Oral squamous cell carcinoma (OSCC) is the 6th most common malignant epithelial neoplasm of the oral cavity with a prevalence of 45% of all cancers found in India. Among the oral, salivary, and pharyngeal cancers, at least 90% are OSCC. It is one of the most underdiagnosed of all cancers despite its straightforward access into the oral cavity and its diagnosis is usually established in the advanced stages, resulting in a lower five-year survival rate. Worldwide, the morbidity and mortality rates attributed to OSCC in females are 3.1/100,000 and males are 6.6/100,000. Globally, OSCC has ascended new magnitudes in terms of afflicting an overwhelming number of people i.e., more than three and a half lakh new cases and 1,77,384 deaths have been recorded since 2018.
Histopathological grading is the hallmark of assessing risk and providing tailored treatment to OSCC patients. The contemporary method of detecting OSCC is dependent on a triad of three main factors: host, tumor, and tumor-host interface. The grading system has advanced over the years with the inclusion of extra-nodal and extracapsular spread (ECS) into the 'N' stage and depth of invasion (DOI) in the 'T' stage. The DOI is different from the clinical tumor thickness and uses MRI and Ultrasound as tools of estimation for the depth of the lesion. This additional classification complements the World health organization (WHO) classification (2017) which had limited features of differentiating the histopathological grading system and previously divided the tumor into three grades: poorly differentiated, well-differentiated, and moderately differentiated sequence. The former WHO grading classification did not seem to associate well with the prognosis and required more tools like biomarkers in conjunction with the present grading system to enhance its prognostic value. Moreover, it did not have features that showed the growth pattern of the tumor; or stromal reactions like local immune response, desmoplasia, tumor stromal ratio, etc.
Description of Moesin
Due to relapse and poor survival rate among OSCC cases, the detection of biomarkers like Moesin has emerged as essential elements in improving the diagnosis, treatment, metastasis, and prognosis of OSCC patients. It is a portion of the Ezrin, Radixin, and Moesin (ERM) fraction of proteins that control the carcinogenesis progression. Moesin unambiguously controls the progression into metastasis by phosphorylation of the C-terminal part of Moesin that sends signals to the actin filament which results in changing the morphology of the cell, cell-to-cell adhesion, cell migration, and tumor incursion. Its overexpression in cancer cells spells poor prognosis.
Pathogenesis of Moesin
Moesin is a biomarker of invasiveness in the advancement of carcinogenesis, especially in the II, III, and IV stages of OSCC as it stereotypically moves from the plasma membrane of the neoplastic cells to the cytoplasm during the malignant alteration of the oral epithelium as it crosslinks between the plasma membrane and actin filament and has a greater incidence of lymph node metastasis. Moesin is usually found in the basal and parabasal layers of the normal oral epithelium and in OSCC patients it is discovered more in the cytoplasm of the malignant cells. The hypothesis inferred behind this enigmatic phenomenon is correlated to the exposure of Phosphorylation of Thr-558 and proteolytic dispensation of CD44 receptor for hyaluronan leading to the shift of moesin moiety from the plasma membrane towards the cytoplasm, thereby increasing the tumor cell migration and annexation into the deeper stratum of another cell causing invasiveness. Moreover, Moesin is not usually found in well-differentiated neoplastic cells which have more keratin pearls.
Rationale and significance of the review
Moesin has emerged as an important and valuable new biomarker along with being a prognostic factor in OSCC as it is a strong factor to predict mortality as its five-year survival rate is 22.7%. Robust expression of Moesin in neoplastic cells predicts an overall survival rate of 6.8% and with a low expression rate the survival rate is pegged at 23.8% in ten years. Therefore, it is worthwhile to study the role of Moesin and its expression in neoplastic cells. Based on this rationale, we aimed to conduct an Aetiology/Risk type and Prognostic type of systematic review with the:
Focussed Guiding Question: Does Moesin as a prognostic biomarker have an influence and an association with histopathological grades of OSCC?
Primary Objective: To evaluate an association between the prognostic significance of Moesin with histopathological grading of oral squamous cell carcinoma (OSCC) to gauge the severity of the condition in terms of 5 to 10-year survival.
Secondary objective: To estimate the detection of Moesin as a biomarker in the membranous, mixed and cytoplasmic sections of the oral squamous cell carcinomatous lesion.
The authors classified it as an aetiology/risk type of systematic review (as it determines to what degree a relationship exists between the exposure and health outcome) and a prognostic type of systematic review (as it identifies the relationships between the specific prognostic factors and outcomes).
The present systematic review protocol is registered under PROSPERO with Trial Registration No: CRD42022375824. The authors (BS, KS, and DK) initiated the systematic review by forming a review team that included the experts in information retrieval and an advisory group i.e reviewers. The timeline set was approximately 8 months from initiation. The authors piloted an exploratory wide-ranging literature search using electronic media (Scopus, EMBASE, Web of Science, Cochrane central register for controlled trials, PubMed and Google Scholar) and manual search from appropriate journals till October 2022. The review was written and conducted as per the PRISMA guidelines (Preferred Reporting Items for Systematic Review and Meta-Analyses). Studies relevant to this review were agreed upon using a tentative search in Pubmed, Scopus, Web of Sciences (http://scientific.thomson.com/products/sci/), Cochrane library (www.cochranelibrary.com)& google scholar. Unpublished literature was searched electronically through ClinicalTrials.govhttp://www.clinicaltrials.gov) and the ISRCTN registry (http://www.controlled-trials.com). The following keyword algorithm in PubMed was applied: “Moesin”, “squamous cell carcinoma of head and neck”, “OSCC”, “Oral Squamous Cell Carcinoma”, “Histopathological, Grading”, “Prognosis”. This search was revised and improvised using the Advanced Search algorithm with the following criteria: English Language; abstracts and full texts illustrating the expression of Moesin among the histopathological grades of OSCC patients and 5 to 10-year survival rates among the cancer patients.
Inclusion criteria: Cross-sectional studies and retrospective studies to evaluate the association between the prognostic significance of Moesin with histopathological grading of oral squamous cell carcinoma (OSCC). They were appraised based on the PICO format (Population, Intervention, Comparison, and Outcome) listed below:
- Population: Studies with Adult Patients (18 years and above) whose definitive OSCC status was established with oral pathological slides were included in this study.
- Intervention: Detection of Moesin (biomarker) in the membranous, mixed, and cytoplasmic sections of the carcinoma.
- Comparison: Comparison of Moesin among the histopathological grades of oral cancer to assess its prognostic value in OSCC cases.
- Outcome: Primary outcome- the expression of Moesin among the different histopathological grades to gauge its prognostic value in terms of 5-10 year survival rates and mortality among OSCC patients.
- Secondary outcome- over-expression of Moesin in the membranous, mixed, and cytoplasmic sections of the carcinoma and lymph node metastasis as a sign of invasiveness.
Exclusion criteria: Studies with patients below 18 years of age; Studies with Moesin as a biomarker in other carcinomas other than the oral cavity were mentioned but not included in the main-stay of the research; Inclusion of literature review articles, short communications, case reports, case series, letters to the editor, and conference abstracts was excluded from this review.
Collection of data and its analysis
The pertinent studies were selected by (SB, KS, and DK) independently and the carefully chosen studies were evaluated according to the inclusion criteria mentioned above and disagreements were resolved by debate before including or excluding the study. The summary of the design of selected and excluded studies is depicted in the PRISMA flow diagram [Figure 1] and then the full-text selected studies were evaluated using GRADE-Pro GDT and Rob (Risk of Bias) 2.0 Tool.
Data extraction and quality management
Two reviewers (SB and KS) extracted and critically analyzed the data and tabulated the findings systematically as study reference; author; country; study design; number and age of the patients; study intervention, comparison, and outcome measures [Tables 1, 2, and 3]. The outcome was appraised and reported quantitatively, and narratively described using: the GRADE-Pro GDT tool (See: Appendix), and the bias of every study was appraised using Cochrane RoB 2.0 tool [Figure 2]
Assessment of data synthesis and heterogeneity
On appraising the data the authors found that the data collected from the seven studies were too heterogeneous for conducting quantitative meta-analysis or subgroup analysis and decided to report the results in a narrative format.
Risk of assessment bias
The Cochrane Risk of Bias tool helped to judge the following: Randomization process (D1); Deviation from intended intervention (D2); Missing outcome data (D3); Measurement of the outcome (D4); Selection of reported result (D5); Overall Risk. The risk of bias based on the appraisal of the studies is then classified into low, high, unclear, and tabulated for convenience [Figure 3].
Addressing missing data
The problem of missing data was handled by emailing or calling the author or co-authors of the study and in case of no response, the data from the study was not discussed at the end of the study in the Discussion segment.
Confidence in the evidence (using Grade System for assessment of outcome measures)
The confidence in the evidence of this research was estimated using the Cochrane GRADE-Pro GDT tool. This tool assigned levels such as high, moderate, low, or very low to the studies included in the review based on the estimated effect or outcome (See: Appendix).
A maiden literature search found 10,659 studies [Figure 1] which included mostly cross-sectional studies on the immunochemistry of tissues of oral squamous cell carcinoma patients. An advanced search narrowed it down to 1228 studies. A detailed search of the specific inclusion criteria reduced the sample of the studies to seven [Figure 1] and the excluded studies are listed [Table 4]
Characteristics of included studies
The seven main studies were tabulated for quantitative, qualitative, and critical analysis [Table 1]. Out of the seven pertinent studies, only two studies were of good quality. The studies included in the review ranged from different countries like Japan, Brazil, China, Baghdad, and the United States, giving the review a vast overall outlook. Most of the studies were cross-sectional and were conducted in university hospitals, cancer hospitals, or tertiary care centers. The tissues samples were stereotypically collected from male patients, more than 55 years of age, and at least 40% of the samples showed marked expression of Moesin in their cytoplasm [Table 1].
Cytoplasmic Moesin expression was higher in the poorly differentiated histopathological stages of OSCC cases as compared to the well-differentiated cases indicative of poor outcome in terms of 5 to 10-year survival rate.
Clinical expediency of Moesin in the OSCC cases
This review has illustrated that Moesin as a biomarker is a representation of tumor aggressiveness, lymph node metastasis, and poor prognosis among OSCC cases and even other non-oral cancers [Figures 4-6]. Advanced carcinoma stages with enhanced Moesin expression in the cytoplasm have shown higher lymph node involvement in 48.8% of cases and muscular infiltration in 86.4% of patients.
Moreover, the manifestation of Moesin in at least 40% of the OSCC cases is strongly associated with histopathological differentiation of the tumor cell.
Moesin and survival rates in OSCC cases
Moesin expression in the cytoplasm in the later stages of cancer in OSCC cases is a hallmark of lowered survival rate (5 years = 38.5%; and 10-year survival rate is 23.8%) and 1.737 higher risks of mortality. This result is echoed across other studies where the survival rate was decreased from 67% to 34.4% in lip carcinoma cases and overall survival rates were pegged at a mean of 247 months and overall survival rates among cases with strong moesin expression in the cytoplasm was 80.3% (5 years) and 65.8%(10 years) 18 [ Table 1; See: Appendix].
Risk of mortality with strong Moesin expression in the cytoplasm
The risk of mortality in terms of Hazard ratio has been elicited in two studies out of the seven Kobayashi et al. 2004(0.209; CI (0.080- 0.554) and Barros et al., 2018(HR * = 1.37(CI = 1.08-2.78) [Figure 4].
As the sample size of this review was small the authors have included hazard ratios in some other studies [Figures 5 and 6] of carcinomas in diverse sites in the body [Figure 6] to give a flavor of the prognostic outcomes of Moesin. Figure 6 shows that Moesin expression in Breast cancer and UADT carcinomas have a higher mortality rate as compared to OSCC cases and this strengthens our conviction that Moesin expression in the cytoplasm of advanced histopathological stages of cancer can be assumed as a sign of poor prognosis in all carcinomas including OSCC patients.
Clinical efficacy of Moesin as a biomarker in OSCC cases
Moesin has emerged as an important biomarker with an enhanced expression in the cytoplasm as compared to the membranous sections during malignant translation of the normal oral epithelium of OSCC cases. The presence of Moesin has materialized as a sign of lymph node metastasis and poor prognosis in terms of reduced survival rates in OSCC patients. This verdict is consistent with previous studies. But Moesin has been corroborated as an unfavorable prognostic biomarker in OSCC cases.
Prognostic value of Moesin in the histopathological grades of OSCC patients
Most studies in this review found that Moesin was strongly associated with the histopathological grading for cancer but was not elicited in a study done in Baghdad where no statistical significance was elicited between the expression of Moesin and its association with the histopathological grading in OSCC cases. In a study on laryngeal squamous cell carcinoma (LSCC), Moesin expression did not show any association with the advanced clinical staging (III and IV). Moreover, Moesin has not been known to be associated with the demographic and clinical features of the patients.
Survival among OSCC cases
Moesin expression in the cytoplasm of OSCC cases spells poor 5 to 10 survival rates. The overall survival rates dip from 67% to almost 34% among OSCC patients. This finding is consistent with even other findings in different types of cancers where the hazard ratio is depicted in Figure 4 and the risk or mortality ranges from 1.73 to 5.8 [Figure 6].
Limitations of the study
The small sample has been the prime limitation of this review as most studies are cross-sectional with no randomized control trials conducted on this issue according to the author's search for relevant studies. Most studies did not calculate or report the Hazard ratio or Odds ratio of Moesin expression making it difficult to elicit the survival rates as a prognostic outcome among OSCC cases. This element of divergence in the conduct of the heterogeneous studies did not allow the authors to conduct a meta-analysis to estimate the size of the effect among the OSCC patients.
Albeit the sample size of this review is inadequate the importance of Moesin as a clinical biomarker among OSCC cases points towards its importance as a prognostic tool to elicit survival and mortality rates among the different histopathological grades of oral carcinoma.
Ethics and dissemination
The authors acknowledge the support they got from (SDS, Krishna Institute of Medical Sciences, KIMSDU, Karad) Ph.D. program for this literary research.
BS, SK, and DK contributed to drafting and revising the protocol of this research by developing the research question, and research design, formulating the research strategy, and extracting & critically appraising the data using the tools mentioned in the protocol. They were responsible for the final draft and publication of the research.
Patient consent for publication
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
Ref no 16: Author(s): Li et al./2015
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