Oral squamous cell carcinoma (OSCC) is the most predominant subtype of oral malignancies, accounting for more than 90% of oral cancer cases globally, and represents a major public health challenge due to high recurrence rates and associated mortality.^1,2 OSCC arises from the squamous epithelium lining the oral cavity and is frequently linked to tobacco use (smoked and smokeless), alcohol, betel-nut chewing, viral infections, and poor oral hygiene.³ Despite advances in diagnostic techniques and multidisciplinary management strategies, including surgery, radiotherapy, and chemoradiation, OSCC continues to demonstrate aggressive clinical behavior with frequent local and regional treatment failures — often manifesting as recurrent disease rather than a new primary tumour.^4,5 The burden of OSCC is especially notable in South and Southeast Asia, where cultural practices such as smokeless tobacco consumption contribute to higher incidence rates compared with Western populations.⁶

The contemporary trends in epidemiology consider the disease burden of recurrence of OSCC after surgery. Recurrence rates were found between 20-40% in the study carried out by Blatt et al., with most recurrences developing within the first two years after curative therapy.⁷ According to Shamsi et al. recurrence was reported in more than 36% of oral cavity cancer patients, where lymph node status and tumour differentiation showed a significant association with recurrence.⁸ In addition, Rubert et al. found the presence of positive surgical margins (<5 mm) increasing the risk of local recurrence 2.72 times (OR = 2.72, 95% CI: 2.04-3.62; p<0.001), whereas clear margins improved the probability of 5-year survival 1.58 times.⁹ Shah et al. found a locoregional recurrence of 16.9%, where perineural invasion emerged as the strongest factor predicting recurrence (OR = 18.42, 95% CI: 5.43-62.46), followed by extracapsular extension and number of positive lymph nodes.¹⁰

Although there is evidence showing high recurrence rate and poor prognosis of recurrent OSCC, the evidence available from tertiary hospitals in Pakistan, such as Ayub Teaching Hospital, Abbottabad, is scarce. The knowledge about the risk factors of recurrence after surgical intervention could be beneficial in terms of stratification of patients and decision making. Moreover, regional risk factors such as the usage of smokeless tobacco emphasize the importance of locally available evidence for OSCC.

This study is based on a retrospective observational study conducted at the Ayub Teaching Hospital located in Abbottabad, Khyber Pakhtunkhwa, Pakistan. The hospital serves a considerable population of northern Pakistan. It is a major healthcare facility. The study was based on a review of medical records of OSCC-affected individuals. The study was carried out between January 2018 and December 2023. Ethical approval was taken from Institutional Medical and Ethical Review Committee with approval code/Ref.No.RC-EA-2025/155 dated on 26 March 2025.The sample size was computed through the single population proportion formula taking into consideration an assumed recurrence rate of 30%,6 confidence interval at 95%, and absolute precision at 10%. The required minimum sample size was computed to be 80 patients. Since the study was retrospective in nature using existing records only, all records that met the inclusion criteria during the period covered by the study were included in the sample. A convenience sampling method was adopted based on the availability of records to recruit a total of 80 patients. The study included OSCC cases diagnosed histopathologically as primary OSCC and those who had received surgical intervention at the study facility. Inclusion Criteria: Patients with histopathological evidence of OSCC as a primary malignancy, received surgical intervention for OSCC at the study facility, and had a record of full clinicopathological data and follow-up records were included in the study. Exclusion Criteria: OSCC cases diagnosed as a secondary malignancy, OSCC cases that were previously treated or had a history of recurrence at presentation, malignancies of unknown primary site, or those with incomplete medical records were excluded. A pre-tested structured data collection proforma was used to document the data, which was gathered from a variety of sources, including clinical records, surgical notes, histology records, and radiographic records. Demographic data (such as age and gender), co-existing conditions, social habits (such as smoking, drinking alcohol, and smoking cigarettes), tumor-related data (such as location, T status, and histological differentiation), pathological risk factors (such as lymphovascular invasion, perineural invasion, and resection margin status), and treatment-related data (such as surgical resection type, reconstructive procedures, adjuvant therapies, and radiation/chemotherapy). Additionally, included were postoperative problems, such as surgical site infections and the date of adjuvant therapy initiation. Tumor recurrence was defined as the recurrence of the original tumor, regional lymph nodes, and distant sites following the primary treatment with surgical resection. The recurrence timings were calculated from four different time points, such as the date of the initial diagnosis, the date when the procedure of surgery took place, the date when recurrence was confirmed, and the date when the most recent follow-up was observed. The Statistical Package for the Social Sciences (SPSS) version 23 was used for entry of data and analysis. For baseline clinicopathological and demographic variables, descriptive statistics were calculated. Frequencies and percentages were used to summarize categorical variables. The chi-square test was used to evaluate relationships between clinicopathological characteristics and recurrence. A statistically significant p-value was defined as ≤ 0.05.

Among the 80 patients with histopathologically confirmed Oral squamous cell carcinoma, recurrence occurred in 47 cases (58.75%), while 33 patients (41.25%) remained disease-free. The cohort's initial characteristics are shown in Table 1. The majority of patients were snuff users (70%) and men (58.8%). 95% of cases had advanced tumor stages (T3–T4), with the buccal mucosa being the most frequently occurring site (45%). The most common treatment modality was surgery alone (51.3%), with 55% showing positive margins and 78.8% showing LVI/PNI. All things considered, the majority of the cohort had advanced-stage disease with unfavorable pathological characteristics. Recurrence was significantly associated with male gender (76.6% vs. 33.3% in females, p < 0.001), presence of comorbidities (76.1% vs. 35.3%, p < 0.001), snuff use (p = 0.020), and advanced tumor stage (T4: 66.7%, T3: 59.6%, p = 0.042). Tumor-related factors showing strong statistical association included buccal mucosa involvement (83.3%, p < 0.001), positive surgical margins (75.0%, p = 0.005), and poorer differentiation (p = 0.007). Treatment-related variables were also significant, including marginal mandibulectomy (81.1%, p = 0.001), treatment modality (p = 0.010), and delay in radiotherapy (60.0% vs. 37.9%, p = 0.013). Lymphovascular and perineural invasion showed higher recurrence in positive cases (63.5%) but did not reach statistical significance (p = 0.097) as indicated in Table 2. Overall, recurrence was significantly influenced by demographic, pathological, and treatment-related factors in this cohort.

Table 1. Distribution of Demographic, Clinicopathological, and Treatment Characteristics of Patients (n = 80).

Abbreviations: OSCC, oral squamous cell carcinoma; T2, tumour stage 2; T3, tumour stage 3; T4, tumour stage 4; RT, radiotherapy; CT, chemotherapy; LVI, lymphovascular invasion; PNI, perineural invasion; n, number of patients.

Table 2. Association Between Clinicopathological Variables and Recurrence in Patients with Oral Squamous Cell Carcinoma (n = 80).

Abbreviations: OSCC, oral squamous cell carcinoma; T2, tumour stage 2; T3, tumour stage 3; T4, tumour stage 4; RT, radiotherapy; CT, chemotherapy; LVI, lymphovascular invasion; PNI, perineural invasion.

In our study, out of 80 surgically treated Oral Squamous Cell Carcinoma (OSCC) patients, recurrence was found in 58.75% of the total cases. Recurrence in OSCC has been found to be significantly associated with male gender, tumor stage, positive surgical margins, poor differentiation, co-morbid conditions, and certain treatment-related variables, including delays in radiotherapy and type of surgical procedure.

The rates of recurrence in OSCC have been found to vary widely in the literature, including a range of 20% to 40% in many studies, with most of the recurrence occurring in the first two years after the initial treatment. This is in line with the high rates of recurrence found in the current study, i.e., 58.75%, particularly in the context of OSCC patients presenting in a late stage of disease. In a study of 39 years, a 40% overall recurrence rate was found, and it was concluded that "high rates of recurrence are a hallmark of OSCC, even in the era of modern treatment modalities".¹¹

Positive surgical margins and tumor stage are known to be predictors of recurrence. Close or involved margins have an impact on local control and recurrence, with recurrence rates significantly higher in patients with positive compared to negative margins, as supported by several studies.¹² A study carried out on an Indian patient pool found positive margins and bone invasion to be significant predictors of recurrence and recurrence-free survival, with p values of 0.006 and 0.001, respectively, thus supporting the findings of the current study with respect to positive margins and advanced T stages.¹³

Perineural invasion (PNI) and lymphovascular invasion (LVI) have been found to be histopathological features affecting OSCC. A meta-analysis of 26,062 patients found PNI to be strongly associated with recurrence and local recurrence-free survival, with HR values of 1.87 to 2.31 and p < 0.001,¹⁴ thus supporting the current findings with respect to LVI/PNI and recurrence. The current study found LVI/PNI to be associated with recurrence, though not statistically significant, with p values of 0.097, possibly due to small sample size.

Further evidence of the clinical importance of these histological risk factors is provided by studies indicating that both PNI and LVI are correlated with nodal metastasis, thus underscoring their value in risk assessment and planning of adjuvant treatment.^15,16 At a mechanistic level, PNI and LVI indicate tumor cell invasion of nerve sheaths and vascular channels, respectively, which are critical routes for tumor spread to other sites from the original tumor site.^17,18 A study of a large cohort of patients has found a strong correlation of both PNI and LVI with locoregional recurrence and reduced recurrence-free survival rates.¹⁹ LVI independently correlated with poor OS and recurrence-free survival rates, and PNI correlated with poor OS,²⁰ thus indicating the aggressive nature of tumor clones capable of escaping local treatment effects of surgery and radiotherapy.

Positive or narrow tumor margins indicate the presence of tumor cells after tumor removal.²¹  This is supported by histopathological studies, which show that if the margins are not adequate (<3–5 mm), there is an increased risk of microscopic tumor cells being present at the resection margin, which can act as the nidus for recurrence.²² Though the exact high-risk cut-off is not clearly defined, the basic idea is that the presence of microscopic disease has a high propensity for recurrence.^23,25 Furthermore, the difficult anatomical sites like the buccal mucosa make the clearance of tumor margins difficult because of the complex spatial relationships with the muscles and neurovascular structures.^24,26 These sites have an aggressive tumor invasion front, which is difficult to clear, as seen in the current study with the high rate of recurrence seen in the buccal mucosa tumors.

Limitations of the Study

This study has some limitations, which need to be taken into account. Firstly, the retrospective nature of the study means that it is difficult to establish cause and effect. Secondly, since it is a single-center study, it is possible that the results might not be representative or generalizable to other patient populations with different demographic, behavioral, and treatment-related characteristics. Thirdly, differences in treatment modalities, expertise, and duration of treatment might have affected the results for recurrence. Lastly, since it has now become evident that molecular and genetic tumor markers have a definite bearing on the likelihood of tumor recurrence, they have not been studied in this patient population.

In summary, an important proportion of OSCC patients (58.75%) had an elevated risk of recurrence even after receiving surgical treatment. This risk was found to be substantially correlated with gender, tumor stage, margins, differentiation, comorbidities, and treatment-related characteristics such delayed radiation. These findings emphasize the significance of timely adjuvant treatment, early identification, clear margins, and close observation for patients with OSCC. Histopathological risk factors including PNI and LVI showed a tendency that suggests their significance in OSCC even though they were statistically insignificant.

Ethical Considerations and Conflict of Interest

Ethical approval was obtained from the Institutional Review Committee of Ayub Teaching Hospital. Patient confidentiality was strictly maintained.

Competing interest statement:

The authors declare no conflict of interest

Abbreviations:

OSCC: Oral Squamous Cell Carcinoma

LVI: Lymphovascular Invasion

PNI: Perineural Invasion