“Clinical Outcomes of Surgically Treated Locally Advanced Oral Cavity Squamous Cell Carcinoma with Infra-Temporal Fossa Involvement: A Tertiary Cancer Centre Experience”

Abstract

Traditionally, patients with T4b oral cavity cancer have been deemed inoperable, leading to palliative treatments, primarily radiation and chemotherapy. In this study, we aim to critically evaluate the outcome of surgical intervention, specifically Infra-temporal fossa (ITF) clearance, about disease-free survival and overall survival rates. This is a retrospective observational study conducted over 2 years. 45 patients with clinical-radiological diagnosis of T4b disease, who had been subjected to surgery with ITF clearance were followed up for 2 years to check for recurrence and mortality. Locoregional recurrence was observed in 20 patients (44.4%) among which 3 patients additionally had distant metastasis. At the last follow-up, the overall mortality noted was 26.7%, with 33 patients still alive, out of which 25 were disease-free. No significant correlation was found between patient or tumor-related factors and recurrence rates except positive soft tissue and close bone margins. Survival analysis revealed a mean disease-free survival (DFS) of 18.57 months and an overall survival (OS) of 21.75 months. Surgical resection is a viable option for a few selected patients with locally advanced oral cavity cancer, with acceptable outcomes.

Introduction

Head and Neck Squamous Cell Carcinoma (HNSCC) is highly prevalent in the Asian subcontinent, with Oral cavity Squamous Cell Carcinoma (OCSCC) being the most frequently encountered subtype, particularly in India [1]. Alarmingly, the majority of OCSCC patients present with advanced stages, which contributes to a poor prognosis [2]. This malignancy constitutes a significant burden on global cancer cases, with head and neck carcinoma representing 30% of new cancer cases in India and being one of the most common cancers among males in the country [3]. Strikingly, over 50% of patients presented at locally advanced stages, notably in the masticator space and infratemporal fossa (ITF), categorizing them as T4b, a classification associated with a particularly poor prognosis.

The complex anatomy of the Infra-temporal fossa (ITF) and Masticator space poses significant diagnostic and therapeutic challenges. The T4b stage, which includes the Masticator space, Pterygoid plates, skull base, or encasement of the Internal Carotid artery, complicates accurate clinical and radiological assessment [4]. Additionally, the intricacies of Masticator space involvement make it challenging to determine the precise stage and disease extent. This is further exacerbated by the associated trismus that limits thorough clinical evaluation.

Conventionally, T4b oral cavity cancers have been deemed inoperable and, thus, are subject to palliative treatment, primarily radiation and chemotherapy [5]. However, this study critically evaluates the outcome of surgical intervention, specifically ITF clearance, against the conventional palliative approach.

By retrospectively analyzing the institute's experience, the research aims to provide valuable insights into the clinicopathological profiles and oncological outcomes, potentially leading to a more tailored and effective management approach for this subset of oral cavity cancers.

Methodology

Study Design

A retrospective observational study aimed to analyze the outcomes of patients with locally advanced oral cavity carcinoma, specifically those classified as T4b, according to the AJCC 8th edition, on clinical and radiological examination with infratemporal fossa (ITF) involvement. After obtaining clearance from the ethical committee, the study was conducted at the Department of Surgical Oncology, SMS Medical College, and Hospital with patients operated on between January 2019 to December 2021 and were followed up until December 2023. Patient charts and medical records were reviewed to identify patients undergoing surgery for oral cavity cancer and screened for inclusion and exclusion criteria.

Inclusion Criteria

1. Patients with biopsy proof of Oral cavity Squamous cell carcinoma (OCSCC).

2. Patients classified as T4b on clinical and radiological examination with infra-temporal fossa (ITF) involvement.

Exclusion Criteria

1. Patients who had received prior radiotherapy for oral cavity malignancy.

2. Histopathological diagnosis other than squamous cell carcinoma.

3. Disease involving pterygomaxillary fissure, the base of the skull, or carotid encasement.

All patients underwent a comprehensive preoperative clinical and radiological examination, which included a contrast-enhanced CT scan of the face and neck, as well as a CT scan of the thorax to check for lung metastasis (Fig. 1).

Fig. 1.

CECT face showing tumor involvement of right ITF involvement

For ITF clearance, patients with involvement of more than two structures in the Masticator space, such as the medial and lateral pterygoid muscles, pterygoid plates, temporalis at the tip of the coronoid, high masseter involvement, and retroantral fat pad, were selected (Fig. 2).

Fig. 2.

Clinical picture showing carcinoma right buccal mucosa (cT4b)

The patients underwent either upfront surgery or surgery after receiving neoadjuvant chemotherapy.

Neo-adjuvant Chemotherapy (NACT) Protocol - Patients with skin edema extending beyond the zygoma superiorly and extensive skin infiltration not amenable to resection with negative margins were treated with neoadjuvant chemotherapy. 3 cycles of Paclitaxel (175 mg/m²) and carboplatin (AUC 5-6) were given 3 weekly.

The surgical procedure involved a standardized ITF compartmental clearance, with clearance boundaries defined medially by the Eustachian tube, laterally by the capsule of the TM joint, and superiorly by the greater wing of the Sphenoid bone. To achieve complete clearance, all muscles, fibro-fatty tissue, neurovascular bundles, retroantral fat, and pterygoid plates in that region were removed (Fig. 3).

Fig. 3.

Intra-operative picture showing post ITF clearance

Adjuvant treatment, either radiotherapy or chemo-radiation, was given to all patients based on the surgical histopathology report. Follow-up was conducted every three months for two years. Radiological investigations were performed when there was clinical suspicion of disease recurrence and confirmed with tissue sampling. Disease-free survival (DFS) and overall survival (OS) were used as study endpoints.

Data Entry and Statistical Analysis

Data entry and statistical analysis were performed using SPSS-PC-25 version. The normal distribution of different parameters was tested by the Shapiro–Wilk normality test. Quantitative data were expressed as mean ± standard deviation or median with interquartile range. Qualitative data were expressed in frequency and percentage. Statistical differences between proportions were tested by the chi-square test or Fisher’s exact test. Survival analysis was conducted using the Kaplan–Meier method. Prognostic factors affecting various disease endpoints were analyzed by the log-rank test for univariate analysis. A p-value less than 0.05 was considered statistically significant.

Results

Between January 2019 and December 2021, a total of 612 patients underwent surgery for oral cavity malignancies at our institution. From this cohort, 61 patients were identified with oral cavity cancer involving the infra-temporal fossa (ITF) based on clinical-radiological examination. After excluding cases with lung metastasis (5 patients), prior radiotherapy treatment (2 patients), the base of skull involvement (3 patients), and those lost to follow-up (6 patients), a final group of 45 patients satisfying inclusion criteria was included in our final analysis.

The majority of patients were in the age group of 41–50 years (40.0%), followed by 51–60 years (31.1%). Male gender was predominant (95.6%) with tobacco use as a universal risk factor (100%). Among them, 38 patients underwent upfront ITF compartment clearance (84.4%), while the remaining 7 patients underwent compartment clearance after receiving neoadjuvant chemotherapy (15.6%). Reconstruction was performed using a pedicled Pectoralis Major Myocutaneous (PMMC) flap in 80% of cases and free flap reconstruction in the remaining 20%. R0 resection was achieved in 93.3% of cases. (Table 1).

Table 1.

Baseline characteristics of study subjects

	No	%
Age group
20–30 years	1	2.2
31–40 years	8	17.8
41–50 years	18	40.0
51–60 years	14	31.1
> 60 years	4	8.9
Gender
Male	43	95.6
Female	2	4.4
Tobacco use
No	0	0
Yes	45	100.0
Surgery vs NACT
Upfront surgery	38	84.4
Post NACT surgery	7	15.6
Type of reconstruction
PMMC	36	80.0
Free flap	9	20.0

Pathological T4b stage was observed in 64.4%, and the majority had a depth of invasion > 1 cm (93.3%). We had 3 cases of N3 nodal disease, all of which had extranodal extension (ENE). On surgical histopathology, all 7 patients who received NACT had an incomplete response. 14 patients (31.1%) showed lymphovascular invasion, and 10 patients (22.2%) had perineural invasion. All our cases had the worst pattern of invasion (WPOI) – V with 29 cases of poorly differentiated carcinoma (64%) and the rest 16 being moderately differentiated. The mucosal margin was close (1–5 mm) in 6 cases and the skin margin was close in 1 case with the rest all clear margins (> 5 mm) and no positive margin (1 mm) in any patient. The bone margin was close in 5 cases and clear in the remaining. The soft tissue margin was found to be positive in 3 and close in 8 patients (Table 2). All patients received adjuvant radiotherapy (EBRT 60 Gy divided into 30 fractions in low-risk and 66 Gy in 33 fractions in high-risk cases) and 3 patients with positive margins received concurrent chemotherapy (weekly cisplatin 30 mg/m2) as well. Only the patients who completed therapy were included in the final analysis. (Table 2).

Table 2.

Baseline Pathological characteristics in study subjects

	No	%
Pathological T stage
pT3	3	6.7
pT4a	13	28.9
pT4b	29	64.4
Pathological N stage
pN0	18	40.0
pN1	17	37.8
pN2	7	15.6
pN3	3	6.7
Depth of invasion
< 1 cm	3	6.7
> 1 cm	42	93.3
Lymphovascular invasion	14	31.1
Perineural invasion	10	22.2
WPOI
0–4 grade	0	0.0
5 grade	45	45.0
Degree of differentiation
Moderately differentiated	16	35.6
Poorly differentiated	29	64.4
R0 resection
No	3	6.7
Yes	42	93.3
Mucosal margin
Close	6	13.3
Clear	39	86.7
Skin margin
Close	1	2.2
Clear	44	97.8
Bone margin
Close	5	11.1
Clear	40	88.9
Soft tissue margin
Positive	3	6.7
Close	8	17.8
Clear	34	75.6
Locoregional recurrence
No	25	55.6
Yes	20	44.4
Mortality
No	33	73.3
Yes	Y12	26.7

Locoregional recurrence was observed in 20 patients (44.4%) among which 3 patients also had distant metastasis. The overall mortality at the last follow-up was 26.7%, with 33 patients still alive, out of which 25 were disease-free.

In our analysis, we explored various factors such as surgical method, type of reconstruction, R0 resection, pathological T stage, pathological N stage, depth of invasion, lymphovascular invasion, perineural invasion, degree of differentiation, WPOI, and margin status about overall mortality and recurrence. However, no statistically significant associations were found between these factors and either overall mortality or recurrence (all p > 0.05) except bone and soft tissue margin status where close bony margin and positive soft tissue margin were found to correlate significantly with recurrence and mortality. (Tables 3,4).

Table 3.

Correlation of different factors with overall recurrence

	No recurrence	Recurrence + nt	P value
Surgery vs NACT
Upfront surgery	21 (55.3%)	17 (44.7%)	1.0
Post NACT	4 (57.7%)	3 (42.3%)
Type of reconstruction
PMMC	18 (50%)	18 (50%)	0.26
Free flap	7 (77.8%)	2 (22.2%)
R0 resection
No	0	3(100%)	0.08
Yes	25 (59.5%)	17 (40.5%)
Pathological T stage
pT3	1 (33.3%)	2 (66.7%)	0.69
pT4a	7 (53.8%)	6 (46.2%)
pT4b	17 (58.6%)	12 (41.4%)
Pathological N stage
pN0	10 (55.6%)	8 (44.4%)	1.0
pN +	15 (55.6%)	12 (44.4%)
Depth of invasion
< 1 cm	0	3 (100%)	0.08
> 1 cm	25 (59.5%)	17 (40.5%)
Lymphovascular invasion
No	20 (64.5%)	11 (35.5%)	0.10
Yes	5 (35.7%)	9 (64.3%)
Perineural invasion
No	19 (54.3%)	16 (45.7%)	0.74
Yes	6 (60%)	4 (40%)
Degree of differentiation
Moderately differentiated	11 (68.8%)	5 (31.2%)	0.18
Poorly differentiated	14 (48.3%)	15 (51.7%)
Mucosal margin
Close	2 (33.3%)	4 (66.7%)	0.23
Clear	23 (59%)	16 (41%)
Skin margin
Close	0	1 (100%)	0.44
Clear	25 (56.8%)	19 (43.2%)
Bone margin
Close	0	5 (100%)	0.01
Clear	25 (62.5%)	15 (37.5%)
Soft tissue margin
Positive	0	3 (100%)	0.01
Close	2 (25%)	6 (75%)
Clear	23 (67.6%)	11 (32.4%)

Table 4.

Correlation of different factors with overall mortality

	No	Yes	P value
Surgery vs NACT
Upfront surgery	28 (73.7%)	10 (26.3%)	1.0
Post NACT	5 (71.4%)	2 (28.6%)
Type of reconstruction
PMMC	24 (66.7%)	12 (33.3%)	0.08
Free flap	9 (100%)	0
R0 resection
No	0	3 (100%)	0.01
Yes	33 (78.6%)	9 (21.4%)
Pathological T stage
pT3	2 (66.7%)	1 (33.3%)	0.92
pT4a	10 (76.9%)	3 (23.1%)
pT4b	21 (72.4%)	8 (27.6%)
Pathological N stage
pNo	14 (77.8%)	4 (22.2%)	0.73
pN +	19 (70.4%)	8 (29.6%)
Depth of invasion
< 1 cm	1 (33.3%)	2 (66.7%)	0.16
> 1 cm	32 (76.2%)	10 (23.8%)
Lymphovascular invasion
No	25 (80.6%)	6 (19.4%)	0.14
Yes	8 (57.1%)	6 (42.9%)
Perineural invasion
No	26 (74.3%)	9 (25.7%)	1.0
Yes	7 (70%)	3 (30%)
Degree of differentiation
Moderately differentiated	13 (81.8%)	3 (18.2%)	0.37
Poorly differentiated	20 (69%)	9 (31%)
Mucosal margin
Close	4 (66.7%)	2 (33.3%)	0.65
Clear	29 (74.4%)	10 (25.6%)
Skin margin
Close	1 (100%)	0	1.0
Clear	32 (72.7%)	12 (27.3%)
Bone margin
Close	0	5 (100%)	0.001
Clear	33 (82.5%)	7 (17.5%)
Soft tissue margin
Positive	0	3 (100%)	< 0.01
Close	5 (62.5%)	3 (37.5%)
Clear	28 (82.4%)	6 (17.6%)

Survival analysis using Kaplan–Meier curves revealed a mean disease-free survival (DFS) of 18.57 months (95% CI: 16.41–20.74) (Fig. 4) while overall survival (OS) was 21.75 months (95% CI: 20.47–23.03) with a median survival of 22 months (Fig. 5).

Fig. 4.

Kaplan Meier survival curve showing disease-free survival

Fig. 5.

Kaplan Meier survival curve showing overall survival

Discussion

The infratemporal fossa is described as an irregular, non-fascial lined space situated medially to the inner surface of the vertical ramus of the mandible and the zygomatic arch [6]. Its contents include the medial and lateral pterygoid muscles, pterygoid plates, insertion of the temporalis muscle, V3 nerve, chorda tympani, otic ganglion, internal maxillary artery, fat, and pterygoid venous plexus. The soft tissue margin plays a crucial role in predicting local control [7] and has defined infratemporal fossa clearance as the removal of all remaining muscles, bone, fibro-fatty tissue, and the neurovascular bundle in the infratemporal fossa, as previously described.

Locally advanced oral cavity cancers (T4a, T4b) have been a challenge to oncologists due to the complex anatomy and infiltration of vital structures in the Masticator space making them relatively inaccessible surgically and hence prone to poor local control with dismal outcomes [8]. Hence, in routine clinical practice, the majority of cT4b cases are deemed inoperable and referred for definitive chemoradiation (CRT) [9]. However, surgical resection offers the best local control and multiple authors have attempted to evaluate the outcomes with ITF clearance and compare it with the addition of CRT [10]. In our study, we have included cT4b cases who were subjected to definitive surgical resection, followed by an evaluation of patient outcome.

Our study was based on retrospective enrolment of patients who underwent ITF clearance for 2 years and were followed up till the study endpoints were reached up to a maximum of 2 years. A total of around 10% of patients with overall operated oral cavity cancer cases were found to be cT4b which was consistent with data from other centres where the reported incidence was in a similar range [11]. Of these, 45 patients were included in our final analysis after exclusion of loss to follow-up.

Most patients were in the middle age group 40–60 years (71%) while the rest were from younger and few from the elderly age bracket. Male gender was predominantly affected by the study population (95%). This was similar to other reported studies where a majority (70–90%) were males. 15% of patients in our study had a clinically inoperable disease and were subjected to NACT followed by surgery. Our protocol was similar to other institutes where we included skin involvement over the zygomatic arch [11, 12]. (Table 1).

It is our institutional practice to reconstruct the defect with a regional flap i.e. Pectoralis major myocutaneous (PMMC) pedicled flap and 80% of our cases underwent the same. However, 20% of patients underwent free flap reconstruction with either a fibular or anterolateral thigh flap which was decided as per the treating surgeon’s discretion. However, this had no bearing on the recurrence rate of the disease (p – 0.26).

Of the 44% of patients who had disease recurrence, 3 had positive margins whereas the rest had a R0 resection. The margin-positive status was because of the proximity of the tumor to vital structures and like that reported previously [9]. However, the resection status was also not clinically significant for the outcome. There was no clinical significance between the recurrence rates among patients based on their pathological T and N staging with p values of 0.69 and 1.0 respectively.

93% of patients had depth of invasion more than 1 cm but this was also not found to correlate with the rate of recurrence (p -0.08). High-risk factors such as lymphovascular invasion and perineural infiltration were almost equal in both groups with p values – 0.1 and 0.74 respectively. In our pathological factors close bony margins and positive soft tissue margins were found to be individually correlating to recurrence and mortality (Table 3, 4). The recurrence was most commonly local and in the ITF region in the majority of cases which was likely due to the anatomical complexity and high chance of residual microscopic disease.

Survival analysis using Kaplan–Meier curves revealed a mean disease-free survival (DFS) of 18.57 months (95% CI: 16.41–20.74) (Fig. 4) while overall survival (OS) was 21.75 months (95% CI: 20.47–23.03) with a median survival of 22 months (Fig. 5). Previously reported recurrence rates vary between 40 to 80% with varying periods of follow-up [11, 13].

In the landmark study by Mair et.al published in Tata Memorial Institute, the authors compared the outcomes of patients with T4a and T4b cases subjected to surgical resection. They excluded supranotch cases among the T4b group and suggested Neoadjuvant chemotherapy for these which contrasted with our study where we operated the supranotch resectable diseases as well. Our criteria for NACT were solely based on skin involvement as mentioned. The three-year recurrence rate and mortality were 58% and 48% in their study as compared to 44% and 26% respectively at 2 years in our case. However, the mean survival was similar in both studies. They also reported perineural invasion and nodal metastasis as individual risk factors for recurrence, but we had differing results where close bony and positive soft tissue margins were found significant [14].

Another observational study by Trivedi et.al which included 30 cases of T4b disease which were treated with surgical compartment resection similar to our protocol showed a better survival with 10% recurrence and mortality and 23-month mean survival [15].

In our center, the pathology reports did not mention the individual structures of ITF involved in the tumor and due to the retrospective nature of our study, it was not feasible to review the specimens. This was a lacunae in our study and should be analyzed in future trials.

Conclusion

Our study demonstrates the possibility of a decent outcome with surgical intervention for locally advanced cases of oral cavity carcinoma with ITF involvement. We believe that surgical resection for the aforementioned subset of patients is a good curative option with acceptable morbidity and recurrence rates. However, the selection should be such that it benefits the patient because the chance of recurrence and local complications with a bulky disease is high, which compromise the overall quality of life. So, a personalized approach is a need of the hour while dealing with such patients and warrants for further research to become the standard of care.

Abbreviation

ITF

Infra-temporal fossa

PMMC

Pectoralis Major Myocutaneous flap

HNSCC

Head and Neck Squamous Cell Carcinoma

OCSCC

Oral cavity Squamous Cell Carcinoma

NACT

Neoadjuvant chemotherapy

DFS

Disease-free survival

OS

Overall survival

CRT

Definitive chemoradiation

CI

Confidence interval

WPOI

Worst pattern of invasion

ENE

Extra nodal extension

Author Contributions

MD and KKL conceived the idea.

RC, PP, and MD designed the study and laid the framework for data collection.

MD and KKL did data collection and data entry.

KKL and SS supervised data entry and did data analyses.

AB and SS laid down the framework for the paper and supervised data analysis.

MD and KKL wrote the manuscript.

PP and MD helped review the literature.

RC and PP helped in the editing and formation of the final draft.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

Declarations

Ethical Standards

Approval from the Institutional Ethics Committee of SMS Medical College, Jaipur was taken for the conduct of this study.

Conflict of Interest

The authors would like to declare there is no funding from the institution or commercial company about this study.

Informed Consent

Well-informed consent from patients taken.