Research Article: Maspin differential expression patterns as a potential marker for targeted screening of esophageal adenocarcinoma/gastroesophageal junction adenocarcinoma

Date Published: April 19, 2019

Publisher: Public Library of Science

Author(s): Sijana H. Dzinic, Zaid Mahdi, M. Margarida Bernardo, Semir Vranic, Haya Beydoun, Nadine Nahra, Amra Alijagic, Deanna Harajli, Aaron Pang, Dan M. Saliganan, Abid M. Rahman, Faruk Skenderi, Berisa Hasanbegovic, Gregory Dyson, Rafic Beydoun, Shijie Sheng, Daotai Nie.


Barrett’s esophagus (BE) is a predisposing factor of esophageal adenocarcinoma/gastroesophageal junction adenocarcinoma (ECA/GEJ Aca). BE patients are stratified and subsequently monitored according to the risk of malignant progression by the combination of endoscopy and biopsy. This study is to evaluate the maspin expression patterns as early diagnostic markers of malignancy in BE patients.

Immunohistochemistry (IHC) staining was performed on 62 archival core biopsies from 35 patients, including BE without dysplasia (intestinal metaplasia, IM), BE with low grade dysplasia, BE with high grade dysplasia, carcinoma in situ, and well to poorly differentiated ECA/GEJ Aca (PD-ECA/GEJ Aca). The intensity and the subcellular distribution of immunoreactivity were evaluated microscopically. Statistical analysis was performed using the χ2 and Fisher exact tests.

The level of epithelial-specific tumor suppressor maspin protein inversely correlated with the progression from IM to PD-ECA/GEJ Aca. Lesions of each pathological grade could be divided into subtypes that exhibited distinct maspin subcellular distribution patterns, including nuclear only (Nuc), combined nuclear and cytoplasmic (Nuc+Cyt), cytoplasmic only (Cyt) and overall negligible (Neg). The Cyt subtype, which was minor in both IM and dysplasia (approximately 10%), was predominant in ECA/GEJ Aca as early as well-differentiated lesions (more than 50%: p = 0.0092). In comparison, nuclear staining of the tumor suppressor TP53 was heterogeneous in dysplasia, and did not correlate with the differentiation grades of ECA/GEJ Aca.

The Cyt subtype of maspin expression pattern in core biopsies of BE patients may serve as a molecular marker for early diagnosis of ECA/GEJ Aca.

Partial Text

The incidence of esophageal adenocarcinoma/gastroesophageal junction adenocarcinoma (ECA/GEJ Aca) has rapidly increased during the last few decades worldwide [1] and is one of the main causes of cancer mortality [2]. The increased incidence of ECA/GEJ Aca is due, in part, to the prevalence of Barrett’s esophagus (BE) in patients of chronic gastroesophageal reflux disease (GERD). There is evidence to support the disease progression sequence of GERD → Barrett’s esophagus (BE) → dysplasia → ECA/GEJ Aca [3–6].

Taking advantage of the full spectrum of pathological changes from normal to invasive poorly differentiated adenocarcinoma in our tissue specimen collection, we provide here the first evidence that epithelial-specific maspin is differentially expressed in the hypothetical sequence of esophageal adenocarcinoma progression. The total level of maspin expression was progressively downregulated from normal GEJ epithelium to MD-ECA/GEJ Aca. Maspin was not detected in a subtype of invasive PD-ECA/GEJ Aca, further consistent with the accumulated evidence that maspin silencing may specifically contribute to the transition of tumor cells to invasive and metastatic phenotypes [22,24,25]. In light of the consensus that the maspin gene is not frequently mutated or deleted in cancer, the level of maspin expression is likely regulated at the level of transcription [41]. Importantly, GEJ lesions of each pathological grade could be divided into subtypes based on maspin subcellular distribution patterns. The progressive increase in the partition of the Cyt subtype revealed a statistically significant dramatic increase overlapping with the transition from HGD to ECA/GEJ Aca in situ.