College of American Pathologists



New Developments in the Diagnosis and Management of Esophageal Carcinoma

Posted May 24, 2012

Feriyl Bhaijee, MB,ChB
CAP Cancer Committee

While squamous cell carcinoma (SCC) is the most common form of esophageal cancer worldwide, esophageal adenocarcinoma (EAC) is steadily increasing in incidence in Western countries.1 The pathogenesis of EAC involves gastroesophageal reflux, which induces glandular metaplasia in the lower esophageal epithelium (Barrett’s esophagus). Subsequent genetic and epigenetic changes in the metaplastic epithelium facilitate the progression to dysplasia and adenocarcinoma in some individuals.2 In addition to the conventional diagnostic and staging modalities for esophageal cancer, recent technological advances include endoscopic ultrasound (EUS), positron emission tomography-computed tomography (PET-CT), and probe-based confocal laser endomicroscopy (pCLE). pCLE is an endoscopic imaging technique that provides dynamic real-time microscopic views of the esophageal mucosa during an ongoing procedure.3 The use of pCLE combined with high-definition white-light endoscopy may improve detection of neoplasia in Barrett’s esophagus by facilitating a presumptive diagnosis of high grade dysplasia prior to tissue biopsy.

Historically, all esophageal cancers, regardless of stage, were removed through partial or complete esophagectomy, with significant morbidity and mortality. However, recent advances in the resection of early esophageal cancers include endoscopic mucosal resection (EMR).4 This endoscopic organ-sparing technique is minimally invasive compared to esophagectomy, with significantly lower morbidity and similar short-term survival rates.5 Combined EMR and photodynamic therapy is a viable alternative to standard esophagectomy in patients with early Barrett’s esophageal adenocarcinoma.6 Moreover, esophagus-preserving therapy likely improves long-term quality of life.5 Accurate microstaging of the lesion and exclusion of lymph node metastases are required to identify lesions that are amenable to curative endoscopic resection.7,8

Elucidation of the genetic changes that promote dysplasia and carcinogenesis in Barrett’s esophagus may lead to the development of biologically-targeted therapeutic options. The HER2 (c-erbB2) proto-oncogene on chromosome 17q11.2-12 encodes epidermal growth factor receptor 2 (HER2), which is targeted by the monoclonal antibody trastuzumab (Herceptin).9 HER2 is overexpressed at the protein level and amplified at the DNA level in 15%–20% of EAC and high-grade dysplasia.10,11

There is limited and conflicting data on the association between HER2 amplification and survival in patients with EAC. Recently, using both chromogenic in situ hybridization and high-density microarrays in a cohort of 232 EAC patients, Hu et al. found no association between HER2 amplification and patient survival.10 While HER2 amplification may not directly correlate with prognosis, it may be able to predict response to HER2 targeted therapy. The recent Trastuzumab for Gastric Cancer (ToGA) trial demonstrated that trastuzumab in combination with chemotherapy can be considered a new standard option for patients with HER2-positive advanced gastric or gastro-esphageal junction cancer.12

In summary, the incidence of esophageal cancer is increasing worldwide and new diagnostic and therapeutic modalities are needed to alleviate the morbidity and mortality thereof. New imaging modalities, such as EUS, PET-CT, and pCLE increase diagnostic accuracy and direct treatment planning. Advances in endoscopic resection techniques offer improved patient outcomes, and procedures such as EMR and photodynamic therapy may replace esophagectomy as the standard of care for early cancers. Finally, elucidation of HER2 overexpression and amplification in the pathogenesis of EAC may facilitate the development of disease-specific therapeutic regimens and the role of trastuzumab therein.


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  2. Reid BJ, Li X, Galipeau PC, Vaughan TL. Barrett’s oesphagus and oesophageal adenocarcinoma: time for a new synthesis. Nat Rev Cancer. 2010;10(2):87–101.
  3. Sharma P, Meining AR, Coron E, et al. Real-time increased detection of neoplastic tissue in Barrett’s esophagus with probe-based confocal laser endomicroscopy: final results of an international multicenter, prospective, randomized, controlled trial. Gastrointest Endosc. 2011;74(3):465–472. Jul 7.
  4. Wang KK, Prasad G, Tian J. Endoscopic mucosal resection and endoscopic submucosal dissection in esophageal and gastric cancers. Curr Opin Gastroenterol. 2010;26(5):453–458.
  5. Zehetner J, DeMeester SR, Hagen JA, et al. Endoscopic resection and ablation versus esophagectomy for high-grade dysplasia and intramucosal adenocarcinoma. J Thorac Cardiovasc Surg. 2011;141(1):39–47.
  6. Pacifico RJ, Wang KK, Wongkeesong LM, Buttar NS, Lutzke LS. Combined endoscopic mucosal resection and photodynamic therapy versus esophagectomy for management of early adenocarcinoma in Barrett’s esophagus. Clin Gastroenterol Hepatol. 2003;1(4):252–257.
  7. Zehetner J, DeMeester SR. Treatment of Barrett’s esophagus with high-grade dysplasia and intramucosal adenocarcinoma. Expert Rev Gastroenterol Hepatol. 2009;3(5):493–498.
  8. Namasivayam V, Wang KK, Prasad GA. Endoscopic mucosal resection in the management of esophageal neoplasia: current status and future directions. Clin Gastroenterol Hepatol. 2010;8(9):743–754;quiz e96.
  9. Baselga J, Tripathy D, Mendelsohn J, et al. Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol. 1996;14(3):737–744.
  10. Hu Y, Bandla S, Godfrey TE, et al. HER2 amplification, overexpression and score criteria in esophageal adenocarcinoma. Mod Pathol. 2011;24(7):899–907. doi:10.1038/modpathol.2011.47.
  11. Schoppmann SF, Jesch B, Friedrich J, et al. Expression of Her-2 in carcinomas of the esophagus. Am J Surg Pathol. 2010;34(12):1868–1873.
  12. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesphageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687–697.

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NewsPath® Editor: Kyle L. Eskue, MD
This newsletter is produced in cooperation with the College of American Pathologists Public Affairs Committee and the NewsPath Editorial Board and may be reproduced in whole or in part as a service to the medical community. Copyright © 2012 by the College of American Pathologists.
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