Oral squamous cell carcinoma (OSCC) is a critical health problem affecting millions of people worldwide. Even though the causes may vary regionally, the course of the disease and suffering prevails undeterred. The potentially malignant period of OSCC is an aspect that provides a beneficial approach to prevention. This period may be manifested as localized or generalized alterations of the epithelium, leading towards carcinogenesis.
Oral submucous fibrosis (OSF) is one such potentially malignant condition that subjects the oral cavity to a widespread alteration in morphology and physiology. The clinical manifestation comprises the classic triad: blanching of the mucosa, burning sensation on irritation with spicy food, and depapillation of the tongue. These will be followed by depigmentation of the lips and loss of elasticity of the mucosa with development of palpable fibrous bands in the oral cavity, progressing from the anterior region to the posterior region of the mouth. There are also apparent woody changes of soft palate and tongue, ultimately resulting in loss of mobility of the tongue along with restricted mouth opening [
This disease takes course due to the chronic exposure of the oral mucosa to carcinogens already identified in a constituent of the betel quid. In Sri Lanka, the betel quid is composed of betel leaf, areca nut, slaked lime, and fermented/dried tobacco leaf. The main etiological factor for OSF is identified as areca nut. Arecoline in areca nut is considered the principal agent while other alkaloids, polyphenols (tannins), and metallic ions (copper) are of contributory significance [
The pathology takes effect due to the unusual proliferation of fibroblasts and increased production of collagen fibres extending from the immediate subepithelial region up to deeper muscle fibres. There are multiple molecular interactions in the extracellular matrix, leading to increased levels of Tissue Inhibitor of Matrix Metalloproteinases (TIMP-1, -2) [
Malignant transformation of OSF is described with possible genetic predisposition [
According to the existing knowledge, the prognostic indicators of OSCC with concomitant OSF have not been thoroughly investigated. The proposed unique nature of OSCC in this altered condition relates to younger age of presentation, better histological degree of differentiation of the tumor, and lesser potential for nodal metastasis [
The objective of the current study is to assess the presence of submucous fibrosis among biopsy-proven OSCC patients, followed up with histopathological evaluation of the degree of fibrosis, level of histological differentiation, and nodal metastasis. Similar studies have been carried out in India where a considerable number of patients present with this chronic progressive pathology, similar to Sri Lanka [
Nevertheless, there are no data of similar context in Sri Lanka regardless of the high numbers that are adding up to the patient population in each year. The current study aims to utilize patients’ data where OSCC has already developed, to assess the prevalence of OSF in histopathological examination while excluding other pathologies that result in fibrosis, namely, scarring, keloid, gingival overgrowths, amyloidosis, oral lichen planus, anemia, and systemic sclerosis [
This study was carried out on similar grounds with the aim of evaluating the association of OSF with the nature of concomitant OSCC, in order to widen the knowledge beneficial to optimum management of these patients.
This is a retrospective analysis of patients diagnosed with OSCC. Data were obtained from the archives of the Department of Oral Pathology at the Faculty of Dental Sciences, Peradeniya. The sample comprised 273 patients.
Demographic and clinical information were recorded. Patients were categorized into two age groups, equal to or below 50 years and above 51.
Haematoxylin and eosin-stained sections of the OSCC specimens were obtained for histopathological analysis. These slides were reevaluated for presence of fibrosis, subepithelial hyalinization, and reduced vascularity as signs of OSF. The specimens with fibrosis were further subjected to grading of the severity of fibrosis. The OSCCs with OSF and the ones without were analyzed according to the degree of histological differentiation of the tumour. In addition to these data, the excisional biopsies were considered separately for the identification of lymph node metastasis, in both categories of OSCC patients.
Patients with biopsy-proven OSCC with adequate information were included in the study. The cases with recurrences or chemoradiation prior to surgical excision were excluded from the study.
Among 273 OSCC patients, 130 (48%) patients were with features of OSF (Table
Summary of the results.
| | | |
---|---|---|---|
| 31 patients <50 years | 33 patients < 50 years | |
99 patients > 51 years | 110 patients >51 years | ||
| M: F | M:F | |
3.2:1 | 2.3:1 | ||
| |||
Betel quid chewing | 99 | 23 | <0.05 |
Quid with alcohol or smoking | 13 | 10 | |
Alcohol and smoking | 0 | 5 | |
All 3 habits | 22 | 9 | |
| |||
Commissure | 1 | 7 | |
Buccal mucosa | 47 | 51 | |
Floor of the mouth | 9 | 10 | |
Tongue | 39 | 38 | |
Alveolar ridge (upper and lower) | 30 | 33 | |
Lip | 2 | 1 | |
Palate | 0 | 5 | |
| |||
Early fibrosis: | |||
EISCC | 02 | 02 | P=0.195 |
WDSCC | 32 | 91 | |
MDSCC | 15 | 42 | |
PDSCC | 05 | 06 | |
Intermediate fibrosis: | |||
EISCC | 03 | ||
WDSCC | 23 | ||
MDSCC | 16 | ||
PDSCC | 01 | ||
Advanced fibrosis: | |||
EISCC | 01 | ||
WDSCC | 16 | ||
MDSCC | 14 | ||
PDSCC | 02 | ||
| 24 (22.6%) | 29 (30.8%) | P=1.89 |
The age distribution of the sample was analyzed. The patients were mostly above 50 years of age in both categories. However, the number of patients who were with OSCC at an age below 50 was greater in the OSF-positive group (23.8% vs. 21.9%). Similarly, the mean age of OSF + OSCC patients was 57.5 years while this value was 59.5 years for those without (Figure
Distribution of OSCC with and without OSF among age groups.
The sample presented a male predilection, in both groups despite the presence or absence of OSF along with OSCC. The male to female ratio in OSCC only patients was 2.3:1. It was 3.2:1 in the group with OSF and OSCC. Similarly, the total study population showed a ratio of 2:7:1. This was not statistically significant at p<0.05.
Information regarding the habits was obtained with regard to betel quid, smoking, and alcohol consumption. Most of the patients had positive habit history. Betel quid chewing with or without smoking or alcohol consumption was observed in all OSF-positive patients. This was statistically significant at p< 0.05 (p= 0.00022). All 3 habits were seen in 26 patients where 65.38% of them were with OSF. In addition, 39 patients were only having the habit of betel quid chewing where 53.84% of them were with OSF. Some patients [
Distribution of habits and its relationship with OSF.
The commonest site among these patients was buccal mucosa followed by tongue. This was comparable to both groups despite the presence or absence of OSF. In OSF patients 34.35% were with OSCC in buccal mucosa while 29% were in tongue. The habit associating the relationship with the site of OSCC in OSF-positive patients can be demonstrated as below (Figure
Relationship with habits including betel quid and primary site.
The majority of the OSCCs were well differentiated followed by moderately and poorly differentiated OSCCs. The degree of differentiation was observed in both groups, namely, with or without OSF. It was revealed that the majority of the OSCCs from both categories are mainly well differentiated. It was 54.9% in the former and 64% in the latter. Presence or absence of OSF had not made a significant difference to the differentiation of the tumor (p=0.373).
Most of the OSF patients were having early fibrosis (41.9%). Intermediate and advanced fibrosis were seen in 32.8% and 25.1%, respectively (Figure
The total number of OSCC excisions with cervical neck dissections was 200. Among these 106 patients were with OSF while 96 were only with OSCC. Lymph node metastasis was seen more among OSCC only patients (30.8% vs 22.6%). But this association was not statistically significant (p=1.89) (Table
Nodal metastasis and its relationship with OSF.
Metastasis present | Metastasis absent | Total | |
---|---|---|---|
OSF + OSCC | 24 (22.6%) | 82 (77.3%) | 106 |
OSCC only | 29 (30.8%) | 65 (69.1%) | 94 |
The management guidelines of OSCC mostly follow curative intent unless the tumor stage or the patient’s condition demands otherwise. Yet poor prognosis of OSCC patients is commonly observed. This draws attention to deficits in intervention.
When different OPMDs are assessed, it is acceptable that OSCC may depict features characteristic to the nature of the initial lesion. Leukoplakia, erythroleukoplakia, proliferative verrucous leukoplakia, verrucous hyperplasia, oral lichen planus, and OSF are such OPMDs where the transformation may occur into OSCC. However the clinical signs and symptoms of the lesions vary from one to another.
Thus, the possible unique nature of OSCC in OSF has been assessed based on the hypothetical phenomenon that it may show a difference in prognosis.
In previous studies it has been shown that the submucosa, in OSF, undergoes pathological changes due to excessive fibrosis, abnormal collagen synthesis, reduced vascularity, and hypoxia [
The 5-year survival rates of patients remain 70-80% with Stage 1 and 2 OSCCs while they drastically reduce to 40% in latter stages of the disease [
This is comparable to the current study as well. When the patients were categorized as below and above 50 years of age groups, the majority were above 50 in general (76.55%). However, as a percentage in OSF with OSCC patients, the patients below 50 years were more (23.8% vs. 21%). A separate analysis was carried out where the categorization was below and above 55 years of age. In this analysis 39.69% of the patients with OSF were below 55years whilst it was 33.09% for the OSCC without OSF group. Yet, there was no statistically significant relationship. According to the literature, mean age values for OSF with OSCC patients range from 44.54 [
Male predilection is observed in the literature when it comes to most OPMD conditions and OSCCs. This is owing to the risk habits which are being practiced more commonly among males, relative to the female community. This may also account for multiple simultaneous habits such as smoking and alcohol, which have synergistic effects on carcinogenesis [
The habit history is an important aspect of OSCC patients. It is applicable to prognosis and to treatment. The rationale of defining the behavior and outcome of OSCC in OSF is also closely linked to its aetiopathogenesis. Therefore, an analysis of habit history is undoubtedly required. In the current study, betel quid consumption was observed in all the patients with OSF and it was a statistically significant finding. Similarly, Singh et al. [
Six patients were observed to have no known risk habits even though they were positive for OSCC which requires further investigation.
The site of OSCC is believed to be a direct indication of the type and nature of oral habits. Thus the Sri Lankan population is known to present with OSCC more commonly in the buccal mucosa, tongue, or the floor of the mouth rather than other subsites of the oral mucosa [
Previous studies demonstrated a significant relationship between thicknesses of fibrosis and the grade of dysplasia in OSF patients [
When the histopathological features were assessed, it was observed in the literature that OSCC in OSF shows favourable histopathological features.
Better degree of histological differentiation of the tumor was one such feature. Chaturvedi et al. [
Nodal metastasis is another feature which is presumed to be less in OSF patients due to the obstruction created by fibrosis in the lamina propria. Gadbail [
Other features pertaining to the prognosis of OSCC patients were observed in multiple studies where they indicated less perineural invasion and less lymphovascular invasion [
The current study was carried out in subjects with histopathologically proven OSCCs where several findings were supportive of the already suggested unique characteristics of concomitant OSCC in OSF. Nevertheless, it is necessary to carry out a prospective analysis of a larger sample size, for better clarification and justification of the findings in the literature.
Concomitant OSCC in OSF is common among males and maybe among younger patients. These tumors show well-differentiated histology and less lymph node involvement. However, a statistical significance was not observed among these variables, when comparing the OSCC patients with OSF to those who are without.
It can also be suggested that the degree of fibrosis may not be a determinant of malignant transformation, higher level of differentiation, or less nodal metastasis.
The data used to support the findings of this study are available from the corresponding author upon request.
The authors declare that they have no conflicts of interest.