Radiogenomic markers enable risk stratification and inference of mutational pathway states in head and neck cancer.

PURPOSE: Head and neck squamous cell carcinomas (HNSCCs) are a molecularly, histologically, and clinically heterogeneous set of tumors originating from the mucosal epithelium of the oral cavity, pharynx, and larynx. This heterogeneous nature of HNSCC is one of the main contributing factors to the lack of prognostic markers for personalized treatment. The aim of this study was to develop and identify multi-omics markers capable of improved risk stratification in this highly heterogeneous patient population. METHODS: In this retrospective study, we approached this issue by establishing radiogenomics markers to identify high-risk individuals in a cohort of 127 HNSCC patients. Hybrid in vivo imaging and whole-exome sequencing were employed to identify quantitative imaging markers as well as genetic markers on pathway-level prognostic in HNSCC. We investigated the deductibility of the prognostic genetic markers using anatomical and metabolic imaging using positron emission tomography combined with computed tomography. Moreover, we used statistical and machine learning modeling to investigate whether a multi-omics approach can be used to derive prognostic markers for HNSCC. RESULTS: Radiogenomic analysis revealed a significant influence of genetic pathway alterations on imaging markers. A highly prognostic radiogenomic marker based on cellular senescence was identified. Furthermore, the radiogenomic biomarkers designed in this study vastly outperformed the prognostic value of markers derived from genetics and imaging alone. CONCLUSION: Using the identified markers, a clinically meaningful stratification of patients is possible, guiding the identification of high-risk patients and potentially aiding in the development of effective targeted therapies.

PRKCA Overexpression Is Frequent in Young Oral Tongue Squamous Cell Carcinoma Patients and Is Associated with Poor Prognosis.

Oral tongue squamous cell carcinomas (OTSCCs) have an increasing incidence in young patients, and many have an aggressive course of disease. The objective of this study was to identify candidate prognostic protein markers associated with early-onset OTSCC. We performed an exploratory screening for differential protein expression in younger (≤45 years) versus older (>45 years) OTSCC patients in The Cancer Genome Atlas (TCGA) cohort (n = 97). Expression of candidate markers was then validated in an independent Austrian OTSCC patient group (n = 34) by immunohistochemistry. Kaplan-Meier survival estimates were computed, and genomic and mRNA enrichment in silico analyses were performed. Overexpression of protein kinase C alpha (PRKCA) was significantly more frequent among young patients of both the TCGA (p = 0.0001) and the Austrian cohort (p = 0.02), associated with a negative anamnesis for alcohol consumption (p = 0.009) and tobacco smoking (p = 0.02) and poorer overall survival (univariate p = 0.02, multivariate p< 0.01). Within the young subgroup, both overall and disease-free survival were significantly decreased in patients with PRKCA overexpression (both p < 0.001). TCGA mRNA enrichment analysis revealed 332 mRNAs with significant differential expression in PRKCA-upregulated versus PRKCA-downregulated OTSCC (all FDR ≤ 0.01). Our findings suggest that PRKCA overexpression may be a hallmark of a novel molecular subtype of early-onset alcohol- and tobacco-negative high-risk OTSCC. Further analysis of the molecular PRKCA interactome may decipher the underlying mechanisms of carcinogenesis and clinicopathological behavior of PRKCA-overexpressing OTSCC.

HS-173, a selective PI3K inhibitor, induces cell death in head and neck squamous cell carcinoma cell lines.

BACKGROUND: The selective PI3K (Phosphatidylinositol 3-kinase) inhibitor HS-173 has anticancer activity in non-small cell lung cancer and pancreatic cancer cells. Of all head and neck squamous cell carcinomas (HNSCC) 20% harbor specific mutations in the genome. The aim of this study was to investigate the effect of HS-173 on HNSCC cell lines. METHODS: The cell lines SCC25, CAL27 and FaDu were incubated with HS-173. Its antiproliferative effect was determined using the CCK­8 cell proliferation assay. Combined incubation with cisplatin was performed and combination index analysis was conducted. To investigate its effect on radiotherapy, cells were irradiated with 2, 4, 6 and 8 Gy, respectively. Synergistic effects of radiation and HS-173 were measured by proliferation assays and clonogenic survival. RESULTS: The use of HS-173 induced significant reduction of cell proliferation across all cell lines. Most interestingly, it showed a synergistic effect with cisplatin treatment. Clonogenic survival revealed a radiosensitizing effect in CAL27 and FaDu cells. The HS-173 caused significant induction of apoptosis in SCC25 and FaDu cells. CONCLUSION: The selective PI3K inhibitor HS-173 is a potent chemosensitizing and also radiosensitizing drug in treatment of HNSCC cell lines and could be an effective treatment in PI3K-mutated HNSCC.

Epithelial stem cell marker LGR6 expression identifies a low-risk subgroup in human papillomavirus positive oropharyngeal squamous cell carcinoma.

OBJECTIVES: R-Spondins (RSPOs) and leucine-rich repeat-containing G-protein coupled receptors (LGRs) play a critical role in embryonic and cancer development through potentiation of WNT/ß-catenin signaling, but their prognostic significance in head and neck squamous cell carcinoma (HNSCC) is still unclear. HNSCC is a group of neoplasms that include, amongst others, oropharyngeal squamous cell carcinoma (OPSCC), some of which are induced by human papillomavirus (HPV). We aimed to investigate the potential prognostic value of RSPO2 and LGR4/5/6 on overall survival (OS) and disease-free survival (DFS) in HNSCC patients. METHODS: We examined RSPO and LGR expression by means of immunohistochemistry in 126 HNSCC patients. Furthermore, in order to validate our findings externally, we examined RSPO2 and LGR6 mRNA expression levels using independent secondary datasets. RESULTS: The five-year OS of our cohort was 59.6%. RSPO2 and LGR4/5/6 expression were not associated with OS or DFS in multivariable analyses. Within the HPV+ cases (n = 26, 33%), however, we observed a difference in OS by RSPO2 expression (5-year OS: RSPO+ 45.4% vs. RSPO2- 84.6%) and LGR6 expression (5-year OS: LGR6+ 52.9% vs. LGR6-100%). Evidence for an interaction of HPV status with RSPO2 and LGR6 was found for OS. Relative to HPV+/LGR6- patients, HPV+/LGR6+ patients were 12 times more likely to die. These results were replicated in the second dataset. CONCLUSION: Our results indicated that the expression status of LGR6 had an influence on the aggressiveness of HPV+ OPSCC, potentially making this receptor a useful marker for identifying patients with a high risk of death.

Intraparotid and cervical lymph nodes metastasis in primary parotid gland carcinoma-impact on clinical outcome.

OBJECTIVE: The aim of this study was to investigate the prognostic value of evaluation of intraparotid and cervical lymph node metastases in primary parotid cancer. STUDY DESIGN: A retrospective medical chart review and histopathologic evaluation of all patients surgically treated for primary parotid cancer during the period 1993 to 2010 was performed. The presence and ratio of intraparotid and cervical lymph node metastases were assessed and determined as primary predictor variables. Overall survival (OS) and disease-free survival (DFS) were defined as primary outcome variables. RESULTS: In total, 50 patients were included. The presence of pathologic cervical lymph nodes (P = .005) and a high cervical lymph node ratio (LNR) (P = .0001) had a significant association with worse OS. Worse DFS was found in patients with a high cervical LNR (P = .001) and intraparotid lymph node metastases (P = .029). In high-grade carcinoma, a high LNR showed worse DFS (P = .05). A high cervical LNR (P = .012) and resection margin status (P = .002) were identified as independent prognostic markers for OS and the presence of intraparotid lymph nodes for DSS (P = .05). CONCLUSIONS: Evaluation of patterns of lymph node metastases provides additional prognostic value in patients with primary parotid gland cancer.

Cross-sectional study on the occurrence of Frey's syndrome following superficial parotidectomy or extracapsular dissection.

BACKGROUND: Most studies that examine postoperative outcomes after parotidectomy in patients with benign parotid gland tumors are based on retrospective chart reviews. Data about long-term results in patients with parotid gland surgery with patient contact are still sparsely published. METHODS: During the period of 1960-2005, a total of 127 patients underwent either extracapsular dissection (ECD) or superficial parotidectomy (SP) and were available for interview. Patients were questioned about their postoperative outcome after parotid gland surgery. RESULTS: The mean follow-up was 21.5 years. A total of 42 and 85 patients underwent ECD and SP, respectively. No significant differences were observed in the rates of permanent facial paralysis (SP 1.2% vs. ECD 7.1%; p = 0.1053) or recurrence (SP 4.7% vs. ECD 11.9%; p = 0.1557), and Frey's syndrome was diagnosed only after SP (10.6% vs. 0% after ECD, p = 0.0293). Frey's syndrome was detected more often compared to retrospective chart analysis. CONCLUSION: We conclude that Frey's syndrome is underdiagnosed after SP without standardized follow-up examinations. Long-term follow-up should be applied to detect and treat gustatory sweating.

Expression of inhibitors of apoptosis proteins in salivary gland adenoid cystic carcinoma: XIAP is an independent marker of impaired cause-specific survival.

OBJECTIVES: Inhibitors of apoptosis proteins are crucial to carcinogenesis since their expression results in evasion of apoptosis. Overexpression of inhibitors of apoptosis has repeatedly been associated with resistance to treatment and poor prognosis in various cancers. The role of inhibitors of apoptosis in adenoid cystic carcinoma of the salivary gland is still unclear. The aim of this study was to investigate the expression of inhibitors of apoptosis and their potential prognostic value in adenoid cystic carcinoma. DESIGN, SETTING AND PARTICIPANTS: Forty-nine patients, diagnosed with adenoid cystic carcinoma of the salivary gland between 1996 and 2016, were retrospectively included in this study. The expression of cIAP1, cIAP2, XIAP, Birc6, Livin and Survivin was assessed using immunohistochemistry, and their association of survival and prognosis was evaluated during a median follow-up of 6.4 years. MAIN OUTCOME MEASURE: Cause-specific survival and recurrence-free survival rates. RESULTS: XIAP, cIAP2, Livin and nuclear Survivin showed high expression levels in adenoid cystic carcinoma in most patients. There was no significant association of cIAP1, cIAP2, Livin, Birc6 and Survivin with outcome. However, high XIAP expression was associated with worse cause-specific survival and worse response to radiotherapy and proved to be an independent marker in multivariable analysis. CONCLUSION: Our data indicate that high expression of XIAP may be used as a prognosticator for poor survival and poor response to radiotherapy in adenoid cystic carcinoma patients.

AF1q Expression Associates with CD44 and STAT3 and Impairs Overall Survival in Adenoid Cystic Carcinoma of the Head and Neck.

Salivary gland malignancies of the head and neck form a heterogeneous group. Adenoid cystic carcinomas are an aggressive entity of salivary gland malignancies characterized by frequent distant metastases and poor response to radio- and chemotherapy. AF1Q is a MLL fusion partner, which can activate Wnt and STAT3 signaling. Recently, overexpression of AF1q has been identified as a poor prognosticator in patients of different malignancies. A total of 46 patients with adenoid cystic carcinoma were immunohistochemically evaluated for expression of AF1q and clinical outcome was analyzed in this context. Additionally, STAT3 and the Wnt downstream target CD44 were investigated and correlated with AF1q. AF1q was overexpressed in 52.2%. Overexpression of AF1q was associated with poorer overall survival (p = 0.03). Additionally, lymph node metastases and solid tumor parts were more frequently observed in AF1qhigh patients (p = 0.07 and 0.05, respectively). AF1q did not influence the occurrence of distant metastases. Expression of AF1q was associated with higher levels of STAT3 and CD44 (p = 0.003 and 0.006, respectively). AF1q is a novel prognostic marker for poor overall survival in adenoid cystic carcinoma patients. The deleterious effects on survival may be a result of promotion of the STAT3 and Wnt pathway.

Impact of pretherapeutic neutrophil-to-lymphocyte ratio, serum albumin, body-mass index, and advanced lung cancer inflammation index on clinical outcome in sinonasal squamous cell carcinoma.

BACKGROUND: Squamous cell carcinoma of the nasal cavity and paranasal sinuses is a rare and aggressive cancer entity with poor survival rates. Data on this group of head and neck tumors are scarce. Inflammation and cachexia-based markers and their impact on clinical outcome have been studied in several cancer groups. The aim of this study was to evaluate their prognostic potential in sinonasal squamous cell carcinoma. PATIENTS AND METHODS: This retrospective analysis included all patients treated for sinonasal squamous cell carcinoma at a tertiary referral center between 2002 and 2015. Patients were divided into groups with low and high pretherapeutic values based on the values of serum albumin (ALB, median 41.6 g/l), neutrophil-to-lymphocyte ratio (NLR, median 3.5), body-mass index (BMI, median 24.7), or advanced lung cancer inflammation index (ALI, median 29.5). Main outcome measures were overall survival (OS) and disease-free survival (DFS). Statistical analysis included calculation of survival differences using log-rank tests, hazard ratios (HR), and respective 95% confidence intervals (CI). RESULTS: 41 patients were included. Low ALB values did not influence OS (median OS not reached in both groups; p = 0.59, HR = 0.75, CI = 0.3-2.1) or DFS (median DFS 0.9 years vs 2.2 years; p = 0.6, HR = 0.8, CI = 0.4-1.8). High NLR was significantly associated with worse OS rates (median OS not reached vs 1.7 years, p = 0.02, HR = 3.4, CI = 1.0-108) but with no influence on DFS (median DFS 3.1 years vs 0.8 years; p = 0.15, HR = 1.8, CI = 0.8-4.2). Similar results were observed for patients with low ALI (median OS 1.7 years vs not reached; p = 0.03, HR = 0.3, CI = 0.1-0.9 and median DFS 0.8 years vs 2.2 years; p = 0.58, HR = 0.8, CI = 0.3-1.8). BMI was the strongest prognosticator in our study. Low pretherapeutic BMI was linked to significantly worse OS (median OS 1.4 years vs not reached; p = 0.003, HR = 0.2, CI = 0.0-0.6) and DFS (median DFS 0.8 years vs not reached; p = 0.02, HR = 0.4, CI = 0.2-0.8). In multivariate analysis BMI was revealed as an independent marker for OS (p = 0.015). No marker reached the level of significance in regard to DFS in multivariate analysis. CONCLUSION: Pretherapeutic BMI had a superior prognostic value in patients with sinonasal squamous cell carcinoma in comparison with other tested variables. BMI may be a simple tool for estimating clinical outcome in SNSCC. However, larger studies are necessary to validate our results.

Overexpression of LAPTM4B-35 is a negative prognostic factor in head and neck squamous cell carcinoma.

Overexpression of LAPTM4B-35 (lysosomal-associated transmembrane protein 4ß-35) is associated with a poor prognosis in numerous malignant tumours. Expression patterns and effects of LAPTM4B-35 on head and neck squamous cell carcinomas (HNSCC) are unknown. The aim of this study was to investigate the prognostic relevance of LAPTM4B-35 in HNSCC. Tissue microarrays were constructed with primary tumours and associated lymph node metastases isolated from 127 patients. The expression of LAPTM4B-35 was investigated by immunohistochemistry and the results were correlated with survival data. LAPTM4B-35 in the primary tumour was highly expressed in 47.2% of the patients (60/127). LAPTM4B-35 expression was significantly associated with tumour stage. Moreover, overexpression of LAPTM4B-35 correlated with a significantly worse disease-free survival (10.23 years vs. not reached) and a higher recurrence rate (40.7% vs. 25%). High expression of LAPTM4B-35 in lymph node metastasis was found in 29.2% of cases. In 19.4% of cases, high LAPTM4B-35 expression was observed in both the primary tumour and corresponding lymph node metastases. In conclusion, our data indicates that overexpression of LAPTM4B-35 is associated with poor prognosis and may therefore serve as a new prognostic marker in HNSCC.

Analysis of Perioperative Platelet Indices and Their Prognostic Value in Head and Neck Cancer Patients Treated with Surgery and Postoperative Radiotherapy: A Retrospective Cohort Study.

OBJECTIVES: Activated platelets might play an important role in tumor progression. Mean platelet volume (MPV) has been used as a surrogate marker for platelet activation, and therefore its value as a marker of tumor prognosis has attracted recent attention. In this study, we aimed to critically evaluate the prognostic significance of the perioperative platelet count (COP), MPV and the MPV/COP ratio in head and neck cancer patients. Additionally, we explored the individual postoperative trajectory of these indices and their association with overall survival (OS) and disease-free survival (DFS). METHODS: We retrospectively evaluated 122 head and neck squamous cell carcinoma patients receiving surgery with curative intent followed by postoperative radiotherapy. Platelet indices were measured preoperatively and on days 1 and 7 postoperatively. OS and DFS were analyzed using Kaplan-Meier estimators, the log-rank test and uni and multivariable Cox models. Cutoffs to dichotomize patients for Kaplan-Meier curves and log-rank tests were empirically chosen at the respective median. The median follow-up was 8.8 years. RESULTS: The adjusted preoperative COP, MPV and MPV/COP ratio were not associated with disease outcome. A low postoperative COP and a high MPV/COP ratio on the first postoperative day were independently associated with worse OS and DFS. In comparison to the preoperative measurements, patients whose COP increased by day 1 post-op showed a better OS (hazard ratio (HR) per 50 G/L increase: 0.73, 95% confidence interval (CI): 0.58-0.93, p = 0.013) and DFS (HR per 50 G/L increase: 0.74, 95% CI: 0.58-0.94, p = 0.018) in multivariable analysis. CONCLUSIONS: Our results suggest that a low postoperative COP and a high MPV/COP ratio represent a negative prognostic factor for OS and DFS. Notably, patients with an increase in COP by day 1 post-op when compared to their preoperative value showed a significantly better OS and DFS.

Evaluation of the cancer stem cell marker DCLK1 in patients with lymph node metastases of head and neck cancer.

BACKGROUND: Lymph node metastases are frequently detected in head and neck squamous cell carcinoma (HNSCC) patients. Little is known about biomarkers expressed in lymph node metastases or their influence on clinical outcome. Doublecortin-like kinase 1 (DCLK1) is one marker that might be associated with outcome, owing to its correlation with stem cell-like characteristics. METHODS: We assessed the expression of DCLK1 in 74 postoperatively irradiated patients in histologically confirmed HNSCC lymph node metastases. Statistical analysis of the association with DCLK1 on clinical outcomes was performed. RESULTS: DCLK1 was expressed in 63.5% of our patient cohort. DCLK1(+) HNSCC patients, compared with those without DCLK1 expression, showed a significantly poorer time to recurrence. Moreover, we observed a significantly poorer time to recurrence in HPV(-) HNSCC patients, and significantly shorter overall and disease-free survival rates in HPV(-) oropharyngeal cancer patients, compared with HPV(+) patients with these cancers. HPV(+) patients showed no significant differences in survival time according to DCLK1 expression. However, recurrent disease occurred in only DCLK1(+) patients. Mulitivariate analysis showed that DCLK1 expression in lymph node metastases is an independent marker for recurrence. CONCLUSION: DCLK1 expression might be associated with poorer clinical outcomes in HNSCC patients, specifically in HPV(-) move patients. However, larger studies are required to verify our results.

Preoperative plasma fibrinogen as a predictive factor for post-tonsillectomy haemorrhage.

OBJECTIVES: To assess whether preoperative plasma fibrinogen is able to predict severe post-tonsillectomy haemorrhage. STUDY DESIGN: Retrospective chart review. METHODS: We included 456 patients who underwent tonsillectomy between 2008 and 2013. Preoperative plasma fibrinogen levels (PFL) were assessed in patients who developed severe bleeding requiring surgical revision under general anesthesia compared to those with uneventful postoperative courses. RESULTS: 414 (90.8%) had no severe post-tonsillectomy haemorrhage. In contrast, 42 (9.2%) patients needed surgical hemostasis. PFL were significantly higher (P = .023) in patients with a severe bleeding. Univariate Cox-regression analysis revealed that elevated preoperative fibrinogen represents a significant worse (P = .003; HR 2.66; 95% CI 1.38-5.10) prognostic factor for postoperative bleeding. Even at multivariable analysis, increased PFLs were a significantly worse prognostic factor for post-tonsillectomy haemorrhage (P = .016; HR 15.4; 95% CI 0.01-0.6). High preoperative PFL was associated with significantly higher risk for post-tonsillectomy haemorrhage within the first 31 days after surgery (65% vs 90%; P = .002). Moreover, accurate negative predictive value (NPV) of 95.1% pointed out that PFL could be used as a reliable preoperative screening marker. CONCLUSIONS: Elevated PFL represents an independent worse prognostic factor for severe bleeding after tonsillectomy and could be helpful to identify patients at higher risk for PTH.

Prognostic value of advanced lung cancer inflammation index in head and neck squamous cell carcinoma.

PURPOSE: The advanced lung cancer inflammation index (ALI) is a useful tool for prediction of outcome in several malignancies. However, to date, its significance in head and neck cancer patients has not been evaluated. METHODS: We retrospectively analyzed data from 93 patients who were diagnosed with head and neck squamous cell carcinoma (HNSCC) and treated with surgical resection and postoperative radiotherapy between 2002 and 2012. The aim of this study was to investigate whether the preoperative ALI is a prognostic indicator for disease-free survival and overall survival in HNSCC patients. RESULTS: A low ALI was significantly associated with a worse 5-year disease-free survival (47.0 vs. 83.5%, p < 0.001), and overall survival (44.4 vs. 73.6%, p = 0.008). Multivariate analysis showed that low ALI was independently associated with disease-free survival (p < 0.001) and overall survival (p = 0.02). CONCLUSION: The ALI could serve as an easily available prognostic indicator for disease-free and overall survival prediction in patients with HNSCC.

Pretreatment assessment of hematologic and inflammatory markers in adenoid cystic carcinoma: neutrophil/lymphocyte ratio is associated with multiple recurrences.

OBJECTIVE: Adenoid cystic carcinoma (ACC) is a rare entity of salivary gland cancer. Inflammatory and hematologic markers and their prognostic and predictive value have been intensively studied in several cancer entities. The aim of this study was to investigate the role of such markers in patients with ACC. STUDY DESIGN: This retrospective analysis investigated hematologic and inflammatory markers in patients with ACC in the period between the years 1996 and 2016. We assessed the preoperative neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, cross-reactive protein and fibrinogen levels. A total of 28 to 31 patients were included, depending on the examined parameter. All markers were evaluated for their effects on outcome and prognostic value. RESULTS: Patients with an elevated preoperative NLR (>2) had a significantly higher multiple recurrence rate (44.4% vs 8.3%; P = .049). Other hematologic markers showed no significant effects on outcome. CONCLUSIONS: This study showed that the NLR may serve as a useful prognosticator for a high risk of multiple recurrences in patients with ACC.

Rising incidences of Warthin's tumors may be linked to obesity: a single-institutional experience.

PURPOSE: Recently, there has been an increase in the number of reported Warthin's tumors, but few risk factors have been described for this benign tumor. Yet, smoking is the only evidently identified risk factor. Obesity and the metabolic syndrome are causally linked to or a risk factor for a variety of diseases. Therefore, we analyzed whether metabolic syndrome, including obesity, might influence the incidence of Warthin's tumors. METHODS: In this retrospective study, we evaluated 197 patients with Warthin's tumor. We assessed the tumor size, the body mass index (BMI), comorbidities related to the metabolic syndrome, and cigarette and alcohol consumption. Additionally, we evaluated several blood parameters and their influence. RESULTS: Warthin's tumor patients had a significantly higher BMI in comparison to patients with other benign parotid gland tumors (29.1 versus 26.2, p < 0.0001). The rate of metabolic syndrome-associated comorbidities was higher in Warthin's tumor patients (62.4% versus 35.2%, p < 0.0001). CONCLUSION: Our results might be the first step to recognize obesity and its consequences as a co-driver in the formation of Warthin's tumors. Nevertheless, further studies are requested to validate our results and to answer the question whether obesity or the metabolic syndrome are integrally linked to Warthin's tumors.

ELMO3 - a Negative Prognostic Marker in Minor Salivary Gland Carcinoma.

Engulfment and cell motility 3 protein (ELMO3) is a protein that is involved in cell migration and promotes the remodeling of the cytoskeleton. Moreover, it is described as a prognostic marker in several cancers. The aim of this study was to evaluate ELMO3 expression in patients with minor salivary gland carcinoma. The expression of ELMO3 was examined by immunohistochemistry. The intensity of staining was evaluated and data was correlated to clinical outcome. Forty-six patients with complete clinical data were included into statistical analysis. ELMO3 expression was observed in 85% of the cases. High staining intensity of ELMO3 correlated with a significantly worse disease free survival (p = .0495) and a higher recurrence rate (p = .0071). In conclusion, it is still difficult to predict the clinical outcome of patients with minor salivary gland carcinoma. Evaluation of ELMO3 might serve as a clinical prognostic marker in future.

Impact of anatomic origin of primary squamous cell carcinomas of the nasal cavity and ethmoidal sinus on clinical outcome.

PURPOSE: Since squamous cell carcinomas (SCCs) of the nasoethmoidal complex are rare and aggressive malignancies, the purpose of this study was to evaluate whether anatomic subsites of SCCs of the nasal cavity and ethmoid sinuses affect clinical outcome. METHODS: We retrospectively analyzed data from 47 patients with primary SCCs of the nasal cavity and ethmoid sinuses who were treated at the Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, between 1993 and 2018. The impact of anatomic subsites of nasoethmoidal SCCs was evaluated with respect to tumor and nodal classification, disease-free survival (DFS) and disease-specific survival (DSS). RESULTS: Of the 47 cases, 17 SCCs (36.2%) originated from lateral nasal wall followed by 13 (27.7%) tumors of the edge of naris to mucocutaneous junction, 11 (23.4%) SCCs of the nasal septum, 3 tumors of the nasal floor (6.4%) and 3 SCCs of the ethmoid sinuses (6.4%), respectively. SCCs of the nasal septum were associated with significantly higher rates of neck node metastasis (p = 0.007), which represented a significantly worse prognostic factor for DSS (HR 7.87; p < 0.001). Moreover, advanced tumor stage (HR 5.38; p = 0.014) and tumor origin of nasal septum (HR 4.05; p = 0.025) were also significantly worse prognostic factors for DSS. Fourteen patients (29.8%) developed recurrent disease, including eight local (17.0%), five regional (10.6%) and one distant (2.1%) recurrence. Elective neck dissection (ND) was associated with lower (0 vs. 20.0%) but not significantly different regional and distant DFS (p = 0.075). CONCLUSION: Anatomic origin of nasal SCC has significant impact on clinical outcome. SCCs of the nasal septum were associated with higher rates of positive neck nodes and worse outcome.

PD-1 and PD-L1 expression in HNSCC primary cancer and related lymph node metastasis - impact on clinical outcome.

AIMS: Expression profiles and clinical impact of programmed cell death ligand 1 (PD-L1) and programmed cell death 1 (PD-1) expressing tumour infiltrating lymphocytes (TILs) in head and neck squamous cell carcinoma (HNSCC) are not elucidated fully. This study evaluates expression patterns in primary HNSCC and related lymph node metastasis and the impact on patients' clinical outcome. METHODS AND RESULTS: Immunohistochemical staining patterns of PD-L1 and PD-1 were evaluated in 129 specimens of primary HNSCC and 77 lymph node metastases. Results were correlated with patients' clinical data. PD-L1 expression was observed in 36% of primary carcinoma and 33% of lymph node metastasis, and correlates significantly with decreased overall survival (OS) (P = 0.01) and disease-free survival (DFS) (P = 0.001) in oral cavity squamous cell carcinoma patients. PD-L1 expression was associated with presence of lymph node metastasis (P = 0.0223). Infiltration of PD-1-expressing lymphocytes correlates significantly with favourable OS (P = 0.001) and DFS (P = 0.001) in oropharyngeal cancer and hypopharyngeal cancer patients OS (P = 0.007) and DFS (P = 0.001). Presence of PD-1 TILs also correlates significantly with better OS (P = 0.005) and DFS (P = 0) in the human papilloma virus (HPV)-negative cohort. Cox regression multivariate analysis revealed PD-1 TIL expression as an independent prognostic marker for OS (P = 0.004) and DFS (P = 0.001) and T stage was validated as negative prognostic marker for OS (P = 0.011). PD-1-expressing lymphocytes (P = 0.0412) and PD-L1 expression (P = 0.0022) patterns correlate significantly in primary cancers and matched lymph node metastases. CONCLUSIONS: Our results characterise the expression profiles of PD-1 axis proteins in HNSCC which might serve as possible clinical prognostic markers.