- Original article
- Open Access
Immunohistochemical prognostic markers of esophageal squamous cell carcinoma: a systematic review
Chinese Journal of Cancer volume 36, Article number: 65 (2017)
Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy, with a high incidence and poor prognosis. In the past several decades, hundreds of proteins have been reported to be associated with the prognosis of ESCC, but none has been widely accepted to guide clinical care. This study aimed to identify proteins with great potential for predicting prognosis of ESCC.
We conducted a systematic review on immunohistochemical (IHC) prognostic markers of ESCC according to the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines. Literature related to IHC prognostic markers of ESCC were searched from PubMed, Embase, Web of Science, and Cochrane Library until January 30th, 2017. The risk of bias of these original studies was evaluated using the Quality in Prognosis Studies (QUIPS) tool.
We identified 11 emerging IHC markers with reproducible results, including eight markers [epidermal growth factor receptor (EGFR), Cyclin D1, vascular endothelial growth factor (VEGF), Survivin, Podoplanin, Fascin, phosphorylated mammalian target of rapamycin (p-mTOR), and pyruvate kinase M2 (PKM2)] indicating unfavorable prognosis and 3 markers (P27, P16, and E-cadherin) indicating favorable prognosis of ESCC.
Strong evidence supports that these 11 emerging IHC markers or their combinations may be useful in predicting prognosis and aiding personalized therapy decision-making for ESCC patients.
Esophageal cancer is the sixth leading cause of cancer death and the eighth most common cancer worldwide, with more than 480,000 new cases and 400,000 deaths each year . Although the incidence of esophageal adenocarcinoma is rising in North America and Europe, esophageal squamous cell carcinoma (ESCC) remains the predominant histological type of esophageal cancer worldwide . Surgery alone or in combination with neoadjuvant chemoradiotherapy, adjuvant radiotherapy, and/or adjuvant chemotherapy remains the main curative modality for ESCC. The clinical treatment decision is based mainly on TNM (tumor, node, metastasis) staging . However, given the insidious symptoms, late clinical presentation, and rapid progression of the disease, the prognosis of ESCC remains extremely poor. In China, ESCC remains the fourth leading cause of cancer-related death , and the 5-year survival rate of ESCC patients who undergo surgery is only 30%–40% .
Better knowledge of patient prognosis would help guide surgery or adjuvant treatment. Molecules identified as critical in carcinogenesis and cancer progression may help classify patients at the same stage into different subgroups in terms of their prognosis, e.g., estrogen receptor (ER) status and human epidermal growth factor receptor-2 (HER2) status in breast cancer patients . Much effort has been made to identify prognostic markers of ESCC. Recently, Chen et al.  comprehensively evaluated the prognostic values of copy number variation (CNV), mutations, and relative expression of genes in ESCC. They identified mutations in neurogenic locus notch homolog protein 1 (NOTCH1) as well as CNVs in MYB proto-oncogene like 2 (MYBL2) and microRNA-4707-5p, and subsequently validated the prognostic values of these genes based on the expression profiles of an independent retrospective ESCC cohort . Many studies have been conducted to evaluate the prognostic values of proteins detected with immunohistochemistry (IHC) in ESCC. Most of these studies were conducted retrospectively, and significant heterogeneity has been noted in the patient populations (regions, races, and disease stages), treatments employed, antibodies used, IHC scoring methods, and length of follow-up. Given these limitations, the prognostic values of most proteins may not be reproducible among different populations. In addition, no IHC biomarker has been accepted into clinical prognostic models in practice, such as the TNM classification for ESCC. Therefore, we conducted a systematic review of the published literature to summarize potential prognostic biomarkers that may be worthy of validation in well-designed, large, prospective trials.
Materials and methods
Data source and study selection
This review was conducted according to the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines . We searched the PubMed, Embase, Web of Science, and Cochrane Library with the key phrases “esophageal squamous cell carcinoma OR oesophageal squamous cell carcinoma OR ESCC” AND “prognosis OR prognostic OR outcome OR survival OR recurrence OR relapse OR response” AND “expression” with the search limited to “humans” until January 30th, 2017.
Two investigators (CW and JW) independently screened the retrieved literature by title and abstract for inclusion in the review. If the suitability of an article was uncertain, the full text was assessed. Disagreements were resolved by consensus or reviewed by a third investigator (ZC). The criteria used to determine study eligibility were as follows: (1) a prospective or retrospective cohort with a minimum of 50 patients; (2) assay of primary ESCC specimens; (3) assessment of the expression of target proteins with IHC; (4) analysis of the associations of markers with disease-specific survival (DSS), disease-free survival (DFS), progression-free survival (PFS), or overall survival (OS); and (5) full text available. Studies were excluded when the target proteins were evaluated in less than four independent original studies. Moreover, when overlapping patient cohorts were used to investigate the prognostic value of one marker in multiple studies, the one with a smaller sample size was excluded from the review. Meta-analyses papers on the prognostic value of the protein of interest were considered and included, whereas the original reports involved in those meta-analyses were excluded. The subsequent original reports on the same protein published after the meta-analyses were also reviewed and described in the present systematic review.
We considered the proteins “emerging markers” according to the criteria as follows: (1) more than half of the original studies revealed that the expression of a given protein was significantly associated with prognosis; (2) the independent prognostic significance of the protein was demonstrated by multivariate analysis in 3 or more original studies.
Data extraction and assessment
Two reviewers (CW and JW) independently extracted data on country, sample size, age, gender, tumor stage, specific proteins, and the results of statistical analyses from the selected original studies. Study quality was assessed using the PRISMA Statement . The Quality in Prognosis Studies (QUIPS) tool  was used to evaluate the risk of bias of these original studies. Since all original studies were retrospective studies, they were not evaluated for items b, c, and e of the second domain (study attrition) . Risk of bias was graded as high, moderate, or low according to prompting items.
Study selection and study characteristics
Dating to January 30th, 2017, a total of 3324 articles were retrieved from PubMed, Embase, Web of Science, and Cochrane Library as illustrated in Fig. 1. A total of 3226 articles were excluded after reviewing titles and abstracts. Two were excluded after full-text review. Finally, 96 studies, including 14 meta-analyses (Table 1) and 82 original studies (Tables 2, 3, 4, 5, 6, 7) analyzing 30 proteins, were included. The characteristics of the original studies are illustrated in Additional file 1: Table S1. All original studies were conducted retrospectively. The sample size varied between 51 and 590 ESCC patients. More than half (53%–98%) of ESCC patients were men in all original studies. The median age of ESCC patients varied between 52 and 66 years old, notably 9 original studies failed to report a median age [10,11,12,13,14,15,16,17,18]. The majority of the original studies were conducted in China (50.0%, 41/82) and Japan (35.3%, 29/82).
Quality assessment was conducted using the QUIPS tool . Approximately one-third (39.0%, 32/82) of these original studies showed a moderate risk of bias for domain 1 (“Study Participation”), primarily due to small participation cohorts (Additional file 2: Table S2). For domain 2 (“Study Attrition”), 73 original studies showed a low risk of bias because of the high follow-up rate for study participants. Seven original studies had moderate bias in domain 2 due to missing data on participants that were lost to follow-up [19,20,21,22,23,24,25]. There was a high risk of bias in domain 2 in 2 studies because of high loss to follow-up rates (50 and 23%) [11, 26]. All original studies provided clear description of prognostic factors and clear definitions of outcomes and thus were all ranked as having a low risk of bias for domain 3 (“Prognostic Factor Measurement”) and domain 4 (“Outcome Measurement”). Moreover, 25 of the 82 original studies conducted only log-rank analyses, without multivariate Cox analysis. These original studies were ranked as having a moderate risk of bias for domain 5 (“Statistical Analysis and Reporting”).
Associations between proliferation-related markers and prognosis of ESCC patients
Seven markers are involved in proliferation-sustaining signalling in ESCC, including epidermal growth factor receptor (EGFR), human epidermal growth factor receptor-2 (HER2), phosphorylated mammalian target of rapamycin (p-mTOR), Cyclin D1, P16, P21, and P27 (Tables 1, 2).
Yu et al.  systematically reviewed 9 original studies published between 1991 and 2010, of which five concerned OS and EGFR overexpression. Significant associations between EGFR overexpression and lymph node status and differentiation grade were noted. Four of the 5 original studies revealed prognostic significance of EGFR overexpression. Meta-analysis demonstrated that EGFR overexpression was associated with short OS.
Recently, Wang et al.  conducted a meta-analysis of original studies published before December 2013 that produced the same conclusion. Five original studies published after December 2013 demonstrated a significant association between EGFR overexpression and poor prognosis [10, 29,30,31,32]. Of note, 3 original studies indicated that EGFR overexpression may be an independent prognostic marker in ESCC patients [10, 30, 32]. Overall, strong evidence has suggested that the strength of this significance warrants confirmation in clinical trials with more homogeneous and well-defined populations.
Although 3 original studies of HER2 in ESCC indicated that patients without HER2 protein expression exhibited a higher survival rate than those with HER2 expression [33,34,35], no evidence suggests that HER2 expression may be an independent prognostic predictor in patients with ESCC.
Four original studies investigated mTOR activation status and its prognostic significance in ESCC [36,37,38,39]. Approximately 50% of the patients in these original studies were p-mTOR-positive. All the 4 original studies indicated that a high level of p-mTOR was associated with unfavorable prognosis. Moreover, the independent prognostic value of p-mTOR in ESCC was demonstrated in 2 original studies [36, 39].
The prognostic significance of Cyclin D1 in ESCC has been extensively studied. Zhao et al.  conducted a meta-analysis of 10 original studies regarding the prognostic significance of Cyclin D1 expression in ESCC published before April 2010 and comprising 1376 patients. Of these 10 original studies, eight identified Cyclin D1 expression as an independent prognostic factor of ESCC. The pooled hazard ratio (HR) for Cyclin D1 expression was 1.78, indicating that the overexpression of Cyclin D1 was significantly associated with poor prognosis of ESCC patients. In 2013, Chen et al.  conducted a systematic review and meta-analysis of tumor biomarkers in predicting prognosis in esophageal cancer. Twelve studies comprising 1295 ESCC patients were enrolled to evaluate the prognostic significance of Cyclin D1 expression in ESCC, and two evaluated the expression of Cyclin D1 using polymerase chain reaction assay (PCR) instead of IHC. The pooled HR was 1.82, which is very consistent with the results of previous studies.
The association of P16 expression with favorable prognosis in ESCC was demonstrated in 3 separate original studies with multivariate analysis [42,43,44]; two studies demonstrated the prognostic value of P16 expression only with univariate analysis [45, 46]. However, no prognostic significance of P16 was shown in two other original studies [11, 20]. Notably, P16 expression combined with other markers may serve as a better prognostic factor in ESCC patients. In the study conducted by Mathew et al. , univariate analysis revealed that pRb−/P16−/P21− (P = 0.03) and P53+/P16−/pRb− (P = 0.02) were prognostic indicators for short OS. In a subsequent original study, the OS rate of patients with P16+/VEGF− was significantly higher than that of other patient groups .
According to the meta-analysis performed by Chen et al. , the pooled HR in ESCC for P21 was 1.28. However, one subsequent original study has confirmed that P21 expression was an independent favorable prognostic factor in ESCC .
Chen et al.  also showed that the pooled HR in ESCC for P27 was 0.51, indicating that P27 was an independent favourable prognostic factor in ESCC.
Associations between growth suppression-related markers and prognosis of ESCC patients
Retinoblastoma-associated protein (Rb) and P53 are two prototypical tumor suppressors that have been hotspots of prognostic marker research for many years (Tables 1, 3).
The prognostic significance of Rb in ESCC has been studied by multiple groups [11, 44, 45, 47,48,49,50,51]. However, only 1 original study reported the association between Rb expression and favorable prognosis with univariate analysis .
Chen et al.  systematically reviewed 20 original studies concerning the relationship between P53 expression and the prognosis of ESCC, and revealed that P53 expression was an unfavorable prognostic marker. However, the pooled HR in ESCC for P53 was close to 1. There were five subsequent original studies [20, 30, 52,53,54], only one of which showed independent prognostic significance of P53 in ESCC .
Associations between apoptosis-related markers and prognosis of ESCC patients
Seven markers function as regulators of apoptosis, including murine double minute gene 2 (MDM2), Survivin, Fas, Bax, Bcl-2, Bcl-x, and Caspase-3 (Tables 1, 4).
The independent prognostic significance of MDM2 expression for patients with ESCC was determined in 2 large original studies [55, 56]. Another study demonstrated that MDM2 expression was an independent prognostic factor exclusively in the p53-negative subgroup . Three reports claimed no association [11, 20, 49].
Two meta-analyses demonstrated that Survivin was an independent unfavorable prognostic factor in ESCC with significant heterogeneity [58, 59]. Li et al.  further indicated that Survivin expression in the nuclei had an unfavorable impact on ESCC patient survival, whereas Survivin expression in the cytoplasm has no prognostic significance. Chen et al.  showed that the pooled HR of Survivin expression estimated for survival was 1.57, but the 95% CI covered 1.00.
The independent prognostic significance of Fas for a favorable outcome of ESCC was demonstrated in 2 original studies [60, 61], but was not confirmed in 2 other original studies [62, 63].
Three of 9 original studies demonstrated the prognostic value of Bax for a good outcome with univariate analysis or log-rank test [13, 45, 64], with 2 original studies demonstrating statistical significance with multivariate analysis [45, 64]. Only one original study of ESCC patients treated with neochemotherapy reported that Bax expression was associated with unfavorable prognosis . No association were identified between Bax expression and clinical outcome of ESCC patients in other studies [62, 66,67,68,69]. This discrepancy may be due to the different treatments employed.
Bcl-2 and Bcl-x
Original studies of the prognostic role of Bcl-2 and Bcl-x in ESCC yielded conflicting results. Most original studies revealed that Bcl-2 or Bcl-x expression had no impact on the clinical outcome of patients with ESCC [63, 65, 66]. The independent prognostic value of Bcl-2 and Bcl-x expression was verified in one study each [62, 67]. Contrasting conclusions were also drawn in other original studies [45, 70].
The largest original study suggested that Caspase-3 expression may be an independent prognostic indicator for primary resectable ESCC . Consistently, Jiang et al.  reported that the up-regulation of Caspase-3 expression was associated with favorable prognosis. However, no independent prognostic significance of Caspase-3 in ESCC was elucidated in 2 other original studies [62, 65].
Associations between angiogenesis-related markers and prognosis of ESCC patients
The prognostic values of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α), key regulators of angiogenesis, have been studied exhaustively in ESCC (Tables 1, 5).
Two meta-analyses revealed the prognostic significance of elevated VEGF expression for poor prognosis among patients with ESCC [41, 71]. Four additional original studies also reported unfavorable prognosis for ESCC patients with VEGF overexpression [15, 52, 72, 73], with the prognostic significance confirmed by multivariate analysis in 2 original studies [15, 72].
Two meta-analyses revealed a significant association of increased HIF-1α expression with unfavorable prognosis in ESCC [74, 75]. There were 2 additional original studies [76, 77] after the meta-analyses. Zhang et al.  confirmed the association of HIF-1α overexpression with poor prognosis in ESCC patients with log-rank test. Furthermore, they revealed that HIF-1α expression in tumor cells was an independent prognostic marker for patients with locoregional or metastatic ESCC with multivariate analysis.
Associations between invasion- and metastasis-related markers and prognosis of ESCC patients
Multiple markers involved in activating invasion and metastasis are summarized, including E-cadherin, α-catenin, β-catenin, Podoplanin, Fascin, and metastasis-associated protein 1 (MTA1) (Tables 1, 6).
Two research groups conducted meta-analyses to investigate the effect of E-cadherin on the prognosis of ESCC [41, 78]. One original study was involved in both meta-analyses, evaluating E-cadherin expression by enzyme-linked immunosorbent assay (ELISA) instead of IHC. Both meta-analyses suggested that reduced E-cadherin expression was a prognostic indicator for short survival in ESCC, although the 95% CI of pooled HR covers 1.00 in the analysis by Chen et al. . One subsequent study also revealed the association between reduced E-cadherin expression and short survival using the log-rank test .
Nakanishi et al.  reported that down-regulation of α-catenin was associated with poor prognosis in patients with ESCC using the log-rank test, but no statistical significant association was revealed in multivariate analysis. Setoyama et al.  demonstrated the independent favorable prognostic significance of α-catenin. Two other original studies revealed no prognostic value of α-catenin in ESCC [26, 81].
Although β-catenin has been studied by many groups, its effect on the prognosis of ESCC remains inconclusive. Two original studies confirmed that β-catenin was an independent prognostic factor for short survival of ESCC patients [23, 82]. By contrast, Hsu et al.  reported that membranous β-catenin expression was associated with good prognosis independently, whereas cytoplasmic β-catenin expression was not associated with patient survival. Other original studies indicated that β-catenin had no effect on the outcome of patients with ESCC [26, 62, 81, 84,85,86].
Podoplanin expression was independently associated with poor outcomes in patients with ESCC as consistently reported by 4 separate original studies [16, 87,88,89]. In one other study, high podoplanin expression was significantly associated unfavorite prognosis only in univariate analysis .
Fascin overexpression independently predicted poor prognosis in ESCC patients in 3 separate original studies [29, 91, 92], but no association between Fascin expression and patient survival was identified in another study .
Luo et al.  conducted a meta-analysis to examine the relationship between MTA1 and survival of patients with solid tumors. Three of the 4 involved original studies determined that MTA1 overexpression was associated with short survival of ESCC patients. The pooled HR of MTA1 overexpression in ESCC was 1.86, with no significant heterogeneity.
Associations between energy metabolism-related markers and prognosis of ESCC patients
Pyruvate kinase M2 (PKM2) is involved in energy metabolism, whose prognostic value in ESCC was studied (Table 7).
Four original studies consistently elucidated the prognostic value of PKM2 expression for poor clinical outcome [17, 24, 95, 96], with the prognostic significance confirmed by multivariate analysis in 3 original studies [17, 95, 96]. These findings provide evidence of the significance of PKM2 expression as a prognostic biomarker in ESCC.
Associations between immune regulation-related markers and prognosis of ESCC patients
Three markers involved in immune regulation, programmed cell death-ligand 1 (PD-L1), C-X-C chemokine receptor type 4 (CXCR4), and cyclooxygenase-2 (COX-2), have been studied for their prognostic implications in ESCC (Tables 1, 7).
Qu et al.  performed a meta-analysis of the prognostic significance of PD-L1 expression in ESCC patients. The study showed that overexpression of PD-L1 tended to be associated with short OS in ESCC; however, the difference did not reach statistical significance (P = 0.07).
The expression of CXCR4 was an unfavorable independent prognostic factor in ESCC in one report . An association of CXCR4 expression and survival was revealed by log-rank test in another 2 original studies, although statistical significance was not achieved in multivariate analysis [99, 100]. However, 2 other original studies claimed no association between CXCR4 expression and the prognosis of ESCC patients [25, 101].
Li et al.  systematically reviewed 12 original studies analyzing the prognostic significance of COX-2 expression in ESCC published before December 2008. A quantitative meta-analysis revealed that COX-2 overexpression was significantly associated with short OS. Chen et al.  performed meta-analyses on 2 original studies involved in Li’s review  and 2 additional relative original studies published after 2008. COX-2 expression was marginally significant as a prognostic marker in ESCC . Ten of 14 original studies enrolled in these meta-analyses revealed that high expression of COX-2 was associated with short survival. However, the prognostic significance was confirmed by multivariate analysis in only one study with more than 50 patients enrolled.
Associations between other markers and prognosis of ESCC patients
Octamer-binding transcription factor 4 (OCT4)
Nagaraja et al.  systematically reviewed 4 original studies of OCT4 expression and the clinical outcome of patients with ESCC published before May 2013. Meta-analysis showed that the positive rate of OCT4 was 53.6%. The HR of OCT4 expression for poor prognosis was 2.9, indicating the unfavourable prognostic role of OCT4 in ESCC.
Reduced MLH1 expression has been demonstrated to be an independent prognostic indicator for poor prognosis in ESCC . Consistently, Uehara et al.  revealed that MLH1 expression was associated with favourable prognosis as determined using log-rank test; they further demonstrated that the combination of MLH1 and Mut-S-Homologon-2 (MSH2) expression was an independent prognostic indicator as determined using multivariate analysis. However, no significant association between MLH1 expression and patient survival was identified in another study .
In this review, we summarized that 8 markers (EGFR, p-mTOR, Cyclin D1, Survivin, VEGF, Podoplanin, Fascin, and PKM2) were associated with poor prognosis and 3 markers (P27, P16, E-cadherin) were associated with good prognosis of ESCC (Additional file 3: Table S3). All these markers were investigated by 4 or more groups. More than half of the original studies revealed that the expression of the given protein was significantly associated with prognosis. In addition, the independent prognostic significance of these markers was demonstrated by multivariate analysis in 3 or more original studies. The strong evidence above suggests that the prognostic significance of these markers warrants prospective confirmation in large, well-defined clinical trials. Moreover, the prognostic significance of HIF-1α, MTA1, and OCT4 has been delineated by meta-analyses. However, these proteins do not meet our criteria for “emerging markers”.
The prognostic values of several markers, such as P53, Rb, and HER2, in ESCC have been studied exhaustively. Studies that evaluated the impact of P53 expression on the outcome of ESCC patients have yielded conflicting results. A meta-analysis conducted by Chen et al.  showed that the pooled HR of P53 for prognosis is approximately 1. Although the prognostic values of Rb and HER2 were evaluated in 4 or more cohorts, no independent prognostic significance was demonstrated, indicating that their prognostic values are, at best, weak.
We have selected prognostic biomarkers based on strong evidence that may help guide clinical practice. Several studies demonstrated that ESCC patients with high EGFR expression showed a higher response rate to EGFR inhibitors and monoclonal antibodies against EGFR as well as longer PFS and/or OS than those with low to moderate EGFR expression [106,107,108,109], although controversial results have also been reported . In addition, the predictive implication of the expression of VEGF and p-mTOR for bevacizumab or everolimus treatment of ESCC patients, respectively, merits further investigation. Although inhibitors of other prognostic markers have not been developed or applied in clinical practice yet, the status of these markers may help clinicians to choose between aggressive and conservative treatments. However, it remains a large challenge to translate these research results into clinical practice. As summarized by Ludwig and Weinstein , biomarkers should be validated in prospective, well-controlled clinical studies of diverse patient populations across multiple institutions with well-established standards for sample preparation, data capture, statistical analysis, and scoring. In IHC marker research, antibodies with high sensitivity and specificity are pivotal, and studies that identify the best scoring methods for each potential marker are warranted.
This systematic review is subject to limitations. We focused primarily on only the prognostic significance of individual markers in this review. Many studies have attempted to evaluate multiple markers simultaneously. In some of the studies, a panel of markers predicted prognosis, although individual markers exhibited no prognostic significance [11, 45]. Due to the wide variety of different combinations of markers, it is beyond the scope of the current review to summarize prognostic panels of markers. However, given the complexity of the transformation process, a panel of molecules involved in different pathways may be able to predict prognosis with higher sensitivity and specificity than individual markers. Therefore, marker panels with putative prognostic value should be generated based on emerging individual prognostic markers.
Here we summarized 11 emerging prognostic markers in ESCC based on sufficient evidence in this systematic review that warrant validation in large prospective clinical trials. These markers might be useful in predicting prognosis and facilitating personalized therapy decision-making for ESCC patients.
C-X-C chemokine receptor type 4
epidermal growth factor receptor
enzyme-linked immunosorbent assay
esophageal squamous cell carcinoma
human epidermal growth factor receptor-2
murine double minute gene 2
metastasis-associated protein 1
MYB proto-oncogene like 2
mammalian target of rapamycin
neurogenic locus notch homolog protein 1
octamer-binding transcription factor 4
polymerase chain reaction assay
programmed cell death ligand 1
pyruvate kinase M2
vascular endothelial growth fac
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.
Rustgi AK, El-Serag HB. Esophageal carcinoma. N Engl J Med. 2014;371(26):2499–509.
Pennathur A, Gibson MK, Jobe BA, Luketich JD. Oesophageal carcinoma. Lancet. 2013;381(9864):400–12.
Chen W, Zheng R, Zeng H, Zhang S. The incidence and mortality of major cancers in China, 2012. Chin J Cancer. 2016;35(1):73.
Mao Y, He J, Gao S, Xue Q. Controversies in the surgical treatment for esophageal carcinoma and future investigation. Zhonghua wei chang wai ke za zhi = Chin J Gastrointest Surg. 2015;18(9):851–4.
Blows FM, Driver KE, Schmidt MK, Broeks A, van Leeuwen FE, Wesseling J, Cheang MC, Gelmon K, Nielsen TO, Blomqvist C, et al. Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: a collaborative analysis of data for 10,159 cases from 12 studies. PLoS Med. 2010;7(5):e1000279.
Chen YB, Jia WH. A comprehensive genomic characterization of esophageal squamous cell carcinoma: from prognostic analysis to in vivo assay. Chin J Cancer. 2016;35(1):76.
Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097.
Hayden JA, van der Windt DA, Cartwright JL, Cote P, Bombardier C. Assessing bias in studies of prognostic factors. Ann Intern Med. 2013;158(4):280–6.
Zhang W, Zhu H, Liu X, Wang Q, Zhang X, He J, Sun K, Liu X, Zhou Z, Xu N, et al. Epidermal growth factor receptor is a prognosis predictor in patients with esophageal squamous cell carcinoma. Annals Thorac Surg. 2014;98(2):513–9.
Mathew R, Arora S, Khanna R, Mathur M, Shukla NK, Ralhan R. Alterations in p53 and pRb pathways and their prognostic significance in oesophageal cancer. Eur J Cancer (Oxford, England: 1990). 2002;38(6):832–41.
Shiozaki A, Nakashima S, Ichikawa D, Fujiwara H, Konishi H, Komatsu S, Kubota T, Okamoto K, Iitaka D, Shimizu H, et al. Prognostic significance of p21 expression in patients with esophageal squamous cell carcinoma. Anticancer Res. 2013;33(10):4329–35.
Ikeguchi M, Maeta M, Kaibara N. Bax expression as a prognostic marker of postoperative chemoradiotherapy for patients with esophageal cancer. Int J Mol Med. 2001;7(4):413–7.
Jiang H, Gong M, Cui Y, Ma K, Chang D, Wang TY. Upregulation of caspase-3 expression in esophageal cancer correlates with favorable prognosis: an immunohistochemical study from a high incidence area in northern China. Dis Esophagus Off J Int Soc Dis Esophagus ISDE. 2010;23(6):487–92.
Tao YS, Ma XY, Chai DM, Ma L, Feng ZZ, Cheng ZN, Lai MD. Overexpression of MMP-1 and VEGF-C is associated with a less favorable prognosis in esophageal squamous cell carcinoma. Onkologie. 2012;35(11):651–6.
Tong L, Yuan S, Feng F, Zhang H. Role of podoplanin expression in esophageal squamous cell carcinoma: a retrospective study. Dis Esophagus Off J Int Soc Dis Esophagus ISDE. 2012;25(1):72–80.
Zhan C, Shi Y, Lu C, Wang Q. Pyruvate kinase M2 is highly correlated with the differentiation and the prognosis of esophageal squamous cell cancer. Dis Esophagus Off J Int Soc Dis Esophagus ISDE. 2013;26(7):746–53.
Tzao C, Hsu HS, Sun GH, Lai HL, Wang YC, Tung HJ, Yu CP, Cheng YL, Lee SC. Promoter methylation of the hMLH1 gene and protein expression of human mutL homolog 1 and human mutS homolog 2 in resected esophageal squamous cell carcinoma. J Thorac Cardiovasc Surg. 2005;130(5):1371–7.
Zhang L, Sun J, Zhang JQ, Yang M, Bai G, Ma XL. Expression and significance of molecular biomarkers in esophageal carcinoma in different nationalities patients in Xinjiang. Genet Mol Res GMR. 2014;13(3):5413–25.
Okamoto H, Fujishima F, Nakamura Y, Zuguchi M, Ozawa Y, Takahashi Y, Miyata G, Kamei T, Nakano T, Taniyama Y, et al. Significance of CD133 expression in esophageal squamous cell carcinoma. World J Surg Oncol. 2013;11:51.
Wang XS, Luo KJ, Bella AE, Bu SS, Wen J, Zhang SS, Hu Y. Caspase-3 expression in metastatic lymph nodes of esophageal squamous cell carcinoma is prognostic of survival. World J Gastroenterol WJG. 2014;20(15):4414–20.
Nakanishi Y, Ochiai A, Akimoto S, Kato H, Watanabe H, Tachimori Y, Yamamoto S, Hirohashi S. Expression of E-cadherin, alpha-catenin, beta-catenin and plakoglobin in esophageal carcinomas and its prognostic significance: immunohistochemical analysis of 96 lesions. Oncology. 1997;54(2):158–65.
Lv J, Cao XF, Ji L, Zhu B, Wang DD, Tao L, Li SQ. Association of beta-catenin, Wnt1, Smad4, Hoxa9, and Bmi-1 with the prognosis of esophageal squamous cell carcinoma. Med Oncol. 2012;29(1):151–60.
Li W, Xu Z, Hong J, Xu Y. Expression patterns of three regulation enzymes in glycolysis in esophageal squamous cell carcinoma: association with survival. Med Oncol. 2014;31(9):118.
Gockel I, Schimanski CC, Heinrich C, Wehler T, Frerichs K, Drescher D, von Langsdorff C, Domeyer M, Biesterfeld S, Galle PR, et al. Expression of chemokine receptor CXCR4 in esophageal squamous cell and adenocarcinoma. BMC cancer. 2006;6:290.
Nair KS, Naidoo R, Chetty R. Microsatellite analysis of the APC gene and immunoexpression of E-cadherin, catenin, and tubulin in esophageal squamous cell carcinoma. Hum Pathol. 2006;37(2):125–34.
Yu WW, Guo YM, Zhu M, Cai XW, Zhu ZF, Zhao WX, Fu XL. Clinicopathological and prognostic significance of EGFR over-expression in esophageal squamous cell carcinoma: a meta-analysis. Hepatogastroenterology. 2011;58(106):426–31.
Wang J, Yu JM, Jing SW, Guo Y, Wu YJ, Li N, Jiao WP, Wang L, Zhang YJ. Relationship between EGFR over-expression and clinicopathologic characteristics in squamous cell carcinoma of the esophagus: a meta-analysis. Asian Pac J Cancer Prev APJCP. 2014;15(14):5889–93.
Cao HH, Zheng CP, Wang SH, Wu JY, Shen JH, Xu XE, Fu JH, Wu ZY, Li EM, Xu LY. A molecular prognostic model predicts esophageal squamous cell carcinoma prognosis. PLoS ONE. 2014;9(8):e106007.
Shang L, Liu HJ, Hao JJ, Jiang YY, Shi F, Zhang Y, Cai Y, Xu X, Jia XM, Zhan QM, et al. A panel of overexpressed proteins for prognosis in esophageal squamous cell carcinoma. PLoS ONE. 2014;9(10):e111045.
Jiang D, Li X, Wang H, Shi Y, Xu C, Lu S, Huang J, Xu Y, Zeng H, Su J, et al. The prognostic value of EGFR overexpression and amplification in Esophageal squamous cell Carcinoma. BMC cancer. 2015;15:377.
Xu KK, Tian F, Chang D, Gong M, Fan JQ, Wang TY. Clinical effect of E-series of prostaglandin receptor 2 and epidermal growth factor receptor signal pathways in the development of esophageal squamous cell carcinoma. Dis Esophagus Off J Int Soc Dis Esophagus ISDE. 2014;27(4):388–95.
Mimura K, Kono K, Hanawa M, Mitsui F, Sugai H, Miyagawa N, Ooi A, Fujii H. Frequencies of HER-2/neu expression and gene amplification in patients with oesophageal squamous cell carcinoma. Br J Cancer. 2005;92(7):1253–60.
Sunpaweravong P, Sunpaweravong S, Puttawibul P, Mitarnun W, Zeng C, Baron AE, Franklin W, Said S, Varella-Garcia M. Epidermal growth factor receptor and cyclin D1 are independently amplified and overexpressed in esophageal squamous cell carcinoma. J Cancer Res Clin Oncol. 2005;131(2):111–9.
Zhan N, Dong WG, Tang YF, Wang ZS, Xiong CL. Analysis of HER2 gene amplification and protein expression in esophageal squamous cell carcinoma. Med Oncol. 2012;29(2):933–40.
Hirashima K, Baba Y, Watanabe M, Karashima R, Sato N, Imamura Y, Hiyoshi Y, Nagai Y, Hayashi N, Iyama K, et al. Phosphorylated mTOR expression is associated with poor prognosis for patients with esophageal squamous cell carcinoma. Ann Surg Oncol. 2010;17(9):2486–93.
Kim SH, Chau GC, Jang YH, Lee SI, Pyo S, Um SH. Clinicopathologic significance and function of mammalian target of rapamycin activation in esophageal squamous cell carcinoma. Hum Pathol. 2013;44(2):226–36.
Li SH, Chen CH, Lu HI, Huang WT, Tien WY, Lan YC, Lee CC, Chen YH, Huang HY, Chang AY, et al. Phosphorylated p70S6K expression is an independent prognosticator for patients with esophageal squamous cell carcinoma. Surgery. 2015;157(3):570–80.
Li SH, Huang EY, Lu HI, Huang WT, Yen CC, Huang WC, Chen CH. Phosphorylated mammalian target of rapamycin expression is associated with the response to chemoradiotherapy in patients with esophageal squamous cell carcinoma. J Thorac Cardiovasc Surg. 2012;144(6):1352–9.
Zhao J, Li L, Wei S, Gao Y, Chen Y, Wang G, Wu Z. Clinicopathological and prognostic role of cyclin D1 in esophageal squamous cell carcinoma: a meta-analysis. Dis Esophagus Off J Int Soc Dis Esophagus ISDE. 2012;25(6):520–6.
Chen M, Huang J, Zhu Z, Zhang J, Li K. Systematic review and meta-analysis of tumor biomarkers in predicting prognosis in esophageal cancer. BMC cancer. 2013;13:539.
Cao F, Zhang W, Zhang F, Han H, Xu J, Cheng Y. Prognostic significance of high-risk human papillomavirus and p16(INK4A) in patients with esophageal squamous cell carcinoma. Int J Clin Exp Med. 2014;7(10):3430–8.
Guan C, Shi H, Wang H, Zhang J, Ni W, Chen B, Hou S, Yang X, Shen A, Ni R. CtBP2 contributes to malignant development of human esophageal squamous cell carcinoma by regulation of p16INK4A. J Cell Biochem. 2013;114(6):1343–54.
Takeuchi H, Ozawa S, Shih CH, Ando N, Kitagawa Y, Ueda M, Kitajima M. Loss of p16INK4a expression is associated with vascular endothelial growth factor expression in squamous cell carcinoma of the esophagus. Int J Cancer J Int du cancer. 2004;109(4):483–90.
Guner D, Sturm I, Hemmati P, Hermann S, Hauptmann S, Wurm R, Budach V, Dorken B, Lorenz M, Daniel PT. Multigene analysis of Rb pathway and apoptosis control in esophageal squamous cell carcinoma identifies patients with good prognosis. Int J Cancer J Int du Cancer. 2003;103(4):445–54.
Fujiwara S, Noguchi T, Takeno S, Kimura Y, Fumoto S, Kawahara K. Hypermethylation of p16 gene promoter correlates with loss of p16 expression that results in poorer prognosis in esophageal squamous cell carcinomas. Dis Esophagus Off J Int Soc Dis Esophagus ISDE. 2008;21(2):125–31.
Ikeguchi M, Oka S, Gomyo Y, Tsujitani S, Maeta M, Kaibara N. Combined analysis of p53 and retinoblastoma protein expressions in esophageal cancer. Annals Thorac Surg. 2000;70(3):913–7.
Ikeguchi M, Sakatani T, Ueta T, Kaibara N. Cyclin D1 expression and retinoblastoma gene protein (pRB) expression in esophageal squamous cell carcinoma. J Cancer Res Clin Oncol. 2001;127(9):531–6.
Nam TK, Lee JH, Cho SH, Chung IJ, Ahn SJ, Song JY, Yoon MS, Chung WK, Nah BS. Low hMLH1 expression prior to definitive chemoradiotherapy predicts poor prognosis in esophageal squamous cell carcinoma. Cancer Lett. 2008;260(1–2):109–17.
Nita ME, Nagawa H, Tominaga O, Tsuno N, Hatano K, Kitayama J, Tsuruo T, Domene CE, Muto T. p21Waf1/Cip1 expression is a prognostic marker in curatively resected esophageal squamous cell carcinoma, but not p27Kip1, p53, or Rb. Ann Surg Oncol. 1999;6(5):481–8.
Wang MT, Chen G, An SJ, Chen ZH, Huang ZM, Xiao P, Ben XS, Xie Z, Chen SL, Luo DL, et al. Prognostic significance of cyclinD1 amplification and the co-alteration of cyclinD1/pRb/ppRb in patients with esophageal squamous cell carcinoma. Dis Esophagus Off J Int Soc Dis Esophagus ISDE. 2012;25(7):664–70.
Huang W, Deng B, Wang RW, Tan QY, Jiang YG. Expression of breast cancer anti-estrogen resistance 1 in relation to vascular endothelial growth factor, p53, and prognosis in esophageal squamous cell cancer. Dis Esophagus Off J Int Soc Dis Esophagus ISDE. 2013;26(5):528–37.
Murata A, Baba Y, Watanabe M, Shigaki H, Miyake K, Karashima R, Imamura Y, Ida S, Ishimoto T, Iwagami S, et al. p53 immunohistochemical expression and patient prognosis in esophageal squamous cell carcinoma. Med Oncol. 2013;30(4):728.
Wang ZB, Peng XZ, Chen SS, Ning FL, Du CJ, Wang K, Ma W, Cheng YF. High p53 and MAP1 light chain 3A co-expression predicts poor prognosis in patients with esophageal squamous cell carcinoma. Mol Med Rep. 2013;8(1):41–6.
Ikeguchi M, Ueda T, Fukuda K, Yamaguchi K, Tsujitani S, Kaibara N. Expression of the murine double minute gene 2 oncoprotein in esophageal squamous cell carcinoma as a novel marker for lack of response to chemoradiotreatment. Am J Clin Oncol. 2002;25(5):454–9.
Sun LL, Wu JY, Wu ZY, Shen JH, Xu XE, Chen B, Wang SH, Li EM, Xu LY. A three-gene signature and clinical outcome in esophageal squamous cell carcinoma. Int J Cancer J Int du Cancer. 2015;136(6):E569–77.
Cheng TH, Hsu PK, Li AF, Hung IC, Huang MH, Hsu HS. Correlation of p53, MDM2 and p14(ARF) protein expression in human esophageal squamous cell carcinoma. J Cancer Res Clin Oncol. 2009;135(11):1577–82.
Li C, Li Z, Zhu M, Zhao T, Chen L, Ji W, Chen H, Su C. Clinicopathological and prognostic significance of survivin over-expression in patients with esophageal squamous cell carcinoma: a meta-analysis. PLoS ONE. 2012;7(9):e44764.
Xia H, Chen S, Huang H, Ma H. Survivin over-expression is correlated with a poor prognosis in esophageal cancer patients. Clin Chim Acta Int J Clin Chem. 2015;446:82–5.
Chan KW, Lee PY, Lam AK, Law S, Wong J, Srivastava G. Clinical relevance of Fas expression in oesophageal squamous cell carcinoma. J Clin Pathol. 2006;59(1):101–4.
Shibakita M, Tachibana M, Dhar DK, Kotoh T, Kinugasa S, Kubota H, Masunaga R, Nagasue N. Prognostic significance of Fas and Fas ligand expressions in human esophageal cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 1999;5(9):2464–9.
Chang MS, Lee HS, Lee BL, Kim YT, Lee JS, Kim WH. Differential protein expression between esophageal squamous cell carcinoma and dysplasia, and prognostic significance of protein markers. Pathol Res Pract. 2005;201(6):417–25.
Takikita M, Hu N, Shou JZ, Wang QH, Giffen C, Taylor PR, Hewitt SM. Biomarkers of apoptosis and survival in esophageal squamous cell carcinoma. BMC cancer. 2009;9:310.
Sturm I, Petrowsky H, Volz R, Lorenz M, Radetzki S, Hillebrand T, Wolff G, Hauptmann S, Dorken B, Daniel PT. Analysis of p53/BAX/p16(ink4a/CDKN2) in esophageal squamous cell carcinoma: high BAX and p16(ink4a/CDKN2) identifies patients with good prognosis. J Clin Oncol Off J Am Soc Clin Oncol. 2001;19(8):2272–81.
Kurabayashi A, Furihata M, Matsumoto M, Ohtsuki Y, Sasaguri S, Ogoshi S. Expression of Bax and apoptosis-related proteins in human esophageal squamous cell carcinoma including dysplasia. Mod Pathol Off J US Can Acad Pathol Inc. 2001;14(8):741–7.
Natsugoe S, Matsumoto M, Okumura H, Nakashima S, Sakamoto F, Sakita H, Baba M, Takao S, Aikou T. Bax and Bcl-X(L) expression are not related to prognosis in patients with advanced esophageal squamous cell carcinoma. Cancer Lett. 2001;174(1):91–7.
Takayama T, Nagao M, Sawada H, Yamada Y, Emoto K, Fujimoto H, Ueno M, Hirao S, Nakajima Y. Bcl-X expression in esophageal squamous cell carcinoma: association with tumor progression and prognosis. J Surg Oncol. 2001;78(2):116–23.
Matsumoto M, Natsugoe S, Nakashima S, Okumura H, Sakita H, Baba M, Takao S, Aikou T. Clinical significance and prognostic value of apoptosis related proteins in superficial esophageal squamous cell carcinoma. Ann Surg Oncol. 2001;8(7):598–604.
Sarbia M, Bittinger F, Grabellus F, Verreet P, Dutkowski P, Willers R, Gabbert HE. Expression of Bax, a pro-apoptotic member of the Bcl-2 family, in esophageal squamous cell carcinoma. Int J Cancer J Int du Cancer. 1997;73(4):508–13.
Torzewski M, Sarbia M, Heep H, Dutkowski P, Willers R, Gabbert HE. Expression of Bcl-X(L), an antiapoptotic member of the Bcl-2 family, in esophageal squamous cell carcinoma. Clin Cancer Res Off J Am Assoc Cancer Res. 1998;4(3):577–83.
Chen M, Cai E, Huang J, Yu P, Li K. Prognostic value of vascular endothelial growth factor expression in patients with esophageal cancer: a systematic review and meta-analysis. Cancer Epidemiol Biomark Prev Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol. 2012;21(7):1126–34.
Hou X, Wei JC, Fu JH, Wang X, Luo RZ, He JH, Zhang LJ, Lin P, Yang HX. Vascular endothelial growth factor is a useful predictor of postoperative distant metastasis and survival prognosis in esophageal squamous cell carcinoma. Ann Surg Oncol. 2015;22(11):3666–73.
Omoto I, Matsumoto M, Okumura H, Uchikado Y, Setoyama T, Kita Y, Owaki T, Kijima Y, Shinchi H, Ishigami S, et al. Expression of vascular endothelial growth factor-C and vascular endothelial growth factor receptor-3 in esophageal squamous cell carcinoma. Oncol Lett. 2014;7(4):1027–32.
Ping W, Sun W, Zu Y, Chen W, Fu X. Clinicopathological and prognostic significance of hypoxia-inducible factor-1alpha in esophageal squamous cell carcinoma: a meta-analysis. Tumour Biol J Int Soc Oncodev Biol Med. 2014;35(5):4401–9.
Sun G, Hu W, Lu Y, Wang Y. A meta-analysis of HIF-1alpha and esophageal squamous cell carcinoma (ESCC) risk. Pathol Oncol Res POR. 2013;19(4):685–93.
Shirakawa M, Fujiwara Y, Sugita Y, Moon JH, Takiguchi S, Nakajima K, Miyata H, Yamasaki M, Mori M, Doki Y. Assessment of stanniocalcin-1 as a prognostic marker in human esophageal squamous cell carcinoma. Oncol Rep. 2012;27(4):940–6.
Zhang L, Ye SB, Li ZL, Ma G, Chen SP, He J, Liu WL, Xie D, Zeng YX, Li J. Increased HIF-1alpha expression in tumor cells and lymphocytes of tumor microenvironments predicts unfavorable survival in esophageal squamous cell carcinoma patients. Int J Clin Exp Pathol. 2014;7(7):3887–97.
Xu XL, Ling ZQ, Chen SZ, Li B, Ji WH, Mao WM. The impact of E-cadherin expression on the prognosis of esophageal cancer: a meta-analysis. Dis Esophagus Off J Int Soc Dis Esophagus Isde. 2014;27(1):79–86.
Ozawa Y, Nakamura Y, Fujishima F, Felizola SJ, Takeda K, Okamoto H, Ito K, Ishida H, Konno T, Kamei T, et al. Decreased expression of ARID1A contributes to infiltrative growth of esophageal squamous cell carcinoma. Tohoku J Exp Med. 2015;235(3):185–91.
Setoyama T, Natsugoe S, Okumura H, Matsumoto M, Uchikado Y, Yokomakura N, Ishigami S, Aikou T. Alpha-catenin is a significant prognostic factor than E-cadherin in esophageal squamous cell carcinoma. J Surg Oncol. 2007;95(2):148–55.
Lin YC, Wu MY, Li DR, Wu XY, Zheng RM. Prognostic and clinicopathological features of E-cadherin, alpha-catenin, beta-catenin, gamma-catenin and cyclin D1 expression in human esophageal squamous cell carcinoma. World J Gastroenterol Wjg. 2004;10(22):3235–9.
Situ DR, Hu Y, Zhu ZH, Wang J, Long H, Rong TH. Prognostic relevance of beta-catenin expression in T2-3N0M0 esophageal squamous cell carcinoma. World J Gastroenterol Wjg. 2010;16(41):5195–202.
Hsu PK, Li AF, Wang YC, Hsieh CC, Huang MH, Hsu WH, Hsu HS. Reduced membranous beta-catenin protein expression is associated with metastasis and poor prognosis in squamous cell carcinoma of the esophagus. J Thorac Cardiovasc Surg. 2008;135(5):1029–35.
Zhao XJ, Li H, Chen H, Liu YX, Zhang LH, Liu SX, Feng QL. Expression of e-cadherin and beta-catenin in human esophageal squamous cell carcinoma: relationships with prognosis. World J Gastroenterol Wjg. 2003;9(2):225–32.
Li AF, Hsu PK, Tzao C, Wang YC, Hung IC, Huang MH, Hsu HS. Reduced axin protein expression is associated with a poor prognosis in patients with squamous cell carcinoma of esophagus. Ann Surg Oncol. 2009;16(9):2486–93.
Deng F, Zhou K, Cui W, Liu D, Ma Y. Clinicopathological significance of wnt/beta-catenin signaling pathway in esophageal squamous cell carcinoma. Int J Clin Exp Pathol. 2015;8(3):3045–53.
Chao YK, Chuang WY, Yeh CJ, Wu YC, Liu YH, Hsieh MJ, Cheng AJ, Hsueh C, Liu HP. Prognostic significance of high podoplanin expression after chemoradiotherapy in esophageal squamous cell carcinoma patients. J Surg Oncol. 2012;105(2):183–8.
Nakashima Y, Yoshinaga K, Kitao H, Ando K, Kimura Y, Saeki H, Oki E, Morita M, Kakeji Y, Hirahashi M, et al. Podoplanin is expressed at the invasive front of esophageal squamous cell carcinomas and is involved in collective cell invasion. Cancer Sci. 2013;104(12):1718–25.
Tanaka M, Kijima H, Shimada H, Makuuchi H, Ozawa S, Inokuchi S. Expression of podoplanin and vimentin is correlated with prognosis in esophageal squamous cell carcinoma. Mol Med Rep. 2015;12(3):4029–36.
Rahadiani N, Ikeda J, Makino T, Tian T, Qiu Y, Mamat S, Wang Y, Doki Y, Aozasa K, Morii E. Tumorigenic role of podoplanin in esophageal squamous-cell carcinoma. Ann Surg Oncol. 2010;17(5):1311–23.
Hashimoto Y, Ito T, Inoue H, Okumura T, Tanaka E, Tsunoda S, Higashiyama M, Watanabe G, Imamura M, Shimada Y. Prognostic significance of fascin overexpression in human esophageal squamous cell carcinoma. Clin Cancer Res Off J Am Assoc Cancer Res. 2005;11(7):2597–605.
Zhao Q, Shen JH, Shen ZY, Wu ZY, Xu XE, Xie JJ, Wu JY, Huang Q, Lu XF, Li EM, et al. Phosphorylation of fascin decreases the risk of poor survival in patients with esophageal squamous cell carcinoma. J Histochem Cytochem Off J Histochem Soc. 2010;58(11):979–88.
Takikita M, Hu N, Shou JZ, Giffen C, Wang QH, Wang C, Hewitt SM, Taylor PR. Fascin and CK4 as biomarkers for esophageal squamous cell carcinoma. Anticancer Res. 2011;31(3):945–52.
Luo H, Li H, Yao N, Hu L, He T. Metastasis-associated protein 1 as a new prognostic marker for solid tumors: a meta-analysis of cohort studies. Tumour Biol J Int Soc Oncodev Biol Med. 2014;35(6):5823–32.
Zhang X, He C, He C, Chen B, Liu Y, Kong M, Wang C, Lin L, Dong Y, Sheng H. Nuclear PKM2 expression predicts poor prognosis in patients with esophageal squamous cell carcinoma. Pathol Res Pract. 2013;209(8):510–5.
Fukuda S, Miyata H, Miyazaki Y, Makino T, Takahashi T, Kurokawa Y, Yamasaki M, Nakajima K, Takiguchi S, Mori M, et al. Pyruvate kinase M2 modulates esophageal squamous cell carcinoma chemotherapy response by regulating the pentose phosphate pathway. Ann Surg Oncol. 2015;22(Suppl 3):1461–8.
Qu HX, Zhao LP, Zhan SH, Geng CX, Xu L, Xin YN, Jiang XJ. Clinicopathological and prognostic significance of programmed cell death ligand 1 (PD-L1) expression in patients with esophageal squamous cell carcinoma: a meta-analysis. J Thorac Dis. 2016;8(11):3197–204.
Zhang L, Ye SB, Ma G, Tang XF, Chen SP, He J, Liu WL, Xie D, Zeng YX, Li J. The expressions of MIF and CXCR4 protein in tumor microenvironment are adverse prognostic factors in patients with esophageal squamous cell carcinoma. J Transl Med. 2013;11:60.
Lu CL, Ji Y, Ge D, Guo J, Ding JY. The expression of CXCR4 and its relationship with matrix metalloproteinase-9/vascular endothelial growth factor in esophageal squamous cell cancer. Dis Esophagus. 2011;24(4):283–90.
Qi J, Li H, Liu N, Xing Y, Zhou G, Wu Y, Liu Y, Chen W, Yue J, Han B, et al. The implications and mechanisms of the extra-nuclear nucleolin in the esophageal squamous cell carcinomas. Med Oncol. 2015;32(3):45.
Sasaki K, Natsugoe S, Ishigami S, Matsumoto M, Okumura H, Setoyama T, Uchikado Y, Kita Y, Tamotsu K, Hanazono K, et al. Expression of CXCL12 and its receptor CXCR4 in esophageal squamous cell carcinoma. Oncol Rep. 2009;21(1):65–71.
Li L, Zhao J, Wu Z, Wang G, Chen G. Meta-analysis: clinicopathological and prognostic significance of cyclooxygenase-2 expression on oesophageal squamous cell carcinoma. Aliment Pharmacol Ther. 2009;30(6):589–96.
Nagaraja V, Eslick GD. Forthcoming prognostic markers for esophageal cancer: a systematic review and meta-analysis. J Gastrointest Oncol. 2014;5(1):67–76.
Kishi K, Doki Y, Yano M, Yasuda T, Fujiwara Y, Takiguchi S, Kim S, Higuchi I, Monden M. Reduced MLH1 expression after chemotherapy is an indicator for poor prognosis in esophageal cancers. Clin Cancer Res Off J Am Assoc Cancer Res. 2003;9(12):4368–75.
Uehara H, Miyamoto M, Kato K, Cho Y, Kurokawa T, Murakami S, Fukunaga A, Ebihara Y, Kaneko H, Hashimoto H, et al. Deficiency of hMLH1 and hMSH2 expression is a poor prognostic factor in esophageal squamous cell carcinoma. J Surg Oncol. 2005;92(2):109–15.
Wang X, Niu H, Fan Q, Lu P, Ma C, Liu W, Liu Y, Li W, Hu S, Ling Y, et al. Predictive value of EGFR overexpression and gene amplification on icotinib efficacy in patients with advanced esophageal squamous cell carcinoma. Oncotarget. 2016;7(17):24744–51.
Xu Y, Zheng Y, Sun X, Yu X, Gu J, Wu W, Zhang G, Hu J, Sun W, Mao W. Concurrent radiotherapy with gefitinib in elderly patients with esophageal squamous cell carcinoma: preliminary results of a phase II study. Oncotarget. 2015;6(35):38429–39.
Zhao C, Lin L, Liu J, Liu R, Chen Y, Ge F, Jia R, Jin Y, Wang Y, Xu J. A phase II study of concurrent chemoradiotherapy and erlotinib for inoperable esophageal squamous cell carcinoma. Oncotarget. 2016;7(35):57310–6.
Chen Y, Wu X, Bu S, He C, Wang W, Liu J, Guo W, Tan B, Wang Y, Wang J. Promising outcomes of definitive chemoradiation and cetuximab for patients with esophageal squamous cell carcinoma. Cancer Sci. 2012;103(11):1979–84.
Jia J, Cui Y, Lu M, Wang X, Li J, Li J, Li Y, Zhang X, Gao J, Zhou J, et al. The relation of EGFR expression by immunohistochemical staining and clinical response of combination treatment of nimotuzumab and chemotherapy in esophageal squamous cell carcinoma. Clin Transl Oncol Off Publ Fed Span Oncol Soc Nat Cancer Inst Mexico. 2016;18(6):592–8.
Ludwig JA, Weinstein JN. Biomarkers in cancer staging, prognosis and treatment selection. Nat Rev Cancer. 2005;5(11):845–56.
YG and JH designed and financed the study. CW performed the literature search and review, data extraction, and drafted the manuscript. JW and ZC participated in the literature search and data extraction. All authors read and approved the final manuscript.
We thank Ms. Meihua Xiong, Ms. Fang Zhou, and Ms. Jing Zhang of the Lab of the Department of Thoracic Surgery for administrative help. We thank Prof. Xiaoli Feng of the Department of Pathology for critical review of the manuscript. The writing and language editing of the manuscript was supported by the National Key R&D Program of China (No. 2016YFC1303200), the National Natural Science Foundation of China (No. 81502060), and Institutional Basic Research Funding (No. NCC2016YKY-06, JK2014B14).
The authors declare that they have no competing interests.
Availability of data and materials
The datasets supporting the conclusions of this article are included within the article and its Additional files 1, 2, 3.
Consent for publication
Ethics approval and consent to participate
Additional file 2: Table S2. Assessment of prognostic biomarker studies for risk of bias using the “Quality Assessment in Prognostic studies” (QUIPS) tool.
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
About this article
Cite this article
Wang, C., Wang, J., Chen, Z. et al. Immunohistochemical prognostic markers of esophageal squamous cell carcinoma: a systematic review. Chin J Cancer 36, 65 (2017). https://doi.org/10.1186/s40880-017-0232-5
- Esophageal squamous cell carcinoma
- Immunohistochemical markers