Standardized Diagnostics Including PET-CT Imaging, Bilateral Tonsillectomy and Neck Dissection Followed by Risk-Adapted Post-Operative Treatment Favoring Radio-Chemotherapy Improve Survival of Neck Squamous Cell Carcinoma of Unknown Primary Patients

Abstract

Background: About five to 10% of cancers in the head and neck region are neck squamous cell carcinoma of unknown primary (NSCCUP). Their diagnosis and treatment are challenging given the risk of missing occult tumors and potential relapse. Recently, we described human papillomavirus (HPV)-related NSCCUP-patients (NSCCUP-P) as a subgroup with superior survival. However, standardized diagnostic workup, novel diagnostic procedures, decision-making in the multidisciplinary tumor board (MDTB) and multimodal therapy including surgery and post-operative radio-chemotherapy (PORCT) may also improve survival.

Methods: For assessing the impact of standardized diagnostic processes simultaneously established with the MDTB on outcome, we split our sample of 115 NSCCUP-P into two cohorts treated with curative intent from 1988 to 2006 (cohort 1; n = 53) and 2007 to 2018 (cohort 2; n = 62). We compared diagnostic processes and utilized treatment modalities applying Chi-square tests, and outcome by Kaplan-Meier plots and Cox regression.

Results: In cohort 2, the standardized processes (regular use of [¹⁸F]-FDG-PET-CT imaging followed by examination under anesthesia, EUA, bilateral tonsillectomy and neck dissection, ND, at least of the affected site) improved detection of primaries (P = 0.026) mostly located in the oropharynx (P = 0.001). From 66.0 to 87.1% increased ND frequency (P = 0.007) increased the detection of extracapsular extension of neck nodes (ECE+) forcing risk factor-adapted treatment by increased utilization of cisplatin-based PORCT that improved 5-years progression-free and overall survival from 60.4 and 45.3 to 67.7% (P = 0.411) and 66.1% (P = 0.025).

Conclusions: Standardized diagnostic workup followed by ND and risk-factor adapted therapy improves survival of NSCCUP-P.

Keywords: cancer of unknown primary (CUP); cisplatin-based postoperative radio-chemotherapy; extracapsular extension of neck nodes (ECE); head and neck cancer (HNC); head and neck squamous cell carcinoma (HNSCC); neck dissection (ND); outcome research.

Figure 1

CONSORT diagram showing the selection criteria of neck squamous cell carcinoma of unknown primary (NSCCUP) patients of the two cohorts before and after standardization of diagnostic workup and therapy as well as the distribution of primary tumors detected leading to exclusion of initially suspect NSCCUP patients.

Figure 2

Kaplan–Meier cumulative survival analyses of neck squamous cell carcinoma of unknown primary (NSCCUP) patients of cohorts 1 and 2 for (A) overall survival; (B) tumor-specific survival; (C) survival according to non-cancer death/death from other cause; (D) disease-free survival; (E) progression-free survival; (F) Time to detection of head and neck squamous cell carcinoma primary; (G) Nodal relapse-free survival and (H) Distant metastasis-free survival. P values shown are from 2-sided log-rank tests.

Figure 3

Kaplan–Meier cumulative survival (KM) plots for overall survival (OS) of squamous cell carcinoma of unknown primary patients (NSCCUP-P) demonstrate the improved outcome achieved by standardized treatment including neck dissection (ND) and cisplatin-based radio-chemotherapy (Cis+) for NSCCUP-P with extracapsular extension of neck nodes (ECE). Besides KM plots, the numbers of patients and events are shown with 75th percentile and median along with their respective 95% confidence interval (95% CI) together with P-values from pairwise comparisons in various strata combining ND, ECE and Cis in cohorts 1 and 2 as well as for all NSCCUP-P.

Figure 4

Kaplan–Meier cumulative survival (KM) plots for tumor-specific survival (TSS) of squamous cell carcinoma of unknown primary patients (NSCCUP-P) demonstrate the improved outcome achieved by standardized treatment including neck dissection (ND) and cisplatin-based radio-chemotherapy (Cis+) for NSCCUP-P with extracapsular extension of neck nodes (ECE). Besides KM plots, the numbers of patients and events are shown with 75th percentile and median along with their respective 95% confidence interval (95% CI) together with P-values from pairwise comparisons in various strata combining ND, ECE and Cis in cohorts 1 and 2 as well as for all NSCCUP-P.

Figure 5

Forest plots for hazard ratio (HR) and 2-sided 95% confidence interval (95% CI) from multivariate Cox proportional hazard models for various outcome measures and survival of neck squamous cell carcinoma of unknown primary (NSCCUP) patients built using the stepwise forward likelihood ratio method. Events represents the numbers of events found for the individual predictor and (%) the percentage of patients experiencing the event among those with the characteristic, and HR, 2-sided 95% CI, and 2-sided P value* the outcome attributable to this characteristic according to the final model for the particular measure. P values^# are 2-sided P values from internal validation using bootstrapping applying 1,000 iterations. P values of independent predictors < 0.05 are in bold.