—  SPECIALTY CONFERENCE  —

Gastrointestinal Pathology

Case 5 - Barrett's Esophagus with Low-grade Dysplasia Involving the Bases of the Crypts, But Without Surface Involvement ("Crypt Dysplasia")

Robert D. Odze
Brigham and Women Hospital
Boston, MA





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Clinical History
The case represents a 56 year old male with an 8 year history of Barrett's esophagus (BE). At initial diagnosis, the patient had long segment BE extending to 5 cm above the gastroesophageal junction (GEJ). At the time of the patient's most recent endoscopic surveillance, the length of esophageal columnar mucosa was 3.5 cm, and there were multiple foci of squamous islands. Four quadrant biopsies were obtained from every 2 cm of columnar-lined esophagus. No other endoscopic abnormalities were detected. The biopsy of interest represents mucosa obtained from 2 cm proximal to the GEJ. The patient has no family history of esophageal or colon cancer, and other biopsies from the upper GI tract (stomach and duodenum) were within normal limits.


Case 5 - Figure 1
Case 5 - Figure 2

Case presentation
The case represents a 56 year old male with an 8 year history of Barrett's esophagus (BE). At initial diagnosis, the patient had long segment BE extending to 5 cm above the gastroesophageal junction (GEJ). At the time of the patient's most recent endoscopic surveillance, the length of esophageal columnar mucosa was 3.5 cm, and there were multiple foci of squamous islands. Four quadrant biopsies were obtained from every 2 cm of columnar-lined esophagus. No other endoscopic abnormalities were detected. The biopsy of interest represents mucosa obtained from 2 cm proximal to the GEJ. The patient has no family history of esophageal or colon cancer, and other biopsies from the upper GI tract (stomach and duodenum) were within normal limits.

The esophageal biopsies show metaplastic columnar epithelium with goblet cells consistent with BE. In addition, there are multiple foci of epithelial atypia limited, for the most part, to the basal portions of the crypts, but without involvement of the surface epithelium. The atypical crypts show cells with markedly enlarged, hyperchromatic and pencil-shaped nuclei, and pseudostratification. Mitoses are increased in number. The lamina propria surrounding the area of crypt atypia shows no evidence of active inflammation. Furthermore, there are no significant architectural abnormalities in the background mucosa. The degree of cytologic atypia of the crypts is similar to that seen in conventional (full crypt and surface epithelium) adenomatous (intestinal-type) dysplasia.

Diagnosis
Barrett's Esophagus with Low-grade Dysplasia Involving the Bases of the Crypts, But Without Surface Involvement ("Crypt Dysplasia").

Discussion

Introduction:
Patients with BE are at increased risk for the development of adenocarcinoma. [1, 2] Adenocarcinoma develops through a metaplasia, dysplasia, carcinoma sequence. [3, 4] In this sequence, it is presumed that the native squamous epithelium converts first to mucinous columnar epithelium, composed of either pure mucous glands, or a mixture of mucous and oxyntic glands, prior to goblet cell metaplasia. [5, 6] Metaplastic epithelium, both goblet and non-goblet cell-type, may progress to cancer via a sequence of molecular and morphologic changes interpreted by pathologists as dysplasia. [7] Morphologic identification of dysplasia in endoscopic mucosal biopsies is the standard method of predicting patients at increased risk of cancer. [8] Microscopically, dysplasia in BE is categorized as either adenomatous or non-adenomatous. [7, 9] Adenomatous (also termed intestinal) type dysplasia is characterized by neoplastic cells that resemble those of a colonic adenoma by showing enlarged, elongated nuclei with clumped chromatin, pseudostratification and scattered goblet cells. Recently, other less common types of dysplasia have been described in BE and these include serrated dysplasia, foveolar (or gastric) dysplasia, and mixed types as well. [9, 10, 11]

Regardless of the type, dysplasia is generally categorized as either low (LGD) or high-grade (HGD) according to a system devised by Reid et al in 1988. [3] In that system, LGD is separated from HGD according to the degree of cytologic and architectural atypia of the crypts and surface epithelium. In 2001, Montgomery et al expanded the criteria by Reid et al, and provided more objective guidelines for distinguishing non-dysplastic BE from true dysplasia. [12]

Historically, it has been recommended that pathologists diagnose dysplasia only when neoplastic-appearing cells involve the full length of the crypts and the surface epithelium. [3, 12] These criteria were based primarily on the belief that (in-situ) neoplastic lesions of the GI tract show loss of differentiation capacity as cells migrate from the bases of crypts to the surface epithelium. In fact, the presence of surface maturation (lack of involvement of surface epithelium with dysplastic cells) has traditionally been regarded as a feature of epithelial regeneration rather than neoplasia. Thus, by convention, crypts that show dysplastic-appearing cells limited to the basal portions of the crypts, but without surface involvement, have been termed either "negative for dysplasia" or "indefinite for dysplasia" because of the appearance of surface maturation. [3, 12]

However, parallel to recent advancements in our understanding of the timing and sequence of molecular events that lead to neoplastic transformation, and with the knowledge that progenitor (stem cells) that lead to neoplastic differentiation are located in the bases of the crypts, and that some clonal molecular abnormalities lead to dysregulation of cell proliferation and differentiation prior to morphologic expression of neoplasia, we now recognize that not all neoplastic precursor lesions of the GI tract necessarily show morphologic features of conventional dysplasia. [13, 14] This is particularly true with regard to the evolution of cancer in patients with BE and inflammatory bowel disease (IBD), where alterations in DNA content, and cell cycle control, and mutations in tumor suppressor genes, such as p53, and p16, occur at an early stage of neoplastic transformation prior to the development of conventional morphologic features of dysplasia. [13]

Morphologic and Biological Features of Early (Crypt) Dysplasia:
Recently, the belief that all neoplastic conditions show lack of cellular differentiation has been challenged. For instance, several types of neoplastic precursor lesions of the GI tract have been identified which either do not show conventional cytologic and/or architectural features of neoplasia, or do not involve the epithelium completely. [13] Examples of such cases include squamous dysplasia of the esophagus, pyloric gland adenomas of the stomach, tubule neck dysplasia of the stomach, and some types of serrated polyps of the colon (sessile serrated adenoma/polyp). [13]

With regard to BE, a recent study by Lomo et al showed that dysplastic-appearing cells may be limited to the crypts in the early phase of development, prior to involvement of the surface epithelium. [15] In that study, the morphologic, immunohistochemical, and molecular findings of 15 patients with dysplasia limited to the basal portions of the crypts were evaluated from a consecutive prospective cohort of 206 high risk patients with BE enrolled in a large endoscopic surveillance program in Seattle, Washington. In that study, compared to non-dysplastic BE, patients with "crypt dysplasia" showed a significantly elevated prevalence rate of p53 positivity, MIB1 proliferation index, and an increased rate of 17p (TP53) LOH and 9P (p16) LOH. The validity of the neoplastic nature of crypt dysplasia was confirmed in a recent study by Zhang et al, in which the basal and superficial aspects of the crypts in non-dysplastic BE, crypt dysplasia, as well as in conventional LGD and HGD, were evaluated for DNA content by image cytometry and high fidelity histograms. [16] In that study, the basal cells of crypt dysplasia showed aneuploidy in 50% of cases, which was similar to the value obtained in cells located at the bases of the crypts in foci of traditional LGD, but the superficial aspects of the crypts and surface epithelium in crypt dysplasia were diploid in all instances. Interestingly, in that study, the DNA ploidy profiles of the basal cells in crypt dysplasia and LGD were similar, which provided evidence in favor of crypt dysplasia as an early phase of development of in-situ neoplasia.

Interobserver Variability:
Several interobserver morphology studies of dysplasia in BE have included lesions, which, in retrospect, likely represents crypt dysplasia. For instance, in the original interobserver study of dysplasia in BE by Reid et al, crypt dysplasia-like cases were not specifically evaluated, but at least one case included in that study shows features similar to crypt dysplasia. [3] This case was interpreted as negative for dysplasia by 5 observers, indefinite for dysplasia by 2, and HGD by 1. In a more recent and comprehensive study by Montgomery et al, some of the cases showed deep cytologic changes suggestive of dysplasia, but with surface maturation, and these were considered indefinite for dysplasia based on uncertainty with regard to the biological significance of surface maturation. [12] In one case that was presented as an image, the lesion was considered negative for dysplasia by 2 observers, indefinite for dysplasia by 15, and LGD by 7. Finally, Kaye et al in 2009 performed an interobserver study with 5 pathologists and 186 BE cases. [17] The authors of that study specifically noted that one area of substantial diagnostic variability related to the interpretation of apparent surface maturation in cases where dysplasia-like features involved only the bases of the crypts. In that study, observers had various opinions regarding the meaning of apparent surface maturation, some interpreting them as consistent with dysplasia, and others as consistent with regeneration. However, the researchers noted that many cases with "undisputed dysplasia" showed "apparent surface maturation" or "only patchy surface involvement" and that "the absence of apparent surface involvement should not deflect from the diagnosis of dysplasia if significant nuclear atypia is present only in the bases of the crypts." In that study, one image of crypt dysplasia showed strong p53 positivity only in the area of maximum atypia in the bases of the crypts.

More recently, our research group performed an interobserver study of BE and associated dysplastic lesions among 6 GI pathologists who evaluated 2 clinical study sets separated by a minimum of 4 months in time. [18] The study sets included 40 and 63 BE cases, respectfully, of which 9 and 15, of the cases were interpreted as crypt dysplasia by the original signout pathologist. In that study, as expected, the highest levels of interobserver agreement were obtained for lesions at the low (negative for dysplasia) and high end (HGD) of the BE neoplasia spectrum. However, overall, the degree of agreement for crypt dysplasia was moderate (Kappa value=0.46), and was, in fact, higher than that obtained for LGD in both study sets. For instance, 4 or more pathologists agreed with the original crypt dysplasia diagnosis in 78% of cases. In that study, the observers agreed that characteristic features of crypt dysplasia include the presence of unequivocal dysplastic cells, similar in appearance to traditional LGD, involving any, or all, of the length of the crypts, in the absence of intercrypt epithelium involvement. Rare cases of crypt dysplasia may show high-grade cytologic features, being composed of markedly enlarged nuclei with increased nuclear/cytoplasm ratio, eosinophilic cytoplasm, irregular nuclear membranes and loss of polarity. [18]

Natural History and Treatment:
More research on the natural history of crypt dysplasia, and dysplasia in general, is needed. In the study by Lomo et al cited above, it was observed that most of the affected patients with crypt dysplasia (87%) also showed synchronous conventional (full crypt and surface epithelium) dysplasia, or adenocarcinoma, in biopsies elsewhere from the patient's esophagus. [15] In a recent long term follow up study (published in abstract form) by Srivastava et al of 20 patients with crypt dysplasia from a cohort of 214 high risk BE patients, 65% showed either synchronous or metachronous conventional dysplasia, or cancer, upon follow up (mean follow up: 90.4 months). [19] In that study, 17% of patients with crypt dysplasia developed conventional LGD, 17% developed HGD, and 5% developed adenocarcinoma upon long term follow up. These data are similar to the data generated from previously published studies regarding the natural history and outcome of patients with LGD. Further outcome studies, utilizing a larger number of cases, and preferably from multiple institutions, should be carried out prior to implementing definitive guidelines for management of BE patients with crypt dysplasia, but without conventional LGD or HGD. Anecdotally, one practical approach, (and one that is carried out at our institution), is to treat patients with crypt dysplasia similar to those who have conventional LGD. This strategy is based primarily on the fact that most cases of crypt dysplasia, as mentioned above, are associated with conventional (full crypt and surface epithelium) dysplasia elsewhere in the patient's esophagus, and that in one long term outcome study, the natural history of BE patients with crypt dysplasia was similar to patients with LGD. [19] Naturally, any patient in whom crypt dysplasia is considered, should have deeper cuts obtained from the tissue blocks in order to rule out synchronous conventional LGD or HGD.

References:
  1. Conio M, Blanchi S, Lapertosa G, et al. Long-term endoscopic surveillance of patients with Barrett's esophagus. Incidence of dysplasia and adenocarcinoma: a prospective study. Am J Gastroenterol 2003;98:1931-9.

  2. Drewitz DJ, Sampliner RE, Garewall HS. The incidence of adenocarcinoma in Barrett's esophagus: a prospective study of 170 patients followed 4.8 years. Am J Gastroenterol 1997;92:212-15.

  3. Reid BJ, Blount PL, Rubin CE, et al. Flow-cytometric and histological progression to malignancy in Barrett's esophagus: prospective endoscopic surveillance of a cohort. Gastroenterology 1992;102:1212-19.

  4. Haggitt RC, Tryzelaar J, Ellis H, et al. Adenocarcinoma complicating columnar epithelium-lined (Barrett's) esophagus. Am J Clin Pathol 1978;90:1-5.

  5. Odze RD. Barrett esophagus: histology and pathology for the clinician. Nat Rev Gastroenterol Hepatol 2009 Aug;6(8):478-90.

  6. Odze RD. Unraveling the mystery of the gastroesophageal junction: A pathologist's perspective. Am J Gastroenterol 2005;100:1853-67.

  7. Odze RD. Diagnosis and grading of dysplasia in Barrett's oesophagus. J Clin Pathol 2006;59:1029-38.

  8. Wang KK, Sampliner RE, Practice Parameters Committee of the American College of Gastroenterology et al. Updated guidelines 2008 for the diagnosis, surveillance and therapy of Barrett's esophagus. Am J Gastroenterol 2008;103:788-97.

  9. Rucker-Schmidt R, Sanchez C, Blount P, et al. Non-adenomatous dysplasia in Barrett's esophagus: a clinical, pathologic and DNA content flow cytometric study. Am J Surg Pathol 2009;33:886-93.

  10. Srivastava A, Sanchez CA, Cowan DS, et al. Foveolar and serrated dysplasia are rare high-risk lesions in Barrett's esophagus: A prospective outcome analysis of 214 patients. Mod Pathol 2010;23(s1):742A.

  11. Brown IS, Whiteman DC, Lauwers GY. Foveolar type dysplasia in Barrett's esophagus. Mod Pathol 2010;23:834-43.

  12. Montgomery E, Bronner MP, Goldblum JR, et al. Reproducibility of the diagnosis of dysplasia in Barrett's esophagus: a reaffirmation. Hum Pathol 2001;32:368-78.

  13. Odze RD, Maley C. Neoplasia without dysplasia: Lessons from Barrett's esophagus and other tubal gut neoplasms. Arch Pathol Lab Med 2010;134:896-906.

  14. Odze RD, Riddell RH, Bosman FT, et al. Premalignant lesions of the digestive system. In Carneiro F, Flejou JF, ed. WHO Classification of Tumours of the Digestive System. 4th Ed. Lyon: IARC Press 2010; 10-12.

  15. Lomo LC, Blount PL, Sanchez CA, et al. Crypt dysplasia with surface maturation: A clinical, pathologic, and molecular study of a Barrett's esophagus cohort. Am J Surg Pathol 2006;30(4):423-35.

  16. Zhang X, Huang Q, Goyal RK, et al. DNA ploidy abnormalities in basal and superficial regions of the crypts in Barrett's esophagus and associated neoplastic lesions. Am J Surg Pathol 2008;32:1327-35.

  17. Kaye PV, Haider SA, Ilyas M, et al. Barrett's dysplasia and the Vienna classification: reproducibility, prediction of progression and impact of consensus reporting and p53 immunohistochemistry. Histopathology 2009;54;699-712.

  18. Coco DP, Goldblum JR, Hornick JL, et al. Interobserver variability in the diagnosis of crypt dysplasia in Barrett's Esophagus. Am J Surg Pathol 2011;35:45-54.

  19. Srivastava A, Coco D, Sanchez CA, et al. Risk of conventional dysplasia and adenocarcinoma in patients with Barrett's esophagus and crypt dysplasia: a prospective follow-up study of 214 patients. Mod Pathol 2010;23(s1):168A.