Esophageal cancer (EC) is the fastest growing cancer by incidence in the United States, according to data published from the National Cancer Institute (Figure 1). The incidence of this once rare cancer has increased by more than 500% since the 1970s,1 and the rate of increase outpaces that of any other cancer type. There are 17,990 new EC cases each year in the U.S. EC remains a highly lethal disease with a 5-year survival rate of 17%.2 Major drivers for the increase of EC incidence include increases in the number of people suffering from gastroesophageal reflux disease (GERD) and Barrett’s esophagus (BE) in the U.S. and other western countries.
|Figure 1. Growth rate of esophageal cancer in the Unites States 1975–2000, data from NCI SEER database.|
According to the American Society of Gastrointestinal Endoscopy, GERD, which affects approximately 30 million adults in the U.S., results in stomach acid bathing the inside lining of the esophagus. In response to chronic episodes of acid reflux, the lining cells of the esophagus begin to change structure and form in order to protect against the acid insult. These changes result in the phenotypic conversion from the normal, stratified epithelial layers of the esophagus to a columnar epithelial phenotype, and the appearance of goblet cells within the lining of the esophagus. The appearance of goblet cells within the epithelium is considered the hallmark of BE (Figure 2).
|Figure 2. Hematoxylin and eosin-stained section of a Barrett’s esophagus biopsy exhibiting columnar epithelium with goblet cells.|
It is estimated that as many as 17 million people may have BE in the United States by prevalence,3 although the number of confirmed clinical cases remains approximately three to four million people.4 BE is considered a pre-cancerous condition and is a known risk factor for the development of EC. However, not all patients, in fact few by percentage, will progress to EC. In fact, in many clinical cases, BE may be considered protective for the esophagus.
Risk stratification: current diagnostic approaches
Gastroenterologists treating patients with BE thus face a major clinical challenge as they try to identify which BE patients are truly at risk for developing EC, versus which patients may have more indolent versions of the disease that will not progress. This uncertainty associated with poor risk stratification tools is troubling for both physicians and their patients. The lack of risk stratification tools results in the increase in endoscopic surveillance for low-risk patients who do not need frequent surveillance endoscopy. Conversely, there is a paradox in that many patients first diagnosed with EC had not undergone an upper GI endoscopy due to GERD or suspected BE. In other words, the current approaches for monitoring GERD patients are inadequate if success is measured by reductions in the incidence of EC.
The typical diagnostic workup for a patient suffering from GERD and BE includes an upper GI endoscopy. During this procedure the gastroenterologist visually inspects the inside lining of the esophagus with an endoscope. Suspected BE tissue is biopsied and evaluated by a pathologist via light microscopy. The pathologist determines the pathologic diagnosis of BE based on the presence of goblet cells in the tissue and assigns a diagnosis of BE with or without dysplasia. EC develops in a defined sequence of changes from benign metaplasia (BM), to low-grade dysplasia (LGD), to high-grade dysplasia (HGD), to adenocarcinoma (EC). Although the risk of progression from BM to EC is very low, treatment options for EC are limited and thus early detection is critical. Current clinical guidelines from the American Gastroenterology Association (AGA) recommend endoscopic screening with biopsies at frequencies ranging from three months to five years, depending on the diagnosis assigned by pathologists.5
If HGD or EC are found, then endoscopic ablative therapies such as cryoablation, radio frequency ablation (RFA), and endoscopic mucosal resection (EMR) or esophagectomy are performed.5,6 Ablative therapies remove the inside layer of cells in the esophagus that are considered dysplastic tissue or BE, allowing healthy esophageal tissue to grow back in its place.
The most common of these procedures performed today is RFA, and clinical guidelines from the AGA support the use of RFA for treatment of HGD. RFA is currently considered a safe and effective treatment for HGD. In addition, the use of RFA for treating low-grade dysplasia (LGD) is becoming more accepted as a method to prevent progression to HGD or cancer.
One of the challenges in treating LGD patients with RFA relates to the uncertainty of LGD as a diagnosis based on standard pathology. Upon expert GI pathologist review of biopsies taken from supposed LGD lesions, many are confirmed to be non-dysplastic Barrett’s esophagus, which is not indicated for RFA according to current clinical guidelines.
Patient management decisions are currently based on histologic evaluation of esophageal biopsies by pathologists. However, this method is limited by intra- and inter-observer variation and cannot predict which patients will develop esophageal cancer.7,8 Pathology analyses are further confounded by ambiguous cases diagnosed as “indefinite for dysplasia,” which results in repeated endoscopies and pathology analyses. Immunohistochemistry for p53 is used in some ambiguous cases to aid diagnosis of dysplasia; however, p53 is only overexpressed in a subset of patients who progress to HGD/EC, and there is no single biomarker that can accurately diagnose BE or predict risk for HGD/EC. Furthermore, standard histopathology approaches fail to view the tissue biopsy as a system of interacting cells and tissues, resulting in missed information available from the tissue section. This results in misclassification of high-risk patients as low-risk, and some low-risk patients as high-risk.
New approaches: “tissue system biology”
New diagnostic approaches to evaluate esophageal biopsies from BE patients are needed that can unlock more cellular and molecular information from biopsies and provide actionable information to physicians managing patient care. These new strategies, referred to as “tissue systems biology” approaches to anatomic pathology testing, will evaluate biopsies as integrated systems of interacting cell types, including premalignant epithelial cells, potential cancer stem cells, immune cells such as macrophages, and stromal cells such as fibroblasts and endothelial cells responsible for tissue growth and remodeling (Figure 3).9
|Figure 3. Tissue systems biology approaches to anatomic pathology testing and Barrett’s esophagus.|
Platforms for multi-channel fluorescence whole slide imaging, quantitative analysis of key tissue system biomarkers in the context of tissue morphology, and multivariate classifiers extract data-rich information from standard tissue biopsies. Multiple epithelial, immune, and stromal biomarkers are labeled by immunofluorescence and imaged on a single tissue slide from an esophageal biopsy of Barrett’s esophagus (Figure 3A). Computer vision and machine learning algorithms segment tissues into individual cells, subcellular compartments, and tissue compartments, such as glands and stroma (Figure 3B), capture hundreds of cell and tissue level measurements of biomarkers and morphology, and quantify complex biological relationships to identify high-risk populations of cells within tissues (Figure 3C). This approach can be applied to produce comprehensive risk prediction for the development of esophageal cancer in patients with Barrett’s esophagus.
Within these approaches tissue structure (morphology) provides important context for phenotypic biomarker expression. The simultaneous evaluation of multiple epithelial, immune, and stromal cell biomarkers from a single tissue biopsy section provides the opportunity to develop improved diagnostic and prognostic tools for physicians and patients dealing with BE. Furthermore, coupling computer vision and machine-learning approaches to tissue biopsy evaluation enables automatic extraction of thousands of quantitative data elements that cannot be seen by the human eye via standard pathology. This data-rich information can then be converted with the aid of multivariate classifiers to novel diagnostic and prognostic tests. These new approaches to tissue biopsy evaluation will lead to improvements in diagnosing BE and making prognoses and may include methods to monitor the recurrence of BE following eradication by ablative technologies.
Improved diagnostic and prognostic testing in BE will lead to improved patient outcomes, including reductions in the incidence of esophageal cancer. In addition, better risk stratification tools will lead to more efficient endoscopic surveillance, since patients identified as high-risk will proceed to available treatment such as RFA while patients identified as low-risk will be spared unnecessary surveillance endoscopies. Ultimately these improvements in efficiency of endoscopic surveillance will also impact the total cost of care for this patient population.
- Pohl H, Welch, HG. The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence. J Natl Cancer Inst. 2005; 97(2):142-146
- ACS. Cancer Facts & Figures 2013. American Cancer Society 2013.
- Hayeck TJ, Kong C, Spechler S.J, Gazelle G S, Hur C. The prevalence of Barrett’s esophagus in the US: estimates from a simulation model confirmed by SEER data. Dis Esophagus. 2010;23(6):451-457
- Market assessment from Cernostics, Inc. Extrapolation of data from Geisinger Health System, Danville, PA, Electronic Health Record Data on patients with Barrett’s esophagus from 2003-2012.
- Spechler SJ, Sharma P, Souza R, Inadomi JM, Shaheen NJ. American Gastroenterological Association medical position statement on the management of Barrett’s esophagus. Gastroenterology .2011;140:1084-1091.
- DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol.2005;100:190-200.
- Reid BJ, Haggitt RC, Rubin CE, et al. Observer variation in the diagnosis of dysplasia in Barrett’s esophagus. Hum Pathol. 1988;19(2):166-178.
- Montgomery E, Bronner MP, Goldblum JR et al. Reproducibility of the diagnosis of dysplasia in Barrett esophagus: a reaffirmation. Hum Pathol. 2001;32(4):368-378.
- Gough A, Lezon T, Faeder J, et al. High content analysis and cellular and tissue systems biology: a bridge between cancer cell biology and tissue-based diagnostics. In The Molecular Basis of Cancer (ed. Mendelsohn, J. et al. Feb 19, 2014).