Survival of patients with oropharyngeal squamous cell carcinomas (OPSCC) in relation to TNM 8 – Risk of incorrect downstaging of HPV-mediated non-tonsillar, non-base of tongue carcinomas

Abstract

Background: TNM-8 staging separates oropharyngeal squamous cell carcinomas (OPSCC) into human papillomavirus (HPV)-mediated and-unrelated OPSCC based on p16INK4a overexpression (p16þ), as surrogate marker for HPV. However, OPSCC is histologically and clinically heterogenous including tonsillar and base of tongue squamous cell carcinomas (TSCC and BOTSCC respectively), and carcinomas of soft palate and walls (otherOPSCC). The significance of HPV is established in TSCC/BOTSCC, while its role in otherOPSCC is unclear, which is not considered in TNM-8. Here, p16þ was therefore evaluated in relation to overall survival (OS) and tumor stage per OPSCC subsite. Patients and methods: All 932 patients, treated with curative intent in Stockholm 2000e2016 with OPSCC, previously analyzed for p16 expression, were included. Clinical data, including stage and OS, was collected retrospectively. Results: Patients with p16þ otherOPSCC had significantly poorer OS compared to patients with p16þ TSCC/BOTSCC (p Z 0.005) and their survival was similar to that of patients with p16-otherOPSCC/TSCC/BOTSCC. Moreover, patients with TNM-8 stage I-II and p16þ otherOPSCC had a significant poorer OS compared to patients with p16þ TSCC/BOTSCC

Long-Term Survival and Recurrence in Oropharyngeal Squamous Cell Carcinoma in Relation to Subsites, HPV, and p16-Status

“…More specifically, the role of HPV on survival differs between tumors arising in lymphoepithelial oropharyngeal sites, i.e., TSCC and BOTSCC, and carcinomas arising in non-lymphoepithelial subsites of the oropharynx, i.e., carcinomas of the soft palate, uvula, and posterior pharyngeal wall (otherOPSCC) [ 17 ]. Therefore, while the prognostic role of HPV and the correlation between HPV infection and p16 + is established in TSCC and BOTSCC, the role of HPV and its correlation to p16 + in otherOPSCC is more ambiguous [ 18 , 19 , 20 , 21 , 22 , 23 , 24 ].…”

Prognostic Markers and Driver Genes and Options for Targeted Therapy in Human-Papillomavirus-Positive Tonsillar and Base-of-Tongue Squamous Cell Carcinoma

“…Shortly after, in 2004, a similar association of HPV with BOTSCC, but not to mobile tongue cancer, was disclosed, with analogous better prognosis for HPV + as compared to HPV − BOTSCC [ 2 ]. It has since then been verified in a plethora of reports that HPV prevalence is much higher in TSCC and BOTSCC, the two major lymphoepithelial- and crypt-containing subsites of OPSCC, as compared to that in other OPSCC subsites, e.g., the soft palate and the pharyngeal wall [ 51 , 52 , 53 , 54 ]. More specifically, in a systematic review of 58 distinct cohorts, the prevalence of HPV was 56% in TSCC/BOTSCC as compared to 19% at other OPSCC subsites [ 51 ].…”

“…More specifically, in a systematic review of 58 distinct cohorts, the prevalence of HPV was 56% in TSCC/BOTSCC as compared to 19% at other OPSCC subsites [ 51 ]. Furthermore, the favorable prognostic value of HPV in TSCC and BOTSCC has been confirmed repeatedly and by now, there is no doubt regarding it, while the prognostic value of HPV at other OPSCC subsites accounting for 10–20% of all OPSCC has not really been verified so far [ 1 , 2 , 3 , 4 , 52 , 53 , 54 , 55 , 56 ]. Notably, in the American Joint Committee on Cancer (AJCC) 8th Edition , the distinction of HPV + OPSCC into different subsites was not considered, and this is, in our opinion, of some concern, especially when conducting and evaluating clinical trials [ 57 , 58 ].…”

“…The golden standard for an active oncogenic HPV infection is therefore the expression of HPV E6 and E7 mRNA, but since this was in the past more difficult to assay for on a regular basis, overexpression of p16 in >70% of the tumor cells was instead used as a surrogate marker for the presence of HPV in OPSCC [ 68 , 69 ]. The concordance between HPV E6 and E7 mRNA expression and p16 overexpression is, however, not complete, since around 10–15% of TSCCs and BOTSCCs expressing p16 are not HPV + , and this discrepancy is even greater at other OPSCC subsites and in other HNSCCs [ 51 , 52 , 53 , 54 , 69 ]. However, it has been shown especially in TSCC and BOTSCC, as well as in OPSCC, that the presence of HPV DNA together with the overexpression of p16 is almost equivalent to the presence of the golden standard [ 69 , 70 ].…”

Psoriasin expression is associated with survival in patients with human papillomavirus-positive base of tongue squamous cell carcinoma

“…Notably, however, accumulated recent data advocate that HPV+ OPSCC should be divided into its sub-sites, when categorizing by HPV status and prognosis, more specifically tonsillar squamous cell carcinoma (TSCC), base of tongue squamous cell carcinoma (BOTSCC) and squamous cell carcinoma of the soft palate and the pharyngeal walls (other OPSCC) (2). Data from others and us clearly indicate that patients with HPV+ TSCC/BOTSCC have a better survival than patients with HPV-TSCC/BOTSCC, but this survival benefit of having HPV was not observed in patients with other OPSCC (3)(4)(5)(6)(7). Nevertheless, although the survival in general is favorable in patients with HPV+ TSCC/BOTSCC, prognostic markers are still needed to identify those few patients with a poor clinical outcome, before treatment can be tapered (8).…”