What are the histological features of early adenocarcinoma of the oesophagus?

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What are the histological features of early adenocarcinoma of the oesophagus?

Introduction

Barrett’s Oesophagus

For more information see What is the histological definition of BO?

Histologic features and grades of dysplasia

For more information see What is the histological definition and grading of dysplasia in patients with BO?

Oesophageal adenocarcinoma

Although there are a great variety of structural manifestations of the development of adenocarcinoma, the key feature that allows a biopsy specimen to be classified as Oesophageal adenocarcinoma is the evidence of invasion of epithelial cells into the connective tissue matrix of the lamina propria. In neoplastic glands, the basal membrane is interrupted, which results in the invasion of epithelial cells into the lamina propria connective tissue matrix. Degrees of differentiation of neoplastic cells vary markedly and thus, histologic grading can describe tumours as being (i) well differentiated, (ii) moderately differentiated, (iii) poorly differentiated, or (iv) undifferentiated.

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Pathologist’s perspective

Early adenocarcinoma in Barrett’s Oesophagus refers to invasion into mucosa or superficial submucosa, but not deeper in the oesophageal wall. These tumours are stage T1 in the current TNM staging system. Adenocarcinoma exists when there is invasion of neoplastic cells beyond the basement membrane of the epithelium. The histological features identifying that invasion has occurred include:[1][2]

1. Single neoplastic cells or small clusters of neoplastic cells in the lamina propria.

2. Complex architectural patterns characterised by solid growth patterns, tight cribriform growth pattern, glands with acute angulation in at least one part of their outline, and a pattern of anastomosing fusion of small glands. Most of these architectural patterns are common to invasive adenocarcinoma in other organs e.g. prostate and endometrium, and are familiar to histopathologists.

3. Neoplastic cells invading overlying squamous epithelium.

4. Desmoplastic stromal reaction. This is useful when present, however, it is recognised that early invasive adenocarcinoma of the oesophagus can invade without eliciting a histologically identifiable stromal reaction.


Solid and tight cribriform growth pattern diagnostic of intramucosal adenocarcinoma - Histological Features.jpg

Solid and tight cribriform growth pattern diagnostic of intramucosal adenocarcinoma


Fused gland pattern of intramucosal adenocarcinoma - Histological Features.jpg

Fused gland pattern of intramucosal adenocarcinoma


Angulated gland pattern of intramucosal adenocarcinoma - Histological Features.jpg

Angulated gland pattern of intramucosal adenocarcinoma


Features that predict the presence of invasive adenocarcinoma in biopsies diagnosed as high grade dysplasia (‘suspicious high grade dysplasia’).

It has been well recognised that significant interobserver variability exists between pathologists in the separation of high grade dysplasia from early invasive adenocarcinoma in biopsy specimens.[3] Recent studies have identified a variety of histological patterns that predict a high likelihood of associated invasive adenocarcinoma (in subsequent specimens) in biopsies with high grade dysplasia. These are summarised below:

1. Zhu et al[4]

- solid or cribriform growth patterns
- ulceration of dysplastic epithelium
- abundant neutrophils within dysplastic epithelium
- dilated neoplastic glands containing necrotic debris
- dysplastic glandular epithelium being incorporated into squamous epithelium

The risk of identifying adenocarcinoma in subsequent resection specimens in this study was: 0 features – 5%; 1 feature – 40%; ≥ 2 features – 80%.

2. Patil et al[5]

- Presence of an endoscopic lesion
- ‘never ending’ glandular pattern
- Sheet like growth
- Angulated glands
- ≥ 3 glands with intraluminal debris
- ≥ 1 focus of single cell infiltration

The last two features were, in particular, highly predictive for the presence of adenocarcinoma.

At present there is no mandated requirement for pathologists to specifically qualify or quantify the features presented in these studies. However, it would be regarded as good practice for pathologists to communicate concern that invasive adenocarcinoma may exist when one or more of these features exist.


High grade dysplasia with an area suspicious for intramucosal carcinoma - Histological features.jpg

High grade dysplasia with an area suspicious for intramucosal carcinoma – necrotic debris in glands and a developing pattern of gland fusion

The issue of duplication of the muscularis mucosae in Barrett’s Oesophagus and its implication for sub staging early adenocarcinoma.

The muscularis mucosae is consistently thickened in Barrett’s Oesophagus. In at least two thirds of cases there is reduplication with the formation of an intervening fibrovascular stroma between the deeper native muscularis mucosae and the superficial new muscle layer. The intervening fibrovascular stroma is sometimes referred to as the ‘neo-submucosa’ while the entire reduplication process is called the ‘musculo-fibrous anomoly’.[6][7] The native submucosa resides beneath the deep native muscularis layer. In mucosal biopsies, adenocarcinoma may appear to invade through a muscle layer, however, because of the musculo-fibrous anomoly, it is not possible for pathologists to determine if invasion is into neo-submucosa or true submucosa. This distinction is prognostically important because invasion of neo-submucosa has a risk for metastasis approximately the same as intramucosal adenocarcinoma (<10%), while the risk for true submucosal invasion is higher (approximately 30%).[8] Correct assessment can be made on endomucosal resection specimens or formal resections.


Musculo-fibrous anomoly in Barrett's Oesophagus - Histological features.jpg

The AJCC (2010) staging of early oesophageal adenocarcinoma subdivides both mucosal invasion (T1a) and submucosal invasion (T1b) into three levels.

T1a is sub-divided as M1-M3 as follows:

  • m1 - In situ (pTis = high grade dysplasia)
  • m2 - into the lamina propria
  • m3 – into the muscularis mucosae

T1b is sub-divided as SM1-3 as follows:

  • sm1 – superficial 1/3 submucosa
  • sm2 – intermediate one third of submucosa
  • sm3 – outer one third of submucosa


AJCC staging system (mucosa)


AJCC staging system (mucosa) - Histological features.jpg


Since the AJCC system does not account for the musculo-fibrous anomaly, a second four tiered system has been recommended by Vieth & Stolte to better define mucosal invasion of adenocarcinomas.[9] In the Stolte sub staging system, T1a is sub-divided as M1-M4 as follows:

  • m1 - into the lamina propria
  • m2 - into the superficial/inner muscularis mucosae
  • m3 - into the space between the layers of the muscularis mucosae
  • m4 - into the outer/true muscularis mucosae

Pathologists are encouraged to report the sub stage of early adenocarcinoma using both systems and it forms part of the structured reporting guidelines for endomucosal resection specimens developed by the Royal College of Pathologists of Australasia.[10]


Stolte staging system (mucosa)

Stolte staging system (mucosa) - Histological features.jpg


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Pathological reporting of endoscopic resection specimens

The histological report of endoscopic mucosal resections should include data that are important for clinical management, particularly the identification of patients who should be considered for oesophagectomy. These are discussed in greater detail in the guidelines for reporting oesophageal and gastro-oesophageal carcinomas provided by the Royal College of Pathologists of Australasia.[11]

The histological features for reporting include the following:

  • Tumour type
  • Grade
  • Tumour size
  • Level of invasion
  • Lymphovascular invasion
  • Perineural invasion
  • Tumour budding
  • Distance of clearance to deep margin

Intramucosal adenocarcinomas without adverse histological features can be managed conservatively by endoscopic resection.[12][13] Additionally, low-risk tumours invading the upper submucosa (SM1, <500Um invasion of submucosa; no poorly differentiated areas; no lymphovascular invasion; clearance to deep margin >1mm) may be amenable to conservative management by endoscopic resection alone after careful histological assessment.[14][15]

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References

  1. Appelman HD. Adenocarcinoma in Barrett mucosa treated by endoscopic mucosal resection. Arch Pathol Lab Med 2009 Nov;133(11):1793-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19886713.
  2. Goldblum JR. Controversies in the diagnosis of Barrett esophagus and Barrett-related dysplasia: one pathologist's perspective. Arch Pathol Lab Med 2010 Oct;134(10):1479-84 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20923304.
  3. Downs-Kelly E, Mendelin JE, Bennett AE, Castilla E, Henricks WH, Schoenfield L, et al. Poor interobserver agreement in the distinction of high-grade dysplasia and adenocarcinoma in pretreatment Barrett's esophagus biopsies. Am J Gastroenterol 2008 Sep;103(9):2333-40; quiz 2341 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18671819.
  4. Zhu W, Appelman HD, Greenson JK, Ramsburgh SR, Orringer MB, Chang AC, et al. A histologically defined subset of high-grade dysplasia in Barrett mucosa is predictive of associated carcinoma. Am J Clin Pathol 2009 Jul;132(1):94-100 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19864239.
  5. Patil DT, Goldblum JR, Rybicki L, Plesec TP, Mendelin JE, Bennett AE, et al. Prediction of adenocarcinoma in esophagectomy specimens based upon analysis of preresection biopsies of Barrett esophagus with at least high-grade dysplasia: a comparison of 2 systems. Am J Surg Pathol 2012 Jan;36(1):134-41 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22067333.
  6. Takubo K, Sasajima K, Yamashita K, Tanaka Y, Fujita K. Double muscularis mucosae in Barrett's esophagus. Hum Pathol 1991 Nov;22(11):1158-61 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/1743701.
  7. Rubio CA, Riddell R. Musculo-fibrous anomaly in Barrett's mucosa with dysplasia. Am J Surg Pathol 1988 Nov;12(11):885-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/3189695.
  8. Abraham SC, Krasinskas AM, Correa AM, Hofstetter WL, Ajani JA, Swisher SG, et al. Duplication of the muscularis mucosae in Barrett esophagus: an underrecognized feature and its implication for staging of adenocarcinoma. Am J Surg Pathol 2007 Nov;31(11):1719-25 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18059229.
  9. Vieth M, Ell C, Gossner L, May A, Stolte M. Histological analysis of endoscopic resection specimens from 326 patients with Barrett's esophagus and early neoplasia. Endoscopy 2004 Sep;36(9):776-81 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15326572.
  10. Royal College of Pathologists of Australasia. Endoscopic Resection (ER) of the Oesophagus and Gastro-Oesophageal Junction. Structured Reporting Protocol(1st Edition 2013). Sydney (NSW): Royal College of Pathologists of Australasia; 2013 [cited 2013 May 12] Available from: http://www.rcpa.edu.au/getattachment/e19e9dbd-a6a7-4f59-b100-67e7af355633/Protocol-endoscopic-resection-oesophagus.aspx.
  11. Royal College of Pathologists of Australasia. Tumours of the oesophagus and gastro-oesophageal junction. Structured reporting protocol (1st Edition, 2013). Sydney (NSW): Royal College of Pathologists of Australasia; 2013 Available from: http://www.rcpa.edu.au/getattachment/caa4ae01-bcdb-4911-a43f-65364faf41bd/Protocol-oesophageal-and-GOJ-cancers.aspx.
  12. Pech O, May A, Manner H, Behrens A, Pohl J, Weferling M, et al. Long-Term Efficacy and Safety of Endoscopic Resection for Patients with Mucosal Adenocarcinoma of the Esophagus. Gastroenterology 2014 Mar 1;146(3):652-660 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24269290.
  13. Dunbar KB, Spechler SJ. The risk of lymph-node metastases in patients with high-grade dysplasia or intramucosal carcinoma in Barrett's esophagus: a systematic review. Am J Gastroenterol 2012 Jun;107(6):850-62; quiz 863 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22488081.
  14. Manner H, Pech O, Heldmann Y, May A, Pohl J, Behrens A, et al. Efficacy, safety, and long-term results of endoscopic treatment for early stage adenocarcinoma of the esophagus with low-risk sm1 invasion. Clin Gastroenterol Hepatol 2013 Jun;11(6):630-5; quiz e45 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23357492.
  15. Westerterp M, Koppert LB, Buskens CJ, Tilanus HW, ten Kate FJ, Bergman JJ, et al. Outcome of surgical treatment for early adenocarcinoma of the esophagus or gastro-esophageal junction. Virchows Arch 2005 May;446(5):497-504 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15838647.

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Appendices


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