Esophagus
Premalignant
Barrett related dysplasia
Author: Dipti M. Karamchandani, M.D.
Editorial Board Member: Debra L. Zynger, M.D.
Deputy Editor-in-Chief: Raul S. Gonzalez, M.D.
Last author update: 12 June 2020
Last staff update: 12 May 2021
Copyright: 2003-2024, PathologyOutlines.com, Inc.
PubMed Search: Barrett[TIAB] related dysplasia esophagus [TI] free full text [SB]
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Laboratory | Prognostic factors | Treatment | Clinical images | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Videos | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2 | Board review style question #3 | Board review style answer #3Cite this page: Karamchandani DM. Barrett related dysplasia. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/esophagusdysplasia.html. Accessed December 26th, 2024.
Definition / general
- Unequivocally neoplastic epithelium without invasion, associated with Barrett esophagus (WHO: Digestive System Tumours, 5th Edition, 2019)
Essential features
- Presence of Barrett esophagus related dysplasia remains greatest risk factor for development of esophageal adenocarcinoma (Am J Surg Pathol 2017;41:e8)
- Pathologic diagnosis and grading of dysplasia is the gold standard marker for assessing risk of neoplastic progression (Am J Surg Pathol 2016;40:e83)
- Atypia in Barrett esophagus dysplasia can be interpreted as negative for dysplasia, indefinite for dysplasia, low grade dysplasia and high grade dysplasia (WHO: Digestive System Tumours, 5th Edition, 2019, Hum Pathol 1988;19:166)
- Diagnosis and grading of Barrett esophagus related dysplasia can be challenging, especially with coexisting inflammation (Hum Pathol 1988;19:166)
- Both low grade dysplasia and high grade dysplasia managed by endoscopic therapy, per the latest American College of Gastroenterology (ACG) guidelines (Am J Gastroenterol 2016;111:30)
Terminology
- Indefinite for dysplasia, low grade Barrett dysplasia and high grade Barrett dysplasia (WHO: Digestive System Tumours, 5th Edition, 2019, Hum Pathol 1988;19:166)
- Vienna classification uses terms noninvasive low grade neoplasia (low grade adenoma / dysplasia) for low grade dysplasia and noninvasive high grade neoplasia for high grade dysplasia (Gut 2000;47:251)
- World Health Organization recognizes both classifications (WHO: Digestive System Tumours, 5th Edition, 2019)
ICD coding
Epidemiology
- Dysplasia develops typically in the setting of Barrett esophagus (Am J Gastroenterol 2016;111:30)
- Barrett esophagus detected in ~ 10- 15% of patients with chronic gastroesophageal reflux disease (GERD) (Am J Gastroenterol 2016;111:30, Gastroenterol Hepatol (NY) 2016;12:449)
- Incidence of low grade dysplasia should be ~2 - 3% but not > 5% in prospectively evaluated patients (Am J Gastroenterol 2010;105:1523)
- Indefinite for dysplasia category should be used in only a small percentage of cases (< 3 - 5%) (Ann Diagn Pathol 2018;37:75)
- For low grade dysplasia, the annual risk of progression to cancer is ~ 0.7% per year (Am J Gastroenterol 2016;111:30)
- For high grade dysplasia, the annual risk of progression to cancer is ~ 7% per year (Am J Gastroenterol 2016;111:30)
Sites
- Distal esophagus, gastroesophageal junction (restricted to metaplastic esophageal mucosa)
Pathophysiology
- Sequential progression from inflammation to metaplasia, dysplasia and carcinoma (Am J Surg Pathol 2016;40:e45)
- Accumulation of multiple genetic and epigenetic alterations causes development and progression of dysplasia (Nat Genet 2014;46:837)
- C-myc and cyclins D1, E and B implicated as oncogenes in neoplastic progression in Barrett esophagus (Am J Surg Pathol 2016;40:e45)
- Inactivation of tumor suppressor proteins p53, p16, p15, p27 and adenomatous polyposis coli (APC) also implicated in Barrett esophagus carcinogenesis (Am J Surg Pathol 2016;40:e45)
- Other mechanisms proposed include increased telomerase expression, increased VEGFA and C, decreased membrane E-cadherin, increased MMP-7 and MMP-9, increased markers of epithelial-mesenchymal transition such as 2EB1/2EB2 and TGF-B1 (Am J Surg Pathol 2016;40:e45)
- As Barrett esophagus epithelial cells progress to cancer, they typically manifest aneuploidy, a marker of genomic instability (Am J Surg Pathol 2016;40:e45)
Etiology
- Known risk factors for development of neoplasia in Barrett esophagus (Am J Gastroenterol 2016;111:30):
- Advancing age
- Increasing length of Barrett esophagus
- Central obesity
- Tobacco usage
- Lack of nonsteroidal anti inflammatory agent use
- Lack of PPI use
- Lack of statin use
Clinical features
- Patients typically have gastroesophageal reflux disease symptoms
- No distinct clinical or radiologic manifestations of Barrett esophagus dysplasia
- Endoscopically, Barrett esophagus dysplasia may be visible as thickened, flat, irregular or plaque-like area, distinct from adjacent nondysplastic Barrett mucosa (Dig Dis Sci 2003;48:1537, Am J Gastroenterol 2016;111:30)
- Mucosal abnormalities (ulceration, stricture, mass, nodules, plaques) associated with increased risk of cancer (Am J Gastroenterol 2016;111:30)
Diagnosis
- Recommended for Barrett esophagus with dysplasia to be reviewed by 2 pathologists, at least 1 with specialized expertise in GI pathology (Am J Gastroenterol 2016;111:30)
- Barrett esophagus surveillance performed with high definition / high resolution white light endoscopy
- Routine use of advanced imaging techniques other than electronic chromoendoscopy not recommended for endoscopic surveillance at this time
- Endoscopic surveillance should employ 4 quadrant biopsies at 1 cm intervals in patients with prior dysplasia (Am J Gastroenterol 2016;111:30)
- Mucosal abnormalities to be sampled separately, preferably with endoscopic mucosal resection (EMR)
- Adjunct use of wide area transepithelial sampling with computer assisted 3 dimensional analysis (WATS) to forceps biopsy markedly improves detection of esophageal dysplasia (United European Gastroenterol J 2018;6:529)
- Overall detection of dysplasia by WATS reported to be increased by 242% (Dis Esophagus 2019;32:doy099)
Laboratory
- No laboratory tests assist in the detection of Barrett esophagus dysplasia
Prognostic factors
- Diagnosis of Barrett esophagus associated dysplasia remains a marker of increased risk of progression to esophageal adenocarcinoma (Am J Surg Pathol 2017;41:e8, Am J Surg Pathol 2016;40:e45)
- Progression rates of low grade dysplasia to high grade dysplasia and dysplasia to carcinoma directly proportional to number of pathologists who agree on dysplasia diagnosis (Am J Surg Pathol 2016;40:e45, Am J Gastroenterol 2007;102:483)
Treatment
- Indefinite for dysplasia:
- Repeat endoscopy after acid suppressive medication optimization for 3 - 6 months
- If indefinite for dysplasia is reconfirmed, surveillance interval of 12 months is recommended (Am J Gastroenterol 2016;111:30, Gastroenterol Hepatol (NY) 2016;12:449)
- Low grade dysplasia:
- Endoscopic eradication therapy preferred treatment modality, endoscopic surveillance every 12 months an acceptable alternative (Am J Gastroenterol 2016;111:30)
- High grade dysplasia:
- Endoscopic therapy (Am J Gastroenterol 2016;111:30, Gastroenterol Hepatol (NY) 2016;12:449)
- Nodular Barrett esophagus: recommend endoscopic mucosal resection of the nodular lesion as initial diagnostic and therapeutic maneuver (Am J Gastroenterol 2016;111:30)
- If endoscopic mucosal resection confirms high grade dysplasia, endoscopic ablative therapy of remaining Barrett esophagus (Am J Gastroenterol 2016;111:30)
- Nonnodular dysplastic Barrett esophagus: radiofrequency ablation currently preferred endoscopic ablative therapy (Am J Gastroenterol 2016;111:30)
- In patients with preablation low grade dysplasia, endoscopic surveillance recommended every 6 months in the first year following complete elimination of intestinal metaplasia (CIEM) and annually thereafter (Am J Gastroenterol 2016;111:30)
- Endoscopic surveillance following complete elimination of intestinal metaplasia for patients with preablation high grade dysplasia recommended every 3 months for the first year, every 6 months in the second year and annually thereafter (Am J Gastroenterol 2016;111:30)
Clinical images
Images hosted on other servers:
Nodule on endoscopy
Endoscopic mucosal resection
Narrow band imaging
Endoscopic treatment of Barrett high grade dysplasia
Wide area transepithelial sampling
Gross description
- Normal appearing or nodule, erosion or polyp
Gross images
Images hosted on other servers:
High grade dysplasia
Microscopic (histologic) description
- Barrett esophagus dysplasia divided into low grade dysplasia and high grade dysplasia; indefinite for dysplasia also a valid interpretation (but not part of a histologic spectrum of progression) (Hum Pathol 1988;19:166)
- Indefinite for dysplasia (Hum Pathol 1988;19:166):
- Histologic features too marked for reactive atypia but not sufficient for a definitive diagnosis of dysplasia
- Cases with significant inflammation or ulceration in which inflammation obscures the findings
- Artifact limits interpretation (thermal effect, denuded surface epithelium, rarely technical issues)
- Low grade dysplasia (Hum Pathol 1988;19:166):
- Unequivocally neoplastic
- Nuclear hyperchromasia, enlargement and stratification identified in the deeper glands and involving the surface epithelium
- Maintenance of nuclear polarity
- Abrupt transition between dysplastic and nondysplastic zones
- Effacement or loss of the 4 surface lines that characterize nondysplastic Barrett mucosa (Surg Pathol Clin 2017;10:781)
- Little (if any) architectural abnormalities
- High grade dysplasia (Hum Pathol 1988;19:166, Am J Gastroenterol 2008;103:2333):
- Greater degree of cytologic atypia in addition to architectural abnormalities
- Architectural abnormalities:
- Irregular size and shape of crypts, crowded crypts with little intervening lamina propria, intraluminal budding or cribriforming, rare dilated glands with intraluminal necrotic debris
- Cytologic features:
- Lack of surface maturation, loss of nuclear polarity, marked nuclear enlargement, pleomorphism and hyperchromasia, irregular nuclear contours
- Loss of nuclear polarity considered an important objective criterion to diagnose high grade dysplasia
- Basal crypt dysplasia (Am J Surg Pathol 2006;30:423):
- Controversial diagnosis
- Cytologic atypia in the basal pits with surface maturation
- Cytologic atypia may be low grade or high grade
- Some authors prefer to use the indefinite for dysplasia category for such lesions, especially with low grade atypia confined to the deep mucosa
- Finding of crypt dysplasia in one biopsy suggests high likelihood of finding conventional dysplasia in other biopsies
- Performing further deeper levels recommended
- Gastric foveolar dysplasia (non adenomatous dysplasia):
- Full thickness atypia with non stratified nuclei (Mod Pathol 2010;23:1, Hum Pathol 2013;44:1146)
- Nuclear enlargement, variably prominent nucleoli
- May appear bland and reactive at low magnification but nuclear alterations seen at high magnification
- Low grade dysplasia:
- Nuclear size 2 - 3 times the size of a small, mature lymphocyte, mostly mucinous cytoplasm and variably prominent nucleoli
- High grade dysplasia:
- Nuclear size at least 3 - 4 times the size of a small, mature lymphocyte, most cases have prominent nucleoli (Mod Pathol 2010;23:1, Hum Pathol 2013;44:1146)
Microscopic (histologic) images
Contributed by Dipti M. Karamchandani, M.D.
Indefinite for dysplasia
Indefinite for dysplasia with surface erosion
Low grade dysplasia
Low grade dysplasia higher power
Low grade dysplasia demarcation
High grade dysplasia
High grade dysplasia higher power
High grade dysplasia intraluminal necrotic debris
Gastric foveolar type dysplasia
Gastric foveolar type dysplasia, higher power
Cytology description
- Used as an adjunct to biopsy in diagnosis of Barrett esophagus and associated neoplasms (Diagn Cytopathol 2003;29:130)
- High degree of diagnostic accuracy of cytology for the diagnosis of Barrett associated high grade dysplasia, with reported sensitivity of 82% and specificity of 95% (Diagn Cytopathol 2003;29:130)
- Observed sensitivity for low grade dysplasia is low (about 31%)
- Cytologically, dysplasia shows haphazard arrangement of cells, nuclear enlargement, nuclear hyperchromasia, nuclear membrane irregularity
Positive stains
- Ancillary stains (such as AMACR and p53) have been studied for diagnosing Barrett related dysplasia; neither proved sufficiently sensitive or specific to be clinically useful in detection and classification of Barrett related dysplasia (Am J Surg Pathol 2016;40:e83, Am J Surg Pathol 2017;41:e8, Am J Surg Pathol 2016;40:e83)
- Both strong or absent (null phenotype) p53 staining considered significant (Am J Surg Pathol 2016;40:e83, Am J Surg Pathol 2017;41:e8)
- Gastrointestinal Pathology Society (GIPS) recommendation for p53 in diagnosing Barrett esophagus dysplasia:
- Additional studies are needed to develop and validate precise criteria before p53 staining can be fully endorsed and incorporated into the morphologic dysplasia diagnosis algorithm (Am J Surg Pathol 2017;41:e8)
- p53 appears promising marker in predicting disease progression but not recommended for routine use at present
Videos
Update on recently developed quality metrics
Sample pathology report
- Esophagus, 36 cm, biopsy:
- Barrett esophagus with low grade dysplasia
- Esophagus, 35 cm, biopsy:
- Barrett esophagus with high grade dysplasia
- Esophagus, 34 cm, biopsy:
- Barrett esophagus with epithelial alterations indefinite for dysplasia
Differential diagnosis
- Reactive atypia versus low grade foveolar dysplasia:
- Full thickness nuclear atypia with nonstratified nuclei suggests low grade gastric foveolar type dysplasia
- Reactive atypia is usually limited to upper mucosa
- Indefinite for dysplasia versus reactive atypia:
- Maintenance of 4 lines in a background of inflammation suggests reactive atypia (Surg Pathol Clin 2017;10:781)
- Indefinite for dysplasia versus low grade dysplasia:
- Nuclear changes extending to the surface epithelium in a background of significant inflammation suggests a diagnosis of indefinite for dysplasia
- High grade dysplasia versus intramucosal adenocarcinoma:
- Histologic features of lamina propria invasion (single cells in more than one focus, never ending glandular pattern, solid sheets of cells, significant cribriforming) is diagnostic of intramucosal adenocarcinoma (Am J Gastroenterol 2008;103:2333)
Additional references
Board review style question #1
Above is a photomicrograph taken from a biopsy obtained from salmon colored mucosa in the distal esophagus extending to about 2 cm proximal to the gastroesophageal junction. What is your diagnosis?
- Barrett esophagus, negative for dysplasia
- Barrett esophagus with epithelial alterations indefinite for dysplasia
- Barrett esophagus with high grade dysplasia
- Barrett esophagus with low grade dysplasia
Board review style answer #1
Board review style question #2
A nodule is found on surveillance endoscopy of a 60 year old patient with a longstanding history of Barrett esophagus. What should be the next step in patient management?
- Endoscopic mucosal resection of the nodule
- Esophagectomy
- Radiofrequency ablation of the nodule
- Use of use of wide area transepithelial sampling with computer assisted 3 dimensional analysis (WATS)
Board review style answer #2
Board review style question #3
- A biopsy diagnosis of low grade dysplasia was made by a pathologist and confirmed by a subspecialized GI pathologist. What is the preferred appropriate management based on the ACG 2016 guidelines?
- Endoscopic ablation therapy
- Endoscopic mucosal resection
- Endoscopic surveillance at 6 months interval
- Endoscopic surveillance at 12 months interval
Board review style answer #3
