Are there biomarkers for the diagnosis (presence) of BO?

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Are there biomarkers for the diagnosis (presence) of BO?

Introduction

Numerous biomarkers have been proposed for the diagnosis of BO, including tissue biomarkers to supplement standard histopathology, serum biomarkers as a non-invasive alternative to endoscopy and biopsy, or use of technology such as magnifying endoscopy to aid in the identification of BO for accurate targeting of biopsies. However, none have been implemented as standard clinical practice.

Accepting the limited observational evidence that early detection and surveillance leads to improved survival,[1][2] to be of clinical value a new biomarker would need to demonstrate improved accuracy compared to current practice, or similar accuracy with other benefits, such as being less invasive. A biomarker would be clinically valuable if it had improved sensitivity (higher true positive rate) compared to standard histopathology examination with acceptable specificity (acceptable false positive rate) and cost. If the new biomarker is more sensitive but less specific than histopathology, its acceptability would need to be assessed by considering the trade-off between the clinical benefits of detecting additional true positive cases that may benefit from surveillance versus the harms of additional false positive results that may lead to unnecessary surveillance procedures.

In the updated 2008 practice guidelines for the diagnosis, surveillance and therapy of Barrett’s Oesophagus, Wang et al[3] proposes the ideal biomarker panel for the diagnosis of BO to be “non-invasive (ie – non-endoscopic) and sensitive – 85% or better”. We have implemented this benchmark in order to evaluate the size of effect. For example, to assign a grade ‘3’ (‘the confidence interval does not include any clinically important effects’), the 95% confidence interval for test sensitivity falls below and does not include the 85% benchmark.

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Biomarkers for the diagnosis of Barrett's Oesophagus

Twenty studies reporting on the clinical performance of biomarkers proposed for the diagnosis of BO were eligible for inclusion in the systematic review. These included:

i) seven diagnostic case control studies[4][5][6][7][8][9][10] and one systematic review[11] reporting on the accuracy of cytokeratin staining pattern to distinguish between BO and gastric intestinal metaplasia. The Nurgalieva review[11] included sixteen studies published from 1983-2005, which included six of the seven studies analysed here as well as nine studies that were ineligible for the present review because they were published prior to the publication of the Ormsby study.[4]

ii) two studies (one perspective diagnostic case control study and one prospective cohort study) reporting on the accuracy of Trefoil Factor 3 (TFF3) collected using a cytosponge to detect BO;[12][13]

iii) six retrospective diagnostic case control studies reporting on the accuracy of different immunohistochemical biomarkers to detect goblet cells and distinguish BO from gastric intestinal metaplasia (Mucin expression[14][15]; Hepatocyte expression[16][17]; Human defensin 5[18]; and CDX2 and Villin[19]);

iv) two studies (one prospective diagnostic case control study and one diagnostic cohort study) reporting on the accuracy of using magnifying endoscopy to detect BO[20][21];

v) one prospective case control study investigating a potential tissue protein biomarker AG2[22] and

vi) one prospective case control study investigating a potential serum biomarker G-17.[23]

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Appendix - Body of evidence assessment

Evidence summary and recommendations

Evidence summary Level References
Seven studies provided low quality evidence for evaluation of cytokeratin staining for distinguishing BO from gastric intestinal metaplasia. Estimates of diagnostic accuracy were inconsistent across studies. III-2, III-3 [4], [5], [6], [7], [9], [8], [10]
Evidence-based recommendationQuestion mark transparent.png Grade
Insufficient evidence exists to recommend cytokeratin staining to aid in the diagnosis of Barrett's Oesophagus.
D


Evidence summary Level References
Four studies provided low quality evidence for evaluation of immunohistochemistry biomarkers for distinguishing Barrett's Oesophagus from cardiac intestinal metaplasia. It was not possible to estimate the clinical accuracy of the biomarkers in the proposed test population due to the methodological limitations in the selection of cases, controls and reporting of the reference standard. III-3, IV [16], [18], [17], [19]
Evidence-based recommendationQuestion mark transparent.png Grade
Insufficient evidence exists to recommend the implementation of immunohistochemistry biomarkers to aid in the diagnosis of Barrett's Oesophagus.
D


Evidence summary Level References
Two studies provided low quality evidence for evaluation of mucin (MUC) immunostaining of non-goblet epithelium for the diagnosis of Barrett's Oesophagus. Test accuracy estimates were inconsistent between these studies but established proof of concept of the test as a potential strategy to overcome problems of sampling error when used in addition to the current method for diagnosis of Barrett's Oesophagus. III-3 [15], [14]
Evidence-based recommendationQuestion mark transparent.png Grade
Insufficient evidence exists to recommend mucin (MUC) expression immunostaining in formalin-fixed, paraffin-embedded tissue to aid in the diagnosis of Barrett's Oesophagus.
D


Evidence summary Level References
Two studies provided a satisfactory evidence base for evaluation of a non-endoscopic capsule sponge device coupled with immunohistochemistry for Trefoil factor 3 (TFF3) for BO screening with estimates of test accuracy approaching that of the current clinical standard. As a non-endoscopic test, the potential clinical impact is substantial. Implementation is dependent on further high quality evidence from representative populations. III-2, III-3 [12], [13]
Evidence-based recommendationQuestion mark transparent.png Grade
Insufficient high quality evidence exists to recommend the non-endoscopic capsule sponge device coupled with immunohistochemistry for trefoil factor 3 (TFF3) to replace the current clinical standard for the diagnosis of Barrett's Oesophagus.
C


Evidence summary Level References
One study provided low quality evidence for evaluation of serum G17 as a biomarker for the diagnosis of Barrett Oesophagus. Reported poor specificity indicates an unacceptably large number of non-BO cases are incorrectly identified as Barrett's Oesophagus by this test. III-3 [23]
Evidence-based recommendationQuestion mark transparent.png Grade
Insufficient evidence exists to recommend the implementation of serum G17 for the diagnosis of Barret's Oesophagus.
D


Evidence summary Level References
One study provided low quality evidence for evaluation of AG2 expression in fresh tissue as a protein biomarker for the diagnosis of Barrett's Oesophagus. Reported sensitivity was poor and well below that of the current clinical standard. III-3 [22]
Evidence-based recommendationQuestion mark transparent.png Grade
Insufficient evidence exists to recommend evaluation of AG2 expression as a protein biomarker in fresh tissue to aid in the diagnosis of Barrett's Oesophagus.
D


Evidence summary Level References
Two studies provided a satisfactory level of evidence for evaluation of the use of magnifying endoscopy to aid in the identification of Barrett's Oesophagus. Evidence was inconsistent between these studies but established proof of concept of the test to overcome problems of sampling error when used in addition to the current method for diagnosis of BO. Neither study gave a valid comparison with current clinical standards for the diagnosis of BO in an appropriate target population. II, III-3 [20], [21]
Evidence-based recommendationQuestion mark transparent.png Grade
Insufficient evidence exists to recommend magnifying endoscopy to aid in the diagnosis of Barrett's Oesophagus.
D


Practice pointQuestion mark transparent.png

Thorough endoscopic sampling (Seattle protocol) coupled with H&E staining of sections and interpretation by trained, expert pathologists is advised for the diagnosis of Barrett’s Oesophagus. More clinical research is required before biomarkers for Barrett's Oesophagus can be implemented as standard clinical practice.

The given value was not understood.

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Issues requiring further clinical research study

  • Proof of concept of mucin (MUC) immunostaining of non-goblet epithelium for the diagnosis of BO has been established by Glickman et al[14] and McIntire et al.[15] Application of a more rigorous study design (such as a prospective cohort study) to this question is required to attain further high quality evidence to establish test accuracy. A valid comparison to the subset of patients missed by sampling error (false negative) using the current clinical standard is required.
  • Further high quality evidence (prospective cohort study or randomised clinical trial) to confirm the accuracy of a non-endoscopic capsule sponge device coupled with immunohistochemistry for Trefoil factor 3 (TFF3) for the diagnosis of BO is required for the test to be considered for implementation as clinical practice. Economic implications of implementation of the test have not yet been investigated.
  • Proof of concept of the use of magnifying endoscopy overcome problems of sampling error and aid in the identification of BO has been established by Endo et al[20] and Norimura et al.[21] Application of a more rigorous study design to this question is required to attain further high quality evidence to establish test accuracy. A valid comparison to the current clinical standard for the diagnosis of BO in an appropriate target population is required.

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References

  1. Cooper GS, Kou TD, Chak A. Receipt of previous diagnoses and endoscopy and outcome from esophageal adenocarcinoma: a population-based study with temporal trends. Am J Gastroenterol 2009 Jun;104(6):1356-62 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19491849.
  2. Corley DA, Mehtani K, Quesenberry C, Zhao W, de Boer J, Weiss NS. Impact of Endoscopic Surveillance on Mortality from Barrett's Esophagus-Associated Esophageal Adenocarcinomas. Gastroenterology 2013 May 11 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23673354.
  3. Wang KK, Sampliner RE, Practice Parameters Committee of the American College of Gastroenterology. Updated guidelines 2008 for the diagnosis, surveillance and therapy of Barrett's esophagus. Am J Gastroenterol 2008 Mar;103(3):788-97 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18341497.
  4. 4.0 4.1 4.2 Ormsby AH, Vaezi MF, Richter JE, Goldblum JR, Rice TW, Falk GW, et al. Cytokeratin immunoreactivity patterns in the diagnosis of short-segment Barrett's esophagus. Gastroenterology 2000 Sep;119(3):683-90 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10982762.
  5. 5.0 5.1 El-Zimaity HM, Graham DY. Cytokeratin subsets for distinguishing Barrett's esophagus from intestinal metaplasia in the cardia using endoscopic biopsy specimens. Am J Gastroenterol 2001 May;96(5):1378-82 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11374671.
  6. 6.0 6.1 Mohammed IA, Streutker CJ, Riddell RH. Utilization of cytokeratins 7 and 20 does not differentiate between Barrett's esophagus and gastric cardiac intestinal metaplasia. Mod Pathol 2002 Jun;15(6):611-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12065774.
  7. 7.0 7.1 Kurtkaya-Yapicier O, Gencosmanoglu R, Avsar E, Bakirci N, Tozun N, Sav A. The utility of cytokeratins 7 and 20 (CK7/20) immunohistochemistry in the distinction of short-segment Barrett esophagus from gastric intestinal metaplasia: Is it reliable? BMC Clin Pathol 2003 Dec 2;3(1):5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14651756.
  8. 8.0 8.1 Schilling D, Spiethoff A, Rosenbaum A, Hartmann D, Eickhoff A, Jakobs R, et al. Does Cytokeratin7/20 immunoreactivity help to distinguish Barrett's esophagus from gastric intestinal metaplasia? Results of a prospective study of 75 patients. Pathol Res Pract 2005;200(11-12):801-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15792123.
  9. 9.0 9.1 Yim HJ, Lee SW, Choung RS, Kim YS, Kim JY, Lee HS, et al. Is cytokeratin immunoreactivity useful in the diagnosis of short-segment Barrett's oesophagus in Korea? Eur J Gastroenterol Hepatol 2005 Jun;17(6):611-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15879722.
  10. 10.0 10.1 White NM, Gabril M, Ejeckam G, Mathews M, Fardy J, Kamel F, et al. Barrett's esophagus and cardiac intestinal metaplasia: two conditions within the same spectrum. Can J Gastroenterol 2008 Apr;22(4):369-75 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18414711.
  11. 11.0 11.1 Nurgalieva Z, Lowrey A, El-Serag HB. The use of cytokeratin stain to distinguish Barrett's esophagus from contiguous tissues: a systematic review. Dig Dis Sci 2007 May;52(5):1345-54 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17373588.
  12. 12.0 12.1 Lao-Sirieix P, Boussioutas A, Kadri SR, O'Donovan M, Debiram I, Das M, et al. Non-endoscopic screening biomarkers for Barrett's oesophagus: from microarray analysis to the clinic. Gut 2009 Nov;58(11):1451-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19651633.
  13. 13.0 13.1 Kadri SR, Lao-Sirieix P, O'Donovan M, Debiram I, Das M, Blazeby JM, et al. Acceptability and accuracy of a non-endoscopic screening test for Barrett's oesophagus in primary care: cohort study. BMJ 2010 Sep 10;341:c4372 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20833740.
  14. 14.0 14.1 14.2 Glickman JN, Shahsafaei A, Odze RD. Mucin core peptide expression can help differentiate Barrett's esophagus from intestinal metaplasia of the stomach. Am J Surg Pathol 2003 Oct;27(10):1357-65 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14508397.
  15. 15.0 15.1 15.2 McIntire MG, Soucy G, Vaughan TL, Shahsafaei A, Odze RD. MUC2 is a highly specific marker of goblet cell metaplasia in the distal esophagus and gastroesophageal junction. Am J Surg Pathol 2011 Jul;35(7):1007-13 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21602660.
  16. 16.0 16.1 Chu PG, Jiang Z, Weiss LM. Hepatocyte antigen as a marker of intestinal metaplasia. Am J Surg Pathol 2003 Jul;27(7):952-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12826887.
  17. 17.0 17.1 Zhang J, Parwani AV, Ali SZ. Hepatocyte paraffin 1 immunoexpression in esophageal brush samples. Cancer 2005 Oct 25;105(5):304-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15918175.
  18. 18.0 18.1 Shen B, Porter EM, Reynoso E, Shen C, Ghosh D, Connor JT, et al. Human defensin 5 expression in intestinal metaplasia of the upper gastrointestinal tract. J Clin Pathol 2005 Jul;58(7):687-94 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15976333.
  19. 19.0 19.1 Shi XY, Bhagwandeen B, Leong AS. CDX2 and villin are useful markers of intestinal metaplasia in the diagnosis of Barrett esophagus. Am J Clin Pathol 2008 Apr;129(4):571-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18343784.
  20. 20.0 20.1 20.2 Endo T, Awakawa T, Takahashi H, Arimura Y, Itoh F, Yamashita K, et al. Classification of Barrett's epithelium by magnifying endoscopy. Gastrointest Endosc 2002 May;55(6):641-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11979244.
  21. 21.0 21.1 21.2 Norimura D, Isomoto H, Nakayama T, Hayashi T, Suematsu T, Nakashima Y, et al. Magnifying endoscopic observation with narrow band imaging for specialized intestinal metaplasia in barrett's esophagus with special reference to light blue crests. Dig Endosc 2010 Apr;22(2):101-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20447202.
  22. 22.0 22.1 Groome M, Lindsay J, Ross PE, Cotton JP, Hupp TR, Dillon JF. Use of oesophageal stress response proteins as potential biomarkers in the screening for Barrett's oesophagus. Eur J Gastroenterol Hepatol 2008 Oct;20(10):961-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18787461.
  23. 23.0 23.1 Sipponen P, Vauhkonen M, Helske T, Kaariainen I, Harkonen M. Low circulating levels of gastrin-17 in patients with Barrett's esophagus. World J Gastroenterol 2005 Oct 14;11(38):5988-92 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16273611.

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Appendices


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