Depth of Invasion and its Correlation with Adverse Tumour Pathological Features in HPV Negative Oropharyngeal Cancer

Introduction

Over the last few decades, there has been a marked increase in the incidence of squamous cell cancer (SCC) of the oropharynx. This also coincides with the increased prevalence of Human papillomavirus (HPV) infection, which is associated with a better prognosis compared to the tobacco-associated tumours in the oropharynx.^1,2

Before advancements in the field of chemo-radiation, these tumours were treated surgically either via trans-oral or open approaches. Trans-oral approaches were technically challenging with limited visualization, frequently resulting in incomplete resections. Open approaches resulted in high morbidity and meant the additional need for tracheostomy and gastrostomy tubes for a longer time.³

With the success of chemo-radiation techniques in realizing organ preservation and challenges with older trans-oral and open techniques, chemo-radiation has emerged as the preferred treatment option for Oropharyngeal squamous cell carcinoma (OpSCC).⁴ What was overlooked in this rapid extrapolation was the long term functional and oncological outcomes. Machtay et al. in a review of the Radiation Therapy Oncology Group (RTOG) intensification trials reported severe late toxicity rates upwards of 40%.⁵

A key drawback that comes with organ preservation protocols is the inability to study the disease biology in a greater detail. Today, as transoral robotic approach is making inroads, surgical resection seems to be a rational choice for treatment intensification.⁶ With lesser morbidity and greater cost-effectiveness, Transoral Robotic Surgery (TORS) seems to emerge as a treatment option in the prognostically better HPV positive tumours.^7-9

The global prevalence of OpSCC is not uniform. The West has a higher incidence of favourable HPV associated tumours, and the ratio almost completely reverses in our subcontinent, where the majority are tobacco-related with poorer outcomes.¹ There is only limited data that is available to understand this tumour biology. This subset behaves similar to oral cavity SCC (OCSCC) with more favourable outcomes and the disease control with primary surgery followed by adjuvant therapy when indicated.⁶

The purpose of this study was to investigate the histopathological correlates and adverse pathological features in tobacco-associated OpSCC and analyze its relationship with tumour depth of invasion.

Methodology

This non-randomized, single center, prospective study was conducted at BLK Cancer Centre, Dr. B L Kapur Memorial Hospital, New Delhi, India. Ethical committee approval was obtained from the Institutional review board. The study included individual data from patients undergoing treatment for OpSCC between January 2019 to April 2020. All these patients were subjected to PET with contrast-enhanced CT (CECT) or MRI.

Patients with primary OpSCC with p16 negative status with operable disease were included in the study. Patients undergoing salvage surgery, those not undergoing neck dissection, or those unfit for surgery were excluded. All the patients meeting the inclusion criteria underwent TORS + neck dissection performed by the first author. The frozen section confirmed clear surgical margins in each case and surgical margin <3 mm was revised to reconfirm with the frozen section. The formalin-fixed surgical specimens were processed for histopathological examination. The reporting was done as per the College of American Pathologist (CAP) guidelines*. An additional factor, depth of invasion (DOI) was included for oropharyngeal tumours.

Patients with a pathologically negative neck with any adverse features in the primary (T3-T4, PNI, lymphovascular invasion [LVI], WOPI 5) were discussed in the Multidisciplinary Tumour Board and recommended adjuvant radiotherapy. In patients with a pathological positive neck (multiple neck node or node >3 cm in size) were recommended adjuvant radiotherapy and those with extra-nodal extension (ENE) were recommended concurrent chemo-radiotherapy.

Patients were followed up every month in the first year, and every three months in the second year. Patients underwent a follow up PET-CT scan at the end of three months of completion of treatment. All patients underwent a thorough loco-regional examination to look for any recurrences. Any suspicious lesion was evaluated and investigated. Recurrences when identified were appropriately managed with salvage surgery or chemotherapy based on the extent and type of recurrence.

Statistical analysis

Pathological adverse features were correlated with the depth of invasion. Univariate and multivariate analysis was carried out and p< 0.05 was considered significant. Chi-square test, Mann Whitney U test and Fischer test were applied to analyze the data set.

Results

A total of 88 patients were available for final analysis. The mean age of the study population was 59 years. In the study cohort, 84 patients were males and four were females. All the cases were tobacco users in one form or the other and were either moderate - high-risk HPV positive and HPV negative. Forty-nine patients had a base of tongue (BOT) primary, and 39 had the primary in the tonsil (Table 1). The mean DOI was 12 mm (Table 2). The adverse pathological features in the study population are tabulated in Table 2. On multivariate analysis, DOI had a statistically significant effect only on PNI, and not on other pathological adverse features (Figure 1). The DOI did not have a statistically significant effect on nodal metastasis, size of the deposit or ENE (Table 2).

On comparing pathological adverse features like PNI, LVI, WPOI and ENE based on a subsite (BOT versus Tonsil), there was no statistically significant difference (Table 3).

Discussion

Adverse pathological parameters have been rather extensively studied in oral cavity cancers and our understanding from these tumours has been translated to oropharyngeal cancers. This was in part due to the widespread use of organ preservation protocols and the morbidity associated with primary surgical approaches in tumours of the oropharynx. However, with an improved understanding of the role of HPV in oropharyngeal cancer and wider acceptability of transoral robotic surgery, greater insights would now be available on tumour behaviour.

Though HPV related OpSCC has a good prognosis, the biological behaviour of HPV unrelated OpSCC remains very closely related to the SCC of oral cavity.⁶ Tumour thickness and depth of invasion (DOI) are predictors for lymph nodal metastasis in OCSCC. Many studies have investigated tumour thickness and DOI in OCSCC as a predictor for prognosis.¹⁰ There is no reliable method of estimating DOI before or at the time of initial surgery. Tumour thickness, which can be more closely measured using preoperative imaging may underestimate the aggressive potential of the tumour.^11-13 The extent of tumour DOI in OCSCC is associated with invasion of the cortical bone and of blood- and/or lymphatic vessels.⁹ In our study, PNI was the only aggressive tumour characteristic associated with DOI. It is well recognized that the status of the clinically positive neck is a major determinant of survival outcome in other head and neck cancers. The identification of factors that predict the presence of occult metastases is important.¹⁴ In our study, DOI in OpSCC did not correlate with occult lymph node metastasis unlike in patients with early-stage oral cavity squamous cell carcinoma.

The major limitation of 8th edition American Joint Committee on Cancer (AJCC) while staging OpSCC is that the main determinant remains the size and better suited for non-surgical treatment modalities.¹⁵ Better and more relevant classification have appeared, keeping in mind the technicalities of surgical removal.^16,17

Conclusion

The understanding of the depth of invasion and its implications on tumour biology in oropharyngeal cancers remains an unexplored avenue. Findings of the present study reiterate the need for a revised and surgically relevant T staging for oropharyngeal cancers.

Compliance with Ethical Standards

IRB approval was obtained for the study. Informed consents were obtained from all patients.

Funding

This study did not receive any funding.

Conflicts of Interest

No conflict of interest between authors.