Introduction

Lip and oral cancer is a global health burden with incidence and mortality rate of 377,713 and 177,757 respectively [1]. Likewise, the associated incidence of oral cavity cancer in India among males and females in 2020 were 104 661 and 31 268, respectively according to Globocan 2020 [2].

Oral squamous cell carcinoma (OSCC) represents the most frequent of all oral neoplasms and it is estimated that more of 90% of all oral neoplasms are OSCC [3]. The incidence of oral squamous cell carcinoma varies markedly by geographic region, and half of all oral cancer cases occur in developing countries [4]. Chronic mucosal irritation, deleterious habits like tobacco chewing, areca nut use, alcohol consumption and viruses like human papillomavirus are some of the etiological factors which have a significant effect on the initiation and development of OSCC [5—7]. OSCC can develop de-novo in apparently normal mucosa and can also be preceded by clinically obvious potentially malignant lesions such as erythroplakia, leukoplakia and oral submucous fibrosis (OSMF) [8].

OSMF is a chronic, progressive disease of oral cavity that mainly affects the population of continental Southeast Asia. The various etiological factors leading to the development of OSMF are chewing areca nut, autoimmunity, vitamin B, C, and iron deficiencies, consumption of spicy foods, human papillomavirus (HPV) infection, and genetic mutations [9, 10]. However, the areca nut chewing along with slaked lime is considered as one of the main causes for the development of OSMF which is characterized by the progressive fibrosis of oral mucosa [11]. The malignant potential of OSMF was first described by Paymaster in 1956, and the malignant transformation rates of OSMF is varied between 3% to 19% [12—14]. Since then, the malignant transformation of OSMF and OSCC arising in the background of OSMF has become a topic of interest. In the current scenario OSCC associated with OSMF is one of the most common clinical presentations of malignancies in Southeast Asian countries [15]. Chourasia et al reported 25.77% of OSCC cases were associated with OSMF [14]. Recently some researchers suggested that OSCC arising in the background of OSMF as a distinct clinicopathological entity due to its younger age of presentation, better tumour staging and histological degree of tumour differentiation and less potential for nodal metastasis [16]. These studies preliminarily analysed the aggressiveness and pathogenesis of OSCC arising in the background of OSMF. Since this area is still under-explored and the available studies are of primitive types with low sample size and unavailability of systematic reviews made the available information ambiguous to arrive at a conclusion.

Therefore, the aim of this review is to systematically evaluate the studies which analysed and compared the demographic data and clinicopathological parameters of OSCC arising in the background of OSMF with conventional OSCC without OSMF.

Material and methods

This review was done in accordance with the guidelines given by Cochrane Handbook of Systematic Review. The search strategy adopted was in agreement with the Cochrane guidelines for systematic reviews. The articles relevant to the search strategy were identified from online search databases PubMed, google scholar and manual search. The articles extracted from the above-mentioned online databases were reviewed based on their title and abstract. The full text of the included articles was retrieved.

Search methodology:

Search: ((((((cancer, squamous cell [MeSH Terms]) OR (carcinoma, squamous cell [MeSH Terms]) OR (carcinomas, squamous cell [MeSH Terms]) OR (cancers, squamous cell [MeSH Terms]) AND (fibrosis, oral submucous [MeSH Terms])) OR (oral submucous fibrosis [MeSH Terms])) OR (fibroses, oral submucous [MeSH Terms])) AND (neoplasm staging [MeSH Terms]) Filters: Humans, English.

In addition to the database search, manual search on internet and cross reference search from articles were also done. Internet search was performed using key words «oral squamous cell carcinoma», «oral submucous fibrosis», «clinicopathological features» and «tumour differentiation».

The inclusion criteria comprise studies done on human tissues, studies published in English language, studies analysed the demographic and clinicopathological parameters of OSCC with OSMF and conventional OSCC. Studies done on animal tissue and cell lines were excluded. Fig. 1 shows the Prisma flow chart depicting the selection of articles in the current review. After retracting the articles, the required data from each article was tabulated, evaluated and interpreted.

Fig. 1. Prisma Flow chart: showing the selection criteria for articles.

Results

The search strategy identified 4 studies which analysed the demographic and clinicopathological features of OSCC with OSMF. Description of the included studies are tabulated in table 1.

Table 1. Description table of included studies

This review has analysed gender, tumour differentiation grading and lymph node status among OSCC case with and without OSMF. Due to heterogeneity of the reviewed articles, a meta-analysis was not performed. The data collected from articles are tabulated and analysed systematically.

Majority of the cases (both OSCC with OSMF and conventional OSCC) reviewed in this article were in males. Males contributed to 73.6% and 82.7% of OSCC and OSCC with OSMF cases respectively. Male predilection is a common factor seen in both OSCC and OSCC with OSMF cases (fig. 2). Buccal mucosa and buccal mucosa along with retromolar trigone, alveolus are the most common sites for OSCC with OSMF and conventional OSCC followed by tongue.

Fig. 2. Bar diagram depicting the gender distribution in percentage among the reported cases of OSCC and OSCC with OSMF.

Nearly half (47%) of the OSCC with OSMF cases showed well differentiated tumour staging (fig. 3) but only 33.4% of the conventional OSCC was well differentiated. 46.7% and 19.6% of the conventional OSCC were moderate and poorly differentiated tumours. The poorly differentiated tumours were seemingly less in OSCC with OSMF (7.6%).

Fig. 3. Bar diagram depicting the histological tumour grading among the reported cases of OSCC and OSCC with OSMF.

Lymph node metastases was present in 49.1% of the OSCC cases, whereas only 40.7% of the OSCC with OSMF showed lymph node metastases (fig. 4).

Fig. 4. Bar diagram depicting the lymph node status among the reported cases of OSCC and OSCC with OSMF.

Discussion

OSMF is a well-known premalignant condition and a chronic debilitating disease resulting in burning sensation of oral cavity blanching of mucosa and reduced mouth opening [17]. It is associated with the habit of areca nut chewing and is more commonly reported in Southeast Asian countries like India [18, 19]. OSMF has a significant rate of malignant transformation, estimated to be between 2% and 8% [20]. According to the recent systematic review by O. Kujan et al., 4% of patients diagnosed with OSMF may develop oral cancer [21].

OSCC with OSMF has gained more clinical attention in the recent decade due to its notable variation from conventional OSCC in clinicopathological presentation [16, 22, 23]. Some researchers analysed the demographic, clinical and histopathologic features of OSCC with OSMF and suggested that OSCC with OSMF can be considered as a separate clinicopathological entity [16, 22, 24, 25]. However, few studies were inconclusive to separate OSCC with OSMF as a distinct clinicopathological entity [23, 26]. The molecular, clinicopathological, pharmacological and prognostic factors, which can affect OSCC with OSMF have to be analysed thoroughly to deduce an opinion regarding the distinctiveness of OSCC with OSMF [23]. To our knowledge, this is the first attempt to systematically analyse and compare the demographic and clinicopathological parameters of OSCC with OSMF and conventional OSCC.

Among the studies included in this review, all the selected articles analysed gender predilection of OSCC with OSMF. According to some of the earlier studies, males were found to be more affected than females in the case of OSCC [27—29]. Males contributed to 82.33% and 74% of the OSCC with OSMF cases and conventional OSCC cases, respectively, of all the cases considered in the study. The increased male predilection among reported cases could be due to the fact that males are considered to be more exposed to risk factors, such as chewing tobacco and increased association of areca nut chewing and development of OSMF [30].

Analysis of histopathological tumour differentiation grading revealed that OSCC cases showed more advanced grading than OSCC with OSMF cases. There is a significant variation in the percentage of well differentiated tumours in OSCC with OSMF (47%) and OSCC (33.4%). Similar results were presented previously by Zhou et al. in 2010 [31]. This could be due to more symptomatic presentation of OSMF as a burning sensation and reduced mouth opening resulting in early diagnosis and treatment. However, none of the studies mentioned previous treatment history for OSMF in patients at their later stage diagnosed as OSCC in the background of OSMF. It is our assumption that the pharmacological management of OSMF as a premalignant lesion may have a significant impact on the aggressiveness on the OSCC arising from OSMF. The genetic memory associated with increased epithelial turn over in OSMF is carried even during the malignant transformation and this can be responsible for a better histological grade of differentiation [32]. These reasons also justify the less number of poorly differentiated squamous cell carcinoma in OSCC with OSMF when compared to OSCC.

There is a significant decrease in presence of lymph node metastasis in OSCC with OSMF when compared to OSCC. This decreased nodal metastasis in OSCC with OSMF could be due to the obstruction or resistance created by fibrosis in the lamina propria [23]. This fibrosis in OSCC with OSMF resulting in collagen with abnormal cross-linkage hence may be resistant to action by matrix metalloproteinases and the process of invasion of tumour cells [33].

Few studies have immunohistochemically analysed OSCC with OSMF and conventional OSCC (table 2). These studies were not included in the present review because of its incompatibility with the inclusion criteria and availability of less number of immunohistochemical studies. The study by A.R. Gadbail et al. and H.H. Alka et al. suggested that there is an increased expression of alpha SMA in conventional OSCC compared to OSCC with OSMF. This suggests a less aggressive nature of OSCC with OSMF [34, 35]. The study by A.R. Gadbail et al. also concluded that there is a decreased expression of Ki67 and CD105 in OSCC with OSMF. This also immunohistochemically delineates the distinctiveness of OSCC with OSMF and its better prognostic factors compared to OSCC. However, the study by H. Quan et al. contradicted the less aggressiveness of OSCC with OSMF by showing the increased expression of PD-1 and PD-L1. They also suggested that PD-L1 can be an unfavourable indicator of prognosis because it inhibits the proliferation of T helper cells thereby allowing the tumour cells to invade without any inhibition. They also proposed the correlation of high PD-1 and PD-L1 expression with the malignant transformation of OSMF into OSCC [36].

Table 2. Immunohistochemical analysis of OSCC and OSCC with OSMF

OSCC arising in the background of OSMF is found to be behaving clinicopathologically different from conventional OSCC. Delineating this as a specific clinicopathological entity may have treatment implications and will reduce the rate of over treatment and thereby ensure a positive impact on the quality of life of the patient. However, delineating it as a specific clinicopathological entity needs extensive multicentre molecular, histopathological, pharmacological, prognostic and survival data analysis studies and their thorough evaluation. Currently there is an increased number of ongoing research in the same field for elaborating the mechanisms of pathogenesis of OSCC with OSMF.

Our systematic review concludes that OSCC with OSMF is more prevalent in males with better histological differentiation of tumour and less lymph node metastasis rates. These results could reaffirm the distinctiveness of OSCC with OSMF yet indecisive to segregate it as a separate clinicopathological entity. However, multifactorial approach employing more number of studies with larger samples size at histopathological and molecular level along with proper habit history, treatment history will be necessary for properly elucidating the pathogenesis of OSSC with OSMF and to clinicopathologically delineate