required further corroboration.

European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN)

The ESPGHAN also released guidelines on the diagnosis and management of EoE in children. “EoE is defined as a chronic, local inflammatory disease of the esophagus, which may cause symptoms of esophageal dysfunction, and is characterized histologically by predominantly eosinophilic infiltrates in the absence of alternative causes of eosinophilic inflammation.” The ESPGHAN clarifies that “Non-Response to PPI is no longer part of the definition of EoE.” The ESPGHAN lists the following recommendations for diagnosis:

Endoscopy and other invasive tests:

• “ESPGHAN EGID WG recommends using endoscopic findings as supportive evidence when evaluating suspected EoE.
• “ESPGHAN EGID WG recommends that esophageal biopsies should be performed whenever a diagnosis of EoE is considered, regardless of the endoscopic appearance of the esophagus.”
• “ESPGHAN EGID WG recommends upper GI endoscopy with biopsies from the upper and lower levels of the esophagus (at least six, particularly targeting visible lesions) for the diagnosis and follow-up of childhood EoE.” “Practice points: The EoE Endoscopic Reference Score (EREFS) is currently the most valid and reliable endoscopic metric and can be used in conjunction with symptoms and histology as supportive evidence at diagnosis and when assessing response to treatment in pediatric EoE.”
• “ESPGHAN EGID WG recommends against the use of pH/impedance monitoring in the diagnosis of EoE, however, it may be useful in select cases to identify associated gastroesophageal reflux.”

Histology

• “ESPGHAN EGID WG recommends the peak value of 15 eos/HPF as the cut-off value in esophageal biopsy specimens, for the histological diagnosis of EoE in an appropriate clinical context.”
• “ESPGHAN EGID WG recommends the use of a standardized eosinophil density reporting tool.”
• “ESPGHAN EGID WG recommends converting eos/HPF values to either eos/mm2 or to a standardized HPF size (CEGIR HPF) to enable comparison of eosinophil densities examined under different microscopes and for collaborative research or consultation: eos/HPF × 1/(area of microscope HPF in mm2) = eos/mm2.” “Practice points: Isolated lower esophageal eosinophilia may pose a higher diagnostic challenge than upper esophageal involvement.”

Allergy testing

• "ESPGHAN EGID WG recommends against using available allergy tests to predict dietary triggers of EoE.”

Biomarkers and non-endoscopic techniques

• “The ESPGHAN EGID WG recommends against the use of currently available biomarkers as the sole basis for the diagnosis or management of pediatric EoE patients.”

American Gastroenterological Association (AGA) and the Joint Task Force on Allergy-Immunology Practice Parameters (JTF) guideline

Regarding allergy-based testing for the purpose of identifying food triggers in patients with Eosinophilic Esophagitis, the AGA/JTF suggest an allergy-based elimination diet over no treatment. The task force notes that “due to the potential limited accuracy of currently available, allergy-based testing for the identification of specific food triggers, patients may prefer alternative medical or dietary therapies to an exclusively testing-based elimination. An important limitation of the studies available so far “involves the degree of inconsistency due to different testing techniques (e.g., skin-prick testing, serum-specific IgE testing, patch testing, or combinations of these) used in different studies.” Additionally, a “sensitivity analysis failed to show any statistically significant difference between studies that used patch testing and those that did not.”

Updated International Consensus Diagnostic Criteria for Eosinophilic Esophagitis: Proceedings of the AGREE Conference

These newly published international diagnostic criteria primarily include endoscopic findings. Although the guidelines emphasize ruling out other diagnoses (in which biomarkers may be useful), it does not mention any serum or genetic factors for EoE itself.

National Comprehensive Cancer Network (NCCN)

The NCCN notes four syndromes that predispose to an increased risk for esophageal and esophagogastric junction (EGJ) cancers; tylosis with non-epidermolytic palmoplantar keratoderma (PPK) with esophageal cancer (including Howel-Evans syndrome), familial Barrett esophagus (FBE), Bloom Syndrome (BS, BLM gene), and Fanconi Anemia (FA, FANC A-E genes). The RHBDF2 gene has been associated with tylosis (with non-epidermolytic palmoplantar keratosis) for genetic risk assessment.

Though FBE may be associated with “one or more autosomally inherited dominant susceptibility alleles,” no gene has been validated. With regards to next generation sequencing, the NCCN concludes that “when limited tissue is available for testing, or the patient is unable to undergo a traditional biopsy, comprehensive genomic profiling via a validated NGS assay performed in a CLIA-approved environment may be used for the identification of ERBB2 amplification, MSI status, MMR deficiency, TMB, NTRK gene fusions, RET gene fusions, and BRAF v600E mutations. The use of IHC, ISH, or targeted PCR should be considered first, followed by NGS testing as appropriate.”

Under microsatellite instability (MSI) and mismatch repair testing, the NCCN recommends “universal testing for MSI by PCR, or NGS, or MMR by IHC should be performed for all newly diagnosed esophageal and EGJ cancers.”

For squamous cell carcinoma, the NCCN recommends performing universal testing for microsatellite instability (MSI) by PCR/NGS or MMR by IHC in all newly diagnosed patients. Universal testing for PD-L1 is recommended in all newly diagnosed patients. They also note that NGS should be considered.

Liquid biopsy aids in identifying genetic mutations in solid cancers by looking at circulating tumor DNA (ctDNA) in blood and can be used in those with advanced disease who cannot undergo clinical biopsies for disease surveillance and management. Detecting mutations in DNA from esophageal and EGJ carcinomas “can identify targetable alterations or the evolution of clones with altered treatment response profiles.” The NCCN has also stated that “a negative result should be interpreted with caution, as this does not exclude the presence of tumor mutations or amplifications.”

The NCCN notes that “testing for MSI by PCR/NGS or MMR [mismatch repair] by IHC should be considered on locally advanced, recurrent, or metastatic esophageal and EGJ cancers in patients who are candidates for treatment with programmed cell death protein 1 (PD-1) inhibitors.”

The NCCN also identifies several targeted therapeutic agents currently approved by the FDA: trastuzumab, pembrolizumab, nivolumab, entrectinib/larotrectinib, selpercatinib, and dabrafenib/trametinib. Trastuzumab is based on HER2 overexpression (NCCN notes that an approved biologic or biosimilar drug to trastuzumab is also appropriate for use) and pembrolizumab can also be added to the regimen for treating HER2, notwithstanding any contraindications.

Treatment with trastuzumab is based on testing for HER2 expression. Treatment with pembrolizumab or nivolumab is based on “testing for MSI by PCR/NGS or MMR by IHC, PD-L1 expression by IHC, or high TMB by NGS.” Select TRK inhibitors have also been FDA-approved for NTRK gene fusion-positive solid tumors. Additionally, selpercatinib for RET gene fusion-positive tumors and dabrafenib/trametinib for tumors with BRAF V600E mutations.

Genetic biomarkers such as aneuploidy and loss of heterozygosity of p53 have been proposed as useful for identifying increased risk of progression in BE patients, but the NCCN remarks that these biomarkers require “further prospective evaluation as predictors of risk for the development of HGD [high-grade dysplasia] and adenocarcinoma of the esophagus in patients with Barrett esophagus.”

The NCCN notes that wide-area transepithelial sampling (WATS) has been used to detect esophageal carcinomas in BE patients. They state, “the use of wide-area transepithelial sampling with computer-assisted 3-dimensional analysis (WATS3D), a relatively new sampling technique combining an abrasive brush biopsy of the Barrett esophagus mucosa with computer-assisted pathology analysis to highlight abnormal cells, may help increase the detection of esophageal dysplasia in patients with Barrett esophagus.” They go on to cite the 2017 study by Vennalaganti and colleagues that shows a 14.4% increase in the number of additional cases of HGD/esophageal adenocarcinoma captured by using WATS. However, the NCCN remarks that the “utility and accuracy of WATS for detecting HGD/adenocarcinoma in patients with Barrett esophagus needs to be evaluated in larger phase III randomized trials.”

American Society for Gastrointestinal Endoscopy (ASGE)

The ASGE recommends the use of WATS^3D as an adjunct to “Seattle protocol biopsy sampling” in patients with known or suspected BE (conditional recommendation, low quality of evidence). The society stated that they had downrated the certainty of the recommendation due to possible risk bios, insistency, and indirectness of the studies that were available at the time of publication since some of the studies had included LGD (whereas others had not) and many of the studies had been sponsored by the test’s manufacturer. The society also had noted that, as of the date of publication, no studies addressing the cost-effectiveness of WATS-3D had been published. It should be noted that since the publication of these guidelines the 2020 cost-effectiveness study by Singer and Smith (2020) has been published.

Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) Technology and Value Assessment Committee (TVAC)

The TAVAC of SAGES evaluated WATS^3D and published their findings and recommendations within the journal Surgical Endoscopy in 2020. They note that WATS^3D is not recommended “as a stand-alone substitute for cold forcep biopsies.” Within their expert panel recommendation section:

• They state that no significant morbidity or mortality is associated with the testing. 
• They also state that “WATS^3D increases diagnostic yield by 38 – 150% for Barrett’s Esophagus, by 40 – 150% for Low Grade Dysplasia; and by 420% for High Grade Dysplasia; when compared to forceps biopsy alone.” 
• WATS^3D testing also “has very high inter-observer agreement for the pathological diagnosis of non-dysplastic and dysplastic Barrett’s Esophagus.”

Regarding value, “Increased detection of pre-malignant diseases of the esophagus by the adjunctive use of WATS^3D supports screening and surveillance by the adjunctive use of WATS^3D during upper endoscopy in appropriate patients.”

American Foregut Society (AFS)

The AFS published a white paper reviewing WATS^3D in 2020. After reviewing the literature, they state, “The American Foregut Society Board has concluded that there are sufficient data to support the routine use of WATS^3D technology in the diagnosis and ongoing evaluation of Barrett’s esophagus.”

American College of Gastroenterology (ACG)

In 2022, the ACG updated the Barrett’s Esophagus guideline and offered recommendations for the diagnosis, screening, surveillance, and endoscopic and medical therapy of BE. No recommendations were made regarding chemoprevention or use of “biomarkers” in routine practice due to “insufficient data.”

Studies do suggest that “biomarkers may be better than routine histology alone” in helping to predict the progression of cancer. However, the ACG notes that no single prediction tool or panel to predict disease progression has been established as having clear clinical utility. There have not been sufficient studies to evaluate the combination of clinical and biomarker variables.

The ACG could not recommend “routine use of p53 IHC or TissueCypher for risk stratification in patients with BE undergoing surveillance” due to unclear clinical validity.

However, the panel did not completely dissuade providers from the use of biomarkers under certain conditions since the predictive performance “has been shown to be better in some cases than the histologic diagnosis.” In the future, and with more clinical studies, this may mean that biomarkers could have predictive value in a subset of patients with BE without dysplasia.

In 2025, ACG released guidelines of the diagnosis and management of EoE. The guidelines include the following recommendations for diagnosis of EoE:

• “We recommend that EoE is diagnosed based on the presence of symptoms of esophageal dysfunction and at least 15 eosinophils per high-power field (eos/hpf) on esophageal biopsy, after evaluating for non-EoE disorders that cause or potentially contribute to esophageal eosinophilia (quality of evidence: low; strength of recommendation: strong).”
• “We recommend using a systematic endoscopic scoring system (e.g., the EoE Endoscopic Reference Score [EREFS]) to characterize endoscopic findings of EoE at every endoscopy (quality of evidence: low; strength of recommendation: strong).”
• “We recommend obtaining at least 6 esophageal biopsies from at least 2 esophageal levels (e.g., proximal/mid and distal), targeting EoE endoscopic findings, if possible, to assess for histologic features consistent with EoE (quality of evidence: low; strength of recommendation: strong).”
• “We recommend that eosinophil counts be quantified on esophageal biopsies from every endoscopy performed for EoE (quality of evidence: low; strength of recommendation: strong).”

European Society for Medical Oncology (ESMO)

No form of molecular testing for diagnosis or risk assessment of esophageal cancer is mentioned in the ESMO 2022 guideline. The 2022 guideline does include a supplementary table listing biomarkers and molecular targets for precision medicines and corresponding scores for outcomes:

(Obermannová, et al., 2022)

Pan-Asian adapted ESMO Clinical Practice Guidelines: a JSMO-ESMO initiative endorsed by CSCO, KSMO, MOS, SSO and TOS

The only biomarker mentioned in these guidelines is HER2; intended “to select patients with metastatic esophageal adenocarcinoma for treatment with…trastuzumab.” The guidelines go on to state that evidence for the role of other biomarkers or agents is “limited.”

State and Federal Regulations, as applicable

Food and Drug Administration (FDA)

Many labs have developed specific tests that they must validate and perform in house. These laboratory-developed tests (LDTs) are regulated by the Centers for Medicare and Medicaid (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA ’88). LDTs are not approved or cleared by the U. S. Food and Drug Administration; however, FDA clearance or approval is not currently required for clinical use.

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.

Applicable service codes: 81194, 81210, 81301, 81404, 81405, 81406, 81479, 88104,  88271, 88272, 88273, 88274, 88275, 88341, 88342, 88344, 88360, 88361, 88367, 88368, 88369, 88373, 88374, 88377, 0095U, 0108U, 0114U, 0398U, 0506U.

BCBSNC may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included.

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Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association. Stroke. Jul 2021;52(7):e364-e467. doi:10.1161/str.0000000000000375

Kang BE, Zhang S, Lesmana H, et al. Venous thromboembolism laboratory testing (factor V Leiden and factor II c.&#x2217;97G&gt;A), 2025 revision: A technical standard of the American College of Medical Genetics and Genomics (ACMG). Genetics in Medicine. 2025;27(8)doi:10.1016/j.gim.2025.101466

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Hickey SE, Curry CJ, Toriello HV. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. Feb 2013;15(2):153-6. doi:10.1038/gim.2012.165

Bashford MT, Hickey SE, Curry CJ, et al. Addendum: ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genetics in Medicine. 2020/12/01 2020;22(12):2125-2125. doi:10.1038/s41436-020-0843-0

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BCBSA Medical Policy Reference Manual [Electronic Version]. 7.01.167, 8/2021

Medical Director review 8/2021

Specialty Matched Consultant Advisory Panel review 11/2021

Medical Director review 11/2021

Medical Director review 4/2023 

Medical Director review 4/2024 

Medical Director review 4/2025

Medical Director review 4/2026

Policy Implementation/Update Information

5/12/20 New policy developed. BCBSNC will provide coverage for esophageal pathology testing when it is determined to be medically necessary because the medical criteria and guidelines are met. Medical Director review 4/2020. Policy noticed 5/12/2020 for effective date 7/21/2020. (jd)

12/8/20 Specialty Matched Consultant Advisory Panel review 11/2020. Medical Director review 11/2020. (jd)

2/9/21 Annual review by Avalon 4th Qtr 2020 CAB. Minor revision to the description section and added the following under Related Policies: “Detection of Circulating Tumor Cells and Cell Free DNA in Cancer Management (Liquid Biopsy) AHS – G2054”. Item #4 under When Not Covered section changed from investigation to “Reimbursement is not allowed…”. Policy guidelines and references updated. Medical Director review 1/2020. (jd)

5/4/21 Reviewed by Avalon 1st Quarter 2021 CAB. Policy guidelines and references updated. Medical Director review 4/2021. (jd)

9/7/21 Minor wording revision for clarity to When Not Covered section item #5 (WATS-3D), policy guidelines updated with evidence summary for WATS-3D, and references updated. Medical Director review 8/2021. (jd)

11/30/21 Specialty Matched Consultant Advisory Panel review 11/2021. Medical Director review 11/2021. (jd)

5/17/22 Reviewed by Avalon 1st Quarter 2022 CAB. Minor revisions to the When Covered section under item 2, now reads as follows: “Mismatch repair (MMR)…”; no change to policy intent. Policy guidelines updated; added Table of Terminology. References updated. Medical Director review 4/2022. (jd)

7/1/22 Off-cycle minor revision: added the following statement to the Description section, “For guidance concerning Tumor Mutational Burden Testing (TMB) and/or Microsatellite instability (MSI) analysis please refer to the AHS-M2178-Microsatellite Instability and Tumor Mutational Burden Testing policy.”; added AHS M2178 to the Related Policies section. (jd)

3/31/23 Updated Billing/Coding section to add code 0386U effective 4/1/23. (tm)

5/16/23 Reviewed by Avalon 1st Quarter 2023 CAB. Description, Policy Guidelines and References updated. Related Policies section removed. The following edits were made to the When Covered section: previous items 1 and 2 combined for clarity to now read "For consideration of therapy with PD-1 inhibitors for individuals with locally advanced, recurrent, or metastatic esophageal, gastric, or esophagogastric junction cancer, reimbursement is allowed for any of the following testing: a. Tumor analysis of PD-L1 expression by immunohistochemistry. b. Mismatch repair (MMR) analysis. Remaining items renumbered (now items 2 and 3) with minor edits for clarity, new item 4 added "For the diagnosis and evaluation of Barrett’s esophagus, low-grade esophageal dysplasia, or high-grade esophageal dysplasia, wide area transepithelial sampling (WATS) is considered medically necessary." Removed previous item 5 from Not Covered section: "Reimbursement is not allowed for wide-area transepithelial sampling (WATS-3D) for the determination of risk, the detection, or the prognosis of Barrett’s esophagus, esophageal cancers, and/or esophagogastric junction cancers." Remaining criteria under Not Covered section edited for clarity. Medical Director review 4/2023. (tm)

6/30/23 Code 0398U added to Billing/Coding section, effective 7/1/23. (tm)

5/15/24 Reviewed by Avalon 1st Quarter 2024 CAB. Description, Policy Guidelines and References updated. Related Policies added to the Description section. Removed code 0386U from Billing/Coding section. Changes to When Covered section: new criteria 1 now reads “For individuals who have been newly diagnosed with cancer of the esophagus or esophagogastric junction (EGJ), reimbursement is allowed for mismatch repair (MMR) analysis by immunohistochemistry (IHC).” Former criteria 1 and 2 combined into new criteria 2 and now reads “For individuals who have been diagnosed with locally advanced, recurrent, or metastatic cancer of the esophagus or EGJ and for whom PD-1 inhibitor treatment is being considered, reimbursement is allowed for tumor analysis of PD-L1 expression by IHC.” Former criteria 2 is now criteria 3: “For individuals who have been diagnosed with inoperable locally advanced, recurrent, or metastatic adenocarcinoma of the esophagus or EGJ and for whom trastuzumab or an approved biologic or biosimilar drug to trastuzumab is being considered for first-line therapy, reimbursement is allowed for HER2 overexpression testing by IHC, fluorescence in situ hybridization (FISH), or other in situ hybridization (ISH).” Former criteria 3 is now criteria 4: “For individuals diagnosed with unresectable locally advanced, recurrent, or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or EGJ and for whom one of the following drugs is being considered as a second-line therapy, the corresponding gene testing is considered medically necessary: a. Larotrectinib or entrectinib: NTRK gene fusion. b. Selpercatinib: RET gene fusion. c. Dabrafenib or trametinib: BRAF V600E mutation.” Changes to the When Not Covered section: Combined former criteria 1 and 2 into new criteria 1: “The use of genetic testing, (e.g., molecular panel tests, gene expression profiling) to diagnose or monitor an individual with eosinophilic esophagitis (EoE) or to assess the risk of an individual developing EoE is considered not medically necessary.” New criteria 2: “Reimbursement is not allowed for wide area transepithelial sampling (WATS) for the diagnosis and evaluation of Barrett’s esophagus, low-grade esophageal dysplasia, or high-grade esophageal dysplasia.” Criteria 3 updated: “Reimbursement is not allowed for assessing for risk of Barrett’s esophagus and/or esophageal, including esophagogastric junction, cancer using a molecular classifier (e.g., BarreGEN test).” Criteria 4 updated: “Epigenetic analysis for the likelihood for Barrett’s esophagus, esophageal, or esophagogastric junction cancer (e.g., methylation analysis, EsoGuard) is considered not medically necessary.” Medical Director review 4/2024. Notification given 5/15/24 for effective date 7/24/24. (tm)

10/1/24 Code 0506U added to Billing/Coding section, effective 10/1/24. (tm)

7/1/25 Reviewed by Avalon 2^nd Quarter 2025 CAB. Description, Policy Guidelines and References updated. Coverage criteria 3 under When Covered section edited to add “methodology” after “other in situ hybridization (ISH)”, no change to policy statement. Note edited to change “5” to “two” to align with guidance in Laboratory Procedures Medical Policy AHS-R2162. Code 81210 added to Billing/Coding section. Medical Director review 4/2025. (tm)

8/5/26 Reviewed by Avalon 2nd Quarter 2026 CAB. Policy Guidelines and References updated. Coverage criteria 4. a. under the When Covered section updated to add repotrectinib as indicated medication, changed “NTRK gene fusion” to “NTRK1/2/3 gene fusion”. Coverage criteria 3 under Not Covered section updated to replace “BarreGEN test” with “TissueCypher^® Barrett's Esophagus Assay”, as BarreGEN is no longer available on the market. Codes 88112, 88160, 88305, and 88312 removed from the Billing/Coding section. Medical Director review 4/2026. (tm)