Predicting prognosis in oral and oropharyngeal cancer
Authors:   , Nauta Irene Heleen 
Published: February 2024

The aim of this thesis was to better predict prognosis in oral and oropharyngeal cancer.

HPV-positive oropharyngeal cancers have a more favorable prognosis than HPV-negative
OPSCC, which has led to important and marked changes in the eighth TNM-classification. In TNM-8, OPSCCs are divided based on p16 immunostaining, with p16-overexpression as surrogate marker for the presence of HPV. In Chapter 2, TNM-8 was evaluated on a consecutive cohort of 1,204 oropharyngeal cancers. It was demonstrated that TNM-8 has a better predictive prognostic power than TNM-7 in patients with p16-positive OPSCC. However, within p16-positive OPSCCs, there is an HPV DNA-negative subgroup with distinct features and a worse overall survival, indicating the importance to perform additional HPV DNA testing when predicting prognosis and particularly for selecting patients for de-intensified treatment regimens.

The prognostic advantage of HPV-positive OPSCC resulted in the initiation of
treatment de-intensification studies. Two randomized controlled trials (RCTs)
reported inferior survival of HPV-positive OPSCC treated with radiotherapy plus
cetuximab compared to standard of care radiotherapy plus cisplatin. In Chapter 3,
we illustrated that the important role of cisplatin in the treatment of HPV-positive
OPSCCs also emerged from causal inference analyses of real-world data.

Five-year disease-specific survival of HPV-positive OPSCC is 80%-90%, indicating
that still a small fraction of patients develop locoregional recurrence (LRR) or distant metastases (DM). In Chapter 4 we investigated whether HPV16 sequence variants might be associated with recurrent/metastatic disease. Recurrent/metastatic disease was significantly associated with common HPV16 sequence variants. In every separate tumor, specific HPV16-variants were found that remained concordant with the corresponding LRR or DM.

The prognostic impact of human papillomavirus (HPV) in oropharyngeal cancer is generally acknowledged, and HPV-status is assessed routinely in OPSCC clinical practice. Meanwhile, figures on HPV attribution in oral cavity squamous cell carcinoma (OCSCC) differ widely, and prognostic impact is uncertain. In Chapter 5, we used a validated, nucleic acid-based workflow to assess HPV prevalence in a consecutive cohort of 940 OCSCCs, and investigated its prognostic impact, In total, 21 of 940 tested OCSCCs (2.2%) were HPV DNA-positive. All HPV DNA-positive tumors were also E6 mRNA-positive and can thus be considered as true HPV-positive. There was no difference in survival between HPV-positive and HPV-negative OCSCC patients. To conclude, HPV prevalence is very low in OCSCC and HPV-status does not affect outcome. Based on these data, determining HPV-status in OCSCC appears irrelevant for clinical management.

A major challenge in the treatment of OCSCC is the occurence of local relapse. Even when surgical margins are tumor-free, local relapses occur frequently and relapse prediction by histology seems difficult. In leukoplakia, an oral potentially malignant disorder, the presence of an architectural form of dysplasia, also known as “architectural dysplasia” (AD) is a risk factor for malignant transformation. In Chapter 6, we investigated whether the presence of AD in OCSCC surgical margins is positively associated with local relapse. We demonstrated that AD is found in the resection margins of 29.6% of OCSCCs. Moreover, OCSCCs with AD have specific demographic, clinical and histopathological features, implying a distinct biological process compared to OCSCCs without AD. Most importantly, the results of the study show that the presence of AD in the surgical margins of OCSCC is
associated with a higher risk of local relapse.

Chapter 7 focuses on the tumor microenvironment of OCSCC. The presence of
tumor-infiltrating T-lymphocytes, especially CD8+ T-cells, are proven to be a strong
prognosticator in various tumor types. Meanwhile, the effect of tumor-infiltrating
B-lymphocytes (TIL-Bs) is still under debate. In Chapter 7 we investigated the prognostic impact of TIL-Bs in OCSCC. We demonstrated that TIL-B cells are independently associated with a more favorable prognosis in OCSCC.